HK1099007A - 4-(pyrazol-3-ylamino) pyrimidine derivatives for use in the treatment of cancer - Google Patents

Description

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

no marking

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. Its two ligands, IGF-I and IGF-II, are mitogenic peptides that signal by interacting with the type 1 insulin-like growth factor receptor (IGF-1R), a heterotetrameric cell surface receptor. Binding to either of these ligands stimulates the activation of the tyrosine kinase domain of the intracellular domain of the β -strand and leads to phosphorylation of some tyrosine residues, leading to recruitment and activation of a variety of signaling molecules. This intracellular domain has been shown to transmit mitogenic, survival, transformation, and differentiation signals in cells. Adams et al (Cellular and Molecular Life Sciences, 57, 1050-. IGF-IIR (also known as the mannose 6-phosphate receptor) lacks this kinase domain and therefore fails to send mitogenic signals, but it can modulate the availability of this cell surface ligand, thereby counteracting the effects of IGF-1R. The IGF binding proteins (IGFBPs) control the availability of circulating IGFs and regulate the release of IGFs from these substances by proteolytic cleavage. These other components of the IGF axis have been reviewed by Collett-Solberg and Cohen (Endocrine, 12, 121-.

There are many indications that IGF signaling is linked to cellular transformation and the initiation and progression of tumors. IGF has been identified as a major survival factor that protects against oncogene-induced cell death (Harrington et al, EMBO J, 13, 3286-3295, 1994). Cells lacking IGF-1R have been shown to be refractory to transformation by a number of different oncogenes, including SV40T antigen and ras, which are effective in transforming corresponding wild-type cells (Sell et al, mol. cell biol., 14, 3604-12, 1994). Upregulation of the IGF axis component has been described to occur in a number of tumor cell lines and tissues, particularly tumors of the breast (Surmcz, Journal of mammy GlandBaliogy & Neoplasia, 5, 95-105, 2000), prostate (Djavan et al, World J.Urol., 19, 225-. In contrast, IGF-IIR has been inferred to be a tumor suppressor and deleted in some cancers (DaCosta et al, journal of Mammary Gland Biology & Neopalasia, 5, 85-94, 2000). Increasing epidemiological studies link increased circulating IGF (or increased ratio of IGF-1 to IGFBP 3) to cancer risk (Yu and Rohan, j.natl.cancer inst., 92, 1472-. Transgenic mouse models also suggest that IGF signaling is involved in the onset of tumor cell proliferation (Lamm and Christofori, Cancer Res.58, 801-.

Several in vitro and in vivo strategies provide major evidence that inhibition of IGF-1R signaling reverses this transformed phenotype and inhibits tumor cell growth. These include neutralizing antibodies (Kalebic et al Cancer Res., 54, 5531-. Antisense oligonucleotides have been shown to inhibit IGF-1R expression to induce apoptosis in cells in vivo (Resnicoff et al, Cancer res., 55, 2463-2469, 1995) and have been considered suitable for use in humans as well (Resnicoff et al, proc. amer. assoc. Cancer res., 40 Abs 4816, 1999). However, none of these approaches are particularly attractive for the treatment of major solid tumor diseases.

Since it is implicated that IGF signaling increases in the growth and survival of tumor cells, and blocking IGF-1R function can reverse this increase, inhibition of the IGF-1R tyrosine kinase domain is a suitable therapy for the treatment of cancer. In vitro and in vivo studies using dominant negative IGF-1R variants support this view. In particular, point mutations in the ATP binding site that block receptor tyrosine kinase activity have been shown to effectively prevent tumor cell growth (Kulik et al, mol. cell. biol., 17, 1595-1606, 1997). There are several sporadic indications that normal cells are less susceptible to apoptosis by inhibition of IGF signalling, suggesting that there may be some therapeutic margin for this type of treatment (Baserga, Trends biotechnol., 14, 150-2, 1996).

There have been few reports of selective IGF-1R tyrosine kinase inhibitors. Parrizas et al describe several tyrphostin inhibitors that are effective in vitro and in vivo (Parrizas et al, Endocrinology, 138: 1427-33 (1997)). These compounds have modest efficacy and are selective for the insulin receptor. Some heteroaryl-aryl ureas that are selective for insulin receptors but are not yet effective against tumor cells in vitro have been described by Telik inc (published PCT patent application WO 00/35455).

Amino-substituted pyrimidine derivatives substituted in the 2-and 4-positions having IGF-IR tyrosine kinase inhibitory activity are described in WO 03/048133. However, there is no disclosure of compounds in which the nitrogen atom of the amino substituent forms part of a heterocyclic ring.

WO 02/50065 discloses that certain pyrazolyl-amino substituted pyrimidine derivatives possess protein kinase inhibitory activity, are particularly useful as inhibitors of Aurora-2 and glycogen synthase kinase-3 (GSK-3), and are useful in the treatment of diseases such as cancer, diabetes and alzheimer's disease. The compounds disclosed therein have a substituted amino substituent at the 2-position of the pyrimidine ring, but they still do not disclose compounds in which the nitrogen atom of the amino substituent forms part of a heterocyclic ring.

Pyrazolyl-amino substituted pyrimidine derivatives having Aurora-2 and glycogen synthase kinase-3 (GSK-3) inhibitory activity, in which the 2-position of the pyrimidine ring is substituted with an N-linked heterocyclic ring, are generally disclosed 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 most of the four hundred compounds listed, the pyrimidine ring is present as part of a fused ring system, however, none of the compounds listed are heterocyclic substituents which are substituted at this position on its own by another ring substituent.

WO 01/60816 discloses that certain substituted pyrimidine derivatives have protein kinase inhibitory activity. No pyrimidine derivative having a pyrazolyl-amino substituent at the 4-position of the pyrimidine ring and a substituted N-linked saturated monocyclic ring at the 2-position of the pyrimidine ring is disclosed in WO 01/60816.

The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:

wherein:

R¹represents trifluoromethyl, or (C1-C6) alkyl, (C3-C8) cycloalkyl or (C3-C8) cycloalkyl (C1-C6) alkyl, each of which may be optionally substituted by one or more substituents independently selected from halogen and (C1-C6) alkoxy;

R²Represents hydrogen, halogen or trifluoromethyl;

R³represents hydrogen, hydroxy or halogen, or (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C8) cycloalkyl (C1-C6) alkoxy, (C1-C6) alkylcarbonyl, (C3-C8) cycloalkylcarbonyl, (C3-C8) cycloalkyl (C1-C6) alkylcarbonyl, (C1-C6) alkoxycarbonyl, amino, (C1-C6) alkylamino, di- [ (C1-C6) alkyl]Amino, (C3-C8) cycloalkylamino, (C3-C8) cycloalkyl (C1-C6) alkylamino, (C1-C6) alkoxyamino, carbamoyl, (C1-C6) alkylcarbamoyl, di- [ (C1-C6) alkylcarbamoyl]Carbamoyl, -C (O) R^3b、-OR^3b、-SR^3b、-NHR^3b-N [ (C1-C6) alkyl group]R^3b、-S(O)_mR^3aor-N (R)^3c)C(O)R^3aWherein R is^3aRepresents (C1-C6) alkyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl or (C1-C6) alkoxy, m is 0, 1 or 2, R is^3bRepresents a saturated 4-, 5-or 6-membered monocyclic heterocycle comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur and R^3cRepresents hydrogen or (C1-C6) alkyl,

or R³Represents a 5-to 6-membered saturated monocyclic heterocyclic ring containing at least one ring heteroatom selected from nitrogen, oxygen and sulfur,

or R³Represents a 5-to 6-membered heteroaromatic ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur,

Or R³Represents a 2, 7-diazaspiro [3.5 ]]A non-alkyl group,

R³each group or ring of (a) may optionally be substituted with one or more groups independently selected from (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkoxy (C1-C6) alkyl(C1-C6) alkoxy (C1-C6) alkoxy, halogen, hydroxy, trifluoromethyl, tri- [ (C1-C4) alkyl]Silyl, cyano, amino, (C1-C6) alkylamino, di- [ (C1-C6) alkyl]Amino, (C3-C8) cycloalkylamino, (C3-C6) cycloalkyl (C1-C3) alkylamino, amino (C1-C6) alkyl, (C1-C6) alkylamino (C1-C6) alkyl, di- [ (C1-C6) alkyl]Amino (C1-C6) alkyl, (C3-C8) cycloalkylamino (C1-C6) alkyl, (C3-C6) cycloalkyl (C1-C3) alkylamino (C1-C6) alkyl, (C1-C6) alkoxycarbonyl, carbamoyl, (C1-C6) alkylcarbamoyl, di- [ (C1-C6) alkyl]Carbamoyl, (C1-C6) alkylthio, (C1-C6) alkylsulfonyl, (C1-C6) alkylsulfinyl, (C1-C6) alkanoyl, wherein R is^3aAnd R^3cIs as defined above for alkanoylamino-N (R)^3c)C(O)R^3aOr a saturated 3-, 4-, 5-, 6-or 7-membered monocyclic substituent which optionally contains one or more heteroatoms selected from nitrogen, oxygen and sulphur, any of which substituents may optionally be substituted by one or more (C1-C4) alkyl, hydroxy or cyano groups;

-NQ¹Represents an N-linked 5-to 6-membered saturated monocyclic ring comprising one nitrogen heteroatom and optionally one or more additional ring heteroatoms selected from nitrogen, oxygen and sulphur;

Q²represents a 5-to 6-membered heteroaromatic ring containing at least one ring heteroatom selected from nitrogen, oxygen and sulfur, which ring is substituted by Q³Is optionally substituted and on any available ring atom by one or more substituents independently selected from (C1-C6) alkyl or (C1-C6) alkoxy (each of which may be optionally substituted by one or more substituents independently selected from halogen, amino, hydroxy and trifluoromethyl), halogen, nitro, cyano, -NR < I > R <⁴R⁵Carboxy, hydroxy, (C2-C6) alkenyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl, (C1-C4) alkoxycarbonyl, (C1-C4) alkylcarbonyl, (C1-C4) alkylcarbonylamino, phenylcarbonyl, -S (O)_p(C1-C4) alkyl, -C (O) NR⁶R⁷and-SO₂NR⁸R⁹Wherein R is substituted with a further substituent of⁴、R⁵、R⁶、R⁷、R⁸And R⁹Each independently represents hydrogen or (C1-C6) alkyl, or R when taken together with the nitrogen atom to which they are attached⁴And R⁵Or R⁶And R⁷Or R⁸And R⁹May each independently form a saturated heterocyclic ring and p is 0, 1 or 2;

Q³represents (C1-C6) alkyl, (C3-C6) cycloalkyl or (C3-C6) cycloalkyl (C1-C6) alkyl or a saturated or unsaturated 5-to 6-membered monocyclic ring which may contain at least one ring heteroatom selected from nitrogen, oxygen and sulfur, and wherein Q ³Optionally substituted with one or more substituents independently selected from (C1-C6) alkyl or (C1-C6) alkoxy, each of which may be optionally substituted with one or more substituents independently selected from halogen, amino, hydroxy and trifluoromethyl, halogen, nitro, cyano, -NR¹⁰R¹¹Carboxy, hydroxy, (C2-C6) alkenyl, (C3-C8) cycloalkyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkylcarbonyl, (C1-C6) alkylcarbonylamino, phenylcarbonyl, -S (O)_n(C1-C6) alkyl, -C (O) NR¹²R¹³and-SO₂NR¹⁴R¹⁵Wherein R is substituted by a substituent of (1)¹⁰、R¹¹、R¹²、R¹³、R¹⁴And R¹⁵Each independently represents hydrogen or (C1-C6) alkyl, or R when taken together with the nitrogen atom to which they are attached¹⁰And R¹¹Or R¹²And R¹³Or R¹⁴And R¹⁵Each independently may form a saturated heterocyclic ring and n is 0, 1 or 2;

and wherein any saturated monocyclic ring optionally bears 1 or 2 oxo or thioxo substituents.

According to another aspect of the present invention there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

R¹represents trifluoromethyl, or (C1-C6) alkyl, (C3-C8) cycloalkyl or (C3-C8) cycloalkyl (C1-C6) alkyl, each of which may be optionally substituted by one or more substituents independently selected from halogen and (C1-C6) alkoxy;

R²represents hydrogen, halogen or trifluoromethyl;

R³Represents hydrogen or halogen, or (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C8) cycloalkyl (C1-C6) alkoxy, (C1-C6) alkylcarbonyl, (C3-C8) cycloalkylcarbonyl, (C3-C8) cycloalkyl (C1-C6) alkylcarbonyl, (C1-C6) alkoxycarbonyl, amino, (C1-C6) alkylamino, di- [ (C1-C6) alkyl]Amino, (C3-C8) cycloalkylamino, (C3-C8) cycloalkyl (C1-C6) alkylamino, (C1-C6) alkoxyamino, carbamoyl, (C2-C6) alkanoylamino, -C (O) R^3b、-OR^3b、-SR^3b、-NHR^3b-N [ (C1-C6) alkyl group]R^3bor-S (O)_mR^3aWherein R is^3aRepresents (C1-C6) alkyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl or (C1-C6) alkoxy, m is 0, 1 or 2, and R^3bRepresents a 5-to 6-membered saturated monocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur,

or R³Represents a 5-to 6-membered saturated monocyclic heterocyclic ring containing at least one ring heteroatom selected from nitrogen, oxygen and sulfur,

R³each group or ring of (A) may optionally be substituted with one or more groups independently selected from (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkoxy (C1-C6) alkoxy, halogen, hydroxy, trifluoromethyl, cyano, amino, (C1-C6) alkylamino, di- [ (C1-C6) alkyl ]Amino, (C3-C8) cycloalkylamino, (C3-C6) cycloalkyl (C1-C3) alkylamino, (C1-C6) alkoxycarbonyl, carbamoyl, (C1-C6) alkylcarbamoyl, di- [ (C1-C6) alkylcarbamoyl]Carbamoyl, (C1-C6) alkylthio, (C1-C6) alkylsulfonyl, (C1-C6) alkylsulfinyl, (C1-6) alkanoylamino or a substituent of a 4-, 5-, 6-or 7-membered saturated monocyclic ring which may optionally contain one or more hetero atoms selected from nitrogen, oxygen and sulfur,

-NQ¹denotes an N-linkage containing one nitrogen heteroatom and optionally one or more additional ring heteroatoms selected from nitrogen, oxygen and sulfurA 5-to 6-membered saturated monocyclic ring of (a);

Q²denotes a 5-to 6-membered heteroaromatic ring containing at least one ring heteroatom selected from nitrogen, oxygen and sulfur, which ring may be substituted by Q³Substituted and optionally substituted on any available ring atom with one or more substituents independently selected from (C1-C6) alkyl or (C1-C6) alkoxy (each of which may be optionally substituted with one or more substituents independently selected from halogen, amino, hydroxy and trifluoromethyl), halogen, nitro, cyano, -NR, and mixtures thereof⁴R⁵Carboxy, hydroxy, (C2-C6) alkenyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl, (C1-C4) alkoxycarbonyl, (C1-C4) alkylcarbonyl, (C1-C4) alkylcarbonylamino, phenylcarbonyl, -S (O) _p(C1-C4) alkyl, -C (O) NR⁶R⁷and-SO₂NR⁸R⁹Wherein R is substituted with a further substituent of⁴、R⁵、R⁶、R⁷、R⁸And R⁹Each independently represents hydrogen or (C1-C6) alkyl, or R when taken together with the nitrogen atom to which they are attached⁴And R⁵Or R⁶And R⁷Or R⁸And R⁹Each independently may form a saturated heterocyclic ring and p is 0, 1 or 2;

Q³represents (C1-C6) alkyl, (C3-C6) cycloalkyl or (C3-C6) cycloalkyl (C1-C6) alkyl or a saturated or unsaturated 5-to 6-membered monocyclic ring which may contain at least one ring heteroatom selected from nitrogen, oxygen and sulfur, and wherein Q³Optionally substituted with one or more substituents independently selected from (C1-C6) alkyl or (C1-C6) alkoxy, each of which may be optionally substituted with one or more substituents independently selected from halogen, amino, hydroxy and trifluoromethyl, halogen, nitro, cyano, -NR¹⁰R¹¹Carboxy, hydroxy, (C2-C6) alkenyl, (C3-C8) cycloalkyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkylcarbonyl, (C1-C6) alkylcarbonylamino, phenylcarbonyl, -S (O)_n(C1-C6) alkyl, -C (O) NR¹²R¹³and-SO₂NR¹⁴R¹⁵Wherein R is substituted by a substituent of (1)¹⁰、R¹¹、R¹²、R¹³、R¹⁴And R¹⁵Each independently represents hydrogen or (C1-C6) alkyl, or R when taken together with the nitrogen atom to which they are attached¹⁰And R¹¹Or R¹²And R¹³Or R ¹⁴And R¹⁵Each independently may form a saturated heterocyclic ring and n is 0, 1 or 2.

According to another aspect of the present invention there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

R¹represents trifluoromethyl, or (C1-C6) alkyl, (C3-C8) cycloalkyl or (C3-C8) cycloalkyl (C1-C6) alkyl, each of which is optionally substituted by halogen or (C1-C6) alkoxy;

R²represents hydrogen, halogen or trifluoromethyl;

R³represents hydrogen or (C1-C6) alkyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkylcarbonyl, (C3-C8) cycloalkylcarbonyl, (C3-C8) cycloalkyl (C1-C6) alkylcarbonyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkylamino, (C3-C8) cycloalkylamino, (C3-C8) cycloalkyl (C1-C6) alkylamino, (C1-C6) alkoxyamino or-S (O)_mR^3aRadical, R³Each of which may be optionally substituted with at least one substituent selected from (C1-C6) alkoxy, (C1-C6) alkoxy (C1-C6) alkoxy, halo, hydroxy, trifluoromethyl, or a 4-, 5-, 6-, or 7-membered saturated monocyclic ring which may optionally contain one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein R is^3aRepresents (C1-C6) alkyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl or (C1-C6) alkoxy and m is 0, 1 or 2;

-NQ¹Represents an N-linked 5-to 6-membered saturated monocyclic ring comprising one nitrogen heteroatom and optionally one or more additional ring heteroatoms selected from nitrogen, oxygen and sulphur;

Q²represents a 5-to 6-membered heteroaromatic ring containing at least one ring heteroatom selected from nitrogen, oxygen and sulfur, which ring is substituted by Q³Substituted and optionally mono on any available ring atomOne or more additional substituents which may be the same or different, selected from (C1-C6) alkyl or (C1-C6) alkoxy, each of which may be optionally substituted with at least one substituent selected from the group consisting of halogen, amino, hydroxy and trifluoromethyl, halogen, nitro, cyano, -NR, hydroxy and trifluoromethyl⁴R⁵Carboxy, hydroxy, (C2-C6) alkenyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl, (C1-C4) alkoxycarbonyl, (C1-C4) alkylcarbonyl, (C1-C4) alkylcarbonylamino, phenylcarbonyl, -S (O)_p(C1-C4) alkyl, -C (O) NR⁶R⁷and-SO₂NR⁸R⁹Wherein R is⁴、R⁵、R⁶、R⁷、R⁸And R⁹Each independently represents hydrogen or (C1-C6) alkyl, or R when taken together with the nitrogen atom to which they are attached⁴And R⁵Or R⁶And R⁷Or R⁸And R⁹Each independently may form a saturated heterocyclic ring and p is 0, 1 or 2;

Q³represents (C1-C6) alkyl, (C3-C6) cycloalkyl or (C3-C6) cycloalkyl (C1-C6) alkyl or a saturated or unsaturated 5-to 6-membered monocyclic ring which may contain at least one ring heteroatom selected from nitrogen, oxygen and sulfur, and wherein Q ³Optionally substituted with at least one substituent selected from (C1-C6) alkyl or (C1-C6) alkoxy, each of which may be optionally substituted with at least one substituent selected from halogen, amino, hydroxy and trifluoromethyl, halogen, nitro, -cyano, -NR¹⁰R¹¹Carboxy, hydroxy, (C2-C6) alkenyl, (C3-C8) cycloalkyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkylcarbonyl, (C1-C6) alkylcarbonylamino, phenylcarbonyl, -S (O)_n(C1-C6) alkyl, -C (O) NR¹²R¹³and-SO₂NR¹⁴R¹⁵Wherein R is substituted by a substituent of (1)¹⁰、R¹¹、R¹⁴、R¹³、R¹⁴And R¹⁵Each independently represents hydrogen or (C1-C6) alkyl, or R when taken together with the nitrogen atom to which they are attached¹⁰And R¹¹Or R¹²And R¹³Or R¹⁴And R¹⁵Can form a full body independentlyAnd heterocycle and n is 0, 1 or 2.

Unless otherwise specified, the term 'alkyl' when used alone or in combination refers to straight or branched alkyl moieties. (C1-C6) alkyl has one to six carbon atoms and includes methyl, ethyl, n-propyl, isopropyl,tertiary carboxylic acidButyl, n-pentyl, n-hexyl and the like. Where a '(C1-C4) alkyl' is referred to, it will be correspondingly understood to refer to straight or branched alkyl moieties having from 1 to 4 carbon atoms. References to each alkyl group such as "propyl" are specifically intended to refer only to the straight chain version, and references to each branched alkyl group such as "isopropyl" are specifically intended to refer only to the branched chain version.

Similarly, the terms '(C1-C6) alkoxy' and '(C1-C4) alkoxy', when used alone or in combination, will be understood to refer to straight or branched chain groups having 1 to 6 or 1 to 4 carbon atoms, respectively, and include groups such as methoxy, ethoxy, propoxy, isopropoxy, and butoxy.

'(C2-C6) alkenyl' refers to straight or branched chain groups having 2 to 6 carbon atoms such as vinyl, isopropenyl, allyl, and but-2-enyl. Similarly, '(C2-C6) alkynyl' refers to straight or branched chain groups having 2 to 6 carbon atoms such as ethynyl, 2-propynyl, and but-2-ynyl.

The term 'cycloalkyl', alone or in combination, refers to a saturated alicyclic moiety having from 3 to 8 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. References to (C3-C6) cycloalkyl are to be understood as referring to saturated alicyclic moieties having 3 to 6 carbon atoms, typical examples of which are set forth above.

The term 'halogen' as used herein includes fluorine, chlorine, bromine and iodine.

The term 'optionally substituted' as used herein means optionally substituted at any suitable available position by a group or groups.

Any substituent herein, for example'R' radical (R)¹To R¹⁵、R^3a、R^3bOr R^3c) Is a suitable value of or-NQ¹、Q²Or Q³Suitable values for the various groups in the group include: -

For halogens: fluorine, chlorine, bromine and iodine;

for C1-C6) alkyl: methyl, ethyl, propyl, isopropyl,Tertiary carboxylic acidButyl and n-substituted

Pentyl and n-hexyl;

for (C2-C6) alkenyl: vinyl, isopropenyl, allyl, and but-2-enyl;

for (C2-C6) alkynyl: ethynyl, 2-propynyl and but-2-ynyl;

for (C1-C6) alkoxy: methoxy, ethoxy, propoxy, isopropoxy and butoxy

A group;

for (C1-C6) alkoxy

(C1-C6) alkoxy: methoxy, methoxy ethoxy, ethoxy methoxy

Phenyl, propoxy methoxy and butoxy methoxy;

for (C1-C6) alkoxy

(C1-C6) alkyl: methoxymethyl, methoxyethyl, ethoxymethyl, propyl

Oxymethyl and butoxymethyl;

For tri- [ (C1-C4) alkyl ]

As the silyl group, trimethylsilyl, triethylsilyl, dimethyl-

Ethyl silyl and methyl-diethyl silyl;

for (C1-C6) alkylthio: methylthio, ethylthio and propylthio;

for (C1-C6) alkylamino: methylamino, ethylamino, propylamino, isopropylamino

A group and a butylamino group;

for di- [ (C1-C6) alkyl ]

For amino groups: dimethylamino group, diethylamino group, amino group,N-ethyl-N-methylammonium

A phenyl group and a naphthyl group;

for amino (C1-C6) alkyl: aminomethyl, aminoethyl, aminopropyl and aminobutyl;

for (C1-C6) alkylamino

(C1-C6) alkyl: methylaminomethyl, methylaminoethyl, methylaminopropyl radicals

Alkyl, ethylaminomethyl, ethylaminoethyl, propylamino

Ylmethyl, isopropylaminoethyl and butylaminomethyl;

For di- [ (C1-C6) alkyl ]

Amino (C1-C6) alkyl: dimethylaminomethyl, dimethylaminoethyl, dimethyl

Aminobutyl, diethylaminomethyl, diethylaminoethyl

A group, a diethylaminopropyl group,N-ethyl-N-methyl amino methyl

A base,N-ethyl-N-methylaminomethyl and diisopropylamino

An ethyl group;

for (C1-C6) alkylcarbonyls

For the root, the ratio of: methylcarbonyl, ethylcarbonyl, propylcarbonyl andtertiary carboxylic acidButylcarbonyl group

A group;

for (C1-C6) alkoxycarbonyl

For the root, the ratio of: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl andtertiary carboxylic acid

A butoxycarbonyl group;

for theN- (C1-C6) alkyl

For carbamoyl groups:N-methylcarbamoyl group,N-ethylcarbamoyl and

N-a propylcarbamoyl group;

For theN， N-two-

[ (C1-C6) alkyl ] amino

For formyl radicals:N， N-dimethylcarbamoyl radical,N-ethyl-N-methylamino radical

Formyl andN， N-a diethylcarbamoyl group;

for (C3-C8) cycloalkyl: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl;

for (C3-C8) cycloalkyl

(C1-C6) alkyl: cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclobutylmethyl

Hexylmethyl and cycloheptylmethyl;

for (C3-C8) cycloalkyl

(C1-C6) alkoxy: cyclopropyl methoxy, cyclobutylmethoxy, cyclopentyl methoxy

Cyclohexyl methoxy and cycloheptyl methoxy;

for (C3-C8) cycloalkylcarbonyls

For the root, the ratio of: cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclo

Hexylcarbonyl and cycloheptylcarbonyl;

for (C3-C8) cycloalkyl

(C1-C6) alkylcarbonyl: cyclopropylmethylcarbonyl, cyclobutylmethylcarbonyl, cyclopentyl

Methylcarbonyl and cyclohexylmethylcarbonyl;

for (C3-C8) cycloalkylamines

For the root, the ratio of: cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclobutylamino

Hexylamino and cycloheptylamino;

for (C3-C8) cycloalkylamines

Alkyl of the radical (C1-C6): cyclopropylaminomethyl, cyclopropylaminoethyl, cyclopropyl

Aminopropyl, cyclobutylaminomethyl, cyclopentylaminoethyl

Cyclopentyl aminopropyl cyclohexyl amino ethyl and cycloheptyl

An arylaminoethyl group;

for (C3-C8) cycloalkyl

(C1-C6) alkylamino: cyclopropylmethylamino, cyclopropylethylamino, cyclopentyl

Methylamino and cyclohexylmethylamino;

for (C3-C8) cycloalkyl

(C1-C6) alkylamino

(C1-C6) alkyl: cyclopropylmethylaminomethyl, cyclopropylmethylaminoethyl

Alkyl, cyclopropylmethylaminopropyl, cyclopropylethylamino

Ethyl, cyclopropylethylaminobutyl, cyclopentylmethyl-amino

Phenylethyl, cyclopentylmethyl-aminobutyl and cyclohexylmethyl

An aminoethyl group;

for (C1-C6) alkoxyamines

For the root, the ratio of: methoxyamino, ethoxyamino, propoxyamino and butanamide

An oxyamino group;

for (C1-C6) alkanoyl: formyl, acetyl, propionyl, butyryl and isobutyryl

A group;

for (C2-C6) alkanoylamines

For the root, the ratio of: acetylamino and propionylamino;

for (C1-C6) alkylsulfonyl

For the root, the ratio of: methylsulfonyl and ethylsulfonyl; and

for (C1-C6) alkyl

For sulfinyl groups: methylsulfinyl and ethylsulfinyl.

'heteroatom' is a nitrogen, sulfur or oxygen atom. In the case where the ring includes a nitrogen atom, these atoms may be substituted as necessary to satisfy the bonding requirements of the nitrogen or the ring may be attached to the remainder of the structure through the nitrogen atom. The nitrogen atoms may also be in the form of N-oxides. The sulfur atom may be S, S (O) or SO₂In the form of (1).

'a 3-, 4-, 5-, 6-, or 7-membered saturated monocyclic ring which may optionally contain one or more heteroatoms selected from nitrogen, oxygen, and sulfur' may be a carbocyclic ring (i.e., an alicyclic hydrocarbon ring having only ring carbon atoms) or may be a heterocyclic ring containing 3 to 7 atoms in which at least one atom is a heteroatom selected from nitrogen, oxygen, and sulfur and the ring is attached through carbon or nitrogen unless otherwise specified. When the '3-, 4-, 5-, 6-or 7-membered saturated monocyclic ring which may optionally contain one or more heteroatoms selected from nitrogen, oxygen and sulfur' is a heterocyclic ring, the heterocyclic ring preferably contains 1 to 4, more preferably 1 to 3, more preferably 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur. Unless otherwise specified, the heterocyclic ring may be carbon or nitrogen linked. Examples of suitable carbocyclic rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The 3-, 4-, 5-, 6-or 7-membered saturated monocyclic heterocycle may suitably be selected from oxiranyl, azetidinyl, dioxanyl, trioxanyl, oxepanyl, dithianyl, trithianyl, oxathianyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, imidazolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and piperazinyl (especially azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and piperazinyl). Saturated heterocycles with 1 or 2 oxo or thio substituents can be, for example, 2-oxopyrrolidinyl, 2-thiopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioimidazolidinyl, 2-oxopiperidinyl, 2, 5-dioxopyrrolidinyl, 2, 5-dioxoimidazolidinyl or 2, 6-dioxopiperidinyl.

In the case where a '5-to 6-membered saturated monocyclic ring' or a '5-to 6-membered saturated monocyclic heterocyclic ring' is referred to, it should be clear that it refers to a ring containing 5 or 6 ring atoms, typical examples of which are listed above. In the case where a '4-, 5-or 6-membered saturated monocyclic ring' or a '4-, 5-or 6-membered saturated monocyclic heterocyclic ring' is concerned, it will be appreciated that the ring comprises 4, 5 or 6 ring atoms, typical examples of which are listed above.

'an N-linked 5-to 6-membered saturated monocyclic ring containing one nitrogen heteroatom and optionally containing one or more additional ring heteroatoms selected from nitrogen, oxygen and sulfur' is a saturated monocyclic heterocyclic ring containing 5 or 6 ring atoms, said ring atoms optionally containing at least one heteroatom selected from nitrogen, oxygen and sulfur in addition to the nitrogen atom through which the ring is attached to the remainder of the structure. Said saturated monocyclic heterocyclic ring containing 5 or 6 ring atoms preferably contains 1 to 3, more preferably 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, in addition to the nitrogen atom through which the ring is attached to the remainder of the structure. Specific examples of such ring systems include pyrrolidinyl, piperidinyl, morpholinyl, and piperazinyl.

'A5-to 6-membered heteroaromatic ring containing at least one ring heteroatom selected from nitrogen, oxygen and sulfur' is a fully saturated aromatic monocyclic ring containing 5 or 6 atoms, at least one of which is a heteroatom selected from nitrogen, oxygen and sulfur, which ring may be carbon or nitrogen linked unless otherwise specified. The 5-to 6-membered heteroaromatic ring preferably contains 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. Specific examples of such ring systems include pyridyl, imidazolyl, isoxazolyl, pyrazolyl, furyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl, thiazolyl, oxazolyl, oxadiazolyl, isothiazolyl, triazolyl, tetrazolyl or thienyl.

'a saturated or unsaturated 5-to 6-membered monocyclic ring which may contain at least one ring heteroatom selected from nitrogen, oxygen and sulfur' is a saturated or fully or partially unsaturated monocyclic ring which contains 5 or 6 atoms, optionally at least one of which is a heteroatom selected from nitrogen, oxygen and sulfur, and unless otherwise specified, the ring may be carbon-or nitrogen-linked. The ring may be alicyclic or aromatic in nature. The aromatic monocyclic ring may be an aryl (e.g. phenyl) or heteroaromatic group, typical examples of which are listed above.

The term 'heterocyclic' as used herein refers to a saturated monocyclic ring system having 3 to 8 ring atoms in which one or more ring carbons is replaced by a heteroatom selected from nitrogen, oxygen and sulfur. The heterocyclic ring preferably contains 1 to 4, more preferably 1 to 3, more preferably 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur. Examples thereof include pyrrolidinyl and piperidinyl.

When R is³Is a 2, 7-diazaspiro [3.5 ]]Nonanyl is preferably attached to the pyrimidine ring via a nitrogen atom, in particular via the nitrogen atom in the 7-position. When the 2, 7-diazaspiro [3.5 ] is present]When the nonanyl group has a substituent, the substituent may be located atWhich carbon or nitrogen atom is available, for example, may be located on any nitrogen atom not attached to the pyrimidine ring. Specific substituted 2, 7-diazaspiro [3.5 ]]Nonanyl may be, for example, 2-, (Tertiary carboxylic acidButoxycarbonyl) -2, 7-diazaspiro [3.5]Nonane.

At R⁴And R⁵Or R⁶And R⁷Or R⁸And R⁹Or R¹⁰And R¹¹Or R¹²And R¹³Or R¹⁴And R¹⁵In the case of saturated heterocyclic rings, the only heteroatom present is R⁴And R⁵Or R⁶And R⁷Or R⁸And R⁹Or R¹⁰And R¹¹Or R¹²And R¹³Or R¹⁴And R¹⁵A nitrogen atom attached thereto. The saturated heterocycle preferably comprises R ⁴And R⁵Or R⁶And R⁷Or R⁸And R⁹Or R¹⁰And R¹¹Or R¹²And R¹³Or R¹⁴And R¹⁵A 4-to 7-membered ring of the nitrogen atom to which it is attached.

R¹Suitably an optionally substituted (C3-C8) cycloalkyl (C1-C6) alkyl (e.g. cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl), but preferably an optionally substituted (C1-C6) alkyl (especially (C1-C4) alkyl, e.g. methyl, ethyl, propyl, isopropyl, methyl, ethyl, propyl, isopropyl, ethyl, propyl, isobutyl, pentyl, hexyl, heptyl, octyl, decyl,tertiary carboxylic acidButyl) or optionally substituted (C3-C8) cycloalkyl (in particular (C3-C6) cycloalkyl, such as cyclopropyl, cyclopentyl, cyclohexyl). R¹In particular unsubstituted (C1-C6), preferably (C1-C4), alkyl or unsubstituted (C3-C8), preferably (C3-C6), cycloalkyl.

In an embodiment of the invention, R¹Represents (C1-C4) alkyl, especially methyl, ethyl orTertiary carboxylic acidButyl, more preferably methyl orTertiary carboxylic acidButyl, more preferably methyl.

In another embodiment, R¹Denotes (C3-C6) cycloalkaneAnd especially cyclopropyl.

R²May be hydrogen or trifluoromethyl, but is preferably halogen (e.g. fluorine, chlorine, bromine or iodine).

In a preferred embodiment, R²Represents chlorine or fluorine (particularly chlorine). In another preferred embodiment, R ²Is hydrogen.

In one embodiment, R³Represents hydrogen, hydroxyl or halogen, or (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C8) cycloalkyl (C1-C6) alkoxy, (C1-C6) alkylcarbonyl, (C1-C6) alkoxycarbonyl, amino, (C1-C6) alkylamino, di- [ (C1-C6) alkyl]Amino, (C3-C8) cycloalkylamino, (C3-C8) cycloalkyl (C1-C6) alkylamino, (C1-C6) alkoxyamino, carbamoyl, (C1-C6) alkylcarbamoyl, di- [ (C1-C6) alkylcarbamoyl]Carbamoyl, -C (O) R^3b、-OR^3b、-NHR^3b-N [ (C1-C6) alkyl group]R^3b、-S(O)_mR^3aor-N (R)^3c)C(O)R^3aWherein R is^3aRepresents (C1-C6) alkyl or (C1-C6) alkoxy, m is 0, 1 or 2, R is^3bRepresents a saturated 4-, 5-or 6-membered monocyclic heterocycle comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur and R^3cRepresents hydrogen or (C1-C6) alkyl, or R³Represents a 5-to 6-membered saturated monocyclic heterocycle containing at least one ring heteroatom selected from nitrogen, oxygen and sulfur, or R³Represents a 5-to 6-membered heteroaromatic ring containing at least one ring heteroatom selected from nitrogen, oxygen and sulfur, or R³Represents a 2, 7-diazaspiro [3.5 ]]A nonyl group. R³Each of these groups or rings in (a) may optionally be substituted by one or more (e.g. one or two, especially one) groups independently selected from (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkoxy (C1-C6) alkyl, (C1-C6) alkoxy (C1-C6) alkoxy, halogen, hydroxy, trifluoromethyl, tris- [ (C1-C4) alkyl ]Silyl, cyano, amino, (C1-C6) alkylamino, di- [ (C1-C6) alkyl]Amino, amino (C1-C6) alkyl, (C1-C6) alkylamino (C1-C6) alkyl, di- [ (C1-C6)1-C6) alkyl]Amino (C1-C6) alkyl, (C1-C6) alkoxycarbonyl, carbamoyl, (C1-C6) alkylcarbamoyl, di- [ (C1-C6) alkyl]Carbamoyl, (C1-C6) alkylthio, (C1-C6) alkylsulfonyl, (C1-C6) alkylsulfinyl, (C1-C6) alkanoyl, wherein R is^3aAnd R^3cIs as defined above for alkanoylamino-N (R)^3c)C(O)R^3aOr 3-, 4-, 5-, 6-or 7-membered saturated monocyclic ring optionally containing one or more heteroatoms selected from nitrogen, oxygen and sulphur, any of which substituents may be optionally substituted by one or more (e.g. one or two, especially one) (C1-C4) alkyl, hydroxy or cyano groups. R³Any of the saturated monocyclic rings of (a) optionally bears 1 or 2 oxo or thioxo substituents.

In another embodiment, R³Represents hydrogen, hydroxy or halogen, or (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C8) cycloalkyl, (C1-C6) alkoxy, (C1-C6) alkoxycarbonyl, amino, (C1-C6) alkylamino, di- [ (C1-C6) alkyl ]Amino, (C3-C8) cycloalkylamino, carbamoyl, (C1-C6) alkylcarbamoyl, di- [ (C1-C6) alkyl]Carbamoyl, -C (O) R^3b、-OR^3b、-NHR^3bor-S (O)_mR^3aWherein R is^3aRepresents (C1-C6) alkyl, m is 0 and R^3bRepresents a 4-, 5-or 6-membered saturated monocyclic heterocycle containing at least one ring heteroatom selected from nitrogen, oxygen and sulphur, or R³Represents a 5-to 6-membered saturated monocyclic heterocycle containing at least one ring heteroatom selected from nitrogen and oxygen, or R³Represents a 5-to 6-membered heteroaromatic ring comprising at least one ring heteroatom selected from nitrogen and oxygen, or R³Represents a 2, 7-diazaspiro [3.5 ]]A nonyl group. R³Each of these groups or rings in (a) may optionally be substituted by one or more (e.g. one or two, especially one) groups independently selected from (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkoxy (C1-C6) alkyl, (C1-C6) alkoxy (C1-C6) alkoxy, halogen, hydroxy, trifluoromethyl, tris- [ (C1-C4) alkyl]Silyl, amino, (C1-C6) alkylamino, di- [ (C1-C6) alkyl]Amino, amino (C1-C6) alkyl, (C1-C6) alkaneOxycarbonyl, carbamoyl, (C1-C6) alkylcarbamoyl, (C1-C6) alkylthio, (C1-C6) alkylsulfonyl, (C1-C6) alkanoyl, wherein R is^3aRepresents (C1-C6) alkyl or (C1-C6) alkoxy and R ^3calkanoylamino-N (R) representing hydrogen or (C1-C6) alkyl^3c)C(O)R^3aOr 3-, 4-, 5-or 6-membered saturated monocyclic ring optionally containing one or more heteroatoms selected from nitrogen, oxygen and sulphur, any of which substituents may optionally be substituted by one or more (e.g. one or two, especially one) (C1-C4) alkyl, hydroxy or cyano groups. R³Any of the saturated monocyclic rings of (a) optionally bears 1 or 2 oxo substituents.

In another embodiment, R³Represents hydrogen, hydroxy or halogen, or (C1-C4) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C1-C3) alkoxy, amino, (C1-C3) alkylamino, di- [ (C1-C3) alkyl]Amino, (C3-C6) cycloalkylamino, carbamoyl, (C1-C3) alkylcarbamoyl, di- [ (C1-C3) alkyl]Carbamoyl, -C (O) R^3b、-OR^3b、-NHR^3bor-S (O)_mR^3aWherein R is^3aRepresents (C1-C3) alkyl, m is 0 and R^3bRepresents a 4-, 5-or 6-membered saturated monocyclic heterocycle containing at least one ring heteroatom selected from nitrogen, oxygen and sulphur, or R³Represents a 5-to 6-membered saturated monocyclic heterocycle containing at least one ring heteroatom selected from nitrogen and oxygen, or R³Represents a 5-to 6-membered heteroaromatic ring comprising at least one ring heteroatom selected from nitrogen and oxygen. R ³Each of these groups or rings in (a) may optionally be substituted by one or more substituents as defined above, in particular by one or more (e.g. one or two, in particular one) substituents independently selected from (C1-C3) alkyl, (C1-C3) alkoxy, (C1-C3) alkoxy (C1-C3) alkyl, (C1-C3) alkoxy (C1-C3) alkoxy, halogen, hydroxy, trifluoromethyl, amino, (C1-C3) alkylamino, di- [ (C1-C3) alkyl]Amino, amino (C1-C3) alkyl, carbamoyl, (C1-C3) alkylcarbamoyl, (C1-C3) alkylthio, (C1-C3) alkylsulfonyl, (C1-C3) alkanoyl, wherein R is^3aRepresents (C1-C3) alkyl or (C1-C3) alkoxyRadical and R^3calkanoylamino-N (R) representing hydrogen or (C1-C3) alkyl^3c)C(O)R^3aOr 3-, 4-, 5-or 6-membered saturated monocyclic ring optionally containing one or more heteroatoms selected from nitrogen, oxygen and sulphur, any of which substituents may optionally be substituted by one or more (e.g. one or two, especially one) (C1-C2) alkyl, hydroxy or cyano groups. R³Any of the saturated monocyclic rings of (a) optionally bears 1 oxo substituent.

In another embodiment, R³Represents hydrogen or (C1-C4) alkyl, (C1-C3) alkoxy or (C3-C5) cycloalkyl or R ³Represents a 5-to 6-membered saturated monocyclic heterocycle comprising at least one ring heteroatom selected from nitrogen and oxygen. R³Each of these groups or rings in (b) may be optionally substituted by one or more (e.g. one or two, especially one) substituents as defined above, especially by one or more substituents independently selected from hydroxy and (C1-C3) alkoxy.

R³Suitable values include, for example, hydrogen, hydroxy, chlorine, fluorine or iodine, or methyl, ethyl, n-propyl, i-propyl, n-butyl,Tertiary carboxylic acidButyl, ethenyl, propenyl, butenyl, pentenyl, ethynyl, propynyl, butynyl, methoxy, ethoxy, propoxy, butenyl, pentenyl,Tertiary carboxylic acidButoxy, cyclopropyl, cyclobutyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxy,Tertiary carboxylic acidButoxycarbonyl, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, cyclobutylamino, cyclohexylamino, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-butylcarbamoyl, N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl, pyrrolidinylcarbonyl, morpholinylcarbonyl, azetidinylcarbonyl, methylthio, ethylthio, piperidinylamino, tetrahydropyranylamino, tetrahydropyranyloxy, pyrrolidinyl, morpholinyl, piperazinyl, oxadiazolyl or 2, 7-diazaspiro [ 3.5.5 ]A non-7-yl group. Each of these groups or rings may optionally beSubstituted by one or more (e.g. one or two, especially one) substituents as defined above.

R³Suitable values include, in particular, hydrogen, hydroxyl, chlorine, fluorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, ethyl, propyl, isobutyl, substituted or unsubstituted aryl, substituted or,Tertiary carboxylic acidButyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, trifluoromethyl, hydroxymethyl, methoxymethyl, ethoxymethyl, (2-methoxyethoxy) methyl, aminomethyl, methylaminomethyl, ethylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, 4-methylpiperazin-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-aminopropan-1-yl, 3-N, N-dimethylaminopropyl, 3- ((.Tertiary carboxylic acidButoxycarbonylamino) prop-1-yl, 3-pyrrolidin-1-ylpropyl, ethenyl, propenyl, butenyl, pentenyl, 3-hydroxyprop-1-en-1-yl, 3-aminopropyl-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-yn-1-yl, propargyl, pentenyl, and hexenyl, 3-methylaminoprop-1-yn-1-yl, 3- (dimethylamino) 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- (imidazolidin-2-one-1-yl) ethoxy, 3-hydroxypropoxy, 2-hydroxypropan-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, ethoxycarbonyl, ethoxy, Tertiary carboxylic acidButoxycarbonyl, N-, (Tertiary carboxylic acidButoxycarbonyl) amino, methylamino, 2-methoxyethylamino, 2-aminoethylamino, 2- (dimethylamino) ethylamino, (N-2-methoxyethyl) -N-methylamino, 3-isopropoxyprop-1-ylamino, 2- (2-hydroxyethoxy) ethylamino, 2- (acetylamino) ethylamino, 2- (morpholin-4-yl) ethylamino, 2-methylprop-1-ylamino, 2-hydroxyprop-1-ylamino, 3-methoxypropylamino, 3-ethoxypropylamino, 2-isopropoxyethylamino, tetrahydrofuran-2-ylmethyl-amino, dimethylamino, N- (2-hydroxyethyl) -N-ethylamino, N-tert-butylamino, N-propylamino, N-, Cyclopropylamino, cyclobutylamino, cyclopentylamino, 4-methylcyclohexylamino, 4-hydroxycyclohexylamino, carbamoyl, N-hydroxycarbamoyl, N-cyclopropylcarbamoyl, N-cyclopentylcarbamoyl, N-carbamoyl, 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, 6, 6-tetramethylpiperidin-4-ylamino, 4-tetrahydropyranylamino, tetrahydropyran-4-oxy, 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, N- (2-methoxyethyl) morpholin-1-yl, N-methylcarbamoyl, N-methylpyrrolidin-1-yl, N- (2-ethoxymethyl) piperazin-1-yl, N- (2-, 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-yl, 4- (cyanoethyl) piperazin-1-ylTertiary carboxylic acidButoxycarbonyl) piperazin-1-yl, 1-formyl-piperazin-4-yl, 4-acetylpiperazin-1-yl, 4- (ethylsulfonyl) piperazin-1-yl, 4-aminopiperidin-1-yl, 4- (N-Tertiary carboxylic acidButoxycarbonylamino) piperidin-1-yl, 3-hydroxypyrrolidin-1-yl, 3-dimethylamino-pyrrolidin-1-yl, cis-3, 4-dihydroxypyrrolidin-1-yl, 5-methyl- [1, 3, 4% ]Oxadiazol-2-yl, 2, 7-diazaspiro [3.5 ]]Non-7-yl and: (Tertiary carboxylic acidButoxycarbonyl) -2, 7-diazaspiro [3.5]Non-7-yl.

R³More particularly suitable values of (A) include, for example, hydrogen, hydroxy, chloro, iodo, 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-aminopropyl-1-yl, 3-N, N-dimethylaminopropyl, 3- (N-methylcarbamoyl) ethyl, 3-methyl-ethyl, 3-methyl-propyl, 3- (methyl-propyl-methyl-1-yl-methyl-Tertiary carboxylic acidButoxycarbonylamino) prop-1-yl, 3-pyrrolidin-1-ylpropyl, vinyl, pent-3-en-1-yl, 3-hydroxyprop-1-en-1-yl, 3-aminopropyl-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-aminopropyl-1-yn-1-yl, methyl ethyl, propyl, butyl, 3-methylaminoprop-1-yn-1-yl, 3- (dimethylamino) prop-1-yn-1-yl, 3- (N-methylacetamino) prop-1-yn-1-yl, 3-acetamido-prop-1-yn-1-yl, methoxy, ethoxy, (5-oxopyrrolidin-2-yl) methoxy (e.g., (2S) - (5-oxopyrrolidin-2-yl) methoxy or (2R) - (5-oxopyrrolidin-2-yl) methoxy), tetrahydrofuran-3-ylmethoxy, 2-hydroxyethoxy, 2-ethoxyethoxy, 2- (2-hydroxyethoxy) ethoxy, N-tert-butyl-ethyl-1-yl, N-butyl-ethyl, 2-methoxyethoxy, (2-methoxyethoxy) ethoxy, 2- { N- [ 2-hydroxyethyl ]-N-methyl-amino } ethoxy, 2-morpholinoethoxy, 2- (2-oxopyrrolidin-1-yl) ethoxy, 2- (imidazolidin-2-one-1-yl) ethoxy, 3-hydroxypropoxy, 2-hydroxypropan-1-yloxy (e.g. (2R) -2-hydroxypropan-1-yloxy), 3-methoxyprop-1-oxy, 2-methoxyprop-1-yloxy (e.g. (2S) -2-methoxyprop-1-yloxy), 3-morpholinoprop-1-yloxy, 3- (methylthio) prop-1-yloxyAryloxy, 3- (methylsulfonyl) propyl-1-oxy, methoxycarbonyl, N-, (Tertiary carboxylic acidButoxycarbonyl) amino, methylamino, 2-methoxyethylamino, 2-aminoethylamino, 2- (dimethylamino) ethylamino, (N-2-methoxyethyl) -N-methylamino, 3-isopropoxyprop-1-ylamino, 2- (2-hydroxyethoxy) ethylamino, 2- (acetylamino) ethylamino, 2- (morpholin-4-yl) ethylamino, 2-methylpropan-1-ylamino, 2-hydroxypropan-1-ylamino (e.g. (2R) -2-hydroxypropan-1-ylamino or (2S) -2-hydroxypropan-1-ylamino), 3-methoxypropylamino, N-ethylmethylamino, N-2-methylethylamino, N-propylamin-1-ylamino, N-propylamino, N-2-ethylamino, N-propylamino, N-1-ylamino, N-propylamino, 3-ethoxypropylamino, 2-isopropoxyethylamino, tetrahydrofuran-2-ylmethylamino (e.g., (2R) -tetrahydrofuran-2-ylmethylamino), dimethylamino, N- (2-hydroxyethyl) -N-ethylamino, cyclobutylamino, 4-methylcyclohexylamino, 4-hydroxycyclohexylamino, carbamoyl, N-hydroxycarbamoyl, N-cyclopropylcarbamoyl, N-cyclopentylcarbamoyl, N-carbamoyl, N- (acetylamino) carbamoyl, N-methylcarbamoyl, 2-hydroxyethylcarbamoyl, N- (2-hydroxypropyl) carbamoyl (e.g., N- ((R) -2-hydroxypropyl) carbamoyl), n- (2, 3-dihydroxypropyl) carbamoyl (e.g., 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 ]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 (e.g., (3R) -3-hydroxypyrrolidin-1-ylcarbonyl), methylthio, 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, morpholino, pyrrolidin-1-yl, and pharmaceutically acceptable salts thereof, 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-yl, 4-, (Tertiary carboxylic acidButoxycarbonyl) piperazin-1-yl, 1-formyl-piperazin-4-yl, 4-acetylpiperazin-1-yl, 4- (ethylsulfonyl) piperazin-1-yl, 4-aminopiperidin-1-yl, 4- (N-Tertiary carboxylic acidButoxycarbonylamino) piperidin-1-yl, 3-hydroxypyrrolidin-1-yl (e.g. (3R) -3-hydroxypyrrolidin-1-yl), 3-dimethylamino-pyrrolidin-1-yl (e.g. (3R) -3-dimethylamino-pyrrolidin-1-yl), cis-3, 4-dihydroxypyrrolidin-1-yl, 5-methyl- [1, 3, 4 ]Oxadiazol-2-yl, 2, 7-diazaspiro [3.5 ]]Non-7-yl and: (Tertiary carboxylic acidButoxycarbonyl) -2, 7-diazaspiro [3.5]Non-7-yl.

R³More particularly suitable values of (A) include, for example, hydrogen, chlorine, iodine, methyl, ethyl, trifluoromethyl, hydroxymethyl, methoxymethyl, ethoxymethyl, (2-methoxyethoxy) methyl, morpholinomethyl, 3-hydroxypropyl, 3-methoxypropyl, 3-N, N-dimethylaminopropyl, vinyl, 3-hydroxyprop-1-en-1-yl, ethynyl, 3-hydroxyprop-1-yn-1-yl, 3-methoxyprop-1-yn-1-yl, 3-aminoprop-1-yn-1-yl, 3-methylaminoprop-1-yn-1-yl, 3- (dimethylamino) prop-1-yn-1-yl, methyl, ethyl, trifluoromethyl, hydroxymethyl, methoxymethyl, ethoxymethyl, (2-methoxyethoxy) methyl, 3-hydroxyprop-1-yn-1-yl, 3-aminopropyl-1-yn-1-yl, 3- (dimethylamino), 3- (N-methylacetamido) prop-1-yn-1-yl, 3-acetamidoprop-1-yn-1-yl, methoxy, ethoxy, (5-oxopyrrolidin-2-yl) methoxy (e.g. (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- (imidazolidin-2-one-1-yl) ethoxy, 3-hydroxypropoxy, 2-hydroxypropan-1-yloxy (e.g. (2R) -2-hydroxypropan-1-yloxy), 3-methoxyprop-1-yloxy, 2-methoxyprop-1-yloxy (e.g. (2S) -2-methoxyprop-1-yloxy), 3-morpholinoprop-1-yloxy, 3- (methylthio) prop-1-yloxy, 3- (methylsulfonyl) propyl-1-oxy, 2-morpholinoethoxy, 2- (2-oxopyrrolidin-1-yl) ethoxy, 3- (methylthio) prop-1-yloxy, 3- (methylsulfonyl) propyl-1-oxy, 2-oxopyrrolidin-1-yloxy, 2- (, Methylamino, 2-methoxyethylamino, 2- (methoxyethyl) amino, 2- (2-hydroxyethoxy) ethylamino, 2- (morpholin-4-yl) ethyl Alkylamino, 2-methylpropan-1-ylamino, 2-hydroxypropan-1-ylamino (e.g. (2R) -2-hydroxypropan-1-ylamino or (2S) -2-hydroxypropan-1-ylamino), 3-methoxypropylamino, 3-ethoxypropylamino, 2-isopropoxyethylamino, tetrahydrofuran-2-ylmethylamino (e.g. (2R) -tetrahydrofuran-2-ylmethylamino), dimethylamino, N- (2-hydroxyethyl) -N-ethylamino, cyclobutylamino, carbamoyl, N-cyclopropylcarbamoyl, N-methylcarbamoyl, 2-hydroxyethylcarbamoyl, N-propylcarbamoyl, N, N- (2-hydroxypropyl) carbamoyl (e.g. N- ((R) -2-hydroxypropyl) carbamoyl), N- (2-methoxyethyl) carbamoyl, N- [2- (methylthio) ethyl]Carbamoyl, pyrrolidin-1-ylcarbonyl, azetidin-1-ylcarbonyl, methylthio, 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-methoxyethyl) piperazin-1-yl, 4- (2-cyanoethyl) piperazin-1-yl, 4-acetylpiperazin-1-yl, azetidin-1-yl, thiomorpholino, and pharmaceutically acceptable salts thereof, 4- (ethylsulfonyl) piperazin-1-yl, 3-hydroxypyrrolidin-1-yl (e.g., (3R) -3-hydroxypyrrolidin-1-yl), 3-dimethylamino-pyrrolidin-1-yl (e.g., (3R) -3-dimethylamino-pyrrolidin-1-yl), and 1-formyl-piperazin-4-yl.

In one embodiment, R³Suitably selected from hydrogen or halogen, or (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkoxy, (C1-C6) alkylcarbonyl, (C1-C6) alkoxycarbonyl, amino, (C1-C6) alkylamino, di- [ (C1-C6) alkyl]Amino, carbamoyl, -C (O) R^3b、-OR^3b、-SR^3b、-NHR^3b-N [ (C1-C6) alkyl group]R3b or-S (O)_mR^3aRadical (wherein R^3aAnd R^3bAs defined above), or a 5-or 6-membered saturated monocyclic heterocyclic ring containing at least one ring heteroatom selected from nitrogen, oxygen and sulphur, each ring or group being optionally substituted by one or more (e.g. one or two, especially one) substituents as defined above.

In a further embodiment of the process of the present invention,R³suitably selected from hydrogen or substituted or unsubstituted alkyl (C1-C6) (preferably (C1-C4) alkyl) such as methyl, ethyl, propyl, isopropyl, methyl, propyl, isopropyl,Tertiary carboxylic acidButyl, (C3-C8) cycloalkyl (preferably (C3-C6) such as cyclopropyl, cyclopentyl, cyclohexyl, (C3-C8) cycloalkyl (C1-C6) alkyl (preferably (C3-C6) cycloalkyl (C1-C4) alkyl) such as cyclopropylmethyl, (C1-C6) alkoxy (preferably (C1-C4) alkoxy) such as methoxy, ethoxy, propoxy, isopropoxy and butoxy, (C1-C6) alkylcarbonyl such as methylcarbonyl, (C3-C8) cycloalkylcarbonyl such as cyclopropylcarbonyl, (C3-C8) cycloalkyl (C1-C6) alkylcarbonyl such as cyclopropylmethylcarbonyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkylamino such as methylamino or ethylamino, (C3-C8) cycloalkylamino, (C3-C8) cycloalkylamino (C8-C8) alkylamino, (C1-C6) alkoxyamino or-S (O) _mR^3aA group of (1).

R³Suitable substituents on (a) include one or more (e.g. one, two or three, especially one or two, more especially one) substituents independently selected from (C1-C6) alkoxy (e.g. methoxy or ethoxy), (C1-C6) alkoxy (C1-C6) alkoxy (e.g. methoxyethoxy) or 3-, 4-, 5-, 6-or 7-membered (e.g. 4-to 7-membered) saturated monocyclic (e.g. cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, piperazinyl) optionally containing one or more heteroatoms selected from nitrogen, oxygen and sulphur.

When substituted, R³Specific substituents of (A) include, for example, one or more (e.g., one or two, especially one) independently selected from (C1-C6) alkyl, (C1-C6) alkoxy, halogen, hydroxy, trifluoromethyl, amino, (C1-C6) alkylamino and di- [ (C1-C6) alkyl]Amino, or a 3-, 4-, 5-, 6-, or 7-membered (e.g., 4-to 7-membered) saturated monocyclic substituent which may optionally contain one or more heteroatoms selected from nitrogen, oxygen, and sulfur.

When R is³When a 3-, 4-, 5-, 6-or 7-membered (e.g. 4-to 7-membered) saturated monocyclic substituent which may optionally contain one or more heteroatoms selected from nitrogen, oxygen and sulfur is carried, the ring is preferably Comprising nitrogen and optionally one or two further heteroatoms selected from nitrogen, oxygen and sulphur. For example, R³The 3-, 4-, 5-, 6-, or 7-membered (e.g., 4-to 7-membered) saturated monocyclic substituent on the above may comprise pyrrolidine.

In one embodiment, R³Represents hydrogen.

-NQ¹Preferably represents a 5-or 6-membered saturated monocyclic ring comprising one nitrogen heteroatom and optionally at least one further ring heteroatom (e.g. one, two, three or four ring heteroatoms, which may be the same or different) selected from nitrogen, oxygen and sulphur.

In one embodiment, the N-linked comprises an-NQ¹The 5-to 6-membered saturated monocyclic ring of (a) optionally contains one or two additional ring heteroatoms (which may be the same or different) selected from nitrogen, oxygen and sulfur.

In another embodiment, -NQ¹Represents a 5-or 6-membered saturated monocyclic ring containing one nitrogen heteroatom.

In a particularly preferred embodiment, -NQ¹Represents pyrrolidinyl or piperidinyl (most preferably pyrrolidinyl).

Ring NQ¹Can be substituted at any position of the ring by a ring Q²And (4) substituting. NQ¹Preferably in the reaction of-NQ¹To a ring atom adjacent to the nitrogen atom of the pyrimidine ring of the compounds of the invention by Q ²And (4) substituting.

Q²Suitably represents a 5-to 6-membered heteroaromatic ring comprising at least one ring heteroatom (e.g. one, two, three or four ring heteroatoms which may be the same or different) selected from nitrogen, oxygen and sulphur and may be, for example, thienyl, pyrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, furyl, thiazolyl, triazolyl, tetrazolyl, imidazolyl, pyrazinyl, pyridazinyl, pyrimidinyl or pyridyl.

Q²Preferably means comprising one or two5-or 6-membered heteroaromatic rings which may be identical or different and are selected from the group consisting of ring heteroatoms of nitrogen and oxygen, such as pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, oxazolyl, tetrazolyl or isoxazolyl (in particular tetrazolyl or isoxazolyl).

In another embodiment, Q²Represents a 5-or 6-membered heteroaromatic ring containing nitrogen and oxygen ring heteroatoms.

In a particularly preferred embodiment, Q²Represents an isoxazolyl ring.

In another embodiment, Q²Denotes a 5-or 6-membered heteroaromatic ring containing one to four nitrogen ring heteroatoms, e.g. Q²May represent pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, pyrazinyl, pyridazinyl, pyrimidinyl or pyridyl.

Q²May be suitably attached to the ring NQ by any available ring atom¹It may be attached, for example, via a ring carbon or nitrogen atom. At Q²In the case of containing at least one ring heteroatom, then Q²Preferably to the ring NQ through a ring carbon atom adjacent to the heteroatom¹The above.

Get rid of Q³In addition to substitution, Q²And is optionally further substituted with at least one (e.g., one, two, three, or four substituents which may be the same or different) substituent independently selected from the group consisting of: (C1-C6) alkyl, especially (C1-C4) alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, methyl, ethyl, isobutyl, methyl, isobutyl, and isobutyl),Tertiary carboxylic acidButyl, n-pentyl or n-hexyl), (C1-C6) alkoxy, in particular (C1-C4) alkoxy (e.g. methoxy, ethoxy, n-propoxy, n-butoxy,Tertiary carboxylic acidButoxy, n-pentoxy or n-hexoxy) ((C1-C6) alkyl and (C1-C6) alkoxy substituents are each optionally substituted by at least one substituent, for example one, two, three or four substituents independently selected from halogen (e.g., fluorine, chlorine, bromine or iodine), amino, hydroxy and trifluoromethyl), halogen (e.g., fluorine, chlorine, bromine or iodine), nitro, cyano, -NR⁴R⁵Carboxy, hydroxy, (C2-C6) alkenyl, especially (C2-C4) alkenyl (e.g. vinyl), (C3-C8) cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), (C3-C8) cycloalkyl (C1-C6) alkyl (e.g. cyclopropylmethyl), (C1-C4) alkoxycarbonyl, in particular (C1-C3) alkoxycarbonyl (such as methoxycarbonyl or ethoxycarbonyl), (C1-C4) alkylcarbonyl, in particular (C1-C3) alkylcarbonyl (e.g.methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl or n-butylcarbonyl), (C1-C4) alkylcarbonylamino, in particular (C1-C3) alkylcarbonylamino (such as methylcarbonylamino or ethylcarbonylamino), phenylcarbonyl, -S (O). _p(C1-C4), in particular (C1-C2) alkyl (such as methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl and ethylsulfonyl), -C (O) NR⁶R⁷and-SO₂NR⁸R⁹(wherein p, R⁶、R⁷、R⁸And R⁹Is as defined above)

R⁴、R⁵、R⁶、R⁷、R⁸And R⁹Each suitably independently represents hydrogen or (C1-C6) alkyl, preferably (C1-C4) alkyl such as methyl, ethyl, propyl or butyl, or R when taken together with the nitrogen atom to which they are attached⁴And R⁵Or R⁶And R⁷Or R⁸And R⁹Each independently may form a saturated heterocyclic ring such as pyrrolidinyl or piperidinyl.

In one embodiment, Q²Optionally substituted with at least one substituent independently selected from (C1-C6) alkyl, (C1-C6) alkoxy, halogen, and (C3-C8) cycloalkyl.

Q³Suitably substituted or unsubstituted (C1-C6) alkyl (preferably (C1-C4) alkyl) such as methyl, ethyl, propyl or butyl, (C3-C8) cycloalkyl (preferably (C3-C6) cycloalkyl) such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, (C3-C8) cycloalkyl (C1-C6) alkyl such as cyclopropylmethyl or saturated optionally containing at least one ring heteroatom (e.g. one, two, three or four heteroatoms) selected from nitrogen, oxygen and sulphurUnsaturated 5-to 6-membered monocycles such as phenyl, pyridyl, imidazolyl, isoxazolyl, pyrazolyl, furyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl, thiazolyl, oxazolyl, isothiazolyl, triazolyl, tetrahydrofuryl or thienyl (especially pyridyl, pyrazinyl, thiazolyl, tetrahydrofuryl or pyrimidinyl).

In one embodiment, Q³Represents a substituted or unsubstituted, saturated or unsaturated, 5-to 6-membered, monocyclic group selected from (C1-C6) alkyl, (C3-C8) cycloalkyl or optionally comprising at least one ring heteroatom selected from nitrogen, oxygen and sulfur. For example, Q³May represent a substituted or unsubstituted group selected from methyl, cyclopropyl, pyridyl, pyrazinyl, thiazolyl, tetrahydrofuranyl or pyrimidinyl.

In another embodiment, Q³Preferably substituted or unsubstituted, 5-to 6-membered unsaturated monocyclic ring selected from (C1-C4) alkyl (especially methyl), (C3-C6) cycloalkyl (especially cyclopropyl) or optionally substituted monocyclic ring comprising one or two ring heteroatoms which may be the same or different selected from nitrogen, oxygen and sulfur, such as imidazolyl, isoxazolyl, pyrazolyl, furyl, pyrazinyl (in particular pyrazin-2-yl), pyridazinyl, pyrimidinyl (in particular pyrimidin-2-yl), pyrrolyl, oxazolyl, isothiazolyl, triazolyl, tetrahydrofuryl or thienyl, in particular pyridyl (preferably pyridin-2-yl or pyridin-3-yl) or thiazolyl (in particular thiazol-2-yl or thiazol-4-yl) or tetrahydrofuryl (in particular tetrahydrofur-3-yl).

For Q³Suitable optional substituents are, for example, one or more (e.g., one, two, three or four) substituents independently selected from the group consisting of: (C1-C6) alkyl or (C1-C6) alkoxy, each of which may be optionally substituted with at least one (e.g., one, two, three, or four substituents) substituent independently selected from the group consisting of halogen, amino, hydroxy, and trifluoromethyl, halogen, nitro, cyano, -NR¹⁰R¹¹Carboxyl, hydroxyl, (C2-C6) alkenyl, (C3-C8) cycloalkyl, (C1-C6) alkoxycarbonyl,(C1-C6) alkylcarbonyl, (C1-C6) alkylcarbonylamino, phenylcarbonyl, -S (O)_n(C1-C6) alkyl, -C (O) NR¹²R¹³and-SO₂NR¹⁴R¹⁵(wherein n, R¹⁰、R¹¹、R¹²、R¹³、R¹⁴And R¹⁵As defined above).

R¹⁰、R¹¹、R¹²、R¹³、R¹⁴And R¹⁵Suitably each independently represents hydrogen or (C1-C6) alkyl such as methyl, or R¹⁰And R¹¹Or R is¹²And R¹³Or R is¹⁴And R¹⁵Each of which, when taken together with the nitrogen atom to which it is attached, may suitably form a saturated heterocyclic ring such as pyrrolidinyl or piperidinyl.

It will be appreciated that the number and nature of the ring substituents in the compounds of the invention will be selected to avoid undesirable stereochemical combinations.

In a preferred group of compounds of formula (I) according to the invention, R¹Represents (C1-C4) alkyl or (C3-C6) cycloalkyl; r ²Represents halogen; r³Represents hydrogen; -NQ¹Represents a 5-or 6-membered saturated monocyclic ring comprising one nitrogen heteroatom and optionally at least one further ring heteroatom selected from nitrogen, oxygen and sulphur; q²Represents a substituted 5-or 6-membered heteroaromatic ring containing one or two ring heteroatoms which may be the same or different selected from nitrogen and oxygen; and Q³Represents (C1-C4) alkyl or (C3-C6) cycloalkyl or an optionally substituted 5-to 6-membered unsaturated monocyclic ring containing one or two ring heteroatoms which may be the same or different, selected from nitrogen, oxygen and sulfur.

Particularly preferred compounds of this group are those in which-NQ¹Represents pyrrolidinyl or piperidinyl (in particular pyrrolidinyl); q²Represents isoxazolyl or tetrazolyl (particularly isoxazolyl); and Q³A compound representing methyl, cyclopropyl, tetrahydrofuryl, pyrazinyl, thiazolyl, pyrimidinyl or pyridyl.

In this groupOther particularly preferred compounds are those in which-NQ¹Represents pyrrolidinyl or piperidinyl; q²Represents isoxazolyl or tetrazolyl; and Q³A compound representing a methyl group, a cyclopropyl group, a thiazolyl group, a tetrahydrofuryl group or a pyridyl group.

Other particularly preferred compounds of this group are those in which-NQ¹Represents pyrrolidinyl or piperidinyl; q ²Represents an isoxazolyl group; and Q³A compound representing a methyl group, a cyclopropyl group, a thiazolyl group or a pyridyl group.

Other particularly preferred compounds of this group are those in which-NQ¹Represents a pyrrolidinyl group; q²Represents an isoxazolyl group; and Q³A compound representing cyclopropyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridyl.

Suitable values for the group of subformulae (I) (which are attached to the 2-position of the pyrimidine ring of formula (I)):

including, for example, 2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl, 2- (3-methylisoxazol-5-yl ] pyrrolidin-1-yl, 3-cyclopropylisoxazol-5-yl ] pyrrolidin-1-yl, 2- [3- (thiazol-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl, 2- [3- (thiazol-4-yl) isoxazol-5-yl ] pyrrolidin-1-yl, 2- [3- (pyridin-3-yl) isoxazol-5-yl ] pyrrolidin-1-yl, 2- (3- (pyridin-2-yl) isoxazol-5-yl) piperidin-1-yl -yl, 2- (3- { tetrahydrofuran-3-yl } isoxazol-5-yl ] pyrrolidin-1-yl, 2- [3- (2-methoxypyridin-3-yl) isoxazol-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- (pyrimidin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl, 2- {3- (3-methoxypyrazin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl and 2- {3- (3-methoxypyrazin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl - {3- (3-hydroxypyrazin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl (which, for the avoidance of any doubt, is pyrrolidin-1-yl or piperidin-1-yl attached to the 2-position of the pyrimidine ring in formula (I)).

Suitable values for the group of the above sub-formula (i) include, in particular, for example, 2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl, 3-cyclopropylisoxazol-5-yl ] pyrrolidin-1-yl, 2- [3- (thiazol-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl, 2- [3- (thiazol-4-yl) isoxazol-5-yl ] pyrrolidin-1-yl, 2- [3- (pyridin-3-yl) isoxazol-5-yl ] pyrrolidin-1-yl, 2- (3- { tetrahydrofuran-3-yl } isoxazol-5-yl ] pyrrolidin-1-yl, 2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidin-1-yl, 2- [3- (pyrazin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl, 2- {3- (pyrimidin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl, 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.

A particular embodiment of the invention is a compound of formula (Ia) or a pharmaceutically acceptable salt thereof:

wherein:

R¹represents trifluoromethyl, or (C1-C6) alkyl, (C3-C8) cycloalkyl or (C3-C8) cycloalkyl (C1-C6) alkyl, each of which may be optionally substituted by one or more substituents independently selected from halogen and (C1-C6) alkoxy;

R²represents hydrogen, halogen or trifluoromethyl;

R³represents hydrogen, hydroxy or halogen, or (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C8) cycloalkyl (C1-C6) alkoxy, (C1-C6) alkylcarbonyl, (C3-C8) cycloalkylcarbonyl, (C3-C8) cycloalkyl (C1-C6) alkylcarbonyl, (C1-C6) alkoxycarbonyl, amino, (C1-C6) alkylamino, di- [ (C1-C6) alkyl ]Amino, (C3-C8) cycloalkylamino, (C3-C8) cycloalkyl (C1-C6) alkylamino, (C1-C6) alkoxyamino, carbamoyl, (C1-C6) alkylcarbamoyl, di- [ (C1-C6) alkylcarbamoyl]Carbamoyl, -C (O) R^3b、-OR^3b、-SR^3b、-NHR^3b-N [ (C1-C6) alkyl group]R^3b、-S(O)_mR^3aor-N (R)^3c)C(O)R^3aWherein R is^3aRepresents (C1-C6) alkyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl or (C1-C6) alkoxy, m is 0, 1 or 2, R is^3bRepresents a saturated 4-, 5-or 6-membered monocyclic heterocycle comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur and R^3cRepresents hydrogen or (C1-C6) alkyl,

or R³Represents a 5-to 6-membered saturated monocyclic heterocyclic ring containing at least one ring heteroatom selected from nitrogen, oxygen and sulfur,

or R³Represents a 5-to 6-membered heteroaromatic ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur,

or R³Represents a 2, 7-diazaspiro [3.5 ]]A non-alkyl group,

R³each group or ring of (A) may optionally be substituted with one or more groups independently selected from (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkoxy (C1-C6) alkyl, (C1-C6) alkoxy (C1-C6) alkoxy, halogen, hydroxy, trifluoromethyl, tris- [ (C1-C4) alkyl]Silyl, cyano, amino, (C1-C6) alkylamino, di- [ (C1-C6) alkyl]Amino, (C3-C8) cycloalkylamino, (C3-C6) cycloalkyl (C1-C3) alkylamino, amino (C1-C6) alkyl, (C1-C6) alkylamino (C1-C6) alkyl, di- [ (C1-C6) alkyl ]Amino (C1-C6) alkyl, (C3-C8) cycloalkylamino (C1-C6) alkyl, (C3-C6) cycloalkyl (C1-C3) alkylamino (C1-C6) alkyl, (C1-C6) alkoxycarbonyl, carbamoyl, (C1-C6) alkylcarbamoyl, di- [ (C1-C6) alkyl]Carbamoyl, (C1-C6) alkylthio, (C1-C6) alkylsulfonyl, (C1-C6) alkylsulfinyl, (C1-C6) alkanoyl, wherein R is^3aAnd R^3cIs as defined above for alkanoylamino-N (R)^3c)C(O)R^3aOr 3-, 4-, 5-, 6-or 7-membered saturated monocyclic ring optionally containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, any of which may optionally be substituted by one or more (C1-C4) alkyl, hydroxy orCyano substituted;

Q²represents a 5-to 6-membered heteroaromatic ring containing at least one ring heteroatom selected from nitrogen, oxygen and sulfur, which ring is substituted by Q³Substituted and optionally substituted on any available ring atom with one or more substituents independently selected from (C1-C6) alkyl or (C1-C6) alkoxy (each of which may be optionally substituted with one or more substituents independently selected from halogen, amino, hydroxy and trifluoromethyl), halogen, nitro, cyano, -NR, and mixtures thereof⁴R⁵Carboxy, hydroxy, (C2-C6) alkenyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl, (C1-C4) alkoxycarbonyl, (C1-C4) alkylcarbonyl, (C1-C4) alkylcarbonylamino, phenylcarbonyl, -S (O) _p(C1-C4) alkyl, -C (O) NR⁶R⁷and-SO₂NR⁸R⁹(wherein R is⁴、R⁵、R⁶、R⁷、R⁸And R⁹Each independently represents hydrogen or (C1-C6) alkyl, or R when taken together with the nitrogen atom to which they are attached⁴And R⁵Or R⁶And R⁷Or R⁸And R⁹May each independently form a saturated heterocyclic ring and p is 0, 1 or 2);

Q³represents (C1-C6) alkyl, (C3-C6) cycloalkyl or (C3-C6) cycloalkyl (C1-C6) alkyl or a saturated or unsaturated 5-to 6-membered monocyclic ring which may contain at least one ring heteroatom selected from nitrogen, oxygen and sulfur, and wherein Q³Optionally substituted with one or more substituents independently selected from (C1-C6) alkyl or (C1-C6) alkoxy, each of which may be optionally substituted with one or more substituents independently selected from halogen, amino, hydroxy and trifluoromethyl, halogen, nitro, cyano, -NR¹⁰R¹¹Carboxy, hydroxy, (C2-C6) alkenyl, (C3-C8) cycloalkyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkylcarbonyl, (C1-C6) alkylcarbonylamino, phenylcarbonyl, -S (O)_n(C1-C6) alkyl, -C (O) NR¹²R¹³and-SO₂NR¹⁴R¹⁵Wherein R is substituted by a substituent of (1)¹⁰、R¹¹、R¹²、R¹³、R¹⁴And R¹⁵Each independently represents hydrogen or (C1-C6) alkyl, or R when taken together with the nitrogen atom to which they are attached¹⁰And R¹¹Or R¹²And R¹³Or R ¹⁴And R¹⁵Each independently may form a saturated heterocyclic ring and n is 0, 1 or 2;

and wherein any saturated monocyclic ring optionally bears 1 or 2 oxo or thioxo substituents.

According to another embodiment of the present invention, there is provided a compound of formula (Ia) or a pharmaceutically acceptable salt thereof, wherein:

R¹represents trifluoromethyl, or (C1-C6) alkyl, (C3-C8) cycloalkyl or (C3-C8) cycloalkyl (C1-C6) alkyl, each of which may be optionally substituted by one or more substituents independently selected from halogen and (C1-C6) alkoxy;

R²represents hydrogen, halogen or trifluoromethyl;

R³represents hydrogen or halogen, or (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C8) cycloalkyl (C1-C6) alkoxy, (C1-C6) alkylcarbonyl, (C3-C8) cycloalkylcarbonyl, (C3-C8) cycloalkyl (C1-C6) alkylcarbonyl, (C1-C6) alkoxycarbonyl, amino, (C1-C6) alkylamino, di- [ (C1-C6) alkyl]Amino, (C3-C8) cycloalkylamino, (C3-C8) cycloalkyl (C1-C6) alkylamino, (C1-C6) alkoxyamino, carbamoyl, (C2-C6) alkanoylamino, -C (O) R^3b、-OR^3b、-SR^3b、-NHR^3b-N [ (C1-C6) alkyl group]R^3bor-S (O)_mR^3aWherein R is^3aRepresents (C1-C6) alkyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl or (C1-C6) alkoxy, m is 0, 1 or 2, and R ^3bRepresents a 5-to 6-membered saturated monocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur,

or R³Represents a 5-to 6-membered saturated monocyclic heterocyclic ring containing at least one ring heteroatom selected from nitrogen, oxygen and sulfur,

R³each group or ring of (A) may optionally be substituted with one or more groups independently selected from (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkoxy (C1-C6) alkoxy, halogen, hydroxy, trifluoromethyl, cyano, amino, (C1-C6) alkylamino, di- [ (C1-C6) alkyl]Amino, (C3-C8) cycloalkylamino, (C3-C6) cycloalkyl (C1-C3) alkylamino, (C1-C6) alkoxycarbonyl, carbamoyl, (C1-C6) alkylcarbamoyl, di- [ (C1-C6) alkylcarbamoyl]Carbamoyl, (C1-C6) alkylthio, (C1-C6) alkylsulfonyl, (C1-C6) alkylsulfinyl, (C1-6) alkanoylamino or a substituent of a 4-, 5-, 6-or 7-membered saturated monocyclic ring which may optionally contain one or more heteroatoms selected from nitrogen, oxygen and sulfur;

Q²represents a 5-to 6-membered heteroaromatic ring containing at least one ring heteroatom selected from nitrogen, oxygen and sulfur, which ring is substituted by Q³Substituted and optionally substituted on any available ring atom with one or more substituents independently selected from (C1-C6) alkyl or (C1-C6) alkoxy (each of which may be optionally substituted with one or more substituents independently selected from halogen, amino, hydroxy and trifluoromethyl), halogen, nitro, cyano, -NR, and mixtures thereof ⁴R⁵Carboxy, hydroxy, (C2-C6) alkenyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl, (C1-C4) alkoxycarbonyl, (C1-C4) alkylcarbonyl, (C1-C4) alkylcarbonylamino, phenylcarbonyl, -S (O)_p(C1-C4) alkyl, -C (O) NR⁶R⁷and-SO₂NR⁸R⁹Wherein R is substituted with a further substituent of⁴、R⁵、R⁶、R⁷、R⁸And R⁹Each independently represents hydrogen or (C1-C6) alkyl, or R when taken together with the nitrogen atom to which they are attached⁴And R⁵Or R⁶And R⁷Or R⁸And R⁹Each independently may form a saturated heterocyclic ring and p is 0, 1 or 2;

Q³represents (C1-C6) alkyl, (C3-C6) cycloalkyl or (C3-C6) cycloalkyl (C1-C6) alkyl or saturated alkyl which may contain at least one ring heteroatom selected from nitrogen, oxygen and sulfurOr an unsaturated 5-to 6-membered monocyclic ring, and wherein Q³Optionally substituted with one or more substituents independently selected from (C1-C6) alkyl or (C1-C6) alkoxy, each of which may be optionally substituted with one or more substituents independently selected from halogen, amino, hydroxy and trifluoromethyl, halogen, nitro, cyano, -NR¹⁰R¹¹Carboxy, hydroxy, (C2-C6) alkenyl, (C3-C8) cycloalkyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkylcarbonyl, (C1-C6) alkylcarbonylamino, phenylcarbonyl, -S (O)_n(C1-C6) alkyl, -C (O) NR ¹²R¹³and-SO₂NR¹⁴R¹⁵Wherein R is substituted by a substituent of (1)¹⁰、R¹¹、R¹²、R¹³、R¹⁴And R¹⁵Each independently represents hydrogen or (C1-C6) alkyl, or R when taken together with the nitrogen atom to which they are attached¹⁰And R¹¹Or R¹²And R¹³Or R¹⁴And R¹⁵Each independently may form a saturated heterocyclic ring and n is 0, 1 or 2.

In such embodiments, Q²In particular, denotes a 5-to 6-membered heteroaromatic ring comprising at least one ring nitrogen and optionally at least one further ring heteroatom selected from nitrogen, oxygen and sulfur. Q²More particularly a 5-to 6-membered heteroaromatic ring comprising at least one ring nitrogen and optionally at least one further ring heteroatom selected from nitrogen and oxygen. For example, Q²May represent isoxazolyl (especially isoxazol-5-yl) or tetrazolyl (especially tetrazol-5-yl). Q²In particular isoxazolyl (e.g. isoxazol-5-yl). The ring Q²Is defined as above Q³Substituted, and optionally further substituted on any available ring atom with one or more additional substituents as defined above.

Another particularly preferred embodiment of the present invention is a compound of formula (Ib):

wherein:

R¹represents trifluoromethyl, or (C1-C6) alkyl, (C3-C8) cycloalkyl or (C3-C8) cycloalkyl (C1-C6) alkyl, each of which may be optionally substituted by one or more substituents independently selected from halogen and (C1-C6) alkoxy;

R²Represents hydrogen, halogen or trifluoromethyl;

R³represents hydrogen, hydroxy or halogen, or (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C8) cycloalkyl (C1-C6) alkoxy, (C1-C6) alkylcarbonyl, (C3-C8) cycloalkylcarbonyl, (C3-C8) cycloalkyl (C1-C6) alkylcarbonyl, (C1-C6) alkoxycarbonyl, amino, (C1-C6) alkylamino, di- [ (C1-C6) alkyl]Amino, (C3-C8) cycloalkylamino, (C3-C8) cycloalkyl (C1-C6) alkylamino, (C1-C6) alkoxyamino, carbamoyl, (C1-C6) alkylcarbamoyl, di- [ (C1-C6) alkylcarbamoyl]Carbamoyl, -C (O) R^3b、-OR^3b、-SR^3b、-NHR^3b-N [ (C1-C6) alkyl group]R^3b、-S(O)_mR^3aor-N (R)^3c)C(O)R^3aWherein R is^3aRepresents (C1-C6) alkyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl or (C1-C6) alkoxy, m is 0, 1 or 2, R is^3bRepresents a saturated 4-, 5-or 6-membered monocyclic heterocycle comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur and R^3cRepresents hydrogen or (C1-C6) alkyl,

or R³Represents a 5-to 6-membered saturated monocyclic heterocyclic ring containing at least one ring heteroatom selected from nitrogen, oxygen and sulfur,

or R³Represents a 5-to 6-membered heteroaromatic ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur,

Or R³Represents a 2, 7-diazaspiro [3.5 ]]A non-alkyl group,

R³each group or ring of (A) may optionally be substituted with one or more substituents independently selected from (C1-C6) alkylA (C1-C6) alkoxy group, a (C1-C6) alkoxy group (C1-C6) alkyl group, a (C1-C6) alkoxy group (C1-C6) alkoxy group, halogen, hydroxy, trifluoromethyl, tri- [ (C1-C4) alkyl group]Silyl, cyano, amino, (C1-C6) alkylamino, di- [ (C1-C6) alkyl]Amino, (C3-C8) cycloalkylamino, (C3-C6) cycloalkyl (C1-C3) alkylamino, amino (C1-C6) alkyl, (C1-C6) alkylamino (C1-C6) alkyl, di- [ (C1-C6) alkyl]Amino (C1-C6) alkyl, (C3-C8) cycloalkylamino (C1-C6) alkyl, (C3-C6) cycloalkyl (C1-C3) alkylamino (C1-C6) alkyl, (C1-C6) alkoxycarbonyl, carbamoyl, (C1-C6) alkylcarbamoyl, di- [ (C1-C6) alkyl]Carbamoyl, (C1-C6) alkylthio, (C1-C6) alkylsulfonyl, (C1-C6) alkylsulfinyl, (C1-C6) alkanoyl, wherein R is^3aAnd R^3cIs as defined above for alkanoylamino-N (R)^3c)C(O)R^3aOr 3-, 4-, 5-, 6-or 7-membered saturated monocyclic ring optionally containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, any of which substituents may be optionally substituted by one or more (C1-C4) alkyl, hydroxy or cyano groups;

Q³Represents (C1-C6) alkyl, (C3-C6) cycloalkyl or (C3-C6) cycloalkyl (C1-C6) alkyl or a saturated or unsaturated 5-to 6-membered monocyclic ring which may contain at least one ring heteroatom selected from nitrogen, oxygen and sulfur, and wherein Q³Optionally substituted with one or more substituents independently selected from (C1-C6) alkyl or (C1-C6) alkoxy, each of which may be optionally substituted with one or more substituents independently selected from halogen, amino, hydroxy and trifluoromethyl, halogen, nitro, cyano, -NR¹⁰R¹¹Carboxy, hydroxy, (C2-C6) alkenyl, (C3-C8) cycloalkyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkylcarbonyl, (C1-C6) alkylcarbonylamino, phenylcarbonyl, -S (O)_n(C1-C6) alkyl, -C (O) NR¹²R¹³and-SO₂NR¹⁴R¹⁵Wherein R is substituted by a substituent of (1)¹⁰、R¹¹、R¹²、R¹³、R¹⁴And R¹⁵Each independently represents hydrogen or (C1-C6) alkyl, or R when taken together with the nitrogen atom to which they are attached¹⁰And R¹¹Or R¹²And R¹³Or R¹⁴And R¹⁵Each independently may form a saturated heterocyclic ring and n is 0, 1 or 2;

and wherein any saturated monocyclic ring optionally bears 1 or 2 oxo or thioxo substituents.

According to another embodiment of the present invention, there is provided a compound of formula (Ib) or a pharmaceutically acceptable salt thereof, wherein:

R¹represents trifluoromethyl, or (C1-C6) alkyl, (C3-C8) cycloalkyl or (C3-C8) cycloalkyl (C1-C6) alkyl, each of which may be optionally substituted by one or more substituents independently selected from halogen and (C1-C6) alkoxy;

R²Represents hydrogen, halogen or trifluoromethyl;

R³represents hydrogen or halogen, or (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C8) cycloalkyl (C1-C6) alkoxy, (C1-C6) alkylcarbonyl, (C3-C8) cycloalkylcarbonyl, (C3-C8) cycloalkyl (C1-C6) alkylcarbonyl, (C1-C6) alkoxycarbonyl, amino, (C1-C6) alkylamino, di- [ (C1-C6) alkyl]Amino, (C3-C8) cycloalkylamino, (C3-C8) cycloalkyl (C1-C6) alkylamino, (C1-C6) alkoxyamino, carbamoyl, (C2-C6) alkanoylamino, -C (O) R^3b、-OR^3b、-SR^3b、-NHR^3b-N [ (C1-C6) alkyl group]R^3bor-S (O)_mR^3aWherein R is^3aRepresents (C1-C6) alkyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl or (C1-C6) alkoxy, m is 0, 1 or 2, and R^3bRepresents a 5-to 6-membered saturated monocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur;

or R³Represents a 5-or 6-membered saturated monocyclic ring containing at least one ring heteroatom selected from nitrogen, oxygen and sulphur,

R³each group or ring of (A) may optionally be substituted with one or more substituents independently selected from (C1-C6) alkyl, (C1)-C6) alkoxy, (C1-C6) alkoxy (C1-C6) alkoxy, halogen, hydroxy, trifluoromethyl, cyano, amino, (C1-C6) alkylamino, di- [ (C1-C6) alkyl ]Amino, (C3-C8) cycloalkylamino, (C3-C6) cycloalkyl (C1-C3) alkylamino, (C1-C6) alkoxycarbonyl, carbamoyl, (C1-C6) alkylcarbamoyl, di- [ (C1-C6) alkylcarbamoyl]Carbamoyl, (C1-C6) alkylthio, (C1-C6) alkylsulfonyl, (C1-C6) alkylsulfinyl, (C1-6) alkanoylamino or a substituent of a 4-, 5-, 6-or 7-membered saturated monocyclic ring which may optionally contain one or more heteroatoms selected from nitrogen, oxygen and sulfur;

Q³represents (C1-C6) alkyl, (C3-C6) cycloalkyl or (C3-C6) cycloalkyl (C1-C6) alkyl or a saturated or unsaturated 5-to 6-membered monocyclic ring which may contain at least one ring heteroatom selected from nitrogen, oxygen and sulfur, and wherein Q³Optionally substituted with one or more substituents independently selected from (C1-C6) alkyl or (C1-C6) alkoxy, each of which may be optionally substituted with one or more substituents independently selected from halogen, amino, hydroxy and trifluoromethyl, halogen, nitro, cyano, -NR¹⁰R¹¹Carboxy, hydroxy, (C2-C6) alkenyl, (C3-C8) cycloalkyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkylcarbonyl, (C1-C6) alkylcarbonylamino, phenylcarbonyl, -S (O)_n(C1-C6) alkyl, -C (O) NR¹²R¹³and-SO₂NR¹⁴R¹⁵Wherein R is substituted by a substituent of (1) ¹⁰、R¹¹、R¹²、R¹³、R¹⁴And R¹⁵Each independently represents hydrogen or (C1-C6) alkyl, or R when taken together with the nitrogen atom to which they are attached¹⁰And R¹¹Or R¹²And R¹³Or R¹⁴And R¹⁵Each independently may form a saturated heterocyclic ring and n is 0, 1 or 2.

In such embodiments, Q³In particular from (C1-C6) alkyl or (C3-C6) cycloalkyl, or a saturated or unsaturated 5-to 6-membered monocyclic ring which may contain at least one ring heteroatom selected from nitrogen, oxygen and sulfur, and wherein Q³Optionally substituted by one or more substituents as defined aboveAnd (4) generation.

A particular embodiment of the invention are compounds of formula (Ic):

or a pharmaceutically acceptable salt thereof,

wherein:

R¹represents trifluoromethyl, or (C1-C6) alkyl, (C3-C8) cycloalkyl or (C3-C8) cycloalkyl (C1-C6) alkyl, each of which may be optionally substituted by one or more substituents independently selected from halogen and (C1-C6) alkoxy;

R²represents hydrogen, halogen or trifluoromethyl;

R³represents hydrogen, hydroxy or halogen, or (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C8) cycloalkyl (C1-C6) alkoxy, (C1-C6) alkylcarbonyl, (C3-C8) cycloalkylcarbonyl, (C3-C8) cycloalkyl (C1-C6) alkylcarbonyl, (C1-C6) alkoxycarbonyl, amino, (C1-C6) alkylamino, di- [ (C1-C6) alkyl ]Amino, (C3-C8) cycloalkylamino, (C3-C8) cycloalkyl (C1-C6) alkylamino, (C1-C6) alkoxyamino, carbamoyl, (C1-C6) alkylcarbamoyl, di- [ (C1-C6) alkylcarbamoyl]Carbamoyl, -C (O) R^3b、-OR^3b、-SR^3b、-NHR^3b-N [ (C1-C6) alkyl group]R^3b、-S(O)_mR^3aor-N (R)^3c)C(O)R^3aWherein R is^3aRepresents (C1-C6) alkyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl or (C1-C6) alkoxy, m is 0, 1 or 2, R is^3bRepresents a saturated 4-, 5-or 6-membered monocyclic heterocycle comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur and R^3cRepresents hydrogen or (C1-C6) alkyl,

Or R³Represents a 5-to 6-membered saturated monocyclic heterocyclic ring containing at least one ring heteroatom selected from nitrogen, oxygen and sulfur,

or R³Represents a 5-to 6-membered heteroaromatic ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur,

or R³Represents a 2, 7-diazaspiro [3.5 ]]A non-alkyl group,

R³each group or ring of (A) may optionally be substituted with one or more groups independently selected from (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkoxy (C1-C6) alkyl, (C1-C6) alkoxy (C1-C6) alkoxy, halogen, hydroxy, trifluoromethyl, tris- [ (C1-C4) alkyl]Silyl, cyano, amino, (C1-C6) alkylamino, di- [ (C1-C6) alkyl]Amino, (C3-C8) cycloalkylamino, (C3-C6) cycloalkyl (C1-C3) alkylamino, amino (C1-C6) alkyl, (C1-C6) alkylamino (C1-C6) alkyl, di- [ (C1-C6) alkyl ]Amino (C1-C6) alkyl, (C3-C8) cycloalkylamino (C1-C6) alkyl, (C3-C6) cycloalkyl (C1-C3) alkylamino (C1-C6) alkyl, (C1-C6) alkoxycarbonyl, carbamoyl, (C1-C6) alkylcarbamoyl, di- [ (C1-C6) alkyl]Carbamoyl, (C1-C6) alkylthio, (C1-C6) alkylsulfonyl, (C1-C6) alkylsulfinyl, (C1-C6) alkanoyl, wherein R is^3aAnd R^3cIs as defined above for alkanoylamino-N (R)^3c)C(O)R^3aOr 3-, 4-, 5-, 6-or 7-membered saturated monocyclic ring optionally containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, any of which substituents may be optionally substituted by one or more (C1-C4) alkyl, hydroxy or cyano groups;

Q²represents a 5-to 6-membered heteroaromatic ring containing at least one ring heteroatom selected from nitrogen, oxygen and sulfur, which ring is substituted by Q³Substituted and optionally substituted on any available ring atom with one or more substituents independently selected from (C1-C6) alkyl or (C1-C6) alkoxy (each of which may be optionally substituted with one or more substituents independently selected from halogen, amino, hydroxy and trifluoromethyl), halogen, nitro, cyano, -NR, and mixtures thereof⁴R⁵Carboxyl, hydroxyl, (C2-C6) alkenyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl, (C1-C4) alkoxycarbonyl, (C1-C4) alkylcarbonyl Radical, (C1-C4) alkylcarbonylamino, phenylcarbonyl, -S (O)_p(C1-C4) alkyl, -C (O) NR⁶R⁷and-SO₂NR⁸R⁹Wherein R is substituted with a further substituent of⁴、R⁵、R⁶、R⁷、R⁸And R⁹Each independently represents hydrogen or (C1-C6) alkyl, or R when taken together with the nitrogen atom to which they are attached⁴And R⁵Or R⁶And R⁷Or R⁸And R⁹Each independently may form a saturated heterocyclic ring and p is 0, 1 or 2;

Q³represents (C1-C6) alkyl, (C3-C6) cycloalkyl or (C3-C6) cycloalkyl (C1-C6) alkyl or a saturated or unsaturated 5-to 6-membered monocyclic ring which may contain at least one ring heteroatom selected from nitrogen, oxygen and sulfur, and wherein Q³Optionally substituted with one or more substituents independently selected from (C1-C6) alkyl or (C1-C6) alkoxy, each of which may be optionally substituted with one or more substituents independently selected from halogen, amino, hydroxy and trifluoromethyl, halogen, nitro, cyano, -NR¹⁰R¹¹Carboxy, hydroxy, (C2-C6) alkenyl, (C3-C8) cycloalkyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkylcarbonyl, (C1-C6) alkylcarbonylamino, phenylcarbonyl, -S (O)_n(C1-C6) alkyl, -C (O) NR¹²R¹³and-SO₂NR¹⁴R¹⁵Wherein R is substituted by a substituent of (1)¹⁰、R¹¹、R¹²、R¹³、R¹⁴And R¹⁵Each independently represents hydrogen or (C1-C6) alkyl, or R when taken together with the nitrogen atom to which they are attached ¹⁰And R¹¹Or R¹²And R¹³Or R¹⁴And R¹⁵Each independently may form a saturated heterocyclic ring and n is 0, 1 or 2;

and wherein any saturated monocyclic ring optionally bears 1 or 2 oxo or thioxo substituents.

According to another embodiment of the present invention, there is provided a compound of formula (Ic), or a pharmaceutically acceptable salt thereof, wherein:

R¹represents trifluoromethyl, or (C1-C6) alkyl, (C3-C8) cycloalkyl or (C3-C8) cycloalkyl (C1-C6) alkyl, each of which may be optionally substituted by one or more substituents independently selected from halogen and (C1-C6) alkoxy;

R²represents hydrogen, halogen or trifluoromethyl;

R³represents hydrogen or halogen, or (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C8) cycloalkyl (C1-C6) alkoxy, (C1-C6) alkylcarbonyl, (C3-C8) cycloalkylcarbonyl, (C3-C8) cycloalkyl (C1-C6) alkylcarbonyl, (C1-C6) alkoxycarbonyl, amino, (C1-C6) alkylamino, di- [ (C1-C6) alkyl]Amino, (C3-C8) cycloalkylamino, (C3-C8) cycloalkyl (C1-C6) alkylamino, (C1-C6) alkoxyamino, carbamoyl, (C2-C6) alkanoylamino, -C (O) R^3b、-OR^3b、-SR^3b、-NHR^3b-N [ (C1-C6) alkyl group]R^3bor-S (O) _mR^3aWherein R is^3aRepresents (C1-C6) alkyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl or (C1-C6) alkoxy, m is 0, 1 or 2, and R^3bRepresents a 5-to 6-membered saturated monocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur;

or R³Represents a 5-or 6-membered saturated monocyclic ring containing at least one ring heteroatom selected from nitrogen, oxygen and sulphur,

R³each group or ring of (A) may optionally be substituted with one or more groups independently selected from (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkoxy (C1-C6) alkoxy, halogen, hydroxy, trifluoromethyl, cyano, amino, (C1-C6) alkylamino, di- [ (C1-C6) alkyl]Amino, (C3-C8) cycloalkylamino, (C3-C6) cycloalkyl (C1-C3) alkylamino, (C1-C6) alkoxycarbonyl, carbamoyl, (C1-C6) alkylcarbamoyl, di- [ (C1-C6) alkylcarbamoyl]Carbamoyl, (C1-C6) alkylthio, (C1-C6) alkylsulfonyl, (C1-C6) alkylsulfinyl, (C1-6) alkanoylamino or optionally containing one or more hetero atoms selected from nitrogen, oxygen and sulfurSubstituted with a 4-to 7-membered saturated monocyclic ring of atoms;

Q²represents a 5-to 6-membered heteroaromatic ring containing at least one ring heteroatom selected from nitrogen, oxygen and sulfur, which ring is substituted by Q ³Substituted and optionally substituted on any available ring atom with one or more substituents independently selected from (C1-C6) alkyl or (C1-C6) alkoxy (each of which may be optionally substituted with one or more substituents independently selected from halogen, amino, hydroxy and trifluoromethyl), halogen, nitro, cyano, -NR, and mixtures thereof⁴R⁵Carboxy, hydroxy, (C2-C6) alkenyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl, (C1-C4) alkoxycarbonyl, (C1-C4) alkylcarbonyl, (C1-C4) alkylcarbonylamino, phenylcarbonyl, -S (O)_p(C1-C4) alkyl, -C (O) NR⁶R⁷and-SO₂NR⁸R⁹Wherein R is substituted with a further substituent of⁴、R⁵、R⁶、R⁷、R⁸And R⁹Each independently represents hydrogen or (C1-C6) alkyl, or R when taken together with the nitrogen atom to which they are attached⁴And R⁵Or R⁶And R⁷Or R⁸And R⁹Each independently may form a saturated heterocyclic ring and p is 0, 1 or 2;

Q³represents (C1-C6) alkyl, (C3-C6) cycloalkyl or (C3-C6) cycloalkyl (C1-C6) alkyl or a saturated or unsaturated 5-to 6-membered monocyclic ring which may contain at least one ring heteroatom selected from nitrogen, oxygen and sulfur, and wherein Q³Optionally substituted with one or more substituents independently selected from (C1-C6) alkyl or (C1-C6) alkoxy, each of which may be optionally substituted with one or more substituents independently selected from halogen, amino, hydroxy and trifluoromethyl, halogen, nitro, cyano, -NR ¹⁰R¹¹Carboxy, hydroxy, (C2-C6) alkenyl, (C3-C8) cycloalkyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkylcarbonyl, (C1-C6) alkylcarbonylamino, phenylcarbonyl, -S (O)_n(C1-C6) alkyl, -C (O) NR¹²R¹³and-SO₂NR¹⁴R¹⁵Wherein R is substituted by a substituent of (1)¹⁰、R¹¹、R¹²、R¹³、R¹⁴And R¹⁵Each independently represents hydrogen or (C1-C6) alkyl, or R when taken together with the nitrogen atom to which they are attached¹⁰And R¹¹Or R¹²And R¹³Or R¹⁴And R¹⁵Each independently may form a saturated heterocyclic ring and n is 0, 1 or 2.

In such embodiments, Q²In particular, denotes a 5-to 6-membered heteroaromatic ring which comprises at least one ring nitrogen and optionally at least one further ring heteroatom selected from nitrogen, oxygen and sulfur. Q²More particularly a 5-to 6-membered heteroaromatic ring comprising at least one ring nitrogen and optionally at least one further ring heteroatom selected from nitrogen and oxygen. For example, Q²May represent isoxazolyl (in particular isoxazol-5-yl). The ring Q²Quilt Q³Substituted, and optionally further substituted on any available ring atom with one or more additional substituents as defined above.

Another particular embodiment of the invention are compounds of formula (Id):

or a pharmaceutically acceptable salt thereof,

wherein:

R¹Represents trifluoromethyl, or (C1-C6) alkyl, (C3-C8) cycloalkyl or (C3-C8) cycloalkyl (C1-C6) alkyl, each of which may be optionally substituted by one or more substituents independently selected from halogen and (C1-C6) alkoxy;

R²represents hydrogen, halogen or trifluoromethyl;

R³represents hydrogen, hydroxy or halogen, or (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C8) cycloalkyl (C1-C6) alkoxy, (C1-C6) alkylcarbonyl, (C3-C8) cycloalkylCarbonyl, (C3-C8) cycloalkyl (C1-C6) alkylcarbonyl, (C1-C6) alkoxycarbonyl, amino, (C1-C6) alkylamino, di- [ (C1-C6) alkyl]Amino, (C3-C8) cycloalkylamino, (C3-C8) cycloalkyl (C1-C6) alkylamino, (C1-C6) alkoxyamino, carbamoyl, (C1-C6) alkylcarbamoyl, di- [ (C1-C6) alkylcarbamoyl]Carbamoyl, -C (O) R^3b、-OR^3b、-SR^3b、-NHR^3b-N [ (C1-C6) alkyl group]R^3b、-S(O)_mR^3aor-N (R)^3c)C(O)R^3aWherein R is^3aRepresents (C1-C6) alkyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl or (C1-C6) alkoxy, m is 0, 1 or 2, R is^3bRepresents a saturated 4-, 5-or 6-membered monocyclic heterocycle comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur and R ^3cRepresents hydrogen or (C1-C6) alkyl,

or R³Represents a 5-to 6-membered saturated monocyclic heterocyclic ring containing at least one ring heteroatom selected from nitrogen, oxygen and sulfur,

or R³Represents a 5-to 6-membered heteroaromatic ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur,

or R³Represents a 2, 7-diazaspiro [3.5 ]]A non-alkyl group,

R³each group or ring of (A) may optionally be substituted with one or more groups independently selected from (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkoxy (C1-C6) alkyl, (C1-C6) alkoxy (C1-C6) alkoxy, halogen, hydroxy, trifluoromethyl, tris- [ (C1-C4) alkyl]Silyl, cyano, amino, (C1-C6) alkylamino, di- [ (C1-C6) alkyl]Amino, (C3-C8) cycloalkylamino, (C3-C6) cycloalkyl (C1-C3) alkylamino, amino (C1-C6) alkyl, (C1-C6) alkylamino (C1-C6) alkyl, di- [ (C1-C6) alkyl]Amino (C1-C6) alkyl, (C3-C8) cycloalkylamino (C1-C6) alkyl, (C3-C6) cycloalkyl (C1-C3) alkylamino (C1-C6) alkyl, (C1-C6) alkoxycarbonyl, carbamoyl, (C1-C6) alkylcarbamoyl, di- [ (C1-C6) alkyl]Carbamoyl, (C1-C6) alkylthio, (C1-C6) alkylsulfonyl, (C1-C6) alkylsulfinyl, (C1-C6) alkanoyl, wherein R is ^3aAnd R^3calkanoylamino-N (R) as defined above^3c)C(O)R^3aOr 3-, 4-, 5-, 6-or 7-membered saturated monocyclic ring optionally containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, any of which substituents may be optionally substituted by one or more (C1-C4) alkyl, hydroxy or cyano groups;

Q³represents (C1-C6) alkyl, (C3-C6) cycloalkyl or (C3-C6) cycloalkyl (C1-C6) alkyl or a saturated or unsaturated 5-to 6-membered monocyclic ring which may contain at least one ring heteroatom selected from nitrogen, oxygen and sulfur, and wherein Q³Optionally substituted with one or more substituents independently selected from (C1-C6) alkyl or (C1-C6) alkoxy, each of which may be optionally substituted with one or more substituents independently selected from halogen, amino, hydroxy and trifluoromethyl, halogen, nitro, cyano, -NR¹⁰R¹¹Carboxy, hydroxy, (C2-C6) alkenyl, (C3-C8) cycloalkyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkylcarbonyl, (C1-C6) alkylcarbonylamino, phenylcarbonyl, -S (O)_n(C1-C6) alkyl, -C (O) NR¹²R¹³and-SO₂NR¹⁴R¹⁵Wherein R is substituted by a substituent of (1)¹⁰、R¹¹、R¹²、R¹³、R¹⁴And R¹⁵Each independently represents hydrogen or (C1-C6) alkyl, or R when taken together with the nitrogen atom to which they are attached ¹⁰And R¹¹Or R¹²And R¹³Or R¹⁴And R¹⁵Each independently may form a saturated heterocyclic ring and n is 0, 1 or 2;

and wherein any saturated monocyclic ring optionally bears 1 or 2 oxo or thioxo substituents.

According to another embodiment of the present invention, there is provided a compound of formula (Id) or a pharmaceutically acceptable salt thereof, wherein:

R¹represents trifluoromethyl, or (C1-C6) alkyl, (C3-C8) cycloalkyl or (C3-C8) cycloalkyl (C1-C6) alkyl, each of which may be optionally substituted by one or more substituents independently selected from halogen and (C1-C6) alkoxySubstituted by substituent groups;

R²represents hydrogen, halogen or trifluoromethyl;

R³represents hydrogen or halogen, or (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C8) cycloalkyl (C1-C6) alkoxy, (C1-C6) alkylcarbonyl, (C3-C8) cycloalkylcarbonyl, (C3-C8) cycloalkyl (C1-C6) alkylcarbonyl, (C1-C6) alkoxycarbonyl, amino, (C1-C6) alkylamino, di- [ (C1-C6) alkyl]Amino, (C3-C8) cycloalkylamino, (C3-C8) cycloalkyl (C1-C6) alkylamino, (C1-C6) alkoxyamino, carbamoyl, (C2-C6) alkanoylamino, -C (O) R^3b、-OR^3b、-SR^3b、-NHR^3b-N [ (C1-C6) alkyl group]R^3bor-S (O)_mR^3aWherein R is ^3aRepresents (C1-C6) alkyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl or (C1-C6) alkoxy, m is 0, 1 or 2, and R^3bRepresents a 5-to 6-membered saturated monocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur;

or R³Represents a 5-or 6-membered saturated monocyclic ring containing at least one ring heteroatom selected from nitrogen, oxygen and sulphur,

R³each group or ring of (A) may optionally be substituted with one or more groups independently selected from (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkoxy (C1-C6) alkoxy, halogen, hydroxy, trifluoromethyl, cyano, amino, (C1-C6) alkylamino, di- [ (C1-C6) alkyl]Amino, (C3-C8) cycloalkylamino, (C3-C6) cycloalkyl (C1-C3) alkylamino, (C1-C6) alkoxycarbonyl, carbamoyl, (C1-C6) alkylcarbamoyl, di- [ (C1-C6) alkylcarbamoyl]Carbamoyl, (C1-C6) alkylthio, (C1-C6) alkylsulfonyl, (C1-C6) alkylsulfinyl, (C1-6) alkanoylamino or a substituent of a 4-to 7-membered saturated monocyclic ring optionally containing one or more hetero atoms selected from nitrogen, oxygen and sulfur;

Q³represents (C1-C6) alkyl, (C3-C6) cycloalkyl or (C3-C6) cycloalkyl (C1-C6) alkyl or may be comprised up toA saturated or unsaturated 5-to 6-membered monocyclic ring having at least one ring heteroatom selected from nitrogen, oxygen and sulfur, and wherein Q ³Optionally substituted with one or more substituents independently selected from (C1-C6) alkyl or (C1-C6) alkoxy, each of which may be optionally substituted with one or more substituents independently selected from halogen, amino, hydroxy and trifluoromethyl, halogen, nitro, cyano, -NR¹⁰R¹¹Carboxy, hydroxy, (C2-C6) alkenyl, (C3-C8) cycloalkyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkylcarbonyl, (C1-C6) alkylcarbonylamino, phenylcarbonyl, -S (O)_n(C1-C6) alkyl, -C (O) NR¹²R¹³and-SO₂NR¹⁴R¹⁵Wherein R is substituted by a substituent of (1)¹⁰、R¹¹、R¹²、R¹³、R¹⁴And R¹⁵Each independently represents hydrogen or (C1-C6) alkyl, or R when taken together with the nitrogen atom to which they are attached¹⁰And R¹¹Or R¹²And R¹³Or R¹⁴And R¹⁵Each independently may form a saturated heterocyclic ring and n is 0, 1 or 2.

In such embodiments, Q³In particular from (C1-C6) alkyl or (C3-C6) cycloalkyl, or a saturated or unsaturated 5-to 6-membered monocyclic ring which may contain at least one ring heteroatom selected from nitrogen, oxygen and sulfur, and wherein Q³Optionally substituted by one or more substituents as defined above.

Specific compounds of the invention include, for example, any one or more compounds of formula (I) selected from the following compounds: -

5-chloro-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

5-chloro-2- [2- (3-methylisoxazol-5-yl) radical]Pyrrolidin-1-yl radical]-4-(5- Tertiary carboxylic acidbutyl-1H-pyrazol-3-ylamino) pyrimidine;

5-chloro-2- [2- (3-methylisoxazol-5-yl ] pyrrolidin-1-yl ] -4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine;

5-chloro-2- [2- (3-cyclopropylisoxazol-5-yl ] pyrrolidin-1-yl ] -4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine;

5-chloro-2- [2- (3-cyclopropylisoxazol-5-yl ] pyrrolidin-1-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

5-chloro-2- [2- (3-methylisoxazol-5-yl ] pyrrolidin-1-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

5-chloro-2- {2- [3- (thiazol-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) 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- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine;

5-chloro-2- {2- [3- (pyridin-3-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

5-chloro-2- {2- [3- (pyridin-3-yl) 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-cyclopropylisoxazol-5-yl) pyrrolidin-1-yl ] -6-methoxymethyl-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine;

5-chloro-2- (2- (3- (pyridin-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-1H-pyrazol-3-ylamino) pyrimidine;

5-chloro-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2- (3- { tetrahydrofuran-3-yl } isoxazol-5-yl ] pyrrolidin-1-yl ] -pyrimidine;

6-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine;

5-chloro-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] piperidin-1-yl } pyrimidine;

5-chloro-2- {2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

5-fluoro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -pyrimidine;

4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -5-fluoro-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine;

S-5-chloro-2- {2- [ 3-methylisoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine;

4- (5-methyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine;

4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine;

4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -6-methyl-2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

4- (5-methyl-1H-pyrazol-3-ylamino) -6-methyl-2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -6-methyl-2- [2- (3-methylisoxazol-5-yl) pyrrolidin-1-yl ] pyrimidine

6-ethyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

6- (3-methoxypropyl) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

6-methoxymethyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -6-methoxymethyl-2- [2- {3- (pyridin-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- (pyridin-3-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

4- (5-methyl-1H-pyrazol-3-ylamino) -6- (pent-3-en-1-yl) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-I-yl ] pyrimidine;

4- (5-methyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -6-trifluoromethylpyrimidine:

4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -6-trifluoromethylpyrimidine;

s-6-ethyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-5-chloro-2- {2- [3- (thiazol-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-5-chloro-2- {2- [3- (pyridin-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- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-5-chloro-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

S-5-chloro-2- {2- [3- (2-methoxypyridin-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- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

6- (3-pyrrolidin-1-ylpropyl) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

6-methoxycarbonyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine;

6- (2-hydroxyethylcarbamoyl) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine;

4- (5-methyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -6- (pyrrolidin-1-ylcarbonyl) pyrimidine;

6-methoxy-4- (5-methyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-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-ethylpiperazinyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl } pyrimidine;

6-N-methylpiperazinyl (piperazyl) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

6-morpholino (morpholino) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine;

6- (3- (N, N-dimethylamino) propyn-1-yl) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- (2- (3- (pyridin-2-yl) isoxazol-5-yl) pyrrolidin-1-yl) pyrimidine;

6-methylamino-4- (5-methyl-1H-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- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine;

6-methoxycarbonyl-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

6- (N-methylcarbamoyl) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

6-morpholinocarbonyl-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

6- (N- (2-methoxyethyl) carbamoyl) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

6- (N-hydroxycarbamoyl) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

6-carbamoyl-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6-methoxycarbonyl-2- {2- [3- (pyridin-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- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6- [ N- (2-methoxyethyl) -N-methylcarbamoyl ] -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6- [ N- (2- (acetylamino) ethyl) carbamoyl ] -2- {2- [3- (pyridin-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- (pyridin-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- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

S-6- [ N- (4-hydroxybutyl) carbamoyl ] -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6- [ N- ((2R) -2, 3-dihydroxypropyl) carbamoyl ] -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6- [ N- (carbamoylmethyl) carbamoyl ] -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6- ((3R) -3-hydroxypyrrolidin-1-ylcarbonyl) -2- {2- [3- (pyridin-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- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6- (N-cyclopropylcarbamoyl) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6- (N-cyclopentylcarbamoyl) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6- (azetidin-1-ylcarbonyl) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

S-6- (N-methylcarbamoyl) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

6- (N-carbamoyl) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

6- [ N- (acetylamino) carbamoyl ] -2- {2- [3- (pyridin-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- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

6-hydroxymethyl-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

6- (morpholinomethyl) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

6- (4-methylpiperazin-1-ylmethyl) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

6- (methylaminomethyl) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

6- (pyrrolidin-1-ylmethyl) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

6-aminomethyl-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6-hydroxymethyl-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6-ethoxymethyl-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6- [ (2-methoxyethoxy) methyl ] -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-5-chloro-2- {2- [3- (pyrazin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6-methyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyrazin-2-yl) isoxazol-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) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine;

S-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -6-methoxy- {2- [3- (pyrazin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine;

6-pyrrolidin-1-yl-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- (2, 2, 6, 6-tetramethylpiperidin-4-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6-iodo-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

S-E-6-[3-( tertiary carboxylic acidButoxycarbonylamino) prop-1-en-1-yl]-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl]A pyrimidine;

s-6-vinyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

S-E-6- (3-hydroxyprop-1-en-1-yl) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

S-6-[3-( tertiary carboxylic acidButoxycarbonylamino) propan-1-yl]-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ]A pyrimidine;

s-6- [ 3-aminopropyl-1-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

S-E-6- [ 3-aminopropyl-1-en-1-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- [ 3-methylaminoprop-1-yn-1-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-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- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- [ 3-hydroxypropan-1-yn-1-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- [2- (trimethylsilyl) ethynyl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-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- (pyridin-2-yl) isoxazol-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- (pyridin-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- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- [2- (ethoxycarbonyl) ethyl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

S-E-6- [2- (methoxycarbonyl) ethen-1-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-ethynyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

6-methoxymethyl-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-methoxymethyl-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-methoxymethyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- [ 3-aminoprop-1-yn-1-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- [2- (N-methylcarbamoyl) ethyl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

S-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidin-1-yl ] pyrimidine;

s-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidin-1-yl ] pyrimidine;

s-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidin-1-yl ] pyrimidine;

6-(N- tertiary carboxylic acidButoxycarbonyl) amino-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl]Pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

6- (4-aminopiperidin-1-yl) 2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

6-(4-(N- tertiary carboxylic acidButoxycarbonylamino) piperidin-1-yl) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl]Pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

6-piperazin-1-yl-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6- {4- [2- (2-hydroxyethoxy) ethyl ] piperazin-1-yl } -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6- (1-formyl-piperazin-4-yl) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

S-6-piperazin-1-yl-2- {2- [3- (pyridin-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- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6- [ (4- (2-hydroxyethyl) piperazin-1-yl) ] -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6- [ (3R) -3-hydroxypyrrolidin-1-yl ] -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6- [ (3R) -3-dimethylamino-pyrrolidin-1-yl ] -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6- (4-tetrahydropyranylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6-morpholino-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6- (2-methoxyethyl) amino-2- {2- [3- (pyridin-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- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6- ((2R) -2-hydroxypropan-1-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6- [ N- (2-hydroxyethyl) -N-ethylamino ] -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6-dimethylamino-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6-methylamino-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6-chloro-2- {2- [3- (pyrazin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

6-morpholino (mopolino) -2- {2- [3- (pyrazin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

6-chloro-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine;

6- (2-hydroxyethoxy) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine;

6-[4-( Tertiary carboxylic acidButoxycarbonyl) piperazin-1-yl]-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl]A pyrimidine;

6- (4-acetylpiperazin-1-yl) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

6-[2-( tertiary carboxylic acidButoxycarbonyl) -2, 7-diazaspiro [3.5]Non-7-yl]-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl]A pyrimidine;

6- (2, 7-diazaspiro [3.5] non-7-yl) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- [4- (2-aminoethyl) piperazin-1-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- [4- (3-hydroxypropyl) piperazin-1-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- [4- (2-cyanoethyl) piperazin-1-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- [4- (2-methoxyethyl) piperazin-1-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

S-6- (4-acetylpiperazin-1-yl) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-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- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- [2- (2-hydroxyethoxy) ethylamino ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- [2- (acetylamino) ethylamino ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- [ 2-aminoethylamino ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- [ 4-methylcyclohexylamino ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- [ 4-hydroxycyclohexylamino ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- [ cis-3, 4-dihydroxypyrrolidin-1-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

S-6-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyrimidin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (3-methoxypyrazin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-morpholino-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyrimidin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-morpholino-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (3-methoxypyrazin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-morpholino-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (3-hydroxypyrazin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- [ 4-methylpiperazin-1-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- [ cyclobutylamino ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- [ 3-isopropoxyprop-1-ylamino ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-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- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

S-6- [2- (dimethylamino) ethylamino ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- [ (2S) -2-hydroxypropan-1-ylamino ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- [ 2-methylpropan-1-ylamino ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- [ 3-methoxypropylamino ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-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- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- [ 3-ethoxypropylamino ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- [ (2R) -tetrahydrofuran-2-ylmethyl-amino ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- (2-isopropoxyethylamino) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

S-6-morpholino-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyrimidin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-methylamino-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyrimidin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-chloro-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyrimidin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-methyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (3-methoxypyrazin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-methoxy-4- (5-cyclopropyl-1H-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- (pyrimidin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine;

s-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine;

s-4- (5-ethyl-1H-pyrazol-3-ylamino) -5-fluoro-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine;

s-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -5-fluoro-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine;

4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -6-methyl-2- {2- [3- (pyrimidin-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- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine;

6- (3-hydroxypropyl) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine;

s-6- (3-hydroxypropyl) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine;

s-6-propyl-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6-chloro-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- (2-hydroxyethoxy) -4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- (2-methoxyethoxy) -4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

S-6-morpholino-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-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- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

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- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- (2-methoxyethoxy) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-pyrrolidin-1-yl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-methoxymethyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-morpholinocarbonyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-carbamoyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

S-5-fluoro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-4- (5-methyl-1H-pyrazol-3-ylamino) -6- (2-hydroxyethoxy) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-4- (5-methyl-1H-oxazol-3-ylamino) -6- (2- { N- [ 2-hydroxyethyl ] -N-methyl-amino } ethoxy) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-4- (5-methyl-1H-pyrazol-3-ylamino) -6- (2-morpholinoethoxy) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-4- (5-methyl-1H-pyrazol-3-ylamino) -6- (methylthio) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

4- (5-methyl-1H-pyrazol-3-ylamino) -6- (tetrahydrofuran-3-ylmethoxy) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-4- (5-methyl-1H-pyrazol-3-ylamino) -6- (2- (2-hydroxyethoxy) ethoxy) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

4- (5-methyl-1H-pyrazol-3-ylamino) -6- (2-methoxyethoxy) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

S-4- (5-methyl-1H-pyrazol-3-ylamino) -6- (3-hydroxypropoxy) -2- [2- {3- (pyridin-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- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-4- (5-methyl-1H-pyrazol-3-ylamino) -6- (2-ethoxyethoxy) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-4- (5-methyl-1H-pyrazol-3-ylamino) -6- (3-morpholinopropan-1-yloxy) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-4- (5-methyl-1H-pyrazol-3-ylamino) -6- (3-methoxypropan-1-yloxy) -2- [2- {3- (pyridin-2-yl) 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- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-4- (5-methyl-1H-pyrazol-3-ylamino) -6- [ (2S) -2-methoxypropan-1-yloxy ] -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-4- (5-methyl-1H-pyrazol-3-ylamino) -6- [3- (methylthio) propan-1-yloxy ] -2- [2- {3- (pyridin-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- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-4- (5-methyl-1H-pyrazol-3-ylamino) -6- [ (2R) -5-oxopyrrolidin-2-yl) methoxy ] -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-4- (5-methyl-1H-pyrazol-3-ylamino) -6- [2- (imidazolidin-2-one-1-yl) ethoxy ] -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-4- (5-methyl-1H-pyrazol-3-ylamino) -6-ethoxy-2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-4- (5-methyl-1H-pyrazol-3-ylamino) -6-hydroxy-2- [2- {3- (pyridin-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 } pyrrolidin-1-yl ] 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-methyl-1H-pyrazol-3-ylamino) -6- [ (2R) -2-hydroxypropan-1-yloxy ] -2- [2- {3- (pyridin-2-yl) isoxazol-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-yl ] pyrimidine;

s-4- (5-ethyl-1H-pyrazol-3-ylamino) -6-methoxy-2- [2- {3- (pyrazin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] 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-methyl-1H-pyrazol-3-ylamino) -6- (tetrahydropyran-4-yloxy) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-5-fluoro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (thiazol-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-5-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (thiazol-4-yl) isoxazol-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 } pyrrolidin-1-yl ] pyrimidine;

s-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2- {3- (thiazol-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2- {3- (thiazol-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

S-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -5-fluoro-2- [2- {3- (thiazol-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (thiazol-2-yl) isoxazol-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-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (thiazol-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] 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) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-methylamino-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (thiazol-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- (4-methylpiperazin-1 yl) -4- (5-methyl-1H-pyrazol-3-ylamino) -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) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

S-6- [3- (methylsulfonyl) propyl-1-oxy ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -6- (2-methoxyethoxy) -2- [2- {3- (pyrazin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-methyl-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2- {3- (3-methoxypyrazin-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) isoxazol-5-yl ] pyrrolidin-1-yl ] pyrimidine;

s-6-chloro-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyrimidin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-methoxy-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyrimidin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-ethyl-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyrimidin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-methylamino-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyrimidin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-ethyl-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyrimidin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

S-6-cyclopropyl-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyrimidin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-cyclopropyl-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyrimidin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- (2-methoxyethoxy) -4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyrimidin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-methyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidin-1-yl ] pyrimidine;

s-5-fluoro-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidin-1-yl ] pyrimidine;

s-5-fluoro-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidin-1-yl ] pyrimidine;

s-6- (2-hydroxyethoxy) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidin-1-yl ] pyrimidine;

s-6-chloro-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidin-1-yl ] pyrimidine;

s-6-chloro-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidin-1-yl ] pyrimidine;

S-6- (2-hydroxyethoxy) -4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidin-1-yl ] pyrimidine;

s-5-fluoro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidin-1-yl ] pyrimidine;

s-6- (2-hydroxyethoxy) -4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidin-1-yl ] 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-1H-pyrazol-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-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidin-1-yl ] pyrimidine;

s-6-methyl-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyrimidin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-methyl-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-morpholino-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2- {3- (3-hydroxypyrazin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine; and

S-6- (3-methoxypropyl) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

and pharmaceutically acceptable salts thereof.

In the case where the compounds of the invention contain one or more asymmetrically substituted carbon atoms, the invention includes all stereoisomers including enantiomers and diastereomers and mixtures including racemic mixtures thereof. Also included are tautomers and mixtures thereof.

The racemates can be separated into the individual enantiomers by known methods (see Advanced Organic Chemistry: 3 rd edition: authorJ March, page 104-107). One suitable method involves forming diastereomeric derivatives by reaction of the racemic material with a chiral auxiliary, followed by separation of the diastereomers, for example by chromatography, and then cleavage of the auxiliary.

It will be appreciated that certain compounds of formula (I) may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It will be appreciated that the invention includes all such solvated forms which modulate the activity of insulin-like growth factor 1 receptor in the human or animal body.

It will also be appreciated that certain compounds of formula (I) may exhibit polymorphic forms and that the present invention includes all such forms which modulate the activity of insulin-like growth factor 1 receptor in the human or animal body.

The compounds of the present invention may be provided in the form of pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts include base salts such as alkali metal salts, e.g. sodium salts, alkaline earth metal salts, e.g. calcium or magnesium salts, organic amine salts, e.g. triethylamine, morpholine, N-methylpiperidine, N-ethylpiperidine, procaine, dibenzylamine, N-dibenzylethylamine or amino acids, e.g. lysine salts. On the other hand, in the case where the compound is sufficiently basic, suitable salts include acid addition salts such as methanesulfonate, fumarate, hydrochloride, hydrobromide, citrate, maleate and salts with phosphoric and sulphuric acid.

The present invention also provides a process for the preparation of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, which comprises:

(i) reacting a compound of formula (II) with a compound of formula (III),

wherein L is¹Represents a leaving group (e.g. halogen or sulfonyloxy such as methanesulfonyloxy or toluene-4-sulfonyloxy) and R¹、R²And R³As described in formula (I), except that any functional group may be protected if desired,

Wherein Q¹And Q²As described for formula (I), except that any functional group may be protected if desired;

or

(ii) Reacting a compound of formula (IV) with a compound of formula (V),

wherein L is²Represents a leaving group (e.g. halogen or sulfonyloxy such as methanesulfonyloxy or toluene-4-sulfonyloxy) and R²、R³、Q¹And Q²As described for formula (I), except that any functional group may be protected if desired,

wherein R is¹As described for formula (I), except that any functional group may be protected if desired;

or

(iii) Reacting a compound of formula (VI) with a compound of formula (VII),

wherein Q¹And Q²As described for formula (I), except that any functional group may be protected if desired,

wherein X representsOxygen atom and q is 1 or X represents a nitrogen atom and q is 2, R²¹Independently represent (C1-C6) alkyl and R²And R³As described for formula (I), except that any functional group may be protected if desired;

or

(iv) Reacting a compound of formula (VIII) with hydrazine,

wherein R is¹、R²、R³、NQ¹And Q²As described for formula (I), except that any functional group may be protected if desired;

or

(v) For R in the formula ³Is (C1-C6) alkoxy, amino, (C1-C6) alkylamino, di- [ (C1-C6) alkyl]Amino, -OR^3b、-SR^3b、-NHR^3b-N [ (C1-C6) alkyl group]R^3bor-S (O)_mR^3a(wherein m is 0 and R^3aAnd R^3bIs as defined above (and the radical R³Optionally substituted by at least one group as defined above) of formula (I) wherein L is³Represents a leaving group (e.g. halogen or sulfonyloxy such as methanesulfonyloxy or toluene-4-sulfonyloxy) and R¹、R²、Q¹And Q²A compound of the formula (IX) as described for formula (I) except that any functional group may be protected if desired

With a compound of the formula H-Xa, where Xa is selected from OR²²、NH₂、NHR²²、N(R²²)₂、NH₂、OR^3b、SR^3b、NHR^3b、N[(C1-C6) alkyl]R^3bAnd SR^3aWherein R is²²Is optionally substituted (C1-C6) alkyl and R^3aAnd R^3bThe respective definitions are as described above, except that any functional group may be protected if desired;

or

(vi) For R in the formula³(ii) is an optionally substituted 5-or 6-membered saturated heterocyclic ring containing at least one ring nitrogen and optionally containing one or more additional heteroatoms selected from nitrogen, oxygen and sulphur, reacting a compound of formula (IX) with a compound of formula (Xb),

wherein Q⁴Is a 5-or 6-membered saturated monocyclic heterocyclic ring optionally containing one or more heteroatoms selected from nitrogen, oxygen and sulfur in addition to the nitrogen atom shown above, which ring may be optionally substituted by at least one group as defined above, or has an optionally substituted 2, 7-diazaspiro [3.5 ] ring ]A nonyl group;

or

(vii) For R³Is (C2-C6) alkenyl or (C2-C6) alkynyl, and the radical R³(ii) for compounds of formula (I) optionally substituted by at least one group as defined above, reacting a compound of formula (IX) with a compound of formula (Xc) or formula (Xc'),

H-C≡C-R²³ (Xc)

wherein R is²³Selected from hydrogen and optionally substituted (1-4C) alkyl or (C1-C4) alkoxycarbonyl;

or

(viii) For R in the formula³As compounds of formula (I) which are attached to the pyrimidine ring via a carbon atom, compounds of formula (IX) are reacted with compounds of formula M-R³By reaction of a compound of (1), wherein R³Suitably selected from R as defined above³And M is a metal radical, e.g. ZnBr, B (OH)₂CuCN or SnBu₃；

(ix) For R in the formula³Is (C1-C6) alkoxycarbonyl (and the radical R³Optionally substituted by at least one group as defined above) of formula (I) wherein R is¹、R²、Q¹And Q²Compounds of formula (X) as defined for formula (I) except that any functional group may be protected if desired

With a compound of formula H-O- (C1-C6) alkyl, wherein (C1-C6) alkyl is optionally substituted by at least one group as defined above and any functional groups may be protected if desired; or

(x) For R in the formula³Is a 5-membered heteroaromatic ring containing at least one heteroatom selected from nitrogen, oxygen and sulfur (and the radical R³Optionally substituted by at least one group as defined above), with suitable starting materials and suitable dehydrating agents. For example, for wherein R³Compounds of formula (I) which are 1, 3, 4-oxadiazolyl, are prepared by reacting a compound of formula (XI) with a suitable dehydrating agent, such as (methoxycarbonylsulfamoyl) triethylammonium hydroxide,

wherein Z represents R as defined above³Any suitable substituent of (A) and R¹、R²、Q¹And Q²As described for formula (I), except that any functional group may be protected if desired; or

(xi) For R in the formula³(ii) Compounds of formula (I) which are (C1-C6) alkyl, (C3-C6) alkenyl, (C3-C6) alkynyl or (C1-C6) alkoxy substituted by at least one group as defined above, compounds of formula (XII) are reacted with a compound of formula H-Xa, (Xb), (Xc') or M-R6 as defined above³The compound (a) is reacted with (b),

wherein L is³Represents a leaving group as defined above, W represents an optionally substituted (C1-C6) alkyl, (C3-C6) alkenyl, (C3-C6) alkynyl or (C1-C6) alkoxy group and R ¹、R²、Q¹And Q²As described for formula (I), except that any functional group may be protected if desired;

and optionally after (i), (ii), (iii), (iv), (v), (vi), (vii), (viii), (ix), (x) or (xi) one or more of the following processes:

conversion of the resulting compound into another compound of the invention

Forming a pharmaceutically acceptable salt of the compound.

Process (i) may 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 N-methylpyrrolidin-2-one, and optionally in the presence of a suitable base, for example an organic amine base such as diisopropylethylamine, at a temperature in the range from 0 ℃ to reflux, preferably at reflux temperature.

Process (ii) may 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 N-methylpyrrolidin-2-one, and optionally in the presence of a suitable acid, for example a mineral acid such as anhydrous hydrogen chloride and at a temperature in the range 0 ℃ to reflux, preferably at reflux temperature.

Processes (i) and (ii) may alternatively each be conveniently reacted under standard Buchwald 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 or an organic base such as tert-butanol-potassium, in the presence of a suitable ligand such as 2, 2 '-di (diphenylphosphino) -1, 1' -binaphthyl, at a temperature in the range of 25 to 80 ℃.

Process (iii) may conveniently be carried out in a suitable inert solvent or diluent such as N-methylpyrrolidone or butanol at a temperature of from 100 to 200 deg.C, especially from 150 to 170 deg.C. The reaction is preferably carried out in the presence of a suitable base such as, for example, sodium methoxide or potassium carbonate.

Process (iv) may be carried out in a suitable inert solvent or diluent, for example an alcohol such as ethanol or butanol, at a temperature of from 50 to 120 ℃, especially from 70 to 100 ℃.

Processes (v) and (vi) may 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 methanol, ethanol, butanol or N-hexanol or an aromatic hydrocarbon such as toluene or N-methylpyrrolidin-2-one, optionally in the presence of a suitable base. Suitable bases are sodium hydride or organic amine bases such as diisopropylethylamine. Further suitable bases are alkali metal alcoholates, such as sodium methylate or sodium ethylate. Processes (v) and (vi) may conveniently be carried out at from 0 ℃ to reflux temperature, especially reflux temperature. These processes can also be conveniently carried out by heating the reactants in a sealed container using a suitable heating means such as a microwave heater.

Process (vii) may conveniently be carried out in the presence of a suitable inert solvent or diluent, for example acetonitrile, THF or dioxane, in the presence of a suitable base and a suitable catalyst. Suitable bases are organic amine bases such as triethylamine or diisopropylethylamine. Suitable catalysts are, for example, copper iodide/palladium (II) chloride-bis (triphenyl) phosphine. Process (vii) may conveniently be carried out at a temperature in the range 0 ℃ to reflux, especially at reflux temperature. Such a process may also conveniently be carried out by heating the reactants in a sealed container using suitable heating means such as a microwave heater.

Process (viii) may conveniently be carried out in the presence of a suitable catalyst in the presence of a suitable inert solvent or diluent, for example THF or dioxane. Suitable catalysts are palladium (O) catalysts, for example tetrakis (triphenyl) phosphine palladium (O). As will be appreciated by those skilled in the art, the palladium (O) catalyst may be prepared in situ. Process (viii) may conveniently be carried out at a temperature in the range 0 ℃ to reflux, especially at reflux temperature.

Process (ix) may conveniently be carried out in the absence of an inert solvent or diluent and at a temperature in the range from room temperature to reflux, especially reflux temperature. Process (ix) is conveniently carried out in the presence of a suitable acid, for example concentrated sulphuric acid.

Process (x) may conveniently be carried out in the presence of a suitable inert solvent or diluent, for example dichloromethane, THF or dioxane. Process (x) may conveniently be carried out at a temperature in the range 0 ℃ to reflux, preferably reflux temperature.

Process (xi) may conveniently be carried out under the conditions of Process (v) discussed above.

The formulae (II), (III), (IV), (V), (VI), (VII), (VIII), Hxa, (Xb), (Xc') and M-R³The compounds of (a) are either commercially available, known in the literature or can be prepared by known techniques, for example by methods similar to those described in WO 03/048133. The compounds of formulae (IX), (X), (XI) and (XII) may be prepared by processes (i) and (ii) above. In the following examples are given Examples of methods for preparing certain of these compounds.

The compounds of formula (I) may be converted to additional compounds of formula (I) using standard techniques known in the art.

Examples of the types of conversion reactions that may be used include the introduction of a substituent by an aromatic substitution reaction or a nucleophilic substitution reaction, the reduction of a substituent, the alkylation of a substituent, and the oxidation of a substituent. The reagents and reaction conditions for such processes are well known in the chemical arts.

Specific examples of aromatic substitution reactions include the introduction of a nitro group with concentrated nitric acid; introduction of the acyl group under Friedel Crafts conditions with, for example, an acid halide and a Lewis acid (e.g., aluminum trichloride); alkyl groups are introduced under Friedel Crafts conditions with alkyl halides and Lewis acids (e.g., aluminum trichloride); and introducing a halogen group. Specific examples of nucleophilic substitution reactions include the introduction of alkoxy or alkylamino, dialkylamino or N-containing heterocyclic rings using standard conditions. Specific examples of the reduction reaction include reduction of a carbonyl group to a hydroxyl group with sodium borohydride or reduction of a nitro group to an amino group by catalytic hydrogenation with a nickel catalyst or by treatment with iron while heating in the presence of hydrochloric acid; and specific examples of the oxidation reaction include oxidation of an alkylthio group (alkylthio) to an alkylsulfinyl group or an alkylsulfonyl group. Other conversion reactions that may be used include acid-catalyzed esterification of carboxylic acids with alcohols.

An example of a suitable conversion reaction is one wherein R is³Conversion of a compound of formula (I) which is (C1-C6) alkenyl to wherein R³Is substituted by di- [ (C1-C6) alkyl]A compound of formula (I) amino or a 4-to 7-membered saturated monocyclic substituted (C1-C6) alkyl group comprising nitrogen and one or more heteroatoms independently selected from nitrogen, oxygen and sulfur. Such conversion can be carried out by standard methods, for example, the alkenyl group can be converted to the dihydroxyalkyl group using osmium tetroxide, oxidized to the corresponding ketone using a suitable oxidizing agent (e.g., sodium periodate), and the ketone group can be converted to the above-defined compound by reaction with a suitable amine in the presence of a suitable reducing agent (e.g., sodium cyanoborohydride)The required substituents.

Another example of a suitable conversion reaction is that in which R is³Conversion of a compound of formula (I) which is an optionally substituted (C1-C6) alkoxycarbonyl group to a compound of formula (I) wherein R³Is an optionally substituted carbamoyl, (C1-C6) alkylcarbamoyl or di- [ (C1-C6) alkyl]Carbamoyl or optionally substituted-C (O) R^3bA compound of formula (I) wherein R^3bIs as defined above. Such transformations can be carried out by standard methods, for example by subjecting R therein to³A compound of formula (I) which is an optionally substituted (C1-C6) alkoxycarbonyl group with ammonia, an optionally substituted primary, secondary or tertiary amine or an optionally substituted H-R ^3bThe reaction is carried out. As will be appreciated by those skilled in the art, such a conversion may be initiated from the carboxylic acid and the active ester prepared, for example, by chlorination of 4- (4, 6-dimethoxy [1, 3, 5 ]]Triazin-2-yl) -4-methyl-morpholinium (morpholinonium) and then reacted with the desired amine.

Another example of a suitable conversion reaction is that in which R is³Conversion of a compound of formula (I) which is (C1-C6) alkoxycarbonyl to a compound of formula (I) wherein R³A compound of formula (I) which is hydroxy- (C1-C6) alkyl. Such conversions can be carried out by standard methods, for example by reduction with lithium borohydride or lithium aluminium hydride.

It will be appreciated that the preparation of the compounds of formula (I) may include the addition and removal of one or more protecting groups at various stages. Protection and deprotection of functional Groups is described in Protective Groups in Organic Synthesis, 2 nd edition, T.W.Greene and P.G.M.Wuts, Wiley-Interscience (1991).

When a pharmaceutically acceptable salt, e.g. an acid addition salt, of a compound of formula (I) is desired, such salt may be obtained, for example, by reacting said compound with a suitable acid in a conventional manner.

As noted above, the compounds of the present invention may contain one or more chiral centers and may therefore exist as stereoisomers. These stereoisomers may be separated by conventional techniques, such as chromatography or fractional crystallization. The enantiomers may be separated by separation of the racemates, for example by fractional crystallization, resolution or HPLC. The separation of diastereomers may be carried out by exploiting their different physical properties, for example by fractional crystallization, HPLC or flash chromatography. Alternatively, a particular stereoisomer can be synthesized starting from chiral starting materials by chiral synthesis without causing racemization or epimerization or by derivatization with a chiral agent. When a particular stereoisomer is isolated, it is suitably isolated substantially free of other stereoisomers, e.g., containing less than 20%, particularly less than 10% and more particularly less than 5% by weight of other stereoisomers.

In the above section relating to the preparation of compounds of formula (I), the expression "inert solvent" refers to a solvent which does not react with the starting materials, reagents, intermediates or products in a manner which would adversely affect the yield of the desired product.

One skilled in the art will appreciate that the steps of the methods described above may be performed in a different order and/or that the reactions may be performed at different stages of the overall route (i.e., different intermediates may be chemically converted to the related species above using a particular reaction) in order to obtain the compounds of the invention in other and, in some cases, more convenient ways.

Compounds of formula (I) have activity as pharmaceuticals, in particular as modulators or inhibitors of insulin-like growth factor-1 receptor (IGF-1R) activity, and are useful in the treatment of proliferative and hyperproliferative diseases/conditions, examples of which include the following cancers:

(1) cancers, including bladder, brain, breast, colon, kidney, liver, lung, ovary, pancreas, prostate, stomach, cervix, colon, thyroid, and skin cancers;

(2) hematopoietic tumors of lymphoid lineage (lymphoblastic tumors) including acute lymphocytic leukemia, B-cell lymphoma and Burketts lymphoma;

(3) Hematopoietic tumors of the myeloid lineage, including acute and chronic myelogenous leukemias and promyelocytic leukemias;

(4) tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; and

(5) other tumors, including melanoma, seminoma, tetratocrcinoma, neuroblastoma and glioma.

The compounds of the invention are particularly useful for the treatment of tumors of the breast and prostate.

Thus according to a further aspect the present invention provides a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof for use in therapy of the human or animal body.

The invention provides, inter alia, the use of a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof for modulating insulin-like growth factor-1 receptor (IGF-1R) activity in a human or animal.

The invention also provides the use of a compound of formula (I) as hereinbefore defined, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in therapy, in particular for modulating insulin-like growth factor-1 receptor (IGF-1R) activity in a human or animal body.

Unless otherwise indicated, it will be appreciated that "treatment" also includes "prevention". The terms "therapeutic" and "therapeutic" are also to be construed accordingly.

In another aspect, the present invention provides a method of treating cancer which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) as hereinbefore defined or a pharmaceutically acceptable salt thereof.

The present invention also provides a method of modulating the activity of insulin-like growth factor-1 receptor (IGF-1R), comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof.

The compounds of formula (I) and pharmaceutically acceptable salts thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the compound/salt (active ingredient) of formula (I) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the mode of administration, said pharmaceutical composition will preferably comprise 0.05 to 99% w (weight percent), more preferably 0.05 to 80% w, more preferably 0.10 to 70% w, and more preferably 0.10 to 50% w of the active ingredient, all weight percents being based on the total composition.

The present invention also provides a pharmaceutical composition comprising a compound of formula (I) as hereinbefore defined or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

The present invention also provides a process for the preparation of a pharmaceutical composition according to the invention which comprises mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined with a pharmaceutically acceptable adjuvant, diluent or carrier.

The pharmaceutical compositions may be administered topically (e.g. to the skin or lungs and/or airways) in the form of, for example, creams, solutions, suspensions, heptafluoroparaffin aerosols and dry powder formulations; or can be administered systemically, e.g., by oral administration in the form of tablets, capsules, syrups, powders or granules; or may be administered parenterally in the form of a solution or suspension; or may be administered subcutaneously; rectally in the form of suppositories; or may be administered transdermally.

The compositions of the invention may be obtained by conventional means using conventional excipients well known in the art. Thus, compositions for oral use may contain, for example, one or more coloring, sweetening, flavoring and/or preservative agents.

Suitable pharmaceutically acceptable excipients for tablet formulations include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or alginic acid (algenicic); binders such as starch; lubricants such as magnesium stearate, stearic acid or talc; preservatives, such as ethyl or propyl p-hydroxybenzoate, and antioxidants, such as ascorbic acid. The tablet formulation may be uncoated or coated to modify its disintegration and subsequent absorption of the active ingredient in the gastrointestinal tract or to improve its stability and/or appearance, in either case using conventional coating agents and methods well 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 soft gelatin capsules wherein the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions generally contain the active ingredient in finely divided form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of alkylene oxides with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxyethylenoxyetanol, 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 long chain aliphatic alcohols, for example heptadecaethyleneoxyethylenoxycetanol, 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 such as polyoxyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl or propyl p-hydroxybenzoate, antioxidants, for example ascorbic acid, colouring agents, flavouring agents, and/or sweetening agents, for example sucrose, saccharin or aspartame.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may also contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water typically comprise the active ingredient and a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those substances mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

The pharmaceutical compositions of the present invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or a mixture of any of these. Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening agents, flavoring agents and preservatives.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, a preservative, a flavouring and/or a colouring agent.

The pharmaceutical compositions may also be in the form of sterile injectable aqueous or oleaginous suspensions and may be prepared according to known methods using one or more of the suitable dispersing or wetting agents and suspending agents already mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally-acceptable non-toxic diluent or solvent, for example as a solution in 1, 3-butanediol.

Suppository formulations may be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore 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 may generally be prepared by formulating the active ingredient with conventional topically acceptable excipients or diluents by conventional methods well known in the art.

Compositions to be administered by insufflation may be in the form of a finely divided powder comprising particles having an average diameter of, for example, 30u or less, which powder itself comprises the active ingredient alone or in addition with one or more physiologically acceptable carriers such as lactose. The powder for insufflation can then conveniently be held in capsules containing, for example, 1 to 50mg of active ingredient, which capsules are used with a turbo-inhaler (turbo-inhaler) device, for example, which is used for insufflation of the known substance cromolyn sodium.

Compositions for administration by inhalation may be in the form of conventional pressurised aerosols arranged to dispense the active ingredient in the form of an aerosol comprising finely divided solid or liquid droplets. Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device may conveniently be arranged to dispense a metered amount of the active ingredient.

It will be appreciated that the dosage administered will vary with the compound used, the mode of administration, the desired treatment, and the condition being indicated. Typical daily dosages, which will be administered if desired in divided doses, will range from 0.5mg to 75mg of active ingredient per kg of body weight, the precise amounts of the compounds employed and the route of administration will depend on the weight, age, sex and condition (condition) of the patient to be treated, according to principles well known in the art.

The anti-proliferative treatment defined above may be applied as a monotherapy or may involve conventional surgery or radiation or chemotherapy in addition to a compound of the invention. Such chemotherapy may include one or more of the following types of antineoplastic agents: -

(i) Antiproliferative/antineoplastic agents used in oncology and combinations thereof, such as alkylating agents (e.g., cisplatin, carboplatin, cyclophosphamide, mechlorethamine, melphalan, chlorambucil, busulfan, and nitrosoureas); antimetabolites (e.g., antifolates such as fluoropyrimidines such as 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytarabine, and hydroxyurea); antitumor antibiotics (e.g., anthracyclines such as doxorubicin, bleomycin, doxorubicin, daunorubicin, epirubicin, idarubicin, mitomycin-C, dactinomycin, and mithramycin); antimitotic agents (e.g. vinca alkaloids such as vincristine, vinblastine, vindesine and vinorelbine and taxanes (taxoids) such as taxol and taxotere); and topoisomerase inhibitors (e.g., etoposide (epipodophyllotoxins) such as etoposide and teniposide, amsacrine, topotecan, and camptothecin);

(ii) Cytostatics such as antiestrogens (e.g., tamoxifen, toremifene, raloxifene, droloxifene, and iodoxyfene), estrogen receptor downregulators (e.g., fulvestrant), antiandrogens (e.g., bicalutamide, flutamide, nilutamide, and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprolide, and buserelin), progestins (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, vorazole, and exemestane), and 5 α -reductase inhibitors such as finasteride;

(iii) substances that inhibit cancer cell invasion (e.g., metalloproteinase inhibitors such as marimastat and inhibitors of urokinase plasminogen activator receptor function);

(iv) inhibitors of growth factor function, e.g. such inhibitors include growth factor antibodies, growth factorsSub-receptor antibodies (e.g., anti-erbB 2 antibody trastuzumab [ Herceptin)^TM]And the anti-erbB 1 antibody cetuximab [ C225]) Farnesyl transferase inhibitors, tyrosine kinase inhibitors and serine/threonine kinase inhibitors, e.g. other inhibitors of the epidermal growth factor family (e.g. EGFR family tyrosine kinase inhibitors such as N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3-morpholinopropoxy) quinazolin-4-amine (gefitinib, AZD1839),N- (3-ethynylphenyl) -6, 7-bis (2-methoxyethoxy) quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N- (3-chloro-4-fluorophenyl) -7- (3-morpholinopropoxy) quinazolin-4-amine (CI 1033)), for example an inhibitor of the platelet derived growth factor family and for example an inhibitor of hepatocyte growth factor;

(v) anti-angiogenic agents such as those which inhibit the action of vascular endothelial growth factor (e.g., anti-vascular endothelial growth factor antibody bevacizumab [ Avastin ]^TM]Compounds such as those disclosed in international patent applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) and compounds which act by other mechanisms (e.g. linoamine, inhibitors of integrin α v β 3 function and angiostatin);

(vi) vascular damaging agents such as bucostatin A4 and the compounds disclosed in International patent applications WO 99/02166, WO00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;

(vii) antisense therapies, e.g., those involving the above-listed targets, such as ISIS 2503, antisense anti-ras (anti-ras antisense);

(viii) Gene therapy including, for example, methods of replacing abnormal genes (aberrant genes) such as abnormal p53 or abnormal BRCA1 or BRCA2, GDEPT (gene-directed enzyme prodrug therapy) methods such as these methods using cytosine deaminase, thymidine kinase or bacterial nitroreductase, and methods for increasing the patient's tolerance to chemotherapy or radiation therapy such as multi-drug resistance gene therapy; and

(ix) immunotherapy approaches, including for example ex vivo and in vivo approaches for increasing the immunogenicity of patient tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4, or granulocyte-macrophage colony stimulating factor, methods of reducing T-cell anergy, methods using transfected immune cells such as cytokine-transfected dendritic cells, methods using cytokine-transfected tumor cell lines, and methods using anti-idiotypic antibodies.

Such combination therapy may be accomplished by administering the components of the therapy simultaneously, sequentially or separately. Such combination products employ the compounds of the present invention in the dosage ranges described above and other pharmaceutically active agents in their approved dosage ranges.

According to this aspect of the invention there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined and an additional antineoplastic agent as hereinbefore defined for use in said combination anti-cancer therapy.

The activity and selectivity of the compounds of the invention may be determined using suitable assays, for example as described in WO 03/048133 and described in detail below.

Examples

The invention will now be further illustrated by the following illustrative examples, in which, unless otherwise specified:

(i) temperatures are given in degrees Celsius (. degree. C.); the operation is carried out at room or ambient temperature, i.e. at a temperature of 18 to 25 ℃;

(ii) drying the organic solution with anhydrous magnesium sulfate; the solvent evaporation is carried out with a rotary evaporator under reduced pressure (600-4000 Pa; 4.5-30mmHg) with a bath temperature of at most 60 ℃;

(iii) chromatography refers to flash chromatography using silica gel; thin Layer Chromatography (TLC) was performed on silica gel plates;

(iv) the reaction process is usually followed by TLC and the reaction time is given by way of example only;

(v) the final product has satisfactory proton Nuclear Magnetic Resonance (NMR) spectra and/or mass spectral data;

(vi) the yields are given for illustration only and are not necessarily those obtained by diligent processing; if more material is needed, the preparation is repeated;

(vii) unless otherwise specified, when given, NMR data is in the form of delta values that primarily distinguish protons, given in parts per million (ppm) relative to Tetramethylsilane (TMS) as an internal standard, at 300MHz, in DMSO-d ₆Is determined in (1). The following abbreviations are used: s, singlet; d, double peak; t, triplet; q, quartet; m, multiplet; b, broad peak;

(viii) chemical symbols have their usual meanings; SI units and symbols are used;

(ix) the solvent ratio is volume: volume (v/v) is given; and

(x) Mass spectra were run with a direct exposure probe using electron energy of 70 electron volts in a Chemical Ionization (CI) mode; when indicated, ionization is accomplished by electron bombardment (EI), Fast Atom Bombardment (FAB), or Electrospray (ESP); the value of m/z is given; typically only ions indicative of the parent mass are reported; and unless otherwise specified, the mass ion (mass) referred to is (MH)⁺；

(xi) The following abbreviations are used:

THF tetrahydrofuran;

EtOAc ethyl acetate;

DCM dichloromethane;

DMSO dimethyl sulfoxide;

DIPEA diisopropylethylamine;

NMP N-methylpyrrolidin-2-one;

tBuOH tertiary carboxylic acidButanol;

TFA trifluoroacetic acid;

DMF N, N-dimethylformamide; and

DMA N, N-dimethylacetamide.

Example 1

5-chloro-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

2, 5-dichloro-4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (method 10 of WO 03/048133) (158mg, 0.648mmol), 2- [3- (pyridin-2-yl) isoxazol-5-yl]A mixture of pyrrolidine (method 12) (212mg, 0.972mmol) and di-isopropyl ethylamine (282 μ L, 1.62mmol) was stirred and heated under nitrogen in n-hexanol (7.0ml) at 140 ℃ for 9 hours. Most of the hexanol was then removed by evaporation and the residue partitioned between ethyl acetate and water. The ethyl acetate layer was separated and washed with 1.0 molar phosphate buffer pH 4(x2), then water, and finally brine. The organic layer was dried (Na)₂SO₄) Filtered and evaporated, and the crude product was absorbed onto a 10gisolute SCX2 ion exchange column. The column was eluted with DCM/methanol (4: 1) to remove neutrals and the product was then eluted with dichloromethane/2M methanolic ammonia (4: 1). The purified product was dissolved in a minimum amount of DCM and a slight excess of 1.0M ether to hydrogen chloride was added to the stirred solution. Some more ether was added thereto and the solid product was collected by filtration, washed with ether and dried to give the hydrochloride salt of the title compound (300mg, 100%).

NMR(DMSO-d6₊d₄Acetic acid at 100 ℃):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 in the same manner as in example 1: -

Example No. 2	Starting material	Name of Compound	Q3	R1	NMR DMSO-d6+d4Acetic acid at 100 deg.C	m/z(MH)+
							2	The followingMethods 13 and A	5-chloro-2- [2- (3-methylisoxazol-5-yl) radical]Pyrrolidin-1-yl radical]-4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine	Methyl radical	Methyl radical	1.93-2.0(m，2H)，2.15(s，3H)，2.20-2.36(m，3H)，3.46-3.55(m，1H)，3.66-3.78(m，1H)，5.19-5.22(m，1H)，5.80(s，1H)，6.02(s，1H)，8.0(s，3H)，8.50(s，1H)。	360
3	Methods 13 and B below	5-chloro-2- [2- (3-methylisoxazol-5-yl) radical]Pyrrolidin-1-yl radical]-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine	Methyl radical	Cyclo-propyl	0.68(d，2H)，0.92(d，2H)，1 80-2.05(m，4H)，2.15(s，3H)，2.22-2.35(m，1H)，3.44-3.58(m，1H)，3.62-3.79(m，1H)，5.22(d，1H)，5.82(s，1H)，6.0(s，1H)，7.98(s，1H)，12.4(s，1H)	386
							4	Methods 13 and C below	5-chloro-2- [2- (3-methylisoxazol-5-yl) radical]Pyrrolidin-1-yl radical]-4- (5-tert-butyl-1H-pyrazol-3-ylamino) pyrimidine	Methyl radical	Tertiary carboxylic acidButyl radical	1.35(s，9H)，2 30-2.40(m，1H)，1.98-2.10(m，3H)，2.14(s，3H)，3.65-3.75(m，2H)，5.32(d，1H)，5.99(s，1H)，6.35(s，1H)，7.99(s，1H)，8.10(s，1H)，11.75(s，1H)。	402

Example No. 2	Starting material	Name of Compound	Q3	R1	NMR DMSO-d6+d4Acetic acid at 100 deg.C	m/z(MH)+
							5	Methods 14 and B below	5-chloro-2- [2- (3-cyclopropylisoxazol-5-yl)]Pyrrolidin-1-yl radical]-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine	Cyclo-propyl	Cyclo-propyl	0.65(m，4H)，0.90(m，4H)，1.97(m，5H)，2.28(m，1H)，3.62(m，2H)，5.25(d，1H)，5.80(s，1H)，6.06(s，1H)，7.93(s，1H)	412
6	Methods 14 and A below	5-chloro-2- [2- (3-cyclopropylisoxazol-5-yl)]Pyrrolidin-1-yl radical]-4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine	Cyclo-propyl	Methyl radical	0.65(m，2H)，0.87(m，2H)，1.95(m，4H)，2 18(s，3H)，2.25(m，1H)，3.66(m，2H)，5.22(d，1H)，5.81(s，1H)，6.13(s，1H)，7.95(s，1H)	386
							7	Methods 15 and A below	5-chloro-2- {2- [3- (thiazol-2-yl) isoxazol-5-yl]Pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine	2-thiazoles	Methyl radical	2.1(m，3H)，2.28(s，3H)，2.47(m，1H)，3.65(m，1H)，3.76(m，1H)，5.36(d，1H)，6.22(s，1H)，6.61(s，1H)，7.77(d，1H)，7.94(d，1H)，7.96(s，1H)	429

Example No. 2	Starting material	Name of Compound	Q3	R1	NMR DMSO-d6+d4Acetic acid at 100 deg.C	m/z(MH)+
							8	Methods 15 and B below	5-chloro-2- {2- [3- (thiazol-2-yl) isoxazol-5-yl]Pyrrolidin-1-yl } -4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine-	2-thiazoles	Cyclo-propyl	0.7(m，2H)，0.9(m，2H)，1.87(m，1H)，2.21(m，3H)，24(m，1H)，3.65(m，1H)，3.79(m，1H)，5.4(d，1H)，6.11(s，1H)，6.65(s，1H)，7.85(d，1H)，7.99(d，1H)，8.01(s，1H)	455
9	Methods 12 and B below	5-chloro-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl]Pyrrolidin-1-yl } -4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine	2-pyridines	Cyclo-propyl	0.66(m，2H)，0.88(m，2H)，1.82(m，1H)，2.1(m，3H)，2.36(m，1H)，3.67(m，1H)，3.77(m，1H)，5.4(d，1H)，6.1(s，1H)，6.61(s，1H)，7.41(t，1H)，7.87(t，1H)，7.92(d，1H)，7.99(s，1H)，8.63(d，1H)	449
							10	Methods 16 and A below	5-chloro-2- {2- [3- (pyridin-3-yl) isoxazol-5-yl]Pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine	3-pyridines	Methyl radical	2.1(m，3H)，2.2(s，3H)，2.4(m，1H)，3.68(m，1H)，3.8(m，1H)，3.57(d，1H)，6.12(s，1H)，6.73(s，1H)，7.45(t，1H)，8.0(s，2H)，8.15(d，1H)，8.65(d，1H)，8.97(s，1H)，11.7(s，1H)。	423

Example No. 2	Starting material	Name of Compound	Q3	R1	NMR DMSO-d6+d4Acetic acid at 100 deg.C	m/z(MH)+
							11	Methods 16 and B below	5-chloro-2- {2- [3- (pyridin-3-yl) isoxazol-5-yl]Pyrrolidin-1-yl } -4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine	3-pyridines	Cyclo-propyl	0.66(m，2H)，0.90(m，2H)，1.90(m，1H)，2.1(m，3H)，2.38(m，1H)，3.67(m，1H)，3.80(m，1H)，5.38(d，1H)，6.12(s，1H)，6.70(s，1H)，7.45(t，1H)，7.97(s，1H)，8.10(d，1H)，8.62(d，1H)，8.95(s，1H)	449

A: 2, 5-dichloro-4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

B: 2, 5-dichloro-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine

C: 2, 5-dichloro-4- (5-)Tertiary carboxylic acidbutyl-1H-pyrazol-3-ylamino) pyrimidines

The preparation of compounds A-C is described in WO 03/048133.

Example 12

2- [2- (3-Cyclopropylisoxazol-5-yl) pyrrolidin-1-yl ] -6-methoxymethyl-4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

A mixture of 4-chloro-2- [2- (3-cyclopropylisoxazol-5-yl ] pyrrolidin-1-yl ] -6-methoxymethylpyrimidine (method 19) (250mg, 0.746mmol), 3-amino-5-methyl-1H-pyrazole (109mg, 1.2mmol) and hydrogen chloride (0.56ml of 4M dioxane solution, 2.24mmol) in NMP (5ml) was heated at 120 ℃ for 18H, the mixture was allowed to cool and then applied directly to an isolute S CX2 ion exchange column, the column was eluted with DCM/methanol (4: 1) to remove neutrals (neutrals), then the product was eluted with 7M methanolic ammonia (methanolic ammonia.) the partially purified product was then purified by silica gel chromatography, eluting with DCM/methanol (100: 0 to 95: 5), the product was triturated with diethyl ether/DCM and triturated and the product was added to 95: 5 The solid product was collected by filtration to give the title compound (100mg, 34%) as a white solid.

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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- [2- (3-Cyclopropylisoxazol-5-yl) pyrrolidin-1-yl ] -6-methoxymethyl-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine

The title compound was prepared by the same method as described in example 12 starting from 3-amino-5-cyclopropyl-1H-pyrazole (method 7 of WO 03/048133) (130mg, 41%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] piperidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

2- [3- (pyridin-2-yl) isoxazol-5-yl ] piperidine (method 16(a)) (137mg, 0.6mmol) was treated as described in example 1, except that the reaction mixture was heated at 140 ℃ for 18 hours, then treated with an ethylene diaminopropylsilica-based scavenger, and then worked up as described in example 1 to give the title compound (35mg, 16%).

NMR(DMSOd6，100℃，400MHz)：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:

example number	Starting material	Name of Compound	R1	R2	R3	Q1	Q2	Q3	NMR(DMSO373K+d4AcOH)	m/z(MH)+
											15	A and method 24 below	5-chloro-2- [2- (3- { tetrahydrofuran-3-yl } isoxazol-5-yl) ]Pyrrolidin-1-yl radical]-4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine	Me	Cl	H	Pyrrolidin-1-yl radical	Isoxazol-5-yl	Tetrahydrofuran-3-yl	2.02(m，4H)，2.21(m，1H)，2.32(m，1H)，3.41(m，1H)，3.6(m，2H)，3.72(m，2H)，3.8(m，1H)，3.92(t，1H)，5.38(d，1H)，6.05(s，1H)，6.1(s，1H)，7.96(s，1H)	416
16	B and method 24 below	5-chloro-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2- (3- { tetrahydrofuran-3-yl } isoxazol-5-yl]Pyrrolidin-1-yl radical]-pyrimidines	Cyclo-propyl	Cl	H	Pyrrolidin-1-yl radical	Isoxazol-5-yl	Tetrahydrofuran-3-yl	0.69(m，2H)，0.89(m，2H)，1.9-2.1(m，5H)，2.21(m，1H)，2.3(m，1H)，3.4(m，1H)，3.6(M，2H)，3.65-3.83(m，3H)，3.94(t，1H)，5.3(d，1H)，6.05(s，1H)，6.09(s，1H)，7.96(s，1H)	442
											17	Methods 29 and 12 below	6-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-2-yl)) Isoxazol-5-yl]Pyrrolidin-1-yl } pyrimidines	Me	H	Cl	Pyrrolidin-1-yl radical	Isoxazol-5-yl	Pyridin-2-yl	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) (not deuterated)	423

Example number	Starting material	Name of Compound	R1	R2	R3	Q1	Q2	Q3	NMR(DMSO373K+d4AcOH)	m/z(MH)+
											18	B and method 16(a) below	5-chloro-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl]Piperidin-1-yl pyrimidines	Cyclo-propyl	Cl	H	Piperidin-1-yl radical	Isoxazol-5-yl	Pyridin-2-yl	0.6(m，2H)，0.87(m，2H)，1.53(m，2H)，1.73(m，2H)，1.85(m，1H)，1.95(m，1H)，2.26(m，1H)，3.0(d，1H)，4.6(d，1H)，6.05(s，1H)，6.13(d，1H)，6.66(s，1H)，7.4(t，1H)，7.87(t，1H)，7.94(d，1H)，8.03(s，1H)，8.62(d，1H)。	463
19	A and method 25 below	5-chloro-2- {2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl]Pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine	Me	Cl	H	Pyrrolidin-1-yl radical	Isoxazol-5-yl	2-methoxy-pyridin-3-yl	2.06(m，3H)，2.2(s，3H)，2.37(m，1H)，3.65(m，1H)，3.75(m，1H)，3.9(s，3H)，5.37(d，1H)，6.15(s，1H)，6.55(s，1H)，7.03(t，1H)，8.0(s，1H)，8.07(d，1H)，8.25(d，1H)	453
											20	Method 27(b) and method 12 below	5-fluoro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl]Pyrrolidin-1-yl } -pyrimidines	Me	F	H	Pyrrolidin-1-yl radical	Isoxazol-5-yl	Pyridin-2-yl	2.1(m，3H)，2.2(s，3H)，2.4(m，1H)，3.6(m，1H)，3.77(m，1H)，5.35(d，1H)，6.15(s，1H)，6.63(s，1H)，7.42(t，1H)，7.9(m，3H)，8.63(s，1H)，8.83(s，1H)，11.53(s，1H)。	407

Example number	Starting material	Name of Compound	R1	R2	R3	Q1	Q2	Q3	NMR(DMSO373K+d4AcOH)	m/z(MH)+
											21	Methods 27 and 12 below	4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -5-fluoro-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl]Pyrrolidin-1-yl } pyrimidines	Cyclo-propyl	F	H	Pyrrolidin-1-yl radical	Isoxazol-5-yl	Pyridin-2-yl	0.7(2H，m)，0.9(2H，m)，1.9(m，1H)，2.12(m，3H)，2.38(m，1H)，3.63(m，1H)，3.74(m，1H)，5.4(d，1H)，6.1(s，1H)，6.63(s，1H)，7.43(t，1H)，7.88(m，3H)，8.62(d，1H)，8.83(s，1H)，11.63(s，1H)。	433
221	B and method 40 below	S-5-chloro-2- {2- [ 3-methylisoxazol-5-yl]Pyrrolidin-1-yl } -4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine	Cyclo-propyl	Cl	H	Pyrrolidin-1-yl radical	Isoxazol-5-yl	Methyl radical	0.68(d，2H)，0.92(d，2H)，1.80-2.05(m，4H)，2.15(s，3H)，2.22-2.35(m，1H)，3.44-3.58(m，1H)，3.62-3.79(m，1H)，5.22(d，1H)，5.82(s，1H)，6.0(s，1H)，7.98(s，1H)，12.4(s，1H)	386
											23	Methods 26 and 42 below	4- (5-methyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl]Pyrrolidin-1-yl } pyrimidines	Me	H	H	Pyrrolidin-1-yl radical	Isoxazol-5-yl	Pyridin-2-yl	2.00(m，3H)，2.15(s，3H)，2.32(m，1H)，3.54(m，1H)，3.80(m，1H)，5.38(d，1H)，6.20(m，1H)，6.66(s，1H)，7.45(m，1H)，7.90(m，4H)，8.62(d，1H)，9.38(br s，1H)，11.76(br s，1H)	389

Example number	Starting material	Name of Compound	R1	R2	R3	Q1	Q2	Q3	NMR(DMSO373K+d4AcOH)	m/z(MH)+
											24	Methods 28 and 12 below	4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl]Pyrrolidin-1-yl } pyrimidines	Cyclo-propyl	H	H	Pyrrolidin-1-yl radical	Isoxazol-5-yl	Pyridin-2-yl	0.60(m，2H)，0.85(m，2H)，1.80(m，1H)，2.00(m，3H)，2.30(m，1H)，3.56(m，1H)，3.80(m，1H)，5.40(d，1H)，6.20(br s，1H)，6.64(s，1H)，7.45(m，1H)，7.90(m，3H)，8.62(d，1H)，9.40(br s，1H)，11.84(br s，1H)	415

A: 2, 5-dichloro-4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

B: 2, 5-dichloro-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine

The preparation of compounds A and B is described in WO 03/048133.

¹Purification was carried out by chromatography on silica eluting with DCM/MeOH (98: 2 to polarity increase to 95: 5).

Example 25

4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -6-methyl-2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

4-hydroxy-6-methyl-2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl]A mixture of pyrimidine (method 30) (200mg, 0.62mmol) in phosphorus oxychloride (7ml) was heated at 70 ℃ under nitrogen for 30 minutes. The volatiles were removed by evaporation and the residue was dissolved in DCM, washed with saturated sodium bicarbonate solution and dried (MgSO)₄) And the solvent was removed by evaporation. The crude product was then treated with 3-amino-5-cyclopropyl-1H-pyrazole (method 7 of WO-03/048133) (120mg, 0.98mmol), and 4M hydrogen chloride in dioxane (0.65ml) in NMP (5ml) as described in example 12 to give the title compound (100mg, 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 in a similar manner to that described in example 25.

Example 26

4- (5-methyl-1H-pyrazol-3-ylamino) -6-methyl-2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Starting materials: 4-hydroxy-6-methyl-2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (method 30) and 3-amino-5-methyl-1H-pyrazole.

Purification by silica gel chromatography eluting with methanol/DCM (8: 92) gave the title compound (42mg, 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-cyclopropyl-1H-pyrazol-3-ylamino) -6-methyl-2- [2- (3-methylisoxazol-5-yl) pyrrolidin-1-yl ] pyrimidine

Starting materials: 4-hydroxy-6-methyl-2- [2- {3- (methyl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (method 31) and 3-amino-5-cyclopropyl-1H-pyrazole (method 7 of WO-03/048133).

Yield: 70mg, 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，1H)；m/z 364[MH]-。

Example 28

6-Ethyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Starting materials: 4-hydroxy-6-ethyl-2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (method 32) and 3-amino-5-methyl-1H-pyrazole.

Yield: 150mg, 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/z417[MH]+。

Example 29

6- (3-methoxypropyl) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Starting materials: 4-hydroxy-6- (3-methoxypropyl) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (method 33) and 3-amino-5-methyl-1H-pyrazole.

Yield: 56mg, 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-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Starting materials: 4-hydroxy-6-methoxymethyl-2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (method 34) and 3-amino-5-methyl-1H-pyrazole.

Yield: 260mg, 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-1H-pyrazol-3-ylamino) -6-methoxymethyl-2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Starting materials: 4-hydroxy-6-methoxymethyl-2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (method 34) and 3-amino-5-cyclopropyl-1H-pyrazole (method 7 of WO-03/048133).

Yield: 245mg, 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-methoxymethyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- {2- [3- (thiazol-2-yl) isoxazol-5-yl ] pyrrolidin-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-1H-pyrazole.

Yield: 32mg, 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- [2- {3- (pyridin-3-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Starting materials: 4-hydroxy-6-methoxymethyl-2- [2- {3- (pyridin-3-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (method 35(a)) and 3-amino-5-methyl-1H-pyrazole.

Yield: 30mg, 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-methyl-1H-pyrazol-3-ylamino) -6- (pent-3-en-1-yl) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Starting materials: 4-hydroxy-6- (pent-3-en-1-yl) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (method 35) and 3-amino-5-methyl-1H-pyrazole.

Yield: 341mg, 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)；m/z 457[MH]+。

Example 35

4- (5-methyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -6-trifluoromethylpyrimidine

Starting materials: 4-hydroxy-6-trifluoromethyl-2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (method 37) and 3-amino-5-methyl-1H-pyrazole.

Yield: 115mg, 38%.

NMR(DMSO)：2.20(m，7H)，3.70(br m，2H)，5.42(br d，1H)，5.95(brs，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-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -6-trifluoromethylpyrimidine

Starting materials: 4-hydroxy-6-trifluoromethyl-2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (method 37) and 3-amino-5-cyclopropyl-1H-pyrazole (method 7 of WO-03/048133).

Yield: 60mg, 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 single enantiomers of the following examples 37 to 42 were prepared by separation of the racemic compounds by chiral HPLC using a Chiralpak AD column with methanol or methanol/ethanol mixture as eluent.

Example 37

S-6-Ethyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

The title compound was prepared by separation of the racemic compound (example 28).

Example 38

S-5-chloro-2- {2- [3- (thiazol-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

The title compound was prepared by separation of the racemic compound (example 7).

Example 39

S-5-chloro-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine

The title compound was prepared by separation of the racemic compound (example 9).

Example 40

S-4- (5-methyl-1H-pyrazol-3-ylamino) -6-methyl-2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

The title compound was prepared by separation of the racemic compound (example 26).

EXAMPLE 41

S-5-chloro-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

The title compound was prepared by separation of the racemic compound (example 1).

Example 42

S-5-chloro-2- {2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

The title compound was prepared by separation of the racemic compound (example 19).

Example 43

6- (3-N, N-dimethylaminopropyl) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Osmium tetroxide (0.070ml of a 2.5% by weight solution in tBuOH) and then water (0.38ml) were added to the stirred 4- (5-methyl-1H-pyrazol-3-ylamino) -6- (pent-3-en-1-yl) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] under nitrogen]Pyrimidine (example 34) (100mg, 2.2mmol) in THF (2 ml). To this was added sodium periodate (150mg, 6.5mmol) and the mixture is stirred for 1 hour. The mixture was diluted with water and extracted with ethyl acetate. The extracts were combined and dried (MgSO)₄) And the volatiles were removed by evaporation. The residue was dissolved in methanol and acetic acid (0.066ml) and a 2M solution of dimethylamine in THF (0.55ml) was added thereto. Sodium cyanoborohydride (28mg) was added rapidly thereto and the mixture was stirred at ambient temperature for 18 hours. Then, the volatile substances were removed by evaporation, and the residue was dissolved in ethyl acetate, washed with a saturated aqueous sodium carbonate solution and then with brine. The volatiles were removed by evaporation and the residue was purified by chromatography on silica eluting with DCM/MeOH/ammonia (100: 0 to polarity increase to 85: 15: 0.3) to give the title compound (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)，5.47(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- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Example 44 was prepared in a similar manner to that described in example 43, starting from 4- (5-methyl-1H-pyrazol-3-ylamino) -6- (pent-3-en-1-yl) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (example 34) and pyrrolidine.

Yield: 6mg, 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)，742(dd，1H)，7.85-7.97(m，2H)，8.63(d，1H)，8.74(s，1H)；m/z 500[MH]+。

Example 45

6-methoxycarbonyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine

A mixture of 2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidin-6-yl carboxylic acid (method 43) (100mg 0.21mmol), methanol (10ml) and 1 drop of 98% sulfuric acid was heated at reflux for 18 hours. The volatiles were removed by evaporation and the residue was dissolved in water. The pH of the resulting solution was adjusted to 12 by careful addition of 10M aqueous sodium hydroxide solution and then extracted with DCM. The extracts were combined and the volatiles were removed by evaporation. The residue was purified by chromatography on silica eluting with DCM/methanol (100: 0 to polarity increase to 95: 5). The purified product was triturated with ether and the resulting solid was collected by filtration to give the title compound (10mg, 8.8%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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-Hydroxyethylcarbamoyl) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine

A mixture of 6-methoxycarbonyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine (example 45) (49.5mg, 0.11mmol) and ethanolamine (2.0ml, 33.7mmol) in methanol (4ml) was heated at 88 ℃ 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 to polarity reduction to 0: 100: 0.2), the product containing fractions were combined and passed through a 50g isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutral impurities, and then the product was eluted with 7M methanolic ammonia. The solvent was removed by evaporation, the residue triturated with ether and the resulting solid collected by filtration to give the title compound (27mg, 57%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -6- (pyrrolidin-1-ylcarbonyl) pyrimidine

Example 47 was prepared in a similar manner to that of example 46 except that the starting material was treated with pure pyrrolidine and the product was purified by chromatography on silica eluting with DCM/methanol (100: 0 to polarity increase to 90: 10) to give the title compound (10mg, 2.8%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-2-yl)) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine

Reacting 6-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl]A mixture of pyrrolidin-1-yl } pyrimidine (example 17) (200mg, 0.47mmol), 25% NaOMe/MeOH solution (0.54ml, 2.3mmol) in methanol (3ml) was heated under sealed conditions at 140 ℃ for 1 h. The mixture was allowed to cool and then the 2M ether was added carefully Hydrogen chloride (ether hydrogen chloride) was prepared and its pH was adjusted to 7. The mixture was then diluted with water and the aqueous mixture was extracted with DCM, the extracts combined and dried (MgSO)₄) And the solvent was removed by evaporation. The residue was triturated with ether and the product was collected by filtration to give the title compound as a white solid (98mg, 50%).

NMR(DMSO)：2.14-2.2(m，6H)，2.38(m，1H)，3.75(m，5H)，5.44(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- [2- (2-methyl-2H-tetrazol-5-yl) pyrrolidin-1-yl ] pyrimidine

1-tert-butoxy-2- (2-methyl-2H-tetrazol-5-yl) pyrrolidine (method 46) (160mg, 0.63mmol) was stirred in TFA (2ml) at ambient temperature for 1H. TFA was removed by evaporation and the resulting product was added to a mixture of 2, 5-dichloro-4 (3-cyclopropyl-1H-pyrazol-5-ylamino) pyrimidine (method 20 of WO 03/048133) (152mg, 0.57mmol) and di-isopropylethylamine (330. mu.L, 1.9mmol) in n-hexanol (4.0 ml). The resulting mixture was stirred and heated at 120 ℃ under nitrogen for 12 hours. To this was added 3- (1, 2-diaminoethyl) propyl-functionalized silica gel (40mg, 0.11mmol), and the mixture was heated at 140 ℃ for 12 hours. The mixture was allowed to cool, filtered and the filtrate was applied directly to an isolute SCX2 ion exchange column. The column was eluted with DCM/MeOH (4: 1) to remove neutral material, then the product was eluted with 7M methanolic ammonia. The product was triturated with ether and the solid product was collected by filtration, washed with ether and dried to give the title compound (82mg, 38%).

NMR(DMSO-d₆At 100 ℃): 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-ethylpiperazino-4- (5-methyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine

A mixture of 6-chloro-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (example 17) (250mg, 0.59mmol) and N-ethylpiperazine (674mg, 5.9mmol) in anhydrous 1, 4-dioxane (5ml) was heated at 150 ℃ under microwave radiation in a sealed vessel for 40 minutes. 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 to polarity reduction to 0: 100: 0.2). The product containing fractions were combined and passed through a 50g isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutrals, then the product was eluted with 7M methanolic ammonia. The solvent was removed by evaporation and purified again by chromatography on silica eluting with DCM/MeOH/ammonia (100: 0 to 89: 20: 1) to give the title compound (200mg, 68%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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 in a similar manner to that described in example 50, but normal phase chromatography was not required and the compounds were isolated by trituration with ether/DCM and collected by filtration.

Example 51

6-N-methylpiperazinyl (piperazyl) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

Starting materials: 6-chloro-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (example 17) and N-methylpiperazine.

Yield: 201mg, 70%.

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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[ MH ]+。

Example 52

6-morpholino-4- (5-methyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine

Starting materials: 6-chloro-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (example 17) and morpholine.

Yield: 239mg and 85 percent.

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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- (N, N-dimethylamino) propyn-1-yl) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- (2- (3- (pyridin-2-yl) isoxazol-5-yl) pyrrolidin-1-yl) pyrimidine

6-bromo-4- (5-methyl-1H-pyrazol-3-ylamino) -2- (2- (3- (pyridin-2-yl) isoxazol-5-yl) pyrrolidine) pyrimidine (method 49) (200mg, 0.43mmol), palladium (II) chloride-bis (triphenylphosphine) (12mg, 0.02mmole), iodinationA mixture of copper (I) (2mg, 0.02mmol), triethylamine (0.300ml, 2.1mmol), 3- (N, N-dimethylamino) propyne (0.070ml, 0.64mmol) in acetonitrile (2ml) was heated at 75 ℃ under microwave radiation in a sealed vessel for 15 minutes. The mixture was dissolved in ethyl acetate, the solution was decanted from insoluble material, the solution was washed with water and dried (MgSO) ₄) And the solvent is removed by evaporation. The residue was purified by chromatography on silica gel eluting with DCM/methanol (90: 10 to polarity increase to 85: 15). The purified product was triturated with ether and collected by filtration to give the title compound (44mg, 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-1H-pyrazol-3-ylamino) -2- [2- (3-pyridin-2-ylisoxazol-5-yl) pyrrolidin-1-yl ] pyrimidine

A mixture of 6-chloro-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (example 17) (250mg, 0.59mmol) and methylamine (4ml of a 2M solution in methanol, 8.0mmol) was heated in a sealed vessel under microwave irradiation at 130 ℃ for 90 minutes. 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 to polarity reduction to 0: 100: 0.2). The product containing fractions were combined and passed through a 50g isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutrals, then the product was eluted with 7M methanolic ammonia. The solvent was removed by evaporation to give the title compound (126mg, 50%) as a yellow solid.

NMR(DMSO-d₆At 100 ℃): 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(m，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- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine

A mixture of 6-chloro-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (example 17) (250mg, 0.59mmol) and 2-methoxyethylamine (443mg, 5.9mmol) in anhydrous 1, 4-dioxane (5ml) was heated at 150 ℃ under microwave radiation in a sealed vessel for 40 minutes. The reaction was worked up as described in example 54 to give the title compound as a cream solid (108mg, 40%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

A mixture of 2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidin-6-yl carboxylic acid (method 43) (1.73g, 4.0mmol), methanol (300ml) and 98% sulfuric acid (1ml) was heated at reflux for 18 hours. The volatiles were removed by evaporation, the residue was dissolved in water and the resulting solution was adjusted to pH 12 with 10M sodium hydroxide. The aqueous solution was extracted with DCM and purified by chromatography on silica eluting with DCM/MeOH (100: 0 to polarity increase to 90: 10) to give the title compound (904mg, 51%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 2.05(m, 3H), 2.15(s, 3H), 2.35(m, 1H), 3.75(m, 5H), 5.50(dd, 1H), 6.05(s, 1H), 6.70s, 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- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

A mixture of 6-methoxycarbonyl-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (example 56) (62.5mg, 0.14mmol), 2N methylamine in methanol (2.0ml, 4.00mmol) and methanol (3.0ml) was heated at 65 ℃ for 1H under microwave radiation. 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 to polarity increase to 90: 10). The purified product was triturated with ether and the resulting solid was collected by filtration to give the title compound (21mg, 34%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 2.10(m, 3H), 2.20(s, 3H), 2.40(m, 1H), 3.75(m, 1H), 3.85(m, 1H), 5.50(dd, 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/z446[ MH ]+。

Example 58

6-Morpholinocarbonyl-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

A mixture of 6-methoxycarbonyl-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (example 56) (200mg, 0.45mmol) and morpholine (0.5ml, 5.73mmol) in dry methanol (5.0ml) was heated at 120 ℃ for 18H. 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 to a polarity reduction of 0: 100: 0.2). The product containing fractions were combined and passed through a 50g isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutrals, then the product was eluted with 7M methanolic ammonia. The solvent was removed by evaporation and the residue was triturated with ether. The resulting solid was collected by filtration to give the title compound (120mg, 52%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

A mixture of 6-methoxycarbonyl-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (example 56) (200mg, 0.45mmol) and 2-methoxyethylamine (5ml, 57.2mmol) was heated at reflux for 18H. The reaction mixture was evaporated, the residue was dissolved in methanol and passed through a 50g isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutrals, then the product was eluted with 7M methanolic ammonia. The solvent was removed by evaporation and the residue was purified by chromatography on silica gel eluting with DCM/methanol (100: 0 to polarity increase to 90: 10). The purified product was triturated with ether and the resulting solid was collected by filtration to give the title compound (78mg, 36%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

A mixture of 6-methoxycarbonyl-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (example 56) (200mg, 0.45mmol), hydroxylamine monohydrochloride (340mg, 4.86mmol) and triethylamine (0.80ml, 5.40mmol) in dry methanol (5ml) was heated at reflux for 18H. 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 to a polarity reduction of 0: 100: 0.2). The product containing fractions were combined and passed through a 50g isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutrals, then the product was eluted with 7M methanolic ammonia. The solvent was removed by evaporation to give the title compound as a foam (40mg, 20%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 2.08(m, 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/z448[ MH]+。

Example 61

6-carbamoyl-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

A mixture of 6-methoxycarbonyl-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (example 56) (200mg, 0.45mmol) and 7N aqueous ammonia solution in methanol (7ml, 49mmol) was heated at 65 ℃ for 1 hour under microwave radiation in a sealed vessel. The reaction mixture was evaporated, dissolved in methanol and passed through a 50g isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutrals, then the product was eluted with 7M methanolic ammonia. The solvent was removed by evaporation and the residue was triturated with ether. The resulting solid was collected by filtration to give the title compound (180.0mg, 93%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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/z432[ MH]+。

Example 62

S-6-methoxycarbonyl-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

A mixture of S-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidin-6-yl carboxylic acid (method 50) (1.73g, 4.0mmol), methanol (300ml) and 98% sulfuric acid (1ml) was heated at reflux for 18 hours. The volatiles were removed by evaporation, the residue was dissolved in water and the resulting solution was adjusted to pH 12 with 10M sodium hydroxide. The aqueous solution was extracted with DCM and purified by chromatography on silica eluting with DCM/MeOH (100: 0 to polarity increase to 90: 10) to give the title compound (904.0mg, 51%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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 63

S-6- (N- (2-methoxyethyl) carbamoyl) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

4- (4, 6-dimethoxy [1, 3, 5] triazin-2-yl) -4-methyl-morpholinium chloride (149.3mg, 0.54mmol) was added to a mixture of S-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidin-6-ylcarboxylic acid (method 50) (200mg, 0.46mmol) and anhydrous DMF (10ml) and the reaction mixture was stirred at ambient temperature for 0.5H until a clear solution formed (indicating successful formation of the active ester). 2-methoxyethylamine (0.50ml, 5.75mmol) was added and the reaction stirred at ambient temperature for an additional 2 hours. The reaction mixture was then passed through a 50g isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutrals, then the product was eluted with 7M methanolic ammonia. The solvent was removed by evaporation and the residue was purified by chromatography on silica gel eluting with DCM/methanol (100: 0 to polarity increase to 90: 10). The purified product was triturated with ether and the resulting solid was collected by filtration to give the title compound (136mg, 58%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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- [ N- (2-methoxyethyl) -N-methylcarbamoyl ] -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

4- (4, 6-dimethoxy [1, 3, 5] triazin-2-yl) -4-methyl-morpholinium chloride (149.3mg, 0.54mmol) was added to a mixture of S-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidin-6-ylcarboxylic acid (method 50) (200mg, 0.46mmol) and anhydrous DMF (10ml) and the reaction mixture was stirred at ambient temperature for 0.5H until a clear solution formed. N- (2-methoxyethyl) -N-methylamine (0.5ml) was added to the reaction and the reaction was stirred at ambient temperature for an additional 2 hours. The reaction mixture was then passed through a 50g isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutrals, then the product was eluted with 7M methanolic ammonia. The solvent was removed by evaporation and the residue was purified by chromatography on silica gel eluting with DCM/methanol (100: 0 to polarity increase to 90: 10). The purified product was then purified again by reverse phase HPLC using a C18 column, eluting with water/acetonitrile/TFA (95: 5: 0.2 to a polarity decrease of 0: 100: 0.2). The product containing fractions were combined and passed through a 50g isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutrals, then the product was eluted with 7M methanolic ammonia. The solvent was removed by evaporation to give the title compound (90mg, 37%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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- [ N- (2- (acetylamino) ethyl) carbamoyl ] -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

4- (4, 6-dimethoxy [1, 3, 5] triazin-2-yl) -4-methyl-morpholinium chloride (149.3mg, 0.54mmol) was added to a mixture of S-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidin-6-ylcarboxylic acid (method 50) (200mg, 0.46mmol) and anhydrous DMF (5ml) and the reaction mixture was stirred at room temperature for 0.5H until a clear solution formed. N-acetyl-1, 2-ethylenediamine (0.22ml, 2.29mmol) was added thereto and the reaction was stirred at room temperature for another 2 hours. The reaction mixture was filtered, volatiles were removed from the filtrate by evaporation and the residue was purified by reverse phase HPLC using a C18 column, eluting with water/acetonitrile/TFA (95: 5: 0.2 to a polarity reduction of 0: 100: 0.2). The product containing fractions were combined and passed through a 50g isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutrals, then the product was eluted with 7M methanolic ammonia. The solvent was removed by evaporation, the residue triturated with ether and collected by filtration to give the title compound (115.7mg, 49%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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 using S-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidin-6-yl carboxylic acid (method 50) and the appropriate amine in a similar manner to the procedure described in example 65.

Example 66

S-6- { N- [ 2-hydroxyethoxy) ethyl ] carbamoyl } -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

Amine starting material: 2- (2-hydroxyethoxy) ethylamine. Yield: 123mg, 49%.

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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- [ N- ((R) -2-hydroxypropyl) carbamoyl ] -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

Amine starting material: (R) -2-hydroxypropylamine. Yield: 137mg, 61%.

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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- [ N- (4-hydroxybutyl) carbamoyl ] -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

Amine starting material: 4-hydroxybutylamine. This product was isolated without trituration (153mg, 66%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 1.45(m, 2H), 1.55(m, 2H), 2.10(m, 3H), 2.19(s, 3H), 2.40(m, 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- [ N- ((2R) -2, 3-dihydroxypropyl) carbamoyl ] -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

Amine starting material: (2R) -2, 3-dihydroxypropylamine. This product was isolated without trituration with water (135mg, 58%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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/z506[ MH]+。

Example 70

S-6- [ N- (carbamoylmethyl) carbamoyl ] -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

This product was prepared with glycine hydrochloride and triethylamine (7.0 equivalents) and isolated without trituration (141mg, 62%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 2.10(m, 3H), 2.18(s, 3H), 2.40(m, 1H), 3.80(m, 2H), 3.85(m, 2H), 5.50(dd, 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/z506[ MH ]+。

Example 71

S-6- ((3R) -3-hydroxypyrrolidin-1-ylcarbonyl) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

Amine starting material: (2R) -3-hydroxypyrrolidine. This product was isolated by trituration (129mg, 56%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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(t, 1H), 7.93(d, 1H), 8.62(d, 1H); m/z 502[ MH]+。

Example 72

S-6- { N- [2- (methylthio) ethyl ] carbamoyl } -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

Amine starting material: 2- (methylthio) ethylamine. This product was isolated by trituration (147mg, 63%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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-cyclopropylcarbamoyl) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

Amine starting material: cyclopropylamine. This product was isolated by trituration (113mg, 52%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

Amine starting material: a cyclopentylamine. This product was isolated by trituration (162mg, 70%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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)H)，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- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

Amine starting material: azetidine. This product was isolated by trituration (153mg, 70%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

This product was prepared with 2N methylamine in THF (10.0 equivalents) and isolated without trituration (145mg, 70%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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-carbamoyl) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

Hydrazine monohydrate (1.6ml, 20.6mmol) was added to a mixture of 6-methoxycarbonyl-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (example 56) (1.54g, 3.45mmol) in methanol (20.0ml) at room temperature. The resulting reaction mixture was heated at reflux for 1 hour and then allowed to cool. The resulting solid was collected by filtration and washed with methanol to give the title compound (1.05g, 68.3%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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/z447[ MH]+。

Example 78

6- [ N- (acetylamino) carbamoyl ] -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

A solution of 6- [ N- (acetylamino) carbamoyl ] -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (2-acetyl-5-methyl-1H-pyrazol-3-ylamino) pyrimidine (method 51) (170mg, 0.32mmol) in methanol (10ml) and 2N sodium hydroxide (0.5ml, 1.0mmol) was stirred at room temperature for 0.5H. The resulting precipitate was collected by filtration to give the title compound (150mg, 96%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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- [1, 3, 4] -oxadiazol-2-yl) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

(Methoxycarbonylaminosulfonyl) triethylammonium hydroxide (inner salt) (90mg, 3.76mmol) was added to a solution of 6- [ N- (acetylamino) carbamoyl ] -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (2-acetyl-5-methyl-1H-pyrazol-3-ylamino) pyrimidine (method 51) (500mg, 0.94mmol) in anhydrous THF (20ml) and the reaction was heated at reflux for 18H. The volatiles were removed by evaporation and the residue was dissolved in methanol (5ml) and 2N aqueous sodium hydroxide (1.0ml) and stirred at ambient temperature for 15 minutes. The methanol was removed by evaporation and the resulting solution was adjusted to pH 7 with 1N hydrochloric acid. The volatiles were removed by evaporation and the residue was purified by chromatography on silica eluting with DCM/MeOH (100: 0 to polarity increase to 90: 10). Then, the purified product was triturated with ether and collected by filtration to give the title compound (200mg, 52%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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-hydroxymethyl-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

A solution of 2M lithium borohydride in THF (22.4ml, 44.8mmol) was added to a mixture of 6-methoxycarbonyl-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (example 56) (4.0mg, 8.96mmol) in dry THF (200 ml). The reaction mixture was stirred at room temperature for 3 hours, and then it was refluxed at room temperature for 1 hour. The mixture was allowed to cool and methanol was added thereto until effervescence ceased, then a 4M solution of hydrogen chloride in dioxane (30ml) was added thereto and the mixture was heated at reflux for 1 hour. The volatiles were removed by evaporation, the residue was dissolved in water and the pH of the resulting solution was adjusted to 9 by careful addition of 10M aqueous sodium hydroxide. The aqueous mixture was extracted with DCM and purified by chromatography on silica eluting with DCM/MeOH (100: 0 to polarity increase to 90: 10) to give the title compound (3.4g, 91%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

A mixture of 6- [ (4-methylphenylsulfonyloxy) methyl ] -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-2-N- [ 4-methylphenylsulfonyl ] -1H-pyrazol-3-ylamino) pyrimidine (method 52) (214mg, 0.295mmol) and morpholine (5ml, 83.2mmol) was heated at reflux for 2 hours. The volatiles were removed by evaporation and the residue was dissolved in methanol (10ml) and 10M aqueous sodium hydroxide (3 ml). The mixture was heated at 60 ℃ for 1 hour. The volatiles were removed by evaporation and the residue was dissolved in water and extracted with dichloromethane. The extracts were combined and the solvent was removed by evaporation. The residue was purified by chromatography on silica eluting with dichloromethane (100%) followed by diethyl ether (100%). The purified product was triturated with ether and collected by filtration to give the title compound (125 mg).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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), 545(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-methylpiperazin-1-ylmethyl) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

A mixture of 6- [ (4-methylphenylsulfonyloxy) methyl ] -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-2-N- [ 4-methylphenylsulfonyl ] -1H-pyrazol-3-ylamino) pyrimidine (method 52) (214mg, 0.295mmol) and 1-methylpiperazine (3.0ml, 27.1mmol) was heated at 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 to a polarity reduction of 0: 100: 0.2). The product containing fractions were combined and passed through a 50g isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutrals, then the product was eluted with 7M methanolic ammonia. The solvent was removed by evaporation to give the title compound (107mg, 71%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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- (methylaminomethyl) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

A mixture of 6- [ (4-methylphenylsulfonyloxy) methyl ] -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-2-N- [ 4-methylphenylsulfonyl ] -1H-pyrazol-3-ylamino) pyrimidine (method 52) (190mg, 0.26mmol) and a solution of 2N methylamine in THF (5ml, 10mmol) was heated in a sealed vessel under microwave radiation at 90 ℃ 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 to a polarity reduction of 0: 100: 0.2). The product containing fractions were combined and passed through a 50g isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutrals, then the product was eluted with 7M methanolic ammonia. The solvent was removed by evaporation to give the title compound (87.1mg, 77%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

A mixture of 6- [ (4-methylphenylsulfonyloxy) methyl ] -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-2-N- [ 4-methylphenylsulfonyl ] -1H-pyrazol-3-ylamino) pyrimidine (method 52) (214mg, 0.295mmol) and pyrrolidine (3.0ml, 27mmol) was heated at 95 ℃ 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 to a polarity reduction of 0: 100: 0.2). The product containing fractions were combined and passed through a 50g isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutrals, then the product was eluted with 7M methanolic ammonia. The solvent was removed by evaporation to give the title compound (77.6mg, 52%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

Sodium azide (44mg, 0.68mmol) was added to a solution of 6- [ (4-methylphenylsulfonyloxy) methyl ] -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1-N- [ 4-methylphenylsulfonyl ] -1H-pyrazol-3-ylamino) pyrimidine (method 52) (159mg, 0.22mmol) in anhydrous DMF (2.0ml) and the mixture was heated at 110 ℃ for 1.5 hours. Then, triphenylphosphine (282.0mg, 1.08mmol) and water (0.10ml) were added thereto and the reaction mixture was heated at 100 ℃ for 1 hour. The mixture was allowed to cool and then passed through a 50g isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutrals, then the product was eluted with 7M methanolic ammonia. The volatiles were removed by evaporation and the residue was dissolved in methanol (5ml) and 10M aqueous sodium hydroxide (0.5ml) and stirred for 1 hour. The volatiles were removed by evaporation and the residue was dissolved in water, which was then extracted with DCM. The extracts were combined, the solvent removed by evaporation and the residue purified by chromatography on silica eluting with DCM/MeOH/ammonia (100: 0 to polarity increase to 80: 20: 1) to give the title compound (48.5mg, 53%) as a solid.

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 2.08(m, 3H), 2.19(s, 3H), 2.35(m, 1H), 3.75(m, 1H), 3.82(m, 3H), 5.55(dd, 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/z418 MH]+。

Example 86

S-6-hydroxymethyl-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

S-6-methoxycarbonyl-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (example 62) was treated by the method described for example 80 to give the title compound.

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

A solution of 1M lithium bis (trimethylsilyl) amide in THF (5.0ml, 5.0mmol) was added to a mixture of S-6-chloromethyl-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-2-N- [ 4-methylphenylsulfonylamino ] -1H-pyrazol-3-ylamino) pyrimidine (method 53) (240mg, 0.41mmol) in anhydrous ethanol (30 ml). The reaction mixture was then heated at 100 ℃ for 48 hours and allowed to cool. A small amount of water was added and the volatiles were removed by evaporation. The residue was purified by chromatography on silica eluting with DCM/MeOH (100: 0 to polarity increase to 90: 10) to give the title compound (29mg, 16%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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- [ (2-methoxyethoxy) methyl ] -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

A solution of 1M lithium bis (trimethylsilyl) amide in THF (5.0ml, 5.0mmol) was added to a mixture of S-6-chloromethyl-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-2-N- [ 4-methylphenylsulfonylamino ] -1H-pyrazol-3-ylamino) pyrimidine (method 53) (240mg, 0.41mmol) in dry 2-methoxyethanol (30 ml). The reaction mixture was then heated at 150 ℃ under microwave irradiation in a sealed vessel for 1.5 hours. A small amount of water was added and the volatiles were removed by evaporation. The residue was purified by chromatography on silica eluting with DCM/MeOH (100: 0 to polarity increase to 90: 10) to give the title compound (69.0mg, 43%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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- {2- [3- (pyrazin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine

A mixture of 2, 5-dichloro-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine (method 20 of WO 03/04133) (195mg, 0.72mmol), S-2- [3- (2-pyrazinyl) isoxazol-5-yl ] pyrrolidine (method 55) (171.5mg, 0.79mmol), N-diisopropylethylamine (0.28ml, 1.58mmol) and N-hexanol (10.0ml) was heated at 125 ℃ for 18 hours. Then, 3- (2-aminoethylamino) propyl-functionalized silica gel (500mg) was added thereto and the reaction mixture was heated at 140 ℃ for an additional 2 hours. The reaction mixture was passed through a 50g isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutrals, then the product was eluted with 7M methanolic ammonia. The solvent was removed by evaporation and the residue was purified by chromatography on silica gel eluting with DCM/methanol (100: 0 to polarity increase to 90: 10). The purified product was triturated with ether and collected by filtration to give the title compound (100mg, 31%)

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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- [3- (pyrazin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine

A mixture of S-2-chloro-6-methyl-4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (method 56) (250mg, 1.12mmol), S-2- [3- (2-pyrazinyl) isoxazol-5-yl ] pyrrolidine (method 55) (266mg, 1.23mmol) and N, N-diisopropylethylamine (0.22ml, 2.52mmol) in N-hexanol (5ml) was heated at 150 ℃ in a sealed vessel under microwave radiation for 6 hours. The solvent was removed by evaporation and the residue was dissolved in methanol and poured onto a 50g isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutral material, and then the product was eluted with 7M methanolic ammonia. The solvent was removed by evaporation to give the title compound (319.6mg, 71%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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- {2- [3- (pyrazin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine

A mixture of S-2, 6-dichloro-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine (method 57) (1.5g, 5.55mmol), S-2- [3- (2-pyrazinyl) isoxazol-5-yl ] pyrrolidine (method 55) (1.32g, 6.11mmol) and N, N-diisopropylethylamine (0.92ml, 6.66mmol) in N-butanol (25ml) was heated at 80 ℃ for 4 hours. The solvent was removed by evaporation and the residue was purified by chromatography on silica eluting with DCM/MeOH (100: 0 to polarity increase to 90: 10) to give the title compound (750mg, 30%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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[ MH]+。

Example 92

S-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyrazin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -6- (2-methoxyethylamino) pyrimidine

A mixture of S-6-chloro-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyrazin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine (example 91) (215mg, 0.48mmol) and 2-methoxyethylamine (4.0ml, 46.1mmol)) was heated at 150 ℃ under microwave radiation in a sealed vessel 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 to polarity reduction to 0: 100: 0.2). The product containing fractions were combined and passed through a 50g isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutrals, then the product was eluted with 7M methanolic ammonia. The solvent was removed by evaporation to give the title compound (78mg, 33%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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- {2- [3- (pyrazin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine

A mixture of S-6-chloro-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyrazin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine (example 91) (215mg, 0.48mmol) and a 2M solution of methylamine in THF (5.0ml) was heated at 150 ℃ for 1.5 hours under microwave irradiation in a sealed vessel. 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 to polarity reduction to 0: 100: 0.2). The product containing fractions were combined and passed through a 50g isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutrals, then the product was eluted with 7M methanolic ammonia. The solvent was removed by evaporation to give the title compound (100mg, 50%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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-1H-pyrazol-3-ylamino) -6-methoxy- {2- [3- (pyrazin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine

A1.33M solution of sodium methoxide in anhydrous methanol (3.0ml, 2.25mmol) was added to a mixture of S-6-chloro-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyrazin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine (example 91) (200mg, 0.45mmol) in anhydrous methanol (2.0ml) and the reaction mixture was heated in a sealed vessel under microwave radiation at 120 ℃ 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 to polarity reduction to 0: 100: 0.2). The product containing fractions were combined and passed through a 50g isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutrals, then the product was eluted with 7M methanolic ammonia. The solvent was removed by evaporation to give the title compound (87.5mg, 44%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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/z446[ MH]+。

Example 95

6-pyrrolidin-1-yl-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

A mixture of 6-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine (example 17) (250mg, 0.59mmol), pyrrolidine (0.5ml, 5.98mmol) and anhydrous 1, 4-dioxane (5.0ml) was heated in a sealed vessel at 100 ℃ for 1 hour under microwave radiation. 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 to a polarity reduction of 0: 100: 0.2). The product containing fractions were combined and passed through a 50g isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutrals, then the product was eluted with 7M methanolic ammonia. The solvent was removed by evaporation and the residue was triturated with ether and collected by filtration to give the title compound (145mg, 54%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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 MH]+。

Example 96

S-6-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

2, 6-twoChloro-4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (method 29) (14.36g, 59mmol), S-2- [3- (pyridin-2-yl) isoxazol-5-yl]A mixture of pyrrolidine (method 42) (12.69g, 59mmol) and N, N-diisopropylethylamine (14.5ml, 83mmol) in xylene (380ml) was heated at 80 ℃ for 2 days. The solvent was removed by evaporation. The residue was triturated with ether and water and the resulting crude solid was collected by filtration, washed with water and dried. The ether was evaporated from the filtrate and DCM was added to the aqueous mixture. Insoluble material was removed by filtration, DCM layer was separated and dried (MgSO)₄). The crude solid initially isolated was dissolved in DCM and added to this solution. The solution was concentrated by evaporation and allowed to stand for 2 days. The resulting solid was collected by filtration, washed with minimal DCM and dried to give the title compound as white crystals (13.3g, 53%).

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[MH]+。

Example 97

S-6- (2, 2, 6, 6-tetramethylpiperidin-4-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

A mixture of S-6-chloro-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (example 96) (200mg, 0.47mmol), 4-amino-2, 2, 6, 6-tetramethylpiperidine (0.4ml, 2.33mmol) and anhydrous 1, 4-dioxane (5.0ml) was heated at 150 ℃ under microwave radiation in a sealed vessel 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 to a polarity reduction of 0: 100: 0.2). The product containing fractions were combined and passed through a 50g isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutrals, then the product was eluted with 7M methanolic ammonia. The solvent was removed by evaporation to give the title compound (122mg, 47%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

S-6-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl in hydroiodic acid (25ml) was added]Pyrimidine (example 96) (2.0g, 4.7mmol), sodium iodide (3.9g, 26mmol) were heated at 50 ℃ for 3 days. The reaction mixture was cooled and poured onto ice, basified with 20% aqueous sodium hydroxide and extracted with DCM. The extracts were combined and dried (MgSO)₄) And the solvent was evaporated to give the title compound (2g, 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(dd，1H)，7.86-8.0(m，2H)，8.63(d，1H)，9.52(s，1H)；m/z 515[MH]+

Example 99

S-E-6- [3- (tert-Butoxycarbonylamino) prop-1-en-1-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

A reaction of 3 to (Tertiary carboxylic acidButoxycarbonylamino) prop-1-en-1-ylboronic acid [2, 3-dihydroxy-2, 3-dimethylbutane]The ester (method 58) (938mg, 3.5mmol) was added to S-6-iodo-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidine-1-radical]Pyrimidine (example 98) (300mg, 0.6mmol), tetrakis (triphenylphosphine) palladium (O) (27mg, 0.02mmol) and 2M aqueous sodium carbonate solution (1.5ml) in a mixture of toluene (8ml) and ethanol (4ml) and the mixture was heated at 140 ℃ under microwave radiation in a sealed container for 15 minutes. The mixture was extracted with EtOAc and the extracts were combined, washed with water and dried (MgSO) ₄). The solvent was removed by evaporation and the residue was purified by column chromatography on silica eluting with DCM/MeOH (100: 0 to polarity increase to 96: 4) to give the title compound (188mg, 60%).

NMR(DMSO)：1.45(s，9H)，2.05-2.18(m，2H)，2.20(s，3H)，2.35-2.46(m，1H)，2.95-3.0(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 in a similar manner to that described in example 99.

Example 100

S-6-vinyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Starting materials: s-6-iodo-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (example 98) and [2, 3-dihydroxy-2, 3-dimethylbutane ] vinyl borate. The product was triturated with ether/DCM/hexane to give the title compound (82mg, 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

S-E-6- (3-hydroxyprop-1-en-1-yl) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Starting materials: s-6-iodo-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (example 98) and [2, 3-dihydroxy-2, 3-dimethylbutane ] 3-acetoxyprop-1-en-1-ylboronic acid. The product was purified by reverse phase HPLC using a C18 column, eluting with water/acetonitrile/TFA (95: 5: 0.2 to polarity decrease to 0: 100: 0.2) to give the title compound (19mg, 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- (tert-Butoxycarbonylamino) propan-1-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Mixing S-E-6- [3-, (Tertiary carboxylic acidButoxycarbonylamino) prop-1-en-1-yl]-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl]A solution of pyrimidine (example 99) (84mg, 0.15mmol), p-toluenesulfonylhydrazide (259mg, 1.4mmol) in dimethylethyl ether (5ml) was warmed to reflux and to this was added sodium acetate (240mg, 2.9mmol) in water (5ml) over 2 h and the mixture was heated at reflux for 18 h. The mixture was diluted with EtOAc, washed with water, then brine, and dried (MgSO)₄) And the solvent was removed by evaporation. The residue was dissolved in methanol and poured onto an SCX2(10g) ion exchange column. The impurities were eluted with methanol and the product was then eluted with 7M methanolic ammonia. Removal of the solvent by evaporation gave the title compoundSubstance (80mg, 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- [ 3-aminopropyl-1-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Reacting S-6- [3-, (S-6-C) in DCM Tertiary carboxylic acidButoxycarbonylamino) propan-1-yl]-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl]The pyrimidine (example 102) (80mg, 0.15mmol) was cooled to about 0 to 5 ℃. Trifluoroacetic acid (TFA) (1ml) was added thereto and the mixture was stirred at 5 ℃ for 1 hour, then at ambient temperature for 1.5 hours. The volatiles were removed by evaporation and the residue was dissolved in methanol, which was poured onto an SCX2(10g) ion exchange column. The impurities were eluted with methanol and the product was then eluted with 7M methanolic ammonia. The solvent was removed by evaporation to give the title compound (40mg, 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

S-E-6- [ 3-aminopropyl-1-en-1-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

S-E-6- [3-, (5ml) in DCM (5ml)Tertiary carboxylic acidButoxycarbonylamino) prop-1-en-1-yl]-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridine)-2-yl) isoxazol-5-yl } pyrrolidin-1-yl]The pyrimidine (example 99) (50mg, 0.09mmol) was cooled to 5 ℃. To this was added TFA (1ml) and the mixture was stirred at 5 ℃ for 1 hour and then at ambient temperature for 4 hours. Volatiles were removed by evaporation, the residue was dissolved in methanol and poured onto an SCX2(10g) ion exchange column. The impurities were eluted with methanol and the product was then eluted with 7M methanolic ammonia. The solvent was removed by evaporation and trituration with ether to give the title compound (25mg, 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- [ 3-methylaminoprop-1-yn-1-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Mixing S-6-iodo-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl]A mixture of pyrimidine (example 98) (500mg, 0.97mmol), 3-methylaminoprop-1-yne (134mg, 1.9mmol) bis (triphenylphosphine) palladium (II) chloride (27mg, 0.04mmol), copper (I) iodide (4mg, 0.02mmol), triethylamine (0.7ml, 5mmol) in acetonitrile (12ml) was heated at 75 ℃ for 15 min under microwave radiation in a sealed vessel. The reaction mixture was extracted with EtOAc, the extracts combined and 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 DCM/MeOH/ammonia (100: 0 to polarity increase to 85: 15: 1) to give the title compound (219mg, 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[MH]+。

Examples 106 to 111

Examples 106 to 111 were prepared in a similar manner to that described in example 105.

Example 106

S-6- [ 3-methoxyprop-1-yn-1-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Starting materials: s-6-iodo-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] 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 to polarity decrease to 0: 100: 0.2). Yield: 70mg, 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[MH]+。

Example 107

S-6- [ 3-hydroxypropan-1-yn-1-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Starting materials: s-6-iodo-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (example 98) and propan-2-yn-1-ol. The product was purified by reverse phase HPLC using a C18 column, eluting with water/acetonitrile/TFA (95: 5: 0.2 to polarity decrease to 0: 100: 0.2). Yield: 50mg, 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[MH]+。

Example 108

S-6- [2- (trimethylsilyl) ethynyl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Starting materials: s-6-iodo-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (example 98) and trimethylsilylacetylene (trimethlilyacetehylene). Yield: 225mg, 50%.

NMR(DMSO)：0.25(s，9H)，2.02-2.19(m，3H)，2.20(s，3H)，2.30-2.42(m，1H)，3.62-3.80(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- [3- (N-methylacetamido) prop-1-yn-1-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Starting materials: s-6-iodo-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (example 98) and 3- (N-methylacetamido) prop-1-yne (method 59). Yield: 50mg, 26%.

NMR(DMSO)：2.02-2.15(m，5H)，2.20(s，3H)，2.31-2.40(m，1H)，2.93(s，3H)，2.97-3.01(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- [3- (dimethylamino) prop-1-yn-1-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Starting materials: s-6-iodo-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] 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 to polarity decrease to 0: 100: 0.2). Yield: 32mg, 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- [ 3-Acylaminoprop-1-yn-1-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Starting materials: s-6-iodo-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (example 98) and 3-acetamidoprop-1-yne (prepared in a manner similar to that of method 59). Yield: 44mg, 24%.

NMR(DMSO)：1.88(s，3H)，2.02-2.17(m，3H)，2.20(s，3H)，2.30-2.42(m，1H)，3.62-3.70(m，1H)，3.72-3.80(m，1H)，4.1(d，2H)，5.45(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，1H)；m/z 484[MH]+。

Example 112

S-6- [2- (ethoxycarbonyl) ethyl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Mixing S-6-iodo-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl-radical]Pyrimidine (example 98) (70mg, 0.14mmol), 3- (ethoxycarbonyl) ethylzinc bromide (0.82ml of 1M in ether), bis (triphenylphosphine) palladium (II) chloride (7mg, 0.01mmol) in THF (2ml) and Dimethylacetamide (DMA) (1ml) were heated in a sealed container at 70 ℃ for 30 minutes under microwave radiation. The mixture was diluted with EtOAc, washed with water and dried (MgSO)₄) And the volatiles were removed by evaporation. The residue was purified by chromatography on silica eluting with methanol/DCM (3: 97) and then further purified by reverse phase HPLC using a C18 column eluting with water/acetonitrile/TFA (95: 5: 0.2 to polarity reduction to 0: 100: 0.2) to give the title compound (20mg, 30%).

NMR(DMSO)：1.12(t，3H)，2.0-2.2(m，3H)，2.19(s，3H)，2.30-2.40(m，1H)，2.55-2.60(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

S-E-6- [2- (methoxycarbonyl) ethen-1-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Mixing S-6-iodo-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ]A mixture of pyrimidine (example 98) (200mg, 0.39mmol), methyl acrylate (0.336ml), 1' -bis (diphenylphosphino) ferrocene palladium (II) chloride (64mg, 0.08mmol), tetrabutylammonium iodide (288mg, 0.78mmol) in DMF (2.5ml), water (0.5ml) and triethylamine (0.5ml) was heated at 130 ℃ under microwave radiation in a sealed vessel for 15 minutes. The mixture was extracted with ethyl acetate, the extracts combined and washed with water and dried (Na)₂SO₄) 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 to polarity decrease to 0: 100: 0.2) to give the title compound (50mg, 28%).

NMR(DMSO)：2.05-2.18(m，3H)，2.20(s，3H)，2.38-2.45(m，1H)，3.73(s，3H)，3.75-3.89(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-ethynyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Potassium carbonate (17mg, 0.12mmol) was added to S-6- [2- (trimethylsilyl) ethynyl group]-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl]A solution of pyrimidine (example 108) (50mg, 0.1mmol) in methanol (1ml) and the mixture stirred at room temperature for 18 h. The mixture was diluted with water and extracted with EtOAc. The extracts were combined, washed with brine and dried (Na) ₂SO₄) And the solvent was removed by evaporation. The residue was triturated with ether and collected by filtration to give the title compound (21mg, 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)，7.85-7.98(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-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

4-hydroxy-6-methoxymethyl-2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (method 34) and 3-amino-5-cyclopropyl-1H-pyrazole (method 7 of WO 03/048133) were treated as described in example 26 to give the title compound (245mg, 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-methoxymethyl-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

The title compound was prepared by separation of the racemic compound by chiral HPLC using a chiralpak AD column (example 115), eluting with methanol/ethanol (85: 15).

Example 117

S-6-methoxymethyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

The title compound was prepared by separation of the racemic compound by chiral HPLC using a chiralpak AD column (example 30), eluting with methanol/ethanol (85: 15).

Example 118

S-6- [ 3-aminoprop-1-yn-1-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Hydrazine hydrate (24. mu.l, 0.49mmol) was added to S-6- [3- (N-phthalimido) prop-1-yn-1-yl in THF (1ml) and ethanol (0.1ml)]-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl]Pyrimidine (method 60) (50mg, 0.09mmol) and the mixture is stirred at room temperature for 1 hour, then it is heated at 60 ℃ for 30 minutes. The mixture was extracted with EtOAc, and the extracts were combined, washed with water and dried (MgSO)₄) And the solvent was removed by evaporation. The residue was subjected to reverse phase HPLC using C18 columnPurification was performed with water/acetonitrile/TFA (95: 5: 0.2 to polarity reduction to 0: 100: 0.2). The product containing fractions were neutralized with aqueous sodium bicarbonate and extracted with DCM and dried (MgSO)₄) And the solvent was removed by evaporation to give the title compound (15mg, 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- [2- (N-methylcarbamoyl) ethyl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Reacting S-6- [2- (ethoxycarbonyl) ethyl ]-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl]Pyrimidine (example 112) (80mg, 0.16mmol), methylamine (3ml of 2M methanol solution) and 1, 8-diazobicyclo [5.4.0 ]]A mixture of undec-7-ene (DBU) (0.1ml, 0.67mmol) was heated at 105 ℃ in a sealed vessel under microwave irradiation for 1.5 hours. The mixture was extracted with EtOAc, and the extracts were combined, washed with water and dried (MgSO)₄) 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 to polarity decrease to 0: 100: 0.2). The product containing fractions were neutralized with aqueous sodium bicarbonate and extracted with DCM and dried (MgSO)₄) And the solvent was removed by evaporation to give the title compound (25mg, 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-ethyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidin-1-yl ] pyrimidine

4- (5-Ethyl-1H-pyrazol-3-ylamino) -2-chloropyrimidine (method 65) (200mg, 0.9mmol), S-2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl]A mixture of pyrrolidine (method 64) (300mg, 1.2mmol) and diisopropylethylamine (0.22ml, 1.4mmol) in hexanol (10ml) was heated at 150 ℃ for 24 h. The residue was cooled and 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 eluting with EtOAc/hexane/methanol (50: 0 to increasing polarity to 98: 0: 2) to give the title compound (212mg, 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 in a similar manner to example 120.

Example 121

S-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidin-1-yl ] pyrimidine

Starting materials: 2-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (method 26) and S-2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidine (method 64). Yield: 147mg, 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- [2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidin-1-yl ] pyrimidine

Starting materials: 2-chloro-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine (method 28) and S-2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidine (method 64). Yield: 143mg, 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- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidin-6-yl carboxylic acid (method 43) (300mg, 0.69mmol) was stirred in t-butanol (30ml) and diphenylphosphoryl azide (286mg, 0.97mmol) was added thereto, and then triethylamine (140. mu.l, 0.99mmol) was added thereto and the mixture was heated at 90 ℃ and stirred for 16 hours. The mixture was concentrated by evaporation and the residue was purified by reverse phase HPLC using a C18 column, eluting with water/acetonitrile/TFA (95: 5: 0.2 to polarity reduction to 0: 100: 0.2). The product containing fractions were passed through a 20g SCX-2 column eluting with methanol and then 2N methanolic ammonia. The solvent was removed by evaporation to give the title compound (40mg, 12%) as a white powder.

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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，1H)；m/z 504[MH]+。

Example 124

6- (4- (N-tert-Butoxycarbonylamino) piperidin-1-yl) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

Reacting 6-chloro-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl]Pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (example 17) (150mg, 0.35mmol) and 4- (N-Tertiary carboxylic acidA mixture of butoxycarbonylamino) piperidine (700mg, 3.5mmol) was added to dioxane (4ml) and heated in a sealed vessel under microwave irradiation at 150 ℃ for 60 minutes. The crude reaction mixture was purified by reverse phase HPLC using a C18 column, eluting with water/acetonitrile/TFA (95: 5: 0.2 to polarity decrease to 0: 100: 0.2). The product containing fractions were passed through an SCX-2 column eluting with methanol and then liberated with 2N methanolic ammonia. The solvent was removed by evaporation to give the title compound (134mg, 64%) as a white solid.

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

Reacting 6- (4- (N-Tertiary carboxylic acidButoxycarbonylamino) piperidin-1-yl) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl]Pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (example 124)) (120mg, 0.20mmol) was stirred in DCM (10ml), trifluoroacetic acid (2ml) was added thereto and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated by evaporation and the residue was dissolved in methanol (10ml) and passed through a 20g SCX-2 ion exchange column eluting the impurities with methanol and then the product with 2M methanolic ammonia. The solvent was removed by evaporation to give the title compound as a cream-colored powder (79mg, 81%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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 in a similar manner to example 124.

Example 125

6-piperazin-1-yl-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

Starting materials: 6-chloro-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (example 17) and piperazine. Yield: 204mg, 73%, white powder form.

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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- {4- [2- (2-hydroxyethoxy) ethyl ] piperazin-1-yl } -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

Starting materials: s-6-chloro-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (example 96) and 2- [2- (hydroxyethoxy) ethyl ] piperazine. Yield: 142mg, 79%, in the form of a pale yellow solid.

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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-formyl-piperazin-4-yl) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

Starting materials: s-6-chloro-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (example 96) and 1-formylpiperazine. Yield: 55mg, 31%, light yellow solid form.

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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 by HPLC purification of example 127: -

Example 128

S-6-piperazin-1-yl-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

Yield: 64mg, 38%, light yellow solid form.

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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, 1H); m/z 473 MH ]+。

Example 129

S-6- (4-isopropylpiperazin-1-yl) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

Starting materials: s-6-chloro-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (example 96) and 1-isopropylpiperazine. Yield: 94mg, 52%, cream colored powder form.

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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- [ (4- (2-hydroxyethyl) piperazin-1-yl) ] -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

Starting materials: s-6-chloro-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (example 96) and 1- (2-hydroxyethyl) piperazine. Yield: 110mg, 61%, in the form of a cream-colored powder.

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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- [ (3R) -3-hydroxypyrrolidin-1-yl ] -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

Starting materials: s-6-chloro-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (example 96) and (3R) -3-hydroxypyrrolidine. Yield: 92mg, 55%, purple powder form.

NMR(DMSO-d₆+d₄-acetic acid, at 100 ℃)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- [ (3R) -3-dimethylamino-pyrrolidin-1-yl ] -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

Starting materials: s-6-chloro-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (example 96) and (3R) -3- (dimethylamino) -pyrrolidine. Yield: 128mg, 73%, brown powder form.

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

S-6-chloro-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (example 96) (150mg, 0.35mmol) was added to 4-aminotetrahydropyran (4ml) and heated in a sealed vessel under microwave irradiation at 150 ℃ for 1 hour. The crude reaction mixture was purified by reverse phase HPLC using a C18 column, eluting with water/acetonitrile/TFA (95: 5: 0.2 to polarity decrease to 0: 100: 0.2). The product containing fractions were passed through a 20g SCX-2 column eluting with methanol and then the product eluted with 2N methanolic ammonia. The solvent was removed by evaporation to give the title compound (52mg, 30%) as a pale brown powder.

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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[ MH ] ]+。

Examples 134 to 139

Examples 134 to 139 were prepared in a similar manner to that described for example 133.

Example 134

S-6-Morpholino-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

Starting materials: s-6-chloro-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (example 96) and morpholine. Yield: 119mg, 71%, light pink powder form.

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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[MH]+。

Example 135

S-6- (2-methoxyethyl) amino-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

Starting materials: s-6-chloro-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (example 96) and 2-methoxyethylamine. Yield: 85mg, 53%, in the form of a pale yellow powder.

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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(dd, 1H), 7.85(t, 1H), 7.90(d, 1H), 8.60(d, 1H); m/z462[ MH ]+。

Example 136

S-6- [ (N-2-methoxyethyl) -N-methylamino ] -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

Starting materials: s-6-chloro-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (example 96) and N- (2-methoxyethyl) -methylamine. yield: 110mg, 66%, cream-colored powder form.

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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-hydroxypropan-1-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

Starting materials: s-6-chloro-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (example 96) and (2R) -2-hydroxypropan-1-ylamine. yield: 52mg, 32%, brown powder form.

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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- [ N- (2-hydroxyethyl) -N-ethylamino ] -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

Starting materials: s-6-chloro-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (example 96) and N- (2-hydroxyethyl) ethylamine. Yield: 113mg, 70%, yellow powder form

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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 ] MH]+。

Example 139

S-6-dimethylamino-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

Starting materials: s-6-chloro-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (example 96) and dimethylamine yield: 86mg, 57%, brown powder form

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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), 540(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- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

S-6-chloro-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (example 96) (150mg, 0.35mmol) was added to 2M methylamine in methanol (4ml) and heated in a sealed vessel under microwave irradiation for 90 minutes at 120 ℃. The mixture was concentrated by evaporation and the residue was purified by reverse phase HPLC using a C18 column, eluting with water/acetonitrile/TFA (95: 5: 0.2 to polarity reduction to 0: 100: 0.2). The product containing fractions were passed through a 20g SCX-2 column eluting with methanol and then 2N methanolic ammonia. The solvent was removed by evaporation to give the title compound (47mg, 32%) as a white powder.

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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, 1H); m/z 418 MH]+。

Example 141

S-6-chloro-2- {2- [3- (pyrazin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

A mixture of S-2- [3- (2-pyrazinyl) isoxazol-5-yl ] pyrrolidine (method 55) (166mg, 0.77mmol), 2, 6-dichloro-4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (method 29) (170mg, 0.70), and N, N-diisopropylethylamine (134. mu.l, 0.77mmol) in xylene was stirred and heated at 70 ℃ for 2 days. A second equivalent of N, N-diisopropylethylamine (134. mu.l, 0.77mmol) was added and the mixture was heated for an additional 2 days. The mixture was concentrated by evaporation and the residue was purified by column chromatography on silica gel eluting with hexane/EtOAc (100: 0 to polarity increasing to 0: 100) to give the title compound as a cream-colored powder (109mg, 37%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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), 5.60(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-morpholino (mopolino) -2- {2- [3- (pyrazin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

S-6-chloro-2- {2- [3- (pyrazin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (example 141) (94mg, 0.22mmol) was added to morpholine (4ml) and heated in a sealed vessel under microwave irradiation for 30 minutes at 150 ℃. The reaction mixture was concentrated by evaporation and purified by column chromatography on silica gel eluting with DCM/2M methanolic ammonia (100: 0 to increasing polarity to 95: 5) to give the title compound as a pale yellow powder (75mg, 72%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine

Reacting S-2- (3- (2-pyridyl) isoxazol-5-yl) pyrrolidine(method 42) (262mg, 1.22mmol) was stirred in N-butanol (40ml) and 2, 6-dichloro-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine (method 57) (300mg, 1.11mmol) was added thereto, followed by N, N-diisopropylamine (233 μ l, 1.33) and the mixture was stirred at 60 ℃ for 2 days. The mixture was concentrated by evaporation, to which was added saturated aqueous sodium bicarbonate (50ml), and the mixture was extracted with DCM (3X 25 ml). The organic extracts were combined, washed with water (50ml) and brine (50ml), dried (MgSO)₄) And the solvent was removed by evaporation. The residue was purified by column chromatography on silica gel eluting with hexane/EtOAc (50: 50 to polarity increase to 0: 100) to give the title compound as a white solid (280mg, 56%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 0.65(m, 2H), 0.85(m, 2H), 1.85(m, 1H), 2.05(m, 2H), 2.15(m, 1H), 2.35(m, 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- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine

Sodium hydride (60% dispersion in oil, 71mg, 1.78mmol) was added to ethylene glycol (4ml) and the mixture was stirred for 5 minutes. S-6-chloro-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine (example 143) (160mg, 0.35mmol) was added thereto and the mixture was heated at 150 ℃ for 45 minutes under microwave irradiation in a sealed vessel. The crude mixture was purified by reverse phase HPLC using a C18 column, eluting with water/acetonitrile/TFA (95: 5: 0.2 to polarity decrease to 0: 100: 0.2). The product containing fractions were poured onto a 20g SCX-2 column, eluted with methanol and then the product was eluted with 2N methanolic ammonia. The solvent was removed by evaporation to give the title compound (23mg, 14%) as a pale yellow powder.

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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, 1H). m/z 475[ MH]+。

Example 145

6- [4- (tert-Butoxycarbonyl) piperazin-1-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Reacting 6-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl]Pyrimidine (example 17) (250mg, 0.6mmol) and N- (S-) (Tertiary carboxylic acidA mixture of butoxycarbonyl) piperazine (222mg, 6.0mmol) in 1, 4-dioxane (4ml) was heated at 160 ℃ for 90 minutes under microwave irradiation in a sealed vessel. The crude reaction mixture was purified by reverse phase HPLC using a C18 column, eluting with water/acetonitrile/TFA (95: 5: 0.2 to polarity decrease to 0: 100: 0.2). The product containing fractions were combined and passed through an isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutral material, and then the product was eluted with 7M methanolic ammonia. The solvent was removed by evaporation to give the desired product as a white solid (85mg, 25%).

NMR(DMSO-d₆At 100 ℃): 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-acetylpiperazin-1-yl) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

The title compound was prepared in a similar manner to the one described in example 145 using 6-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (example 17) and 4-acetylpiperazine. Yield: 182mg, 60%.

NMR(DMSO-d₆At 100 ℃): 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, 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- [2- (tert-Butoxycarbonyl) -2, 7-diazaspiro [3.5] non-7-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Reacting 6-chloro-N- (3-methyl-1H-pyrazol-5-yl) -2- [2- (3-pyridin-2-ylisoxazol-5-yl) pyrrolidin-1-yl]Pyrimidin-4-amine (example 17) (300mg, 0.7mmol) and 2-, (Tertiary carboxylic acidButoxycarbonyl) -2, 7-diazaspiro [3.5]A mixture of nonane (949mg, 4.2mmol) in 1, 4-dioxane (8ml) was heated at 160 ℃ for 120 minutes under microwave irradiation in a sealed vessel. The mixture was allowed to cool and the volatiles were removed by evaporation. The residue was purified by column chromatography on silica eluting with DCM/MeOH/ammonia (100: 0 to polarity increase to 90: 10: 1) to give the product as a pale purple solid (235mg, 55%).

NMR(DMSO-d₆At 100 ℃): 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-diazaspiro [3.5] non-7-yl) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Mixing 6- [2-, (Tertiary carboxylic acidButoxycarbonyl) -2, 7-diazaspiro [3.5 ]Non-7-yl]-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl]A mixture of pyrimidine (example 147) (110 mg, 0.19mmol) and TFA (2ml) was stirred at room temperature for 60 min. The volatiles were removed by evaporation, the residue was dissolved in DCM and poured onto an isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutral material, and then the product was eluted with 7M methanolic ammonia. The solvent was removed by evaporation to give the desired product as a yellow solid. (66mg, 68%).

NMR(DMSO-d₆At 100 ℃): 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- [4- (2-aminoethyl) piperazin-1-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

A mixture of S-6-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (example 96) (100mg, 0.24mmol), 1- (2-aminoethyl) piperazine (186mg, 1.4mmol) in 1, 4-dioxane (4ml) was heated at 150 ℃ for 120 minutes under microwave radiation in a sealed vessel. The crude reaction mixture was purified by reverse phase HPLC using a C18 column, eluting with water/acetonitrile/TFA (95: 5: 0.2 to polarity decrease to 0: 100: 0.2). The product containing fractions were combined and passed through an isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutral material, and then the product was eluted with 7M methanolic ammonia. The solvent was removed by evaporation, the residue triturated with ether and the product collected by filtration to give the title compound as a white solid (68mg, 55%).

NMR(DMSO-d₆At 100 ℃): 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 in a similar manner to that described in example 149.

Example 150

S-6- [4- (3-hydroxypropyl) piperazin-1-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Starting materials: s-6-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (example 96) and 1- (3-hydroxypropyl) -piperazine. Yield: 84mg, 66%.

NMR(DMSO-d₆At 100 ℃): 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- [4- (2-cyanoethyl) piperazin-1-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Starting materials: s-6-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (example 96) and 1- (2-cyanoethyl) piperazine. Yield: 69mg, 36%.

NMR(DMSO-d₆At 100 ℃): 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 s, 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- [4- (2-methoxyethyl) piperazin-1-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Starting materials: s-6-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (example 96) and 1- (2-methoxyethyl) piperazine. Yield: 84mg, 44%.

NMR(DMSO-d₆At 100 ℃): 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-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Starting materials: s-6-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (example 96) and 1-acetylpiperazine. Yield: 66mg, 36%.

NMR(DMSO-d₆At 100 ℃): 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[MH]+。

Example 154

S-6- [4- (ethylsulfonyl) piperazin-1-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Starting materials: s-6-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (example 96) and 1- (ethylsulfonyl) piperazine. Yield: 122mg, 60%.

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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/z566[ MH ]+。

Example 155

S-6- [2- (2-hydroxyethoxy) ethylamino ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Starting materials: s-6-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (example 96) and 2- (2-hydroxyethoxy) ethyl-amine. Yield: 84mg, 48%.

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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- [2- (acetylamino) ethylamino ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Starting materials: s-6-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (example 96) and 2- (acetylamino) ethylamine. Yield: 39mg, 22%.

NMR(DMSO-d₆At 100 ℃): 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 by HPLC purification: -

Example 157

S-6- [ 2-aminoethylamino ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Yield: 15mg, 9%.

NMR(DMSO-d₆At 100 ℃): 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(br s, 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- [ 4-methylcyclohexylamino ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Starting materials: s-6-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (example 96) and 4-methylcyclohexylamine. Yield: 112mg, 48%.

NMR(DMSO-d₆At 100 ℃): 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，1H)；m/z 500[MH]+。

example 159

S-6- [ 4-Hydroxycyclohexylamino ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Starting materials: s-6-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (example 96) and 4-hydroxycyclohexylamine. The title compound was prepared in a manner similar to that of example 149 except that the reaction was heated at 180 ℃ for 6 hours. Yield: 83mg, 35%.

NMR(DMSO-d₆At 100 ℃): 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[ MH]+。

Example 160

S-6- [ cis-3, 4-dihydroxypyrrolidin-1-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

A mixture of S-6-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (example 96) (100mg, 0.24mmol), cis-3, 3-dimethyl-2, 4-dioxa-7-aza-bicyclo [3.3.0] octane (203mg, 1.4mmol) in 1, 4-dioxane (3ml) was heated at 150 ℃ for 120 minutes under microwave radiation in a sealed vessel. The reaction mixture was cooled, the volatiles were removed by evaporation and the residue was purified by column chromatography on silica gel eluting with DCM/MeOH/ammonia (100: 0 to polarity increase to 90: 10: 1). The purified product was dissolved in methanol (4ml) and 2M hydrochloric acid (4ml) and stirred at ambient temperature for 120 minutes. The crude reaction mixture was purified by reverse phase HPLC using a C18 column, eluting with water/acetonitrile/TFA (95: 5: 0.2 to polarity decrease to 0: 100: 0.2). The product containing fractions were combined and passed through an isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutral material, and then the product was eluted with 7M methanolic ammonia. The solvent was removed by evaporation, the residue triturated with ether and collected by filtration to give the title compound as a white solid (22mg, 19%).

NMR(DMSO-d₆At 100 ℃): 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(br s, 1H), 5.90(br s, 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-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyrimidin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

A mixture of 2, 6-dichloro-4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (method 29) (134mg, 0.55mmol), S-2- [3- (pyrimidin-2-yl) isoxazol-5-yl ] pyrrolidine (method 66) (130mg, 0.6mmol), N-diisopropylethylamine (78mg, 0.6mmol), and xylene (5ml) was heated at 70 ℃ for 3 days. The crude product was passed through an isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutral material, and then the product was eluted with 7M methanolic ammonia. The solvent was removed by evaporation and the residue was purified by silica gel column chromatography eluting with EtOAc/hexane (0: 100 to polarity increase to 100: 0). The purified product was triturated with ether and collected by filtration to give the title compound as a white solid (110mg, 47%).

NMR(DMSO-d₆At 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- [2- {3- (3-methoxypyrazin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

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

Example 163

S-6-Morpholino-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyrimidin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

A mixture of S-6-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyrimidin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (example 161) (100mg, 0.24mmol) in morpholine (3ml) was heated at 150 ℃ under microwave irradiation in a sealed vessel for 40 minutes. The crude reaction mixture was purified by reverse phase HPLC using a C18 column, eluting with water/acetonitrile/TFA (95: 5: 0.2 to polarity decrease to 0: 100: 0.2). The product containing fractions were combined and passed through an isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutral material, and then the product was eluted with 7M methanolic ammonia. The solvent was removed by evaporation and the residue triturated with ether to give the title compound as a white solid (53mg, 46%).

NMR(DMSO-d₆At 100 ℃): 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/z476[ MH ]]+。

Example 164

S-6-Morpholino-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (3-methoxypyrazin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

The title compound was prepared in a similar manner to the one described in example 163, starting from S-6-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (3-methoxypyrazin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (example 162) and morpholine. Yield: 15mg, 12%.

NMR(DMSO-d₆At 100 ℃): 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, 1H); m/z 506[ MH]+。

Purification by HPLC also isolated from this same reaction example 165: -

Example 165

S-6-Morpholino-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (3-hydroxypyrazin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Yield: 32mg, 26%.

NMR(DMSO-d₆At 100 ℃): 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，1H)；m/z 492[MH]+。

example 166

S-6- [ 4-methylpiperazin-1-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

A mixture of S-6-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (example 96) (150mg, 0.36mmol) in 1-methylpiperazine (3ml) was heated at 150 ℃ under microwave irradiation in a sealed vessel for 40 minutes. The mixture was cooled and purified directly by reverse phase HPLC using a C18 column, eluting with water/acetonitrile/TFA (95: 5: 0.2 to polarity reduction to 0: 100: 0.2). The product containing fractions were combined and passed through an isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutral material, and then the product was eluted with 7M methanolic ammonia. The solvent was removed by evaporation, the residue triturated with hexane and collected by filtration to give the title compound as a white solid (152mg, 87%).

NMR(DMSO-d₆At 100 ℃): 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 in a similar manner to that described for example 166.

Example 167

S-6- [ cyclobutylamino ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Starting materials: s-6-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (example 96) and cyclobutyl amine. Yield: 79mg, 37%.

NMR(DMSO-d₆At 100 ℃): 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- [ 3-Isopropoxyprop-1-ylamino ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Starting materials: s-6-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (example 96) and 3-isopropoxypropan-1-ylamine. Yield: 89mg and 38 percent.

NMR(DMSO-d₆At 100 ℃): 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- [2- (morpholin-4-yl) ethylamino ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Starting materials: s-6-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (example 96) and 2- (morpholin-4-yl) ethylamine. The product was triturated with ether. Yield: 100mg, 41%.

NMR(DMSO-d₆At 100 ℃): 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- [2- (dimethylamino) ethylamino ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Starting materials: s-6-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (example 96) and 2- (dimethylamino) ethylamine. Yield: 90mg, 40%.

NMR(DMSO-d₆At 100 ℃): 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[ MH ]]+。

Example 171

S-6- [ (2S) -2-hydroxypropan-1-ylamino ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Starting materials: s-6-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (example 96) and (2S) -2-hydroxypropan-1-ylamine. Yield: 28mg, 13%.

NMR(DMS0-d₆At 100 ℃): 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, 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[ MH ]+。

Example 172

S-6- [ 2-methylpropan-1-ylamino ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

A mixture of S-6-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (example 96) (200mg, 0.47mmol) and isobutylamine (2ml) was heated at 150 ℃ under microwave irradiation in a sealed vessel for 30 minutes. The reaction was allowed to cool and poured into aqueous sodium bicarbonate. The resulting precipitate was collected by filtration, washed with water and dried in vacuo to give the title compound as an orange solid (170mg, 79%).

NMR(DMSO-d₆At 100 ℃): 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[ MH]+。

Examples 173 to 179

Examples 173 to 179 were prepared in a similar manner to that described in example 172.

Example 173

S-6- [ 3-methoxypropylamino ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Starting materials: s-6-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (example 96) and 3-methoxypropylamine. Yield: 160mg, 72%.

NMR(DMSO-d₆At 100 ℃): 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- [ 4-ethylpiperazin-1-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Starting materials: s-6-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (example 96) and 1-ethylpiperazine. Yield: 200mg, 85%.

NMR(DMSO-d₆At 100 ℃): 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[ MH]+。

Example 175

S-6- [ 3-ethoxypropylamino ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Starting materials: s-6-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (example 96) and 3-ethoxypropylamine. Yield: 105mg, 46%.

NMR(DMSO-d₆At 100 ℃): 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- [ (2R) -tetrahydrofuran-2-ylmethyl-amino ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Starting materials: s-6-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (example 96) and (2R) -tetrahydrofuran-2-ylmethylamine. yield: 196mg, 86%.

NMR(DMSO-d₆At 100 ℃): 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[ MH ]+。

Example 177

S-6- (2-Isopropoxyethylamino) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Starting materials: s-6-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (example 96) and 2-isopropoxyethylamine. Yield: 180mg, 78%.

NMR(DMSO-d₆At 100 ℃): 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[ MH]+。

Example 178

S-6-Morpholino-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyrimidin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Starting materials: s-6-chloro-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyrimidin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (example 180) and morpholine. Yield: 145mg, 66%.

NMR(DMSO-d₆At 100 ℃): 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/z502[MH]+。

Example 179

S-6-methylamino-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyrimidin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Starting materials were: a solution of S-6-chloro-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyrimidin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (example 180) and excess 2M methylamine in ethanol was heated at 120 ℃ for 90 minutes. Yield: 125mg, 64%.

NMR(DMSO-d₆At 100 ℃): 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- [2- {3- (pyrimidin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

A mixture of 2, 6-dichloro-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine (method 57) (910mgs, 3.4mmol), S-2- [3- (pyrimidin-2-yl) isoxazol-5-yl ] pyrrolidine (method 66) (800mg, 0.37mmol), N-diisopropylethylamine (480mg, 0.37mmol), and 1-butanol (20ml) was heated at 75 ℃ 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 to a polarity reduction of 0: 100: 0.2). The product containing fractions were combined and passed through an isolutesCX-2 ion exchange column. The column was eluted with methanol to elute any neutral material, and then the product was eluted with 7M methanolic ammonia. The solvent was removed by evaporation to give the title compound (850mg, 55%).

NMR(DMSO-d₆At 100 ℃): 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-1H-pyrazol-3-ylamino) -2- [2- {3- (3-methoxypyrazin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

A mixture of 2-chloro-6-methyl-4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (method 56) (63mg, 0.26mmol), S-2- [3- (2-methoxypyrazin-3-yl) isoxazol-5-yl ] pyrrolidine (method 68) (70mg, 0.28mmol), diisopropylethylamine (0.09ml, 0.52mmol), and 1-hexanol (3ml) was heated at 120 ℃ for 6 hours. The crude reaction mixture was purified by reverse phase HPLC using a C18 column, eluting with water/acetonitrile/TFA (95: 5: 0.2 to polarity decrease to 0: 100: 0.2). The product containing fractions were combined and passed through an isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutral material, and then the product was eluted with 7M methanolic ammonia. The solvent was removed by evaporation, the residue triturated with ether and collected by filtration to give the title compound as a white solid (49mg, 44%).

NMR(DMSO-d₆At 100 ℃): 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-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyrimidin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Sodium hydride (88mg, 1.1mmol) was added to methanol (2ml) and the mixture was stirred for 5 min. S-6-chloro-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyrimidin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (example 180) (200mg, 0.44mmol) was added thereto and the mixture was heated at 120 ℃ for 30 minutes under microwave irradiation in a sealed vessel. The reaction mixture was allowed to cool and poured into cold aqueous ammonium chloride solution. The resulting precipitate was collected by filtration and dissolved in methanol. The solution was poured into water and the precipitate was collected by filtration, washed with water and dried in a vacuum oven to give the title compound as a white solid (81mg, 41%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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-methoxyethoxy) -4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyrimidin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

The title compound is prepared in a manner similar to the method described in example 182 starting from S-6-chloro-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyrimidin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (example 180) and 2-methoxyethanol. Yield: 80mg, 37%.

NMR(DMSO-d₆At 100 ℃): 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-ethyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine

A mixture of 4- (5-ethyl-1H-pyrazol-3-ylamino) -2-chloropyrimidine (method 65) (224mg, 1.0mmol), S-2- (3- (2-pyridinyl) isoxazol-5-yl) pyrrolidine (method 42) (268mg, 1.25mmol), and N, N-diisopropylamine (322mg, 0.43ml, 2.5mmol) in 1-hexanol (10ml) was heated at 150 ℃ for 18 hours. The solvent was removed by evaporation and the residue suspended in aqueous sodium bicarbonate (25ml) and extracted with EtOAc (4 × 25 ml). The organic extracts were combined, washed with brine (2X 25ml) and dried (MgSO) ₄) And the solvent was removed by evaporation. The residue was triturated with ether, collected by filtration and dried to give the title compound as a tan solid (202mg, 50%).

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(brs，1H)；m/z 403[MH]+。

Example 185

S-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine

4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2-chloropyrimidine (method 28) (224mg, 1.0mmol) and S-2- (3- (2-pyridinyl) isoxazol-5-yl) pyrrolidine (method 42) were treated by the method described in example 184 to give the title compound as a tan crystalline solid (210mg, 50%).

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(br m，1H)，6.20(br m，1H)，6.65(s，1H)，7.47(m，1H)，7.85(br s，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-Ethyl-1H-pyrazol-3-ylamino) -5-fluoro-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine

2-chloro-4- (5-ethyl-1H-pyrazol-3-ylamino) -5-fluoropyrimidine (method 69) and S-2- (3- (2-pyridinyl) isoxazol-5-yl) pyrrolidine (method 42) are treated as described in example 184. The product was purified by column chromatography on silica gel eluting with a mixture of EtOAc/hexane (50: 50 to increasing polarity to 100: 0) to give the title compound as a pale yellow solid (221mg, 53%).

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- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine

2-chloro-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -5-fluoropyrimidine (method 27) and S-2- (3- (2-pyridinyl) isoxazol-5-yl) pyrrolidine (method 42) are treated as described in example 184. The product was purified by column chromatography on silica gel eluting with a mixture of EtOAc/hexanes (50: 50 to increasing polarity to 100: 0) to give the title compound as a pale yellow solid (192mg, 44%).

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- {2- [3- (pyrimidin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine

A mixture of 2-chloro-6-methyl-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine (method 70) (210mg, 0.84mmol), S-2- [3- (pyrimidin-2-yl) isoxazol-5-yl ] pyrrolidine (method 66) (200mg, 0.92mmol), N-diisopropylethylamine (0.16ml, 1.18mmol), and anhydrous 1-hexanol (4.0ml) was heated at 150 ℃ in a sealed vessel under microwave radiation for 45 minutes. The reaction mixture was allowed to cool and then purified directly by reverse phase HPLC using a C18 column, eluting with water/acetonitrile/TFA (95: 5: 0.2 to a polarity reduction of 0: 100: 0.2). The product containing fractions were poured onto a 10g isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutrals, then the product was eluted with 7M methanolic ammonia. The solvent was removed by evaporation, the residue triturated with ether and collected by filtration to give the title compound (212mg, 59%).

NMR(DMSO-d₆At 100 ℃): 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, 1H); m/z 430[ MH]+。

Example 189

4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -6-methyl-2- {2- [3- (pyrazin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine

2-chloro-6-methyl-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine (method 70) and S-2- [3- (pyrazin-2-yl) isoxazol-5-yl ] pyrrolidine (method 55) were treated as described in example 188 to give the title compound (218mg, 71%).

NMR(DMSO-d₆At 100 ℃): 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- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine

2-chloro-6-methyl-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine (method 70) and S-2- (3- (2-pyridinyl) isoxazol-5-yl) pyrrolidine (method 42) were treated as described in example 188 to give the title compound (242mg, 66%).

NMR(DMSO-d₆At 100 ℃): 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-hydroxypropyl) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine

3-amino-1H-5-methylpyrazole (87mg, 0.894mmol) was added to 4-chloro-6- (3-hydroxypropyl) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl with stirring]Pyrrolidin-1-yl } pyrimidine (method 71) (230mg, 0.596mmol) in dry NMP (3 ml). 6M hydrogen chloride in dioxane (298. mu.l, 1.19mmol) was added and the reaction stirred and heated under nitrogen at 120 ℃ for 20 h. The reaction was allowed to cool and the reaction mixture was applied to a 10g isolute SCX2 ion exchange column. The column was eluted with methanol to remove neutral substances, and then the product was eluted with 2M methanolic ammonia. The solvent was removed from the product-containing fractions by evaporation and the residue was purified by flash chromatography on silica gel, eluting with methanol/DCM (5: 95). Then, the purified product was dissolved in ethyl acetate and washed with water, dried (Na) ₂SO₄) And the solvent was removed by evaporation. The residue was triturated with DCM/hexane andthis was collected by filtration to give the title compound (99mg, 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

S-6- (3-hydroxypropyl) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine

The S enantiomer of example 191 was separated by chiral HPLC using a Chiralpak AD column using methanol as eluent.

Example 193

S-6-propyl-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

Bis (triphenylphosphine) palladium (II) chloride (34mg) was added to stirring S-6-iodo-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl]Pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (example 98) (250mg, 0.486mmol) in anhydrous dimethylacetamide (7.5ml) and anhydrous THF (2.5 ml). Then, a 0.5M solution of n-propylzinc bromide in THF (3.9ml, 1.94mmol) was added and the reaction was stirred at ambient temperature for 24 hours. A further portion of 0.5M n-propylzinc bromide in THF (3.9ml, 1.94mmol) was added and the reaction stirred for a further 24 hours. Then, water and ethyl acetate were added to the reaction mixture and the mixture was filtered to remove insoluble materials. The filtrate layer was separated and the organic layer was washed with water and saturated brine and dried (Na) ₂SO₄) 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 to polarity decrease to 0: 100: 0.2) to give the title product as a white solid (115mg, 55%).

NMR(DMSO-d₆At 373deg 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- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

2, 6-dichloro-4- (5-ethyl-1H-pyrazol-3-ylamino) pyrimidine (method 72) and S-2- (3- (2-pyridyl) isoxazol-5-yl) pyrrolidine (method 42) were treated as described in example 143 to give the title compound (80mg, 48%);

NMR(DMSO-d₆at 100 ℃): 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 s, 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-hydroxyethoxy) -4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

S-6-chloro-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (example 194) and ethylene glycol were treated as described in example 208 to give the title compound (80mg, 49%).

NMR(DMSO-d₆ 100℃)：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-ethyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

S-6-chloro-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (example 194) and 2-methoxyethanol were treated as described in example 208 to give the title compound (122mg, 56%).

NMR(DMSO-d₆At 100 ℃): 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- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

S-6-chloro-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (example 194) and morpholine were treated as described in example 166 to give the title compound (67mg, 30%).

NMR(DMSO-d₆At 100 ℃): 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- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

S-6-chloro-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (example 194) and 1-methylpiperazine were treated as described in example 166 to give the title compound (110mg, 49%).

NMR(DMSO-d₆At 100 ℃): 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- [2- {3- (2-pyrazinyl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

2, 6-dichloro-4- (5-ethyl-1H-pyrazol-3-ylamino) pyrimidine (method 72) and S-2- [3- (2-pyrazinyl) isoxazol-5-yl ] pyrrolidine (method 55) were treated as described in example 141 to give the title compound (800mg, 48%).

NMR(DMSO-d₆At 100 ℃): 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, 1H); m/z 439 MH]+。

Examples 200 to 207

The following single enantiomers were prepared by separation of the racemic compound by chiral HPLC.

Example 200

S-6-methoxy-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

The title compound was prepared by separation of the racemic compound by chiral HPLC using chiralpak AD column (example 48), eluting with methanol.

Example 201

S-6- (2-methoxyethoxy) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

The title compound was prepared by separation of the racemic compound by chiral HPLC using chiralpak AD column (example 214), eluting with methanol.

Example 202

S-6-pyrrolidin-1-yl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

The title compound was prepared by separation of the racemic compound by chiral HPLC using a Chiralpak AS column (example 95), eluting with methanol.

Example 203

S-6-methoxymethyl-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2- (3-cyclopropylisoxazol-5-yl) pyrrolidin-1-yl ] pyrimidine

The title compound was prepared by separation of the racemic compound by chiral HPLC using a Chiralpak AS column (example 13), eluting with methanol/ethanol (85: 15).

Example 204

S-6-Morpholinocarbonyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

The title compound was prepared by separation of the racemic compound by chiral HPLC using a chiralpak AD column (example 58), eluting with methanol/ethanol (85: 15).

Example 205

S-6-carbamoyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

The title compound was prepared by separation of the racemic compound by chiral HPLC using a chiralpak AD column (example 61), eluting with methanol/ethanol (85: 15).

Example 206

S-5-fluoro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

The title compound was prepared by separation of the racemic compound by chiral HPLC using a Chiralpak AS column (example 20) eluting with methanol.

Example 207

S-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

The title compound was prepared by separation of the racemic compound by chiral HPLC using a Chiralpak AS column (example 23), eluting with methanol.

Example 208

S-4- (5-methyl-1H-pyrazol-3-ylamino) -6- (2-hydroxyethoxy) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Sodium hydride (94mg, 2.35mmol) was added portionwise to ethylene glycol (4 ml). The mixture was stirred for 10 minutes and S-6-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl was added thereto ]Pyrimidine (example 96) (200mg, 0.47 mmol). The reaction was heated at 150 ℃ 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 and dried (Na)₂SO₄) And the solvent was removed by evaporation. The residue was purified by reverse phase HPLC using C18 column, water/acetonitrile/TFA: (70: 30: 0.2 to a polarity reduction of 30: 70: 0.2). The product containing fractions were poured onto an SCX-2 column, washed with methanol to elute neutral impurities, and then the product was eluted with 3N methanolic ammonia. The solvent was removed by evaporation and the residue was triturated with ether (ether) to give the title compound (131mg, 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 in a similar manner to that described in example 208. The reaction time is 30 minutes to 2 hours. In some cases, 10 equivalents of alcohol (alcohol) and 1 to 2ml of 2-propanone are used as solvents. The reaction can be quenched with glacial acetic acid instead of hydrochloric acid; and the reaction mixture can be directly subjected to HPLC purification without aqueous workup.

Example number	Starting material	Name of Compound	NMR(DMSO 373K+d4AcOH)	m/z(MH)+
					209	Example 96 and N, N-bis (2-hydroxyethyl) methylamine	S-4- (5-methyl-1H-pyrazol-3-ylamino) -6- (2- { N- [ 2-hydroxyethyl]-N-methyl-amino } ethoxy) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl]Pyrimidines	2.10(m, 3H), 2.19(s, 3H), 2.27(s, 3H), 2.4(m, 1H), 2.69(t, 2H), 3.95(m, 2H), 3.45(t, 2H), 3.72(m, 2H), 4.23(t, 2H), 5.4(d, 1H), 5.75(s, 1H), 5.96(s, 1H), 6.69(s, 1H), 7.43(m, 1H), 7.9(m, 2H), 8.6(s, 1H), 8.63(d, 1H), 11.45(br s, 1H) are not deuterated	506
210	Example 96 and 2-Morpholinoethanol	S-4- (5-methyl-1H-pyrazol-3-ylamino) -6- (2-morpholinoethoxy) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl]Pyrimidines	2.08(m, 3H), 2.19(s, 3H), 2.36(m, 5H), 2.58(t, 2H), 3.51(t, 4H), 3.92(m, 2H), 4.23(m, 2H), 5.4(d, 1H), 5.77(s, 1H), 5.97(s, 1H), 7.43(m, 1H), 7.91(m, 2H), 8.6(s, 1H), 8.63(d, 1H), 11.48(br s, 1H) are not deuterated	518
					211	Fruit of Chinese wolfberryEXAMPLE 96 and Methanethiol	S-4- (5-methyl-1H-pyrazol-3-ylamino) -6- (methylthio) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ]Pyrimidines	2 08(m，3H)，2.17(s，3H)，2.35(m，4H)，3.7(m，1H)，3.79(m，1H)，5.42(d，1H)，5.99(s，1H)，6 27(s，1H)，6 65(s，1H)，7.4(m，1H)，7.86(m，1H)，7.93(d，1H)，8 62(d，1H)	435

Example number	Starting material	Name of Compound	NMR(DMSO 373K+d4AcOH)	m/z(MH)+
					212	Example 17 and tetrahydrofuran-3-ylmethanol	4- (5-methyl-1H-pyrazol-3-ylamino) -6- (tetrahydrofuran-3-ylmethoxy)) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl]Pyrimidines	1.57(m，1H)，1.92(m，1H)，2.09(m，3H)，2.2(s，3H)，2.36(m，1H)，3.44(m，1H)，2.52(m，1H)，3.58(m，1H)，3.6-3.8(m，4H)，4.09(m，2H)，5.38(d，1H)，5.74(s，1H)，5.99(s，1H)，6.68(s，1H)，7.41(m，1H)，7.87(m，1H)，7.95(d，1H)，8.64(d，1H)	489
213	Example 96 and 2- (2-Hydroxyethoxy) ethanol	S-4- (5-methyl-1H-pyrazol-3-ylamino) -6- (2- (2-hydroxyethoxy) ethoxy) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl]Pyrimidines	2.07(m，3H)，2.16(s，3H)，2.35(m，1H)，3.41(m，2H)，2.46(m，2H)，3.61(m，2H)，3.72(m，2H)，4.25(t，2H)，5.49(d，1H)，5.74(s，1H)，5.95(s，1H)，6.66(s，1H)，7.4(m，1H)，7.85(m，1H)，7.93(d，1H)，8.62(d，1H)	493
					214	Example 17 and 2-Methoxyethanol	4- (5-methyl-1H-pyrazol-3-ylamino) -6- (2-methoxyethoxy) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl]Pyrimidines	2.08(m，3H)，2.16(s，3H)，2.36(m，1H)，3.19(s，3H)，3.47(m，2H)，3.66(m，1H)，3.77(m，1H)，4.24(m，2H)，5.38(d，1H)，5.68(s，1H)，5.96(s，1H)，6.66(s，1H)，7.38(m，1H)，7.83(m，1H)，7.92(d，1H)，8.61(d，1H)	463

Example number	Starting material	Name of Compound	NMR(DMSO 373K+d4AcOH)	m/z(MH)+
					215	Example 96 and 1, 3-propanediol	S-4- (5-methyl-1H-pyrazol-3-ylamino) -6- (3-hydroxypropoxy) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl]Pyrimidines	1.68(m，2H)，2.0(m，3H)，2.09(s，3H)，2.29(m，1H)，3.39(t，2H)，3.63(m，2H)，4.14(m，2H)，5.32(d，1H)，5.65(s，1H)，5.85(s，1H)，6.58(s，1H)，7.34(t，1H)，7.78(t，1H)，7.84(d，1H)，8.55(d，1H)	463
216	Example 96 and 2- (2-methoxyethoxy) ethanol	S-4- (5-methyl-1H-pyrazol-3-ylamino) -6- [2- (2-methoxyethoxy) ethoxy]-2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl]Pyrimidines	2.07(m，3H)，2.16(s，3H)，2.47(m，1H)，3.2(s，3H)，3.38(m，2H)，3.48(m，2H)，3.59(m，2H)，3.72(m，2H)，4.24(t，2H)，5.39(d，1H)，5.72(s，1H)，5.95(s，1H)，6.66(s，1H)，7.4(m，1H)，7.86(m，1H)，7.92(d，1H)，8.63(d，1H)	507
					217	Example 96 and 2-Ethoxyethanol	S-4- (5-methyl-1H-pyrazol-3-ylamino) -6- (2-ethoxyethoxy) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ]Pyrimidines	1.05(t，3H)，2.08(m，3H)，2.17(s，3H)，2.39(m，1H)，3.4(q，2H)，3.56(m，2H)，3.73(m，2H)，4.25(m，2H)，5.4(d，1H)，5.77(s，1H)，5.97(s，1H)，6.69(s，1H)，7.45(m，1H)，7.92(m，2H)，8.63(m，2H)，11.5(br s，1H)	477

Example number	Starting material	Name of Compound	NMR(DMSO 373K+d4AcOH)	m/z(MH)+
					218	Example 96 and 3-Morpholinoprop-1-ol	S-4- (5-methyl-1H-pyrazol-3-ylamino) -6- (3-morpholinopropan-1-yloxy) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl]Pyrimidines	1.84(m，2H)，2.09(m，3H)，2.17(s，3H)，2.38(m，1H)，2.65(m，4H)，2.94(br s，2H)，3.62(m，4H)，3.73(m，2H)，4.22(m，2H)，5.4(d，1H)，5.77(s，1H)，5.98(s，1H)，6.69(s，1H)，7.45(m，1H)，7.92(m，2H)，8.65(m，2H)	532
219	Example 96 and 3-Methoxypropan-1-ol	S-4- (5-methyl-1H-pyridine)Azol-3-ylamino) -6- (3-methoxypropan-1-yloxy) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl]Pyrimidines	1.83(m，2H)，2.08(m，3H)，2.17(s，3H)，2.32(m，1H)，3.2(s，3H)，3.37(t，2H)，3.72(m，2H)，4.19(t，2H)，5.4(d，1H)，5.76(s，1H)，5.96(s，1H)，6.67(s，1H)，7.45(m，1H)，7.92(m，2H)，8.61(s，1H)，8.65(d，1H)	477
					220	Example 96 and N- (2-hydroxyethyl) -pyrrolidin-2-one	S-4- (5-methyl-1H-pyrazol-3-ylamino) -6- [2- (2-oxopyrrolidin-1-yl) ethoxy]-2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl]Pyrimidines	1.87(m，2H)，2.1(m，3H)，2.17(m，5H)，2.38(m，1H)，3.33(t，2H)，3.45(m，2H)，3.75(m，2H)，4.27(m，2H)，5.41(d，1H)，5.76(s，1H)，5.96(s，1H)，6.69(s，1H)，7.44(m，1H)，7.93(m，2H)，8.65(d，2H)，11.5(br s，1H)	516

Example number	Starting material	Name of Compound	NMR(DMSO 373K+d4AcOH)	m/z(MH)+
					221	Example 96 and (2S) -2-methoxypropan-1-ol	S-4- (5-methyl-1H-pyrazol-3-ylamino) -6- [ (2S) -2-methoxyprop-1-yloxy]-2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl]Pyrimidines	1.04(d，3H)，2.1(m，3H)，2.19(s，3H)，2.39(m，1H)，3.21(s，3H)，3.53(m，1H)，3.74(m，2H)，4.11(d，2H)，5.39(d，1H)，5.79(s，1H)，5.97(s，1H)，6.68(s，1H)，7.45(m，1H)，7.91(m，2H)，8.65(d，2H)，11.5(br s，1H)	477
222	Example 96 and 3-Methylthiopropan-1-ol	S-4- (5-methyl-1H-pyrazol-3-ylamino) -6- [3- (methylthio) propan-1-yloxy]-2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl]Pyrimidines	1.88(m，2H)，2.01(s，3H)，2.09(m，3H)，2.18(s，3H)，2.37(m，1H)，2.5(under DMSOpeak，2H)，3.72(m，2H)，4.22(t，2H)，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)	493
					223	Example 96 and (5S) -5-hydroxymethyl-pyrrolidin-2-one	S-4- (5-methyl-1H-pyrazol-3-ylamino) -6- [ (2S) -5-oxopyrrolidin-2-yl) methoxy ]-2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl]Pyrimidines	1.74(m，1H)，2.1(m，6H)，2.18(s，3H)，2.39(m，1H)，3.73(m，3H)，4.1(m，2H)，5.4(d，1H)，5.78(s，1H)，5.94(s，1H)，6.7(s，1H)，7.25(s，1H)，7.44(m，1H)，7.92(m，2H)，8.63(d，2H)	502

Example number	Starting material	Name of Compound	NMR(DMSO 373K+d4AcOH)	m/z(MH)+
					224	Example 96 and (5R) -5-hydroxymethyl-pyrrolidin-2-one	S-4- (5-methyl-1H-pyrazol-3-ylamino) -6- [ (2R) -5-oxopyrrolidin-2-yl) methoxy]-2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl]Pyrimidines	1.75(m，1H)，2.1(m，6H)，2.18(s，3H)，2.38(m，1H)，3.74(m，3H)，4.1(m，2H)，5.4(d，1H)，5.8(s，1H)，5.97(s，1H)，6.71(s，1H)，7.3(s，1H)，7.45(m，1H)，7.91(m，2H)，8.65(d，2H)，11.5(br s，1H)	502
225	Example 96 and 2-1- (2-hydroxyethyl) imidazolidin-2-one	S-4- (5-methyl-1H-pyrazol-3-ylamino) -6- [2- (imidazolidin-2-one-1-yl) ethoxy]-2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl]Pyrimidines	2.08(m，3H)，2.17(s，3H)，2.37(m，1H)，3.18(t，2H)，3.32(m，4H)，3.72(m，2H)，4.25(m，2H)，5.41(d，1H)，5.78(s，1H)，5.86(s，1H)，5.97(s，1H)，6.7(s，1H)，7.44(m，1H)，7.92(m，2H)，8.65(d，2H)，11.5(br s，1H)	517
					226	Practice ofExample 96 and ethanol subformulation a	S-4- (5-methyl-1H-pyrazol-3-ylamino) -6-ethoxy-2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl]Pyrimidines	1.2(t，3H)，2.09(m，3H)，2.17(s，3H)，2.38(m，1H)，3.72(m，2H)，4.19(q，2H)，5.39(d，1H)，5.75(s，1H)，5.97(s，1H)，6.68(s，1H)，7.45(m，1H)，7.91(m，2H)，8.57(s，1H)，8.65(d，1H)，11.46(br s，1H)	433
227	EXAMPLE 96 and (2R) -1, 2-propanediol subformula a	S-4- (5-methyl-1H-pyrazol-3-ylamino) -6-hydroxy-2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl]Pyrimidines	2.1(m，3H)，2.18(s，3H)，2.36(m，1H)，3.62(m，1H)，3.8(m，1H)，5.45(s，1H)，5.53(s，1H)，5.84(s，1H)，6.77(s，1H)，7.47(m，1H)，7.94(m，2H)，8.34(s，1H)，8.68(d，1H)	405

Example number	Starting material	Name of Compound	NMR(DMSO 373K+d4AcOH)	m/z(MH)+
					228	Example 242 and 2-Methoxyethanol	S-4- (5-methyl-1H-pyrazol-3-ylamino) -6- (2-methoxyethoxy) -2- [2- {3- (thiazol-2-yl) isoxazol-5-yl } pyrrolidin-1-yl]Pyrimidines	2.07(m，3H)，2.13(s，3H)，2.37(m，1H)，3.18(s，3H)，3.48(m，2H)，3.68(m，1H)，3.75(m，1H)，4.24(m，2H)，5.37(d，1H)，5.75(s，1H)，5.93(s，1H)，6.65(s，1H)，7.81(s，1H)，7.98(s，1H)，8.6(s，1H)，11.43(s，1H)	469
229	Example 242 and ethylene glycol	S-4- (5-methyl-1H-pyrazol-3-ylamino) -6- (2-hydroxyethoxy) -2- [2- {3- (thiazol-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ]Pyrimidines	2.09(m，3H)，2.17(s，3H)，2.38(m，1H)，3.61(m，2H)，3.72(m，2H)，4.17(m，2H)，4.33(s，1H)，5.4(d，1H)，5.78(s，1H)，5.94(s，1H)，6.68(s，1H)，7.85(d，1H)，7.99(d，1H)，8.62(s，1H)，11.48(s，1H)	455
					230	EXAMPLE 96 and (2R) -1, 2-propanediol subformula b	S-4- (5-methyl-1H-pyrazol-3-ylamino) -6- [ (2R) -2-hydroxypropan-1-yloxy]-2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl]Pyrimidines	1.07(d，3H)，2.09(m，3H)，2.18(s，3H)，2.38(m，1H)，3.42(m，1H)，3.71(m，2H)，3.85-4.07(m，2H)，4.3(d，1H)，5.4(d，1H)，5.76(br d，1H)，5.94(s，1H)，6.67(s，1H)，7.43(m，1H)，7.9(m，2H)，8.6(s，1H)，8.64(d，1H)，11.45(br s，1H)	463

Example number	Starting material	Name of Compound	NMR(DMSO 373K+d4AcOH)	m/z(MH)+
					231	Example 199 and 2-Methoxyethanol sub-Process c	S-4- (5-Ethyl-1H-pyrazol-3-ylamino) -6- (2-methoxyethoxy) -2- [2- {3- (pyrazin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl]Pyrimidines	1.18(t，3H)，2.1(m，3H)，2.4(m，1H)，2.55(q，2H)，3.21(s，3H)，3.53(m，2H)，3.73(m，2H)，4.25(t，2H)，5.41(d，1H)，5.77(s，1H)，6.0(s，1H)，6.77(s，1H)，8.65(s，1H)，8.7(m，2H)，9.16(s，1H)，11.51(s，1H)	478
232	Example 199 and methanol sub-Process c	S-4- (5-Ethyl-1H-pyrazol-3-ylamino) -6-methoxy-2- [2- {3- (pyrazin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl]Pyrimidines	1.2(t，3H)，2.12(m，3H)，2.42(m，1H)，2.56(q，2H)，3.75(s，3H)，3.78(m，2H)，5.47(d，1H)，5.8(s，1H)，6.02(s，1H)，6.7(s，1H)，8.66(s，1H)，8.72(m，2H)，9.16(s，1H)	434
					233	Example 243 and ethylene glycol sub-Process c	S-4- (5-cyclopropyl-1H-pyri-dineAzol-3-ylamino) -6- (2-hydroxyethoxy) -2- [2- {3- (thiazol-2-yl) isoxazol-5-yl } pyrrolidin-1-yl]Pyrimidines	0.64(d，2H)，0.87(d，2H)，1.82(m，1H)，2.07(m，3H)，2.38(m，1H)，3.62(m，2H)，3.71(m，2H)，4.15(m，2H)，4.33(t，1H)，5.4(d，1H)，5.75(s，1H)，5.9(s，1H)，6.67(s，1H)，7.83(d，1H)，7.98(d，1H)，8.64(s，1H)，11.55(s，1H)	481

Sub-method

a. The reaction quenched with glacial acetic acid mixture was purified directly with hplc.

b. The reaction was quenched with glacial acetic acid, diluted with water, then extracted with DCM and dried (Na)₂SO₄) Evaporated and then purified with hplc.

c. The reaction was quenched with saturated ammonium chloride solution, then extracted with DCM and dried (Na)₂SO₄) Evaporated and then purified with hplc.

Example 234

S-4- (5-methyl-1H-pyrazol-3-ylamino) -6- (tetrahydropyran-4-yloxy) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Cesium fluoride (681mg, 3.5mmol) and S-6-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl]Pyrimidine (example 96) (300mg, 0.71mmol) was heated in tetrahydro-4-pyranol (pyranol) (3ml) in a sealed vessel at 200 ℃ for 2 hours under microwave irradiation. The reaction mixture was diluted with water and extracted with DCM. The extracts were combined, washed with brine and dried (Na)₂SO₄) And the solvent was removed by evaporation. The residue was purified by reverse phase HPLC using a C18 column, using water/acetonitrile/TFA (70: 30: 0).2 to polarity decrease to 30: 70: 0.2). The product containing fractions were poured onto an SCX-2 column, washed with methanol and the product was eluted with 7N methanolic ammonia. The solvent was removed by evaporation to give the title compound (107mg, 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，1H)；m/z 489[MH]+。

Example 235

S-5-fluoro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (thiazol-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

A mixture of 2-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -5-fluoropyrimidine (method 27(b)) (175mg, 0.77mmol), S-2- (3- (thiazol-2-yl) isoxazol-5-yl) pyrrolidine (method 77) (187mg, 0.85mmol), and diisopropylethylamine (0.28ml, 1.6mmol) in 1-hexanol (3ml) was heated at 130 ℃ for 48 hours. The solvent was removed by evaporation and the residue was purified by column chromatography eluting with EtOAc/hexane (1: 1 to polarity increase to 2: 1). The purified product was triturated with ether and collected by filtration to give the title compound (79mg, 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 in a similar manner to that described in example 235.

Example number	Starting material	Name of Compound	NMR(DMSO373K+d4AcOH)	m/z(MH)+
					236	Method 73 and 2, 5-dichloro-4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine	S-5-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (thiazol-4-yl) isoxazol-5-yl } pyrrolidin-1-yl]Pyrimidines	2.09(m，3H)，2.18(s，3H)，2.35(m，1H)，3.65(m，1H)，3.75(m，1H)，5.35(d，1H)，6.17(s，1H)，6.51(s，1H)，7.95(s，1H)，8.06(s，1H)，9.04(s，1H)	429
237	Method 77 and method 69	S-5-fluoro-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2- {3- (thiazol-2-yl) isoxazol-5-yl } pyrrolidin-1-yl]Pyrimidines	1.19(t，3H)，2.09(m，3H)，2.38(m，1H)，2.58(q，2H)，3.64(m，1H)，3.75(m，1H)，5.38(d，1H)，6.17(s，1H)，6.62(s，1H)，7.85(d，1H)，7.91(d，1H)，7.98(d，1H)，8.85(br s，1H)，11.69(br s，1H)	427
					238	Method 77 and method 26	S-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (thiazol-2-yl) isoxazol-5-yl } pyrrolidin-1-yl]Pyrimidines	2.09(m，3H)，2.17(s，3H)，2.36(m，1H)，3.66(m，1H)，3.78(m，1H)，5.43(d，1H)，6.0(s，1H)，6.29(d，1H)，6.64(s，1H)，7.77(d，1H)，7.85(d，1H)，7.95(d，1H)	395
239	Method 77 and method 65 submethod d	S-4- (5-Ethyl-1H-pyrazol-3-ylamino) -2- [2- {3- (thiazol-2-yl) isoxazol-5-yl } pyrrolidin-1-yl]Pyrimidines	1.18(t，3H)，2.09(m，3H)，2.3(m，1H)，2.55(q，2H)，3.68(m，1H)，3.77(m，1H)，5.43(d，1H)，6.07(s，1H)，6.3(s，1H)，6.64(s，1H)，7.86(m，2H)，7.98(d，1H)，8.92(s，1H)，11.57(s，1H)	409

Example number	Starting material	Name of Compound	NMR(DMSO373K+d4AcOH)	m/z(MH)+
					240	Method 77 and method 28 sub-method d	S-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2- {3- (thiazol-2-yl) isoxazol-5-yl } pyrrolidin-1-yl]Pyrimidines	0.65(d，2H)，0.87(d，2H)，1.85(m，1H)，2.06(m，3H)，2.37(m，1H)，3.67(m，2H)，5.43(d，1H)，5.96(s，1H)，6.27(s，1H)，6.59(s，1H)，7.82(m，2H)，7.97(d，1H)，8.89(s，1H)，11.55(s，1H)	421
241	Method 77 and method 27 sub-method d	S-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -5-fluoro-2- [2- {3- (thiazol-2-yl) isoxazol-5-yl } pyrrolidin-1-yl]Pyrimidines	0.67(m，2H)，0.88(m，2H)，1.83(m，1H)，2.08(m，3H)，2.35(m，1H)，3.64(m，1H)，3.75(m，1H)，5.38(d，1H)，6.09(s，1H)，6.61(s，1H)，7.86(d，1H)，7.91(d，1H)，7.99(d，1H)，8.83(s，1H)	439

Sub-method

d. The crude product was purified by hplc, the product containing fractions were poured onto an SCX-2 ion exchange column, eluted with methanol to remove neutral impurities and then eluted with methanolic ammonia.

Example 242

S-6-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (thiazol-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

2, 6-dichloro-4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (method 29) and S-2- (3- (thiazol-2-yl) isoxazol-5-yl) pyrrolidine (method 77) were treated as described in example 96. The crude product was purified by column chromatography on silica gel eluting with EtOAc/hexanes (7: 3). The purified product was triturated with ether and collected by filtration to give the title compound as a white solid (0.89g, 57%).

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-chloro-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2- {3- (thiazol-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

2, 6-dichloro-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine (method 57) and S-2- (3- (thiazol-2-yl) isoxazol-5-yl) pyrrolidine (method 77) were treated as described in example 242 to give the title compound as a white solid (183mg, 29%).

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-Morpholino-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (thiazol-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

S-6-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (thiazol-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (example 242) (150mg, 0.35mmol) and morpholine (3ml) were heated at 120 ℃ under microwave irradiation in a sealed vessel for 30 minutes. The reaction mixture was purified by reverse phase HPLC using a C18 column, eluting with water/acetonitrile/TFA (97.5: 2.5: 0.2 to a polarity reduction of 60: 40: 0.2). The product containing fractions were poured onto an SCX-2 column, washed free of neutral impurities with methanol and then eluted with 3.5N methanolic ammonia. The solvent was removed by evaporation, the residue triturated with ether and collected by filtration to give the title compound as a cream solid (72mg, 43%).

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，1H)；m/z 480[MH]+。

Examples 245 to 248

Examples 245 to 248 were prepared in a similar manner to that described in example 244.

Example number	Starting material	Name of Compound	NMR(DMSO 373K+d4AcOH)	m/z(MH)+
					245	Example 199 and morpholine	S-6-Morpholino-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyrazin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl]Pyrimidines	1.18(t，3H)，2.07(m，3H)，2.37(m，1H)，2.53(q，2H)，3.37(m，4H)，3.58(m，4H)，3.72(m，2H)，5.41(d，1H)，5.76(s，1H)，5.98(s，1H)，6.73(s，1H)，8.35(s，1H)，8.7(m，2H)，9.14(s，1H)，11.45(s，1H)	489
246	Example 242 and 2-methoxyethylamine procedure e	S-6- (2-methoxyethylamino) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (thiazol-2-yl) isoxazol-5-yl } pyrrolidin-1-yl]Pyrimidines	2.05(m，3H)，2.15(s，3H)，2.33(m，1H)，2.68(s，3H)，3.71(m，2H)，5.4(d，1H)，5.49(s，1H)，5.83(s，1H)，5.99(s，1H)，6.65(s，1H)，7.83(d，1H)，7.97(d，1H)，8.19(br s，1H)	424
					247	Example 242 and Methylamin method f	S-6-methylamino-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (thiazol-2-yl) isoxazol-5-yl } pyrrolidin-1-yl]Pyrimidines	2.05(m，3H)，2.14(s，3H)，2.35(m，1H)，3.19(s，3H)，3.3(m，4H)，3.69(m，2H)，5.37(d，1H)，5.54(s，1H)，5.86(s，1H)，6.62(s，1H)，7.8(d，1H)，7.95(d，1H)	468
248	Example 242 and 1-methylpiperazine method g	S-6- (4-methylpiperazin-1 yl) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (thiazol-2-yl) isoxazol-5-yl } pyrrolidin-1-yl]Pyrimidines	2.05(m，3H)，2.15(s，3H)，2.26(m，4H)，2.36(m，1H)，3.37(m，4H)，3.71(m，2H)，5.35(d，1H)，5.77(s，1H)，5.94(s，1H)，6.64(s，1H)，7.85(d，1H)，7.98(d，1H)，8.26(br s，1H)	493

Sub-method

e. Heating at 150 ℃ for 90 minutes.

f. A solution of methylamine in ethanol. Heating at 130 ℃ for 90 minutes 5g post reaction treatment: dilution with water, extraction with EtOAc, drying (Na)₂SO₄) And the volatile materials were evaporated. The residue was purified by column chromatography on silica eluting with methanol/DCM/aqueous ammonia (5: 95: 0, then 5: 94: 1).

Example 249

S-6-methyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (thiazol-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

2-chloro-6-methyl-4- (5-methyl-1H-pyrazol-3-ylamino) -pyrimidine (method 56) (200mg, 0.89mmol), S-2- (3- (thiazol-2-yl) isoxazol-5-yl) pyrrolidine (method 77) (218mg, 0.98mmol) and N, N-diisopropylethylamine (0.37ml, 2.1mmol) were suspended in 1-hexanol (4ml) and heated in a sealed vessel under microwave radiation at 150 ℃ for 3 hours. The reaction mixture was purified by reverse phase HPLC using a C18 column, eluting with water/acetonitrile/TFA (97.5: 2.5: 0.2 to a polarity reduction of 60: 40: 0.2). The product containing fractions were poured onto an SCX-2 ion exchange column and washed with methanol to remove neutral material, then the product was eluted with 3.5N methanolic ammonia. The solvent was removed by evaporation, the residue triturated with ether and collected by filtration to give the title compound as a white solid (164mg, 45%).

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- [3- (methylsulfonyl) propyl-1-oxy ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Potassium peroxymonosulfate, potassium bisulfate, and potassium sulfate complex (oxone) ^TM) (227mg, 0.37mmol) in water (1.3ml) was added dropwise to a stirred solution of S-4- (5-methyl-1H-pyrazol-3-ylamino) -6- [3- (methylthio) propan-1-yloxy)]-2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl]Pyrimidine (example 222) (130mg, 0.26mmol) in THF (1.3 ml). The mixture was stirred at room temperature for 2 hours, then diluted with water and adjusted to pH 8 with 1M aqueous potassium hydroxide solution. The mixture was extracted with ethyl acetate (× 3) and the organic extracts were combined, washed with brine and dried (Na)₂SO₄). The solvent was removed by evaporation and the residue was purified by reverse phase HPLC using a C18 column, washed with water/acetonitrile/TFA (70: 30: 0.2 to polarity reduction to 30: 70: 0.2). The product containing fractions were poured onto an SCX-2 ion exchange column, which was washed with methanol and then eluted with 3.5N methanolic ammonia. The solvent was removed by evaporation, the residue triturated with ether and collected by filtration to give the title compound as a cream solid (45mg, 33%).

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- {2- [3- (pyrazin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine

S-6-chloro-2- {2- [3- (pyrazin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine (example 91) and 2-methoxyethanol were treated in a similar manner to that of example 208 except that the crude product was purified by silica gel column chromatography eluting with hexane/EtOAc (80: 20 to polarity increase to 0: 100) to give the title compound (70mg, 21%) as a pale yellow powder.

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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- {2- [3- (pyrimidin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-ethyl-1H-pyrazol-3-ylamino) pyrimidine

Treatment of 2, 6-dichloro-4- (5-ethyl-1H-pyrazol-3-ylamino) pyrimidine (method 72) and S-2- [3- (pyrimidin-2-yl) isoxazol-5-yl ] pyrrolidine (method 66) in a manner similar to that described in example 161 gave the title compound (364mg, 49%) as a white powder.

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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- {2- [3- (pyrimidin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-ethyl-1H-pyrazol-3-ylamino) pyrimidine

S-6-chloro-2- {2- [3- (pyrimidin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-ethyl-1H-pyrazol-3-ylamino) pyrimidine (example 252) was treated in a similar manner to the method described in example 94 to give the title compound (118mg, 80%) as a pink powder.

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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- {2- [3- (pyrimidin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-ethyl-1H-pyrazol-3-ylamino) pyrimidine

A mixture of S-2- [3- (pyrimidin-2-yl) isoxazol-5-yl ] pyrrolidine (method 66) (198mg, 0.91mmol), 6-ethyl-2-chloro-4- (5-ethyl-1H-pyrazol-3-ylamino) pyrimidine (method 79) (210mg, 0.83mmol), and di-isopropylethylamine was heated in hexanol (4ml) at 150 ℃ under microwave irradiation for 60 minutes. The crude reaction mixture was passed through a 10g SCX column eluting with methanol, then the product was eluted 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 to polarity increase to 90: 10) to give the title compound as a pale brown powder (78mg, 22%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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- {2- [3- (pyrimidin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-ethyl-1H-pyrazol-3-ylamino) pyrimidine

Treatment of S-6-chloro-2- {2- [3- (pyrimidin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-ethyl-1H-pyrazol-3-ylamino) pyrimidine (example 252) in a similar manner to the procedure described in example 140 gave the title compound as a brown solid (20mg, 13%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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(, 1H), 8.85(d, 2H); m/z 433[ MH]+。

Example 256

S-6-Ethyl-2- {2- [3- (pyrimidin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine

Treatment of 6-ethyl-2-chloro-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine (method 80) and S-2- [3- (pyrimidin-2-yl) isoxazol-5-yl ] pyrrolidine (method 66) in a similar manner to the method described in example 254 gave the title compound as a brown powder (230mg, 68%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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- {2- [3- (pyrimidin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine

Treatment of 6-cyclopropyl-2-chloro-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine (method 81) and S-2- [3- (pyrimidin-2-yl) isoxazol-5-yl ] pyrrolidine (method 66) in a manner similar to that described in example 254 gave the title compound as a brown powder (89mg, 27%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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- {2- [3- (pyrimidin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-ethyl-1H-pyrazol-3-ylamino) pyrimidine

Treatment of 6-cyclopropyl-2-chloro-4- (5-ethyl-1H-pyrazol-3-ylamino) pyrimidine (method 82) and S-2- [3- (pyrimidin-2-yl) isoxazol-5-yl ] pyrrolidine (method 66) in a similar manner to the method described in example 254 gave the title compound as a brown powder (80mg, 49%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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- {2- [3- (pyrimidin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-ethyl-1H-pyrazol-3-ylamino) pyrimidine

S-6-chloro-2- {2- [3- (pyrimidin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-ethyl-1H-pyrazol-3-ylamino) pyrimidine (example 252) and 2-methoxyethanol were treated in a similar manner to that described in example 208 except that the crude product was purified by silica gel column chromatography eluting with DCM/2M methanolic ammonia (100: 0 to polarity increased to 95: 5) to give the title compound as a white solid (118mg, 47%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 1.15(t, 3H), 2.00-2.20m, 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- {2- [3- (3-methoxypyrazin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-ethyl-1H-pyrazol-3-ylamino) pyrimidine

A mixture of 2-chloro-6-methyl-4- (5-ethyl-1H-pyrazol-3-ylamino) pyrimidine (method 83) (105mg, 0.44mmol), S-2- [3- (2-methoxypyrazin-3-yl) isoxazol-5-yl ] pyrrolidine (method 68) (120mg, 0.49mmol), diisopropylethylamine (0.12ml, 0.69mmol) and hexanol (3ml) was heated in a sealed vessel at 150 ℃ under microwave radiation for 1 hour. The crude reaction mixture was poured onto an isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutral material, and then the product was eluted with 7M methanolic ammonia. 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 to polarity increase to 90: 10) to give the title compound as a pale tan solid (86mg, 44%).

NMR(DMSO-d₆At 100 ℃): 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-chloro-2- {2- [3- (3-methoxypyrazin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-ethyl-1H-pyrazol-3-ylamino) pyrimidine

A mixture of 2, 6-dichloro-4- (5-ethyl-1H-pyrazol-3-ylamino) pyrimidine (method 72) (570mg, 2.2mmol), S-2- [3- (2-methoxypyrazin-3-yl) isoxazol-5-yl ] pyrrolidine (method 68) (600mgs, 2.4mmol), diisopropylethylamine (310mg, 2.4mmol) in 1-butanol (10ml) was heated at 75 ℃ for 16H. The solvent was removed by evaporation and the residue was purified by column chromatography on silica gel eluting with hexane/EtOAc (80: 20 to polarity increase to 0: 100) to give the title compound as a white foam (450mg, 44%).

NMR(DMSO-d₆At 100 ℃): 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-methyl-2- {2- [3- (3-methoxypyrazin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine

Treatment of 2-chloro-6-methyl-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine (method 70) and S-2- [3- (2-methoxypyrazin-3-yl) isoxazol-5-yl ] pyrrolidine (method 68) in a manner similar to that described in example 260 provided the title compound (88mg, 40%).

NMR(DMSO-d₆At 100 ℃): 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 MH]+。

Example 263

S-6-Morpholino-2- {2- [3- (3-methoxypyrazin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-ethyl-1H-pyrazol-3-ylamino) pyrimidine

A mixture of S-6-chloro-2- {2- [3- (3-methoxypyrazin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-ethyl-1H-pyrazol-3-ylamino) pyrimidine (example 261) (250mg, 0.5mmol) in morpholine (3ml) was heated at 70 ℃ in a sealed vessel under microwave irradiation for 2 hours. The crude reaction mixture was purified by reverse phase HPLC using a C18 column, eluting with water/acetonitrile/TFA (95: 5: 0.2 to polarity decrease to 0: 100: 0.2). The product containing fractions were combined and passed through an isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutral material, and then the product was eluted with 7M methanolic ammonia. The solvent was removed by evaporation and the residue triturated with hexane, which was collected by filtration to give the title compound as a white solid (81mg, 31%).

NMR(DMSO-d₆At 100 ℃): 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- [2- {3- (3-hydroxypyrazin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] -4- (5-ethyl-1H-pyrazol-3-ylamino) -pyrimidine

The title compound was isolated as a by-product from the preparation of example 263 (30mg, 11%).

NMR(DMSO-d₆At 100 ℃): 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- {2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

6-methyl-2-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (method 56) (200mg, 0.9mmol), S-2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl]A mixture of pyrrolidine (method 64) (262mg, 1.1mmol) and diisopropylethylamine (0.22ml, 1.25mmol) in hexanol (5ml) was heated at 150 ℃ for 105 minutes under microwave radiation in a sealed vessel. By steaming The volatiles were removed and the residue was dissolved in EtOAc, washed with water and dried (MgSO)₄) And the solvent is removed by evaporation. The residue was purified by silica gel column chromatography eluting with EtOAc/hexanes (1: 1) to give the title compound (160mg, 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- {2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine

2-chloro-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -5-fluoropyrimidine (method 27) (150mg, 0.6mmol), S-2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl]A mixture of pyrrolidine (method 64) (194mg, 0.8mmol), diisopropylethylamine (0.29ml, 1.6mmol) in hexanol (10ml) was heated at 150 ℃ for 24 h. The mixture was cooled, the volatiles were 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 column chromatography on silica gel eluting with EtOAc/hexanes (50: 50 to increasing polarity to 70: 30) to give the title compound (95mg, 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，1H)；m/z 463[MH]+。

Example 267

S-5-fluoro-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidin-1-yl ] pyrimidine

Treatment of 2-chloro-4- (5-ethyl-1H-pyrazol-3-ylamino) -5-fluoropyrimidine (method 69) and S-2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidine (method 64) in a similar manner to the one described in example 266 gave the title compound (67mg, 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-methyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidin-1-yl ] pyrimidine

Treatment of 2-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -5-fluoropyrimidine (method 27(b)) and S-2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidine (method 64) in a similar manner to the one described in example 266 gave the title compound (140mg, 37%).

NMR(DMSO)：2.01-2.15(m，3H)，2.20(s，3H)，2.30-2.40(m，1H)，3.61-3.69(m，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- [2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidin-1-yl ] pyrimidine

2, 6-dichloro-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine (method 57) (300mg, 1.1mmol), S-2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl]A mixture of pyrrolidine (method 64) (299mg, 1.22mmole), diisopropylethylamine (0.46ml) in xylene (10ml) was heated at 80 ℃ for 18 hours. Removing the solvent by evaporation The residue was dissolved in EtOAc, washed with water and dried (MgSO₄) And the solvent was removed by evaporation. The residue was purified by column chromatography on silica gel eluting with EtOAc/hexanes (45: 55) to give the title compound (300mg, 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- [2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidin-1-yl ] pyrimidine

Treatment of 2, 6-dichloro-4- (5-ethyl-1H-pyrazol-3-ylamino) pyrimidine (method 72) and S-2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidine (method 64) in a similar manner to the procedure described in example 269 gave the title compound (240mg, 44%).

NMR(DMSO)：1.2(t，3H)，2.02-2.20(m，3H)，2.32-2.45(m，1H)，2.55(q，2H)，3.62-3.80(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-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidin-1-yl ] pyrimidine

Treatment of 2, 6-dichloro-4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (method 29) and S-2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidine (method 64) in a similar manner to the procedure described in example 269 gave the title compound (240mg, 44%).

m/z 463[MH]+。

Example 272

S-6- (2-hydroxyethoxy) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidin-1-yl ] pyrimidine

Sodium hydride (106mg, 2.65mmol) was added to ethylene glycol (4ml) and the mixture was stirred for 10 min. To this was added S-6-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl]Pyrrolidin-1-yl radical]Pyrimidine (example 271) (180mg, 0.4mmol) and the mixture was heated at 150 ℃ under microwave irradiation in a sealed vessel for 30 minutes. The mixture was cooled, diluted with aqueous ammonium chloride and extracted with EtOAc. The extracts were combined and dried (MgSO)₄) And the solvent is removed by evaporation. The residue was purified by column chromatography on silica gel eluting with EtOAc/hexanes (50: 50 to polarity increase to 90: 10) to give the title compound (60mg, 32%).

NMR(DMSO)：2.01-2.18(m，3H)，2.14(s，3H)，2.35-2.42(m，1H)，3.64(s，2H)，3.68-3.77(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[MH]+。

Example 273

S-6- (2-hydroxyethoxy) -4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidin-1-yl ] pyrimidine

S-6-chloro-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidin-1-yl ] pyrimidine (example 269) and ethylene glycol were treated in a similar manner to the method described in example 272 to give the title compound (50mg, 20%).

NMR(DMSO)：0.62-0.70(m，2H)，0.82-0.90(m，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-ethyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidin-1-yl ] pyrimidine

S-6-chloro-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidin-1-yl ] pyrimidine (example 270) and ethylene glycol were treated in a similar manner to the method described in example 272 to give the title compound (37mg, 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-methyl-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyrimidin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Treatment of 2-chloro-6-methyl-4- (5-ethyl-1H-pyrazol-3-ylamino) pyrimidine (method 83) and S-2- [3- (pyrimidin-2-yl) isoxazol-5-yl ] pyrrolidine (method 66) in a similar manner to the method described in example 260 gave the title compound (77mg, 56%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 1.15(t, 3H), 2.00-2.15(m, 6H), 2.35(m, 1H), 2.55(q, 2H), 3.65(m, 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 MH]+。

Example 276

S-6-methyl-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Treatment of 2-chloro-6-methyl-4- (5-ethyl-1H-pyrazol-3-ylamino) pyrimidine (method 83) and S-2- (3- (2-pyridinyl) isoxazol-5-yl) pyrrolidine (method 42) in a similar manner to the method described in example 260 gave the title compound (134mg, 51%).

NMR(DMSO-d₆At 100 ℃): 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- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

Treatment of 2-chloro-6- (3-methoxypropyl) -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (method 87) and S-2- (3- (2-pyridinyl) isoxazol-5-yl) pyrrolidine (method 42) in a similar manner to the method described in example 249 gave the title compound (60mg, 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)，5.44(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]+。

Method

Preparation of starting materials: -

The starting materials for the above examples are commercially available or can be prepared from known materials using standard methods. For example, the following reactions are used to illustrate, without limitation, some of the starting materials used in the above reactions.

Methods 1 and 2

The following compounds were prepared in a manner similar to that described for 3-methoxybenzaldehyde oxime in method 35 of WO 03/048133.

Method	Starting material	Name of Compound	NMR(CDCl3)	m/z(MH)+
					1a	#	Cyclopropylaldoxime (cyclopropopylcarboxaldehydeoxime)	0.60(m，2H)，0.90(m，2H)，1.60(m，0.25H)，2.30(m，0.75H)，6.05(d，0.75H)，6.95(d，0.25H)，8.60(br s，0.25H)，9.00(br s，0.75H)	n/a
2b	#	Thiazol-2-yl aldoximes	7.75(d，0.4H)，7.91(d，0.4H)，7.97(d，0.6H)，8.00(m，1.2H)，8.33(s，0.4H)，11.95(br s，0.4H)，12.18(br s，0.6H)	n/a

^aAbout 3: 1 mixture # of E/Z isomers is commercially available

^bAbout 3: 2 mixture of E/Z isomers

Method 3

5- (tert-Butoxycarbonylaminomethyl) -3-cyclopropylisoxazole

The title compound was prepared starting from cyclopropylaldoxime (method 1) using a method similar to that described in method 69 of WO 03/048133 and was used without purification.

Method 4

5- (tert-Butoxycarbonylaminomethyl) -3- (thiazol-2-yl) isoxazole

The title compound is prepared in two steps starting from thiazol-2-yl aldoxime (method 2) by a method similar to the methods 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-aminomethyl-3-cyclopropylisoxazole

Mixing 5 to (Tertiary carboxylic acidButoxycarbonylaminomethyl) -3-cyclopropylisoxazole crude (method 3) (37.4g, 0.157mol) and 3M hydrochloric acid (80ml) were heated in methanol (100ml) at 50 ℃ for 2 h. The methanol was removed by evaporation and the aqueous residue was washed with DCM. The pH of the aqueous layer was adjusted to 12 by careful addition of 40% aqueous sodium hydroxide solution and then extracted with DCM (× 4). The extracts were combined, washed with brine and then dried (Na) ₂SO₄) And the volatile material was removed by evaporation to give the title compound as an oil (11.5g, 53%).

NMR(CDCl₃)：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-aminomethyl-3- (thiazol-2-yl) isoxazoles

The title compound is prepared from 5-, (Tertiary carboxylic acidButoxycarbonylaminomethyl) -3- (thiazol-2-yl) isoxazole (method 4) was prepared starting from a method similar 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

[3- (pyridin-2-yl) isoxazol-5-yl ] methyl [ (1E) -phenylmethylene ] amine

Freshly distilled benzaldehyde (373mg, 3.5mmol) was added to a solution of 5-aminomethyl-3- (pyridin-2-yl) isoxazole (method 70 of WO 03/048133) (0.614mg, 3.5mmol) in anhydrous DCM (18 ml). Then, 4  molecular sieve (1.75g) was added thereto and the mixture was gently stirred 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 (900mg, 97%).

NMR(CDCl₃)：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 in the same manner as in example 7: -

Method	Starting material	Name of Compound	NMR	m/z(MH)+
					8	#	(3-methylisoxazol-5-yl) methyl [ (1E) -phenylmethylene- ]Amines as pesticides	2.20(s，3H)，4.84(s，2H)，6.28(s，1H)，7.42-7.48(m，3H)，7.78(dd，2H)，8.50(s，1H)	n/a
9	Method 5	(3-Cyclopropylisoxazol-5-yl) methyl [ (1E) -phenylmethylene-]Amines as pesticides	CDCl30.80(m，2H)，1.00(m，2H)，2.00(m，1H)，4.80(s，2H)，5.85(s，1H)，7.42(m，2H)，7.78(dd，2H)，8.38(s，1H)	227
					10	Method 6	[3- (thiazol-2-yl) isoxazol-5-yl]Methyl [ (1E) -phenylmethylene group]Amine 2-	5.0(s，2H)，6.95(s，1H)，7.47(m，3H)，7.77(m，2H)，7.96(d，1H)，8.05(d，1H)，8.56(s，1H)	n/a
11	5-aminomethyl-3- (pyridin-3-yl) isoxazole #	[3- (pyridin-3-yl) isoxazol-5-yl]Methyl [ (1E) -phenylmethylene group]Amines as pesticides	4.97(s，2H)，6.6(s，1H)，7.43(m，4H)，7.82(d，2H)，8.15(d，1H)，8.47(s，1H)，8.67(d，1H)，9.02(S，1H)	n/a

Method 68 of # WO03/048133

# is commercially available

Method 12

2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidine

N-butyllithium (7.5ml of a 1.82M solution in hexane, 13.74mmol) was added to a stirred solution of 2, 2, 6, 6-tetramethylpiperidine (2.5ml, 14.9mmol) in THF (99ml) at-78 ℃ under nitrogen so that the temperature remained below-65 ℃. The solution was then stirred at-78 ℃ for 15 minutes. Then, [3- (pyridin-2-yl) isoxazol-5-yl ] was added thereto over a period of 5 minutes]Methyl [ (1E) -phenylmethylene group]A solution of the amine (method 7) (3.0g, 11.45mmol) in dry THF (51ml) was maintained at a temperature at or below-70 deg.C and the mixture was stirred at-78 deg.C for 15 minutes. Then, 1-chloro-3-iodopropane (1.53ml, 14.31mmol) was added dropwise thereto over 1 minute, and then the mixture was stirred at-78 ℃ for 15 minutes, allowed to warm to ambient temperature and stirred at room temperature for 18 hours. To the reaction mixture was added diethyl ether, then water was added and the mixture was stirred vigorously for 5 minutes. The layers were separated and the organic layer was washed with water and then brine and dried (Na) ₂SO₄) And evaporating to obtain crude alkylated imine. This imine was directly dissolved in ethanol (24ml) and 2M hydrochloric acid (48ml) was added thereto. The mixture was stirred at ambient temperature for 18 hours. The ethanol was removed by evaporation, water was again added thereto and the aqueous layer was washed with diethyl ether (× 2). The pH of the aqueous solution was adjusted to 11.5 by addition of solid sodium carbonate and 40% aqueous sodium hydroxide solution near the end point. This aqueous solution was stirred at ambient temperature for 2 hours during which time 40% sodium hydroxide was added to maintain the pH of the solution at 11.5.

The resulting solution of the crude product is purified by one of two methods: -

Purification method A

Then, to the crude aqueous solution was added DCM (70ml) and di-tert-butyl dicarbonate (2.74g, 12.57mmol) and the mixture was stirred vigorously at ambient temperature for 2.5 h. The layers were separated and the organic layer was washed with water, then brine and dried (Na)₂SO₄) The volatile materials were removed by evaporation. The residue was purified by column chromatography on a Biotage 40M silica gel cartridge eluting with DCM/EtOAc (93: 7) to give 1- (tert-butoxycarbonyl) -2- [3- (pyridin-2-yl) isoxazol-5-yl as a waxy solid ]Pyrrolidine (181g, 50%).

NMR (mixture of rotamers-peaks assigned to the peaks of the major rotamers): 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 to (Tertiary carboxylic acidButoxycarbonyl) -2- [3- (pyridin-2-yl) isoxazol-5-yl]Pyrrolidine (0.56g, 1.78mmol) was stirred at ambient temperature in a mixture of ethanol (5ml) and 2M hydrochloric acid (1.5ml) for 18 hours, then it was heated at 60 ℃ for a further 2 hours. The reaction was concentrated by evaporation and water was added thereto. The pH of the solution was adjusted to 12.5 near the end by adding solid sodium carbonate and 40% aqueous sodium hydroxide. The aqueous solution was extracted with DCM (× 4), the organic extracts combined and dried (Na)₂SO₄) Evaporation gave the title compound as a brown oil (183mg, 48%).

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[MH]+。

Purification method B

The crude aqueous solution was extracted with DCM (× 4), the organic extracts combined and dried (Na)₂SO₄) And the solvent was removed by evaporation. Column-coloring the residue with silica gelThe spectrum was purified by eluting with diethyl ether followed by DCM/MeOH (100: 0 to polarity increase to 95: 5) to give the title compound.

Methods 13 to 16a

Examples 13 to 16a were prepared in the same manner as in example 12: -

Method	Starting material	Name of Compound	NMR	m/z(MH)+
					13b，c	Method 8	2- (3-methylisoxazol-5-yl) pyrrolidine	1.97-1.73(m，3H)，2.02-2.12(m，1H)，2.18(s，3H)，2.82-2.90(m，2H)，4.18-4.22(m，1H)，6.14(s，1H)	153
14b	Method 9	2- (3-Cyclopropylisoxazol-5-yl) pyrrolidine	CDCl30.78(m，2H)，0.98(m，2H)，1.95(m，4H)，2.15(m，1H)，3.15(m，2H)，4.25(m，1H)，5.75(s，1H)	179
					15b	Method 10	2- [3- (thiazol-2-yl) isoxazol-5-yl]Pyrrolidine as a therapeutic agent	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)	222

Method	Starting material	Name of Compound	NMR	m/z(MH)+
					16a，d16(a)bef	Method 11 method 7	2- [3- (pyridin-3-yl) isoxazol-5-yl]Pyrrolidine 2- [3- (pyridin-2-yl) isoxazol-5-yl]Piperidine derivatives	1.77(m，3H)，2.1(m，1H)，2.88(t，2H)，4.35(m，1H)，6.93(s，1H)，7.5(t，1H)，8.22(d，1H)，8.65(d，1H)，9.02(s，1H)1.43(m，4H)，1.75(m，1H)，1.93(m，1H)，2.63(m，2H)，2.95(d，1H)，3.87(d，1H)，6.8(s，1H)，7.47(t，1H)，7.93(m，2H)，8.67(d，1H)	216230

^aPurification by purification method A

^bPurification by purification method B

^cPurifying by chromatography, eluting with diethyl ether and then DCM/methanol (100: 0 to polarity increasing to 90: 10)

^dBy 1- (tert-butoxycarbonyl) -2- [3- (pyridin-3-yl) isoxazol-5-yl]pyrrolidine-NMR (mixture of rotamers-peaks assigned as 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]+。

^fPrepared with 4-chloro-1-iodobutane

^eBy 1- (tert-butoxycarbonyl) -2- [3- (pyridin-3-yl) isoxazol-5-yl]Piperidine prepared-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) pyrrolidin-1-carboximidamide

A mixture of 2- (3-cyclopropylisoxazol-5-yl) pyrrolidine (method 14) (2.05g, 11.5mmol) and formamidinesulfonic acid (1.425g, 11.5mmol) in dry methanol (30ml) was heated at 60 ℃ for 18 h. The solvent was removed by evaporation and the residue was dissolved in water. The aqueous solution was washed with water and then water was removed by evaporation. The residue was triturated with ether/DCM and the solid product collected and dried under vacuum at 50 ℃ for 18 h to give the mono-sulphate salt of the title compound (1.839mg, 41%); m/z 221[ MH ] +.

Method 18

2- [2- (3-Cyclopropylisoxazol-5-yl ] pyrrolidin-1-yl ] -4-hydroxy-6-methoxymethylpyrimidine

Sodium bis- (trimethylsilyl) amide (3.65ml of a 2M solution in THF, 7.3mmol) was added to a solution of 2- (3-cyclopropylisoxazol-5-yl) pyrrolidine-1-carboximidamide monosulfate (method 17) (1.83g, 6.09mmol) and methyl 4-methoxyacetoacetate (0.867ml, 6.7mmol) in methanol (30ml) and the mixture was heated at reflux for 4 h. The solvent was removed by evaporation and the residue was purified by chromatography on silica gel eluting with DCM/methanol (100: 0 to polarity increase to 95: 5). The purified product was triturated with ether and the solid was then recrystallized from methanol to give the title compound as a white solid (565mg, 29%).

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- [2- (3-cyclopropylisoxazol-5-yl ] pyrrolidin-1-yl ] -6-methoxymethylpyrimidine

2- [2- (3-cyclopropyl-isoxazol-5-yl)]Pyrrolidin-1-yl radical]A mixture of (E) -4-hydroxy-6-methoxymethylpyrimidine (method 18) (563mg, 1.78mmol) and phosphorus oxychloride (1ml, 10.7mmol) was heated at reflux for 45 minutes. The volatiles were removed by evaporation and the residue was dissolved in DCM, washed with saturated aqueous sodium bicarbonate and dried (Na)₂SO₄) And (4) evaporating. The residue was purified by chromatography on silica eluting with DCM/diethyl ether (100: 0 then 80: 20) to give the title compound as a yellow oil (511mg, 81%).

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-aminomethyl-3- (tetrahydrofuran-3-yl) isoxazoles

This compound was prepared using suitable starting materials in a manner similar to that described in methods 3 and 5.

NMR(DMSO)：1.88(m，3H)，2.25(m，1H)，3.44(m，1H)，3.62(m，1H)，3.7-3.82(m，4H)，3.96(m，1H)，6.25(s，1H)；m/z 169[MH]+。

Method 22

[3- (tetrahydrofuran-3-yl) isoxazol-5-yl ] methyl [ (1E) -phenylmethylene ] amine

This compound is prepared by a method similar 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(m，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

[3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] methyl [ (1E) -phenylmethylene ] amine

This compound is prepared in a similar manner to that described in method 7, starting from 5-aminomethyl-3- (2-methoxypyridin-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- [3- (tetrahydrofuran-3-yl) isoxazol-5-yl ] pyrrolidine

This compound is prepared by a method similar to that described in method 12, starting with 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- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidine

This compound is prepared by a method similar 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-1H-pyrazol-3-ylamino) pyrimidine

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

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 are prepared by methods similar 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: 546mg, 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，1H)；m/z 254[MH]+。

Method 27(b)

2-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -5-fluoropyrimidine

Yield: 3.02g, 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-1H-pyrazol-3-ylamino) pyrimidine

Yield: 323mg, 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，1H)；m/z 236[MH]+。

Method 29

2, 6-dichloro-4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

A mixture of 2, 4, 6-trichloropyrimidine (1.0g, 5.4mmol), 3-amino-5-methyl-1H-pyrazole (0.53g, 5.4mmol), and sodium carbonate (0.57g, 5.4mmol) in ethanol (25ml) was stirred at room temperature for 18 hours. Water was added thereto and the resulting precipitate was collected by filtration, washed with water and a small amount of methanol, and dried to give the title compound (1.15g, 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[MH]+。

Method 30

4-hydroxy-6-methyl-2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

A mixture of 4-hydroxy-6-methyl-2-thiomethylpyrimidine (362mg, 2.3mmol) and 2- [3- (2-pyridyl) isoxazol-5-yl ] pyrrolidine (500mg, 2.3mmol) was placed under a nitrogen atmosphere and heated at 150 ℃ for 18 hours. The mixture was purified by chromatography on silica eluting with DCM/MeOH (100: 0 to polarity increase to 96: 4) to give the title compound (420mg, 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-hydroxy-6-methyl-2- [2- (3-methylisoxazol-5-yl) pyrrolidin-1-yl ] pyrimidine

This compound was prepared using a method similar to that described for method 30, using the appropriate starting materials to give the title compound (270mg, 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/z261[MH]+。

Method 32

6-Ethyl-4-hydroxy-2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

A mixture of ethyl propionylacetate (350mg, 2.4mmol), 2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-carboximidamide trifluoroacetate (method 38) (901mg, 2.43mmol), sodium methoxide (144mg, 7.7mmol) in butanol (10ml) was heated at 120 ℃ for 18 hours. The mixture was allowed to cool and poured directly onto isolute SCX2 ion exchange column. The column was eluted with DCM/MeOH (4: 1) to remove neutral material, then the product was eluted with 7M methanolic ammonia. The solvent was evaporated and the residue was purified by chromatography on silica eluting with DCM/MeOH (98: 2 to polarity increase to 95: 5) to give the title compound (360mg, 46%).

NMR(DMSO)：0.99(t，3H)，2.0-2.1(m，3H)，2.2-2.3(m，3H)，3.48(m，1H)，3.74-3.80(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 are prepared in a similar manner to the method described in method 32 using the appropriate starting materials.

Method 33

4-hydroxy-6- (3-methoxypropyl) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Yield: 575mg, 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-hydroxy-6- (methoxymethyl) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Yield: 1g, 48 percent.

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[MH]+。

Method 35

4-hydroxy-6- (pent-3-en-1-yl) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Yield: 1g, 33%.

NMR(DMSO)：1.42(s，3H)，2.0-2.15(m，5H)，2.2-2.38(m，3H)，3.52(q，1H)，3.73-3.80(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) to 37

The compounds of methods 35(a) through 37 are prepared in a manner similar to the method described in method 30 using the appropriate starting materials.

Method 35(a)

4-hydroxy-6- (methoxymethyl) -2- [2- {3- (pyridin-3-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Prepared using 4-hydroxy-6-methoxymethyl-2-methylthiopyrimidine as starting material.

Yield: 804mg, 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，1H)；m/z 354[MH]+。

Method 36

4-hydroxy-6-methoxymethyl-2- [2- {3- (thiazol-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

Prepared using 4-hydroxy-6-methoxymethyl-2-methylthiopyrimidine as starting material.

Yield: 451mg, 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- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] -6-trifluoromethylpyrimidine

Prepared using 2-ethylsulfanyl-4-hydroxy-6-trifluoromethylpyrimidine as starting material.

Yield: 710mg, 30%.

NMR(CDCl₃)：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- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidine-1-carboximidamide (trifluoroacetate)

TFA (30ml) was added to cooled N, N' -di (R) (N-methyl) at 0 deg.CTertiary carboxylic acidButoxycarbonyl) -2- [3- (pyridin-2-yl) isoxazol-5-yl]Pyrrolidine-1-carboximidamide (method 39) in DCM (150 ml). The mixture was stirred at 0 ℃ for 1 hour, allowed to warm to ambient temperature and stirred for a further 18 hours. The volatiles were removed by evaporation and the residue was triturated with DCM/ether/hexane. The product was collected by filtration to give the title compound (2.2g, > 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' -bis (tert-butoxycarbonyl) -2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidine-1-carboximidamide

2- [3- (pyridin-2-yl) isoxazol-5-yl]Pyrrolidine (method 12) (1.5g, 7mmol) was added to N, N' -di (R) (1Tert butylOxycarbonyl) -N "- (trifluoromethylsulfonyl) guanidine (2.59g, 6.6mmol) and triethylamine (0.975ml) in DCM and the mixture was stirred at ambient temperature for 8 hours. The mixture was then washed with water and dried (MgSO ₄) And the volatiles were removed by evaporation. Removing residuesThe residue was purified by chromatography on silica eluting with DCM/methanol (100: 0 to polarity increase to 98: 2) to give the title compound (2.3g, 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-butyllithium (6.29ml of a 1.6M hexane solution, 10.1mmol) was added to a solution of acetoxime (368mg, 5.0mmol) in anhydrous THF (20ml) cooled to-5 ℃ under nitrogen so that the temperature of the reaction was maintained at a temperature below 0 ℃. Upon complete addition, the mixture was stirred at 0 ℃ for 1 hour. Then, N- (R) is added thereto at a rate to maintain the reaction temperature at a temperature lower than 0 deg.CTertiary carboxylic acidA solution of butoxycarbonyl) -L-proline N '-methoxy-N' -methylamide (1.0g, 3.87mmol) in dry THF (30 ml). Upon complete addition, the mixture was stirred at 0 ℃ for 3.5 hours. The reaction mixture was quenched with 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 triturated with iso-hexane to give solid intermediate oxime (617 mg). This oxime (617mg, 2.28 mmol) and triethylamine (0.41ml, 2.96mmol) were dissolved in anhydrous THF (20ml) and methanesulfonyl chloride (0.19ml, 2.54mmol) was added thereto at ambient temperature and the mixture was stirred at ambient temperature 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 intermediate mesylate as an oil. This mesylate was added to 4M hydrogen chloride in 1, 4-dioxane (15ml, 90mmol) and the mixture was heated at reflux for 30 min. The mixture was allowed to cool and then poured onto a 50g isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutral material, and then the product was eluted with 7M methanolic ammonia. The solvent was removed by evaporation and the residue was purified by chromatography on silica eluting with DCM/MeOH (100: 0 to polarity increase to 90: 10) to give the title compound as an oil (273mg, 46%).

NMR(CDCl₃)：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

S-N-tert-Butoxycarbonyl-2- (3- (2-pyridyl) isoxazol-5-yl) pyrrolidine

13% sodium hypochlorite solution in water (4.6ml) was added to a vigorously stirred S-N-Tertiary carboxylic acidButoxycarbonyl-2-ethynylpyrrolidine (prepared as described in Bull. Soc. Chim. Fr.1997, 134, 141-144 and J.Med. chem.1994, 37, 4455-4463) (1.0g, 5.2mmol) and pyridin-2-ylaldoxime (577mg, 4.72mmol) in dichloromethane (15 ml). After complete addition, the reaction was stirred at 0 ℃ for 2.5 hours. Then, the mixture was diluted with water and dichloromethane, and layer partitioning and separation were performed. The organic layer was washed with water and brine in this order and dried (Na)₂SO₄) And the volatiles were removed by evaporation. The residue was purified by chromatography on silica eluting with 10% isohexane/ethyl acetate (90: 10 to increasing polarity to 75: 25) to give the title compound as a waxy solid (0.69g, 47%).

Nmr (dmso) (major rotamers): 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]+。Rotationα_D-104.8(c ═ 1.0, methanol).

Method 42

S-2- (3- (2-pyridinyl) isoxazol-5-yl) pyrrolidine

Trifluoroacetic acid (2.3ml) was added to the stirred S-N-Tertiary carboxylic acidTo a solution of butoxycarbonyl-2- (3- (2-pyridyl) isoxazol-5-yl) pyrrolidine (method 41) (0.744g, 2.36mmol) in dichloromethane (12 ml). The reaction was stirred at 0 ℃ for 1 hour, then at ambient temperature for 18 hours. The volatile materials were removed by evaporation and the residue was dissolved in distilled water (23 ml). The pH of the solution was adjusted to 10.5 by careful addition of solid sodium carbonate, followed by 40% aqueous sodium hydroxide near the end point. The aqueous solution was extracted with dichloromethane (× 4), the organic extracts combined and dried (Na)₂SO₄) And the solvent was removed by evaporation to give the title compound (0.446g, 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]+。Rotationα_D-15.2(c ═ 1.0, methanol).

Method 43

2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidin-6-yl carboxylic acid

A solution of 2-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidin-6-yl carboxylic acid sodium salt (method 44) (58mg, 0.21mmol) and 2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidine (method 12) (54mg, 0.25mmol) in water (4ml) was heated at 110 ℃ for 18 hours. The solid product was isolated from the hot reaction mixture by filtration, washed with cold water and dried. The product was then triturated with ether to give the title compound (48.1mg, 53%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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/z433[ MH]+。

Method 44

2-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidin-6-ylmethanoic acid sodium salt

A mixture of 2, 4-dichloropyrimidin-6-ylcarboxylic acid (method 45) (528mg, 2.73mmol), 3-amino-5-methylpyrazole (279mg, 2.87mmol) and sodium carbonate (578mg, 5.46mmol) in water (10ml) was heated at 50 ℃ for 18 h. The mixture was allowed to cool and the product was collected by filtration, washed with water and dried to give the title compound (430mg, 77%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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 (50g, 0.32mol), phosphorus oxychloride (298ml, 3.2mol) and N, N-dimethylaniline (44.7ml, 0.35mol) was heated at 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 ether, decolorized with charcoal, filtered and the volatiles were removed from the filtrate by evaporation. The residue was treated with hot iso-hexane, insoluble material was removed by filtration and the solvent was removed by evaporation of the filtrate to give the title compound (29.05g, 47.6%).

NMR(DMSO-d₆)：8.15(s，1H)；m/z 191[MH]-。

Method 46

1-tert-butoxy-2- (2-methyl-2H-tetrazol-5-yl) pyrrolidine

Will 1-Tertiary carboxylic acidA mixture of butoxy-2- (2H-tetrazol-5-yl) pyrrolidine (method 47) (500mg, 2.2mmol), cesium carbonate (1.43g, 4.4mmol), iodomethane (0.41ml, 6.6mmol) in acetonitrile (15ml) was stirred at room temperature for 12 hours. Pouring the solution from the solid material and then dissolving the solutionThe solution was partitioned between water and ethyl acetate. The organics were separated and dried (MgSO) ₄) And the volatiles were removed by evaporation. The residue was purified by chromatography on silica eluting with isohexane/ethyl acetate (100: 0 to increasing polarity to 0: 100) to give the title compound as a clear oil (175mg, 33%).

NMR(CDCl₃)：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-tert-butoxy-2- (2H-tetrazol-5-yl) pyrrolidine

Will be provided withTertiary carboxylic acidA mixture of butoxy-2-cyanopyrrolidine (3g, 15.3mmol), sodium azide (1.49g, 23.0mmol) and ammonium chloride (1.22g, 23mmol) in DMF (15ml) was heated at 95 ℃ for 48 h. The reaction was then partitioned between ethyl acetate and water. The organics were separated and dried (MgSO)₄) And the volatiles were removed by evaporation. The residue was triturated with ether and collected by filtration to give the title compound as a white solid (0.79g, 22%).

NMR(CDCl₃)：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-1H-pyrazol-3-ylamino) pyrimidine

A mixture of 2, 4, 6-tribromopyrimidine (3.5g, 11mmol), 5-methyl-1H-pyrazole (1.077g, 11mmol), sodium carbonate (1g) in ethanol (50ml) was stirred at ambient temperature under nitrogen for 18H. The volatiles were removed by evaporation and the residue was dissolved in DCM and a minimum amount of methanol. The resulting solution was washed with water and dried (Na) ₂SO₄) And the solvent volume was reduced by evaporation. The product precipitated out and was collected by filtration to give the title compound (1.7g, 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- (pyridin-2-yl) isoxazol-5-yl) pyrrolidine) pyrimidine

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

S-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidin-6-yl carboxylic acid

2-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidin-6-yl carboxylic acid sodium salt (method 44) and S-2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidine (method 42) were treated as described in method 43 to give the title compound.

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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/z433[ MH]+。

Method 51

6- [ N- (acetylamino) carbamoyl ] -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (2-acetyl-5-methyl-1H-pyrazol-3-ylamino) pyrimidine

Acetyl chloride (0.28ml, 3.94mmol) was added to a mixture of 6-hydrazide-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (example 77) (800mg, 1.79mmol) and triethylamine (0.6ml, 4.13mmol) in dry THF (20ml) at 0 deg.C. The reaction was allowed to warm to ambient temperature and stirred for an additional 1 hour. The volatiles were removed by evaporation, the residue triturated with water and collected by filtration to give the title compound (911mg, 96%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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 MH ]+。

Method 52

6- [ (4-Methylphenylsulfonyloxy) methyl ] -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-2-N- [ 4-methylphenylsulfonyl ] -1H-pyrazol-3-ylamino) pyrimidine

P-toluenesulfonyl chloride (3.0g, 15.7mmol) was added to a mixture of 6-hydroxymethyl-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (example 80) (3.13g, 7.49mmol), triethylamine (2.5ml, 18mmol) in dry THF (50 ml). The resulting mixture was stirred at room temperature for 1 hour, and then it was heated under 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 eluting with DCM (100%) followed by ether (100%) to give the title compound (containing 31% of the 6-chloromethyl derivative) (1.69g, 31%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-2-N- [ 4-methylphenylsulfonyl ] -1H-pyrazol-3-ylamino) pyrimidine

P-toluenesulfonyl chloride (624mg, 3.26mmol) was added to a mixture of S-6-hydroxymethyl-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (example 86) (570.4mg, 1.36mmol) and N, N-diisopropylethylamine (0.467ml, 3.40mmol) in dry THF (20 ml). The mixture was stirred at room temperature for 1 hour, and then heated under 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 removed by evaporation and the residue purified by chromatography on silica gel eluting with dichloromethane (100%) then ether (100%) to give the title compound (403mg, 50%).

NMR(DMSO-d₆+d₄-acetic acid at 100 ℃): 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

Pyrazine-2-aldoximes

A solution of 1N lithium aluminium hydride in THF (73.8ml, 73.8mmol) was added to a suspension of pyrazine-2-carboxylic acid methyl ester (20g, 145mmol) in dry THF (300.0ml) at-78 deg.C while maintaining the reaction temperature below-72 deg.C. At the complete addition, the reaction mixture was stirred at-78 ℃ 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 (116ml) and extracted with DCM. The extracts were combined, washed with saturated aqueous sodium bicarbonate and the solvent was evaporated. The residue was purified by chromatography on silica eluting with DCM/diethyl ether (100: 0, then 80: 20, then 0: 100) to give pyrazine-2-aldehyde (15.67g, 100%). It was immediately dissolved in chloroform (200ml) cooled to 0 ℃ and hydroxylamine monohydrochloride (11.02g, 159.5mmol) and triethylamine (24.2ml, 117.4mmol) were added thereto. Then, the reaction mixture was stirred at room temperature for 0.5 hour, and the solvent was removed by evaporation. The residue was suspended in diethyl ether (500ml) and the insoluble material was removed by filtration. The filtrate was evaporated and the residue was purified by chromatography, eluting with DCM/diethyl ether (100: 0, then 80: 20, then 0: 100) to give the title compound (5.5g, 31%) as a solid.

NMR(DMSO-d₆)：8.15(s，1H)，8.62(dd，2H)，8.99(s，1H)。

Method 55

S-2- [3- (2-pyrazinyl) isoxazol-5-yl ] pyrrolidine

A solution of 13% sodium hypochlorite in water (5.95ml, 12.51mmol) was added to S-N-Tertiary carboxylic acidButoxycarbonyl-2-ethylnl pyrrolidine (1.344g, 6.88mmol), pyrazine-2-aldoxime (770mg, 6.26mmol) and DCM (50ml) were added while maintaining the reaction temperature below-3 ℃. The reaction mixture was then stirred at ambient temperature for 5 hours. Water was added thereto, the organic layer was separated and the solvent was evaporated. The residue was dissolved in 4M hydrogen chloride in 1, 4-dioxane (20ml) and methanol (30ml) and the mixture was heated at reflux for 1 h. The mixture was allowed to cool, the volatiles were removed by evaporation, and the residue was dissolved in waterThe pH of the solution was adjusted to 12 with 10M aqueous sodium hydroxide. The aqueous mixture was extracted with DCM, the extracts were combined, evaporated and the residue was purified by chromatography on silica gel, extracted with DCM, then with ether/DCM (20: 80) and finally with methanol/DCM (2: 98 to polarity increase to 10: 90). The purified product was then triturated with ether and collected by filtration to give the title compound (344mg, 25%).

NMR(DMSO-d₆)：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[MH]+。

Method 56

2-chloro-6-methyl-4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine

Solid sodium carbonate (1.2g, 11.3mmol) was added to a solution of 2, 4-dichloro-6-methylpyrimidine (1.7g, 10.3mmol) and 5-amino-3-methyl-1H-pyrazole (1.0g, 10.3mmol) in anhydrous ethanol (50ml) and the mixture was stirred and heated at 42 ℃ for 3 days. The mixture was allowed to cool, insoluble material was removed by filtration and the filter pad was washed with ethanol (10 ml). Volatiles were removed from the filtrate by evaporation, maintaining the bath temperature below 40 ℃. The residue was immediately purified by chromatography on silica eluting with methanol/DCM (5: 95 to polarity increase to 20: 80) to give the title compound as a white solid (758mg, 33%).

NMR(CDCl₃)：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-1H-pyrazol-3-ylamino) pyrimidine

2, 4, 6-trichloropyrimidine and 3-amino-5-cyclopropyl-1H-pyrazole (method 7 of WO 03/048133) were treated as described in method 29 to give the title compound (12g, 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-ylboronic acid [2, 3-dihydroxy-2, 3-dimethylbutane ] ester

Borane methyl sulfide complex (8.4ml of 2M THF solution) was added dropwise to a solution of α -pinene (5.4ml, 34mmol) in THF (10ml) at 0 ℃ and the mixture was stirred for 1 hour. The mixture was allowed to warm to ambient temperature, stirred for 2 hours, and then cooled to 0 ℃. Then, 3-, (ii) is slowly added thereto Tertiary carboxylic acidA solution of butoxycarbonylamino) prop-1-yne (2.0g, 13mmol) in THF (5ml) and the mixture was stirred at ambient temperature for 18 h. The mixture was cooled to 0 ℃ and acetaldehyde (14.3ml, 0.25mmol) was added dropwise thereto. The mixture was stirred for 5 hours, then excess acetaldehyde was added thereto and the solvent was removed by evaporation. 2, 3-dihydroxy-2, 3-dimethylbutane (2.4g, 20mmol) in heptane was added and the mixture was stirred at ambient temperature for 18 hours. The mixture was washed with water and dried (Na)₂SO₄) And the solvent was evaporated. The residue was purified by column chromatography on silica gel eluting with EtOAc/hexanes (10: 90 to polarity increase to 18: 82) to give the title compound, which was used as is.

Method 59

3- (N-methylacetamido) prop-1-yne

Acetic anhydride (1.2ml, 12.7mmol) was added dropwise to a solution of N-methylpropargylamine (400mg, 5.8mmol) and 4-dimethylaminopyridine (70mg, 0.67mmol) 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 eluting with methanol/DCM (5: 95 then 10: 90) to give the title compound (136mg, 22%).

NMR(DMSO)：1.99(s，3H)，2.98(s，3H)，4.12(s，2H)，4.15(s，1H)。

Method 60

S-6- [3- (N-phthalimido) prop-1-yn-1-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine

S-6-iodo-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine (example 98) and 3- (N-phthalimido) prop-1-yne were reacted by the method described in example 105 to give the title compound (150mg, 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)，5.68(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-chloropyridin-3-yl aldoximes

A solution of hydroxylamine hydrochloride (533mg, 7.6mmol) in water (1.8ml) was added dropwise to sodium hydroxide (708mg, 17mmol) in water (2 ml). Then, the resulting solution was added dropwise to a solution of 2-chloropyridin-3-ylaldehyde (1g, 7mmol) in ethanol (7ml), water (7ml) and ice (15 g). The mixture was stirred at room temperature for 18 hours. The mixture was neutralized to pH7 with 6M hydrochloric acid. The solid product was collected by filtration, washed with water and dried to give the title compound (800mg, 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

S-N- (tert-butoxycarbonyl) -2- [3- (2-chloropyridin-3-yl) isoxazol-5-yl ] pyrrolidine

Sodium hypochlorite (5.3ml of a 13% aqueous solution) was added dropwise to the vigorously stirred 2-chloropyridin-3-ylaldoxime (method 61) (800mg, 5.1mmol) and S-N- Tertiary carboxylic acidButoxycarbonyl-2-ethynylpyrrolidine (prepared as described in Bull. Soc. Chim. Fr.1997, 134, 141-144 and J.Med. chem.1994, 37, 4455-4463) (1.99g, 10.2mmol) in DCM (20 ml). The mixture was warmed 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/hexanes (20: 80) to give the title compound (955mg, 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

S-N- (tert-butoxycarbonyl) -2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidine

Mixing S-N-, (Tertiary carboxylic acidButoxycarbonyl) -2- [3- (2-chloropyridin-3-yl) isoxazol-5-yl]A mixture of pyrrolidine (method 62) (950mg, 2.7mmol) and sodium methoxide (740mg, 13.7mmol) in methanol (25ml) was heated at reflux for 18 h. The reaction mixture was cooled and diluted with EtOAc. The solution was washed with water and dried (Na)₂SO₄) And the solvent was removed by evaporation. The residue was purified by chromatography on silica eluting with EtOAc/hexanes (15: 85) to give the title compound (675mg, 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- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidine

2M hydrochloric acid (25ml) was added to S-N-, (S-N-) (S Tertiary carboxylic acidButoxycarbonyl) -2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl]Pyrrolidine (method 63) (670mg, 2mmol) in methanol (25ml) and the mixture stirred at room temperature for 2.5 days. The mixture was concentrated by evaporation, adjusted to pH 7 with 40% aqueous sodium hydroxide and extracted with DCM. The extracts were combined and dried (MgSO)₄) And the solvent was removed by evaporation to give the title compound (300mg, 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-1H-pyrazol-3-ylamino) -2-chloropyrimidine

A mixture of 2, 4-dichloropyrimidine (2.97g, 20mmol), 5-amino-3-ethyl-1H-pyrazole (2.44g, 22mmol) and N, N-diisopropylethylamine (3.8ml, 22mmol) in dry THF (75ml) was heated at 60 deg.C for 18H. The volatiles were removed by evaporation and the residue triturated with a mixture of DCM and water. The solid product was collected by filtration, washed with water and diethyl ether, and dried to give the title compound (1.55g, 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- [3- (pyrimidin-2-yl) isoxazol-5-yl ] pyrrolidine

13% aqueous sodium hypochlorite solution (4.25ml, 7.45mmol) was slowly added to S-N-Tertiary carboxylic acidButoxycarbonyl-2-ethynylpyrrolidine (prepared as described in Bull. Soc. Chim. Fr.1997, 134, 141-144 and J.Med. chem.1994, 37, 4455-4463) (1.45g, 7.45mmol) and pyrimidine-2-aldoxime (0.47g, 3.82 mm) ol, Khimiya Geterotsikh Soedinenii (1972), 10, 1422-4) in DCM (15 ml). The reaction mixture was allowed to warm to ambient temperature and then stirred for 12 hours. The mixture was diluted with ethyl acetate, the layers were separated, and the solvent was removed from the organic layer by evaporation. The residue was purified by column chromatography on silica gel eluting with EtOAc/hexanes (0: 100 to polarity increase to 100: 0). The product fractions were evaporated to give a gold colored oil which solidified to a solid on standing (250mgs, 20%). This solid was then dissolved in TFA (2ml) and stirred at ambient temperature for 45 minutes. The reaction was evaporated to dryness and the residue was dissolved in DCM and poured onto an isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutral material, and then the product was eluted with 7M methanolic ammonia. Fractions containing the product were evaporated to give the title compound as an orange solid (125mg, 15%).

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[MH]+。

Method 67

3-methoxypyrazine-2-aldoxime

A mixture of 3-methoxypyrazine-2-aldehyde (Tetrahedron (1999), 56(2), 265-273) (2.1g, 15mmol), hydroxylamine hydrochloride (1.27g, 18mmol), ethanol (20ml) and triethylamine (4.17ml, 30mmol) was heated at 60 ℃ for 90 minutes. The volatiles were removed by evaporation and the residue was purified by column chromatography on silica eluting with hexane/EtOAc (100: 0 to increasing polarity to 0: 100) to give the title compound as a white solid (740mg, 32%).

NMR(DMSO-d₆)：3.96(s，3H)，8.22(s，2H)，8.23(m，1H)，11.89(s，1H)。

Method 68

S-2- [3- (2-methoxypyrazin-3-yl) isoxazol-5-yl ] pyrrolidine

Sodium hypochlorite (5.23ml of a 13% aqueous solution, 9.16mmol) was slowly added to the stirred S-N-Tertiary carboxylic acidButoxycarbonyl-2-ethynylpyrrolidine (prepared as described in Bull. Soc. Chim. Fr 1997, 134, 141-144 and J.Med. chem.1994, 37, 4455-4463) (1.07g, 5.50mmol), 3-methoxypyrazine-2-carboxaldoxime (method 67) (0.7g, 4.58mmol) in DCM (40 ml). The reaction was allowed to warm to ambient temperature and then stirred for 12 hours. The layers were separated and the solvent was removed from the organic layer and the residue was purified by silica gel column chromatography eluting with hexane/EtOAc (100: 0 to increasing polarity to 0: 100). On standing, the purified product solidified to a solid, which was dissolved in TFA (10ml) and the mixture was stirred at room temperature for 30 min. The volatiles were removed by evaporation and the residue was dissolved in DCM and poured onto an isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutral material, and then the product was eluted with 7M methanolic ammonia. The solvent was removed by evaporation to give the title compound as a brown oil (260mgs, 23%).

NMR(DMSO-d₆)：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[M[H]+。

Method 69

2-chloro-4- (5-ethyl-1H-pyrazol-3-ylamino) -5-fluoropyrimidine

5-amino-1H-3-ethylpyrazole and 2, 4-dichloro-5-fluoropyrimidine were treated as described in method 65 to give the title compound as an off-white crystalline solid (1.89g, 78%).

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-1H-pyrazol-3-ylamino) pyrimidine

Sodium carbonate (2.15g, 20.25mmol) was added to a stirred solution of 2, 4-dichloro-6-methylpyrimidine (3g, 18.4mmol) and 3-amino-1H-5-cyclopropylpyrazole (2.25g, 18.4mmol) in anhydrous ethanol (40ml) and the mixture was stirred at 40 ℃ for 4 days. Insoluble material was removed by filtration and the filter pad was washed with ethanol. Volatiles were removed from the filtrate by evaporation while maintaining the bath temperature below 40 ℃. The residue was immediately purified by column chromatography on silica eluting with methanol/DCM (0: 100 to polarity increase to 20: 80) to give the title product as a white solid (1.9g, 46%).

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-chloro-6- (3-hydroxypropyl) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine

2.5% w/v osmium tetroxide inTertiary carboxylic acidA solution in butanol (0.47ml) was added to 4-chloro-6- (pent-3-en-1-yl) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl with vigorous stirring ]Pyrrolidin-1-yl } pyrimidine (prepared as described in example 34) in a solution of THF (10.5ml) and water (2.8 ml). Then, solid sodium periodate (951mg, 4.44mmol) was added thereto. 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 and dried (Na)₂SO₄) And the solvent is removed by evaporation. The residue was dissolved in THF (13.5ml) and distilled water (5.0ml) and sodium borohydride (59mg, 1.59mmol) was added thereto. The reaction was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and water, and layer partitioning and layer separation were performed. The ethyl acetate layer was washed with water and saturated brine and dried (Na)₂SO₄) 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 (205mg, 36%)。

NMR(DMSO-d₆/300MHz)：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，1)，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-1H-pyrazol-3-ylamino) pyrimidine

2, 4, 6-trichloropyrimidine and 3-amino-5-ethyl-1H-pyrazole (method 6 of WO 03/048133) were treated as described in method 29 to give the title compound (2.48g, 51%).

NMR(DMSO-d₆At 100 ℃): 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

The S-N-Tertiary carboxylic acidButoxycarbonyl-2- (3- (thiazol-4-yl) isoxazol-5-yl) pyrrolidine (method 74) (334mg, 1.04mmol were treated as described in method 42 to give the title compound (217mg, 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，1H)；m/z 222[MH]+

Method 74

S-N-tert-Butoxycarbonyl-2- (3- (thiazol-4-yl) isoxazol-5-yl) pyrrolidine

A solution of triethylamine (0.7ml, 5.4mmol) in THF (2ml) was added dropwise to stirred thiazole-4-chloroaldoxime (method 75) cooled to 0 deg.C (730mg, 4.5mmol) and S-N-Tertiary carboxylic acidButoxycarbonyl-2-ethynylpyrrolidine (as described in Bull. Soc. Chim. Fr.1997, 134, 141-144 and J.Med. chem.1994, 37, 4455-4463)Prepared as such) (0.96g, 4.95mmol) in THF (20 ml). The mixture was allowed to warm to ambient temperature and stirred for 18 hours. The solvent was removed by evaporation, the residue partitioned between DCM and water and the insoluble material removed by filtration. Layer separation was performed, the solvent was removed from the organic layer, and the residue was purified by silica gel column chromatography eluting with hexane/EtOAc (3: 1 to polarity increase to 3: 2) to give the recovered acetylene (634mg) and the title compound (334mg, 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-chloroaldoxime

N-chlorosuccinimide (600mg, 4.5mmol) was added to a solution of thiazole-4-aldoxime (method 76) (579mg, 4.5mmol) in DMF (4ml) cooled to 0 ℃. The reaction was stirred at 0 ℃ for 1 hour, allowed to warm to ambient temperature and stirred for an additional 2 hours. The mixture was diluted with ether and water. The ether layer was separated and washed with water and brine, the solid product was collected by filtration and the filtrate was dried (Na)₂SO₄) The solvent was removed by evaporation to give the solid product. The two solid batches were combined to give the crude title compound (730mg, 100%).

NMR(DMSO)：8.12(s，1H)，9.15(s，1H)，12.42(s，1H)；m/z 163[MH]+

Method 76

Thiazole-4-aldoximes

Thiazole-4-aldehyde (Synthesis 1987, 998) was treated as 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- (thiazol-2-yl) isoxazol-5-yl) pyrrolidine

3M hydrochloric acid (26ml) was added to S-N-Tertiary carboxylic acidA solution of butoxycarbonyl-2- (3- (thiazol-2-yl) isoxazol-5-yl) pyrrolidine (method 78) (8.32g, 26mmol) in methanol (26ml) was added and the mixture was stirred at room temperature for 18 h, then at 60 ℃ for 1 h. Volatiles were removed by evaporation, the aqueous layer was washed with DCM, adjusted to pH 11-12 with 40% aqueous sodium hydroxide and extracted with DCM (× 6). The extracts were combined and dried (Na) ₂SO₄) And the solvent was removed by evaporation. The residue was purified by silica gel column chromatography eluting with methanol/DCM (5: 95) to give the title compound as a yellow oil (4.01g, 70%).

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

S-N-tert-Butoxycarbonyl-2- (3- (thiazol-2-yl) isoxazol-5-yl) pyrrolidine

N-chlorosuccinimide (10.6g, 80mmol) was added portionwise to a solution of thiazole-2-aldoxime (method 2) (10.35g, 80mmol) in DMF (30ml) cooled to-5 ℃. The reaction was stirred at-5 ℃ for 1 hour and then allowed to warm slowly to ambient temperature over 3 hours. The mixture was diluted with ether, EtOAc and water. The solid product was collected by filtration. The organic layer was separated, washed with water and brine and dried (Na)₂SO₄) And the solvent was removed by evaporation, maintaining the bath temperature at ambient temperature to give the solid product. The two solid batches were combined, dissolved directly in THF (200ml) and the solution was added dropwise to S-N-Tertiary carboxylic acidButoxycarbonyl-2-ethynylpyrrolidine (prepared as described in Bull. Soc. Chim. Fr.1997, 134, 141-144 and J.Med. chem.1994, 37, 4455-4463) (31g, 160mmol) and triethylamine (13.4ml, 96mmol) in THF (200ml) and the mixture was slowly warmed to a temperature of Ambient temperature and stir 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 and dried (Na)₂SO₄) And the solvent was removed by evaporation. The residue was purified by column chromatography on silica gel eluting first with EtOAc/hexanes (1: 4 to polarity increase to 1: 1) to elute the starting acetylene recovered and then the title compound as an orange oil (8.32g, 32%).

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-ethyl-1H-pyrazol-3-ylamino) pyrimidine

2, 4-dichloro-6-ethyl-pyrimidine (J.Am.chem.Soc.1936, 58, 78) (1.33g7.53mmol) was stirred in ethanol (50ml) and 5-ethyl-1H-3-amino-pyrazole (method 6 of WO 03/048133) (0.836g, 7.53mmol) was added thereto, followed by addition of sodium carbonate (1.25g) and stirring of the mixture at 40 ℃ for 4 days, then at 55 ℃ overnight. The insoluble inorganic matter was removed by filtration and the solvent was removed from the filtrate by evaporation. Water (100ml) was added to it and the mixture was extracted with EtOAc (3X 50 ml). The extracts were combined, washed with water (50ml), brine (50ml) and 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 to increasing polarity to 0: 100) to give the title compound as a white solid (210mg, 11%).

NMR(DMSO-d₆At 100 ℃): 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

Treatment of 2, 4-dichloro-6-ethyl-pyrimidine (j.am. chem. soc.1936, 58, 78) and 5-cyclopropyl-1H-3-amino-pyrazole (method 7 of WO 03/048133) in a manner similar to that described in method 79 gave the title compound as a yellow powder (464mg, 32%).

NMR(DMSO-d₆At 100 ℃): 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

Treatment of 2, 4-dichloro-6-cyclopropylpyrimidine (chem. abs.1969, 71, 61412y) and 5-cyclopropyl-1H-3-amino-pyrazole (method 7 of WO 03/048133) in a manner similar to that described in method 79 gave the title compound as a pink solid (200mg, 23%).

NMR(DMSO-d₆At 100 ℃): 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-1H-pyrazol-3-ylamino) pyrimidine

Treatment of 2, 4-dichloro-6-cyclopropylpyrimidine (chem. abs.1969, 71, 61412y) and 5-ethyl-1H-3-amino-pyrazole (W003/048133, method 6) in a manner similar to that described in example 79 gave the title compound as a pink solid (200mg, 23%).

NMR(DMSO-d₆At 100 ℃): 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-1H-pyrazol-3-ylamino) pyrimidine

2, 4-dichloro-6-methylpyrimidine and 5-amino-3-ethyl-1H-pyrazole (method 6 of WO 03/048133) were treated in a similar manner to the method described in method 56 to give the title compound (450mg, 42%).

NMR(DMSO-d₆At 100 ℃): 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 (5.33g, 30.6mmol) in ethanol (20ml) was added to a mixture of thiourea (3.29g, 43.3mmol) and sodium ethoxide in ethanol (22.4ml of a 21% wt/wt solution) heated at 80 ℃ and the mixture was stirred at 75 ℃ for 18 h. The volatiles were removed by evaporation, the residue was dissolved in water and the pH of the solution was adjusted to 3 with 2M hydrochloric acid. The mixture was cooled on ice and the precipitated solid was collected by filtration and dried to give the title compound (2.52g, 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) (3.9g, 19.5mmol) and chloroacetic acid (1.89g, 19.9mmol) in water (20ml) was heated at 120 ℃ for 24 h. The mixture was allowed to cool, its pH was adjusted to 7 with sodium hydroxide solution and extracted with EtOAc. The extracts were combined and dried (Na)₂SO₄) And the solvent was removed by evaporation to give the titled compound as a solidCompound (1.9g, 55%).

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) (1.9g 10.2mmol) and N, N-dimethylaniline (2ml) in phosphorus oxychloride (20ml) was heated at 90 ℃ for 30 minutes. The mixture was allowed to cool, ice water was added thereto and the mixture was extracted with EtOAc. The extracts were combined, washed with 2M hydrochloric acid and dried (Na)₂SO₄) 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 (1.5g, 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 (method 86) and 3-amino-1H-5-methylpyrazole were treated as described for method 70 to give the title compound (200mg, 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]+。

Pharmacological analysis

Method for detecting inhibition of Igf-1r kinase activity and downstream signaling and selectivity for insulin receptor kinase and Egfr signaling

Abbreviations used:

PBS (PBS/T) is phosphate buffered saline, pH7.4 (with 0.05% 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 triphosphate

DMEM is Dulbecco's modified eagle's Medium

FBS/FCS is fetal calf/calf serum

HBSS is a Hanks balanced salt solution

HRP is horse radish peroxidase

SDS is sodium dodecyl sulfate

IGF-I (IGF-1R) is insulin-like growth factor-I (IGF-1 receptor)

EGF is an epidermal growth factor

IGF-1R kinase assay

a) Protein cloning, expression and purification

A DNA molecule encoding a fusion protein comprising glutathione-S-transferase (GST), a thrombin cleavage site and the IGF-1R intracellular domain (amino acids 930-1367), and subsequently referred to as GST-IGFR, was constructed and cloned into pFastBac1(Life Technologies Ltd, UK) using standard Molecular biology techniques (Molecular Cloning-A Laboratory Manual, second edition, 1989; Sambrook, Fritsch and Maniatis; Cold spring Harbour Laboratory Press).

Recombinant viruses were made according to the manufacturer's protocol.

Briefly, GST-The pFastBac-1 vector for IGFR was transformed into e.coli DH10Bac cells containing a baculovirus genome (bacmid DNA) and by a transposition event in the cells, regions of the pFastBac vector containing a gentamicin-tolerant gene and a GST-IGFR expression cassette (expression cassette) including a baculovirus polyhedrin promoter were directly transposed into the bacmid DNA. By selecting for gentamicin, kanamycin, tetracycline and X-gal, the resulting white colonies should contain recombinant bacmid DNA encoding GST-IGFR. Bacmid DNA was extracted from small-scale cultures of some BH10Bac white colonies and transfected into Spodoptera frugiperda Sf21 cells grown in TC100 medium containing 10% serum (Life Technologies Ltd, UK) as directed by the manufacturer. Viral particles were harvested by collecting cell culture medium 72 hours after transfection. Infection of 100ml with 0.5ml of medium contained 1X 10⁷Suspension culture of Sf21s at individual cells/ml. Cell culture media was harvested 48 hours after infection and virus titers were determined using standard plaque assay procedures. Sf9 and "High 5" cells were infected with viral stocks at a multiplicity of infection (MOI) of 3 to determine expression of recombinant GST-IGFR.

The GST-IGFR protein is purified by affinity chromatography using glutathione-agarose, followed by elution with glutathione. Briefly, cells were lysed in 50mM HEPES pH7.5(Sigma, H3375), 200mM NaCl (Sigma, S7653), Complete Protease Inhibitor cocktail (Roche, 1873580) and 1mM DTT (Sigma, D9779), hereinafter referred to as lysis buffer. The clarified lysate supernatant was loaded onto a chromatographic column packed with glutathione sepharose (Amersham Pharmacia Biotech UK Ltd.). The contaminants were washed from the matrix with lysis buffer until the UV absorption at 280nm returned to baseline. Elution was performed with lysis buffer containing 20mM reduced glutathione (Sigma, D2804) and fractions containing GST fusion proteins were pooled and dialyzed into glycerol containing buffer containing 50mM HEPES, pH7.5, 200mM NaCl, 10% glycerol (v/v), 3mM reduced glutathione and 1mM DTT.

b) Kinase Activity assay

The activity of the purified enzyme was measured by phosphorylation of synthetic poly GluAlaTyr (EAY) 6: 3: 1 peptide (Sigma-Aldrich Company Ltd, UK, P3899) in a 96-well format plate using an ELISA detection system.

b.i) reagents used therein

Stock solution

200mM HEPES, pH 7.4 were stored at 4 ℃ (Sigma, H3375)

1M DTT was stored at-20 ℃ (Sigma, D9779)

100mM Na₃VO₄Is stored at 4 ℃ (Sigma, S6508)

1M MnCl₂Was stored at 4 ℃ (Sigma, M3634)

1mM ATP was stored at-20 deg.C (Sigma, A3377)

The Neat Triton X-100 was stored at room temperature (Sigma, T9284)

10mg/ml BSA was stored at 4 deg.C (Sigma, A7888)

Enzyme solution

GST-IGF-1R fusion protein, 75ng/ml in 100mM HEPES, pH 7.4, 5mM DTT, 0.25mM Na₃VO₄0.25% Triton X-100, 0.25mg/ml BSA.

Cofactor solution

100mM HEPES，pH 7.4，60mM MnCl₂，5mM ATP。

Poly EAY substrate

Sigma substrate poly (Glu, Ala, Tyr) 6: 3: 1 (P3899). Prepared up to 1mg/ml in PBS and stored at-20 ℃.

Test board

Nunc Maxisorp 96-well immunoplates (Life Technologies Ltd, UK).

Antibodies

Anti-phosphotyrosine antibody, monoclonal, obtained from Upstate Biotechnology inc, NY, USA (UBI 05-321). Mu.l of each assay plate was diluted with 11ml PBS/T + 0.5% BSA. Sheep-anti-mouse IgG HRP-conjugated secondary antibodies were obtained from Amersham Pharmacia Biotech UKLtd (NXA 931). Mu.l of stock solution was diluted to 11ml PBS/T + 0.5% BSA per assay plate.

TMB solution

1mg of TMB tablets (Sigma T5525) were dissolved in 1ml of DMSO (Sigma, D8779) in the dark at room temperature for 1 hour. This solution was added to 9ml of freshly prepared 50mM phosphate-citrate buffer pH 5.0+ 0.03% sodium perborate [ 1 buffer capsule per 100ml of distilled water (Sigma P4922) ].

The stop solution was 1M H₂SO₄(Fisher Scientific UK.Cat.No.S/9200/PB08)。

Test compounds

Dissolved in DMSO to 10mM, then diluted with distilled water, in assay wells, in 1-2% DMSO, to give a final concentration range of 200 to 0.0026. mu.M.

b.ii) protocol

The poly EAY substrate was diluted to 1. mu.g/ml with PBS and then dispensed into 96-well plates in an amount of 100. mu.l per well. The plate was sealed and incubated overnight at 4 ℃. Excess poly EAY solution was discarded and the plate was washed (2x PBS/T; 250. mu.l PBS per well) and blotted dry between washes. The plate was then washed again (1X 50mM HEPES, pH 7.4; 250. mu.l per well) and blotted dry (this is important to remove background phosphate levels). Mu.l of test compound solution was added to each well along with 40. mu.l of kinase solution. Then, 50. mu.l of the cofactor solution was added to each well and the plate was incubated at room temperature for 60 minutes.

The plate was emptied (its contents discarded) and washed twice with PBS/T (250. mu.l per well) and blotted dry between washes. To each well 100. mu.l of diluted anti-phosphotyrosine antibody was added and the plate was incubated at room temperature for 60 min.

The plate was again emptied and washed twice with PBS/T (250 ul per well) and blotted between washes. To each well 100 μ l of diluted sheep-anti-mouse IgG antibody was added and the plate was left at room temperature for 60 minutes. The contents were discarded and the plate was washed twice with PBS/T (250. mu.l per well) and blotted dry between each time. 100 μ l of TMB was added to each well and the plates were incubated at room temperature for 5-10 minutes (these solutions turned blue in the presence of horseradish peroxidase).

50 μ l H per well₂SO₄To stop the reaction (turn the blue solution yellow) and read the plate at 450nm in a Versamax plate reader (Molecular Devices Corporation, CA, USA) or similar conditions.

The compounds of the examples were found to have an IC50 of less than 100 μ M in the above assay.

c) Inhibition of IGF-stimulated cell proliferation

Lammers et al have described the construction of murine fibroblasts (NIH3T3) that overexpress the human IGF-1 receptor (EMBO J, 8, 1369-1375, 1989). These cells exhibit a proliferative response to IGF-I, which can be measured by BrdU incorporated into newly synthesized DNA. The inhibition of IGF-stimulated proliferation was used in the following assay to determine compound potency:

c.i) reagents used:

cell proliferation ELISA, BrdU (colorimetric) [ Boehringer Mannheim (Diagnostics and Biochemicals) Ltd, UK.Cat No. 1647229 ]. DMEM, FCS, glutamine, HBSS (all from Life Technologies ltd., UK). FBS (HyClone SH30068.02, Perbio Science UK Ltd) with charcoal/dextran removed. BSA (Sigma, a 7888).

Human recombinant IGF-1 Animal/media grade (GroPep Limited ABN 78008176298, Australia. Cat No. IU 100).

Preparation and storage of IGF

100 μ g of freeze-dried IGF was reconstituted in 100ul 10mM HCl.

400 μ l of 1mg/ml BSA in PBS was added

25 μ l aliquots @200 μ g/ml IGF-1

Stored at-20 ℃.

For the tests:

mu.l stock IGF +12.5ml growth medium gave 8X 160ng/ml stock.

Complete growth medium

DMEM, 10% FCS, 2mM glutamine.

Starvation medium

DMEM, 1% FCS with charcoal/dextran removed, 2mM glutamine.

Test compounds

Compounds were first dissolved in DMSO to 10mM and then diluted with DMEM + 1% FCS + glutamine to give a concentration of 100 to 0.0.45 μ M per test well, with a final DMSO concentration of 1-0.00045%.

c.ii) protocol of the assay

Day 1

Exponentially growing NIH3T3/IGFR cells were harvested and grown in complete growth medium at 1.2X 10 per well⁴The number of each cell is 100 mul volume was seeded into flat bottom 96-well tissue culture grade plates (Costar 3525).

Day 2

Growth medium was carefully removed from each well with a multichannel pipette. These wells were carefully washed three times with 200 μ l HBSS. To each well 100 μ l starvation medium was added and the plate was incubated for an additional 24 hours.

Day 3

Add 50. mu.l of 4 × test compound concentrate to the appropriate wells. These cells were incubated with compound alone for 30 minutes before IGF was added. For cells treated with IGF, a suitable volume (i.e., 25. mu.l) of starvation medium was added to bring the final volume up to 200. mu.l per well, followed by addition of 25. mu.l IGF-1 at 160ng/ml (to give a final concentration of 20 ng/ml). Control cells not stimulated with IGF were also supplemented with an appropriate volume (i.e., 50. mu.l) of starvation medium to bring the final volume of each well up to 200. mu.l. The plate was incubated for an additional 20 hours.

Day 4

BrdU incorporated into cells (after a 4 hour incorporation period) was evaluated using BrdU Cell promotion Elisa according to the manufacturer's protocol.

The compounds of the examples were found to have an IC50 of less than 50 μ M in the above assay.

d) Analysis of mechanism of action

Inhibition of IGF-IR mediated signal transduction was determined by measuring changes in phosphorylation of IGF-IR, Akt and MAPK (ERK1 and 2) in response to IGF-I stimulation of MCF-7 cells (ATCC No. HTB-22). Selectivity was measured in the same cell line with the effect on MAPK phosphorylation in response to EFG.

d.i) reagents used:

RPMI1640 medium, RPMI1640 medium without phenol red, FCS, glutamine (all obtained from Life Technologies ltd., UK).

FBS (HyClone SH30068.02, Perbio Science UKLtd) with charcoal/dextran removed.

SDS(Sigma，L4390)。

2-mercaptoethanol (Sigma, M6250).

Bromophenol blue (Sigma, B5525).

Ponceau S (Sigma, P3504).

Tris base (TRIZMA)^TM base，Sigma，T1503)。

Glycine (Sigma, G7403).

Methanol (Fisher Scientific UK. Cat. No. M/3950/21).

Powdered milk (Dried milk powder) (Marvel)^TM，Premier Brands UK Ltd.)。

Human recombinant IGF-1 Animal/media grade (GroPep Limited ABN 78008176298, Australia. Cat No. IU 100).

Human recombinant EGF (Promega Corporation, Wis., USA. Cat. No. G5021).

Complete growth medium

RPMI1640, 10% FCS, 2mM glutamine

Starvation medium

RPMI1640 medium without phenol red, FCS 1% charcoal/dextran removed, 2mM glutamine.

Test compounds

Compounds were first dissolved in DMSO to 10mM and then diluted with phenol red free RPMI1640 medium + 1% FCS +2mM glutamine to a range of 100 to 0.0.45 μ M per assay well with DMSO at a final concentration of 1-0.00045%.

Western transfer buffer

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

Laemmli buffer x 2:

100mM Tris-HCl pH6.8, 20% glycerol, 4% SDS.

Sample buffer x 4:

200mM 2-mercaptoethanol, 2% bromophenol blue in distilled water.

A primary antibody

Rabbit anti-human IGF-1R β (Santa Cruz Biotechnology Inc., USA, Cat. Nosc-713)

Rabbit anti-insulin/IGF-1R [ pYpY^1162/1163]Dual Phosphospecific(BioSourceInternational Inc，CA，USA.Cat No.44-8041)。

Mouse anti-PKB α/Akt (Transduction Laboratories, KY, USA. Cat. No. P67220)

Rabbit anti-Phospho-Akt (Ser473) (Cell Signalling Technology Inc, MA, USA. Cat. No. # 9271).

Rabbit anti-p 44/p42 MAP kinase (Cell Signalling Technology Inc, MA, USA. Cat. No. # 9102).

Rabbit anti-Phospho p44/p42 MAP kinase (Cell Signalling Technology Inc, MA, USA. Cat. No. # 9101).

Mouse anti-actin clone AC-40(Sigma-Aldrich Company Ltd, UK, A4700).

Antibody dilutions

Antibodies	Dilution in PBST	Secondary antibodies in PBST
			IGFR	1: 200, with 5% milk	Anti-rabbit, with 5% milk
Phospho-IGFR	1: 1000 with 5% milk	Anti-rabbit, with 5% milk
			Akt	1: 1000 with 5% milk	Anti-mouse, with 5% milk
PhosphoAkt	1: 1000 with 5% milk	Anti-rabbit, with 5% milk
			MAPK	1: 1000 with 5% milk	Anti-rabbit, with 5% milk
Phospho-MAPK	1: 1000 with 5% milk	Anti-rabbit, with 5% milk
			Actin	1: 1000 with 5% milk	Anti-mouse, with 5% milk

Second antibody

Goat anti-rabbit, HRP linked (Cell Signalling Technology Inc, MA, usa. cat. no. # 7074).

Sheep-anti-mouse IgG HRP-conjugated (Amersham Pharmacia Biotech ukltd. cat. No. nxax931).

Anti-rabbits were diluted 1: 2000 in PBST + 5% milk.

Anti-mice were diluted 1: 5000 in PBST + 5% milk.

d.ii) protocol

Cell processing

MCF-7 cells were plated at 1X 10⁵The number of individual cells/well was plated in 1ml of complete growth medium into 24-well plates. The plate was cultured for 24 hours to pellet the cells. The medium was removed and the plate was gently washed 3 times with PBS (2 ml/well). To each well 1ml of starvation medium was added and the plate was cultured for 24 hours to serum starve the cells.

Then, 25. mu.l of each compound dilution was added thereto and the cells and compounds were incubated at 37 ℃ for 30 minutes. After 30 minutes incubation of the compounds, 25. mu.l IGF (for a final concentration of 20 ng/ml) or EGF (for a final concentration of 0.1 ng/ml) were added to each well as appropriate and the cells were incubated with IGF or EGF for 5 minutes at 37 ℃. The medium was removed (pipetted off) and 100 μ l of 2 × Laemmli buffer was added. The plates were stored at 4 ℃ until the cells were harvested. (Laemmli buffer should be added to these cells and harvested within 2 hours.)

To harvest the cells, the Laemmli buffer/cell mixture was repeatedly drawn down and discarded with a pipette and transferred to a 1.5ml Eppendorf tube. The harvested cell lysate is stored at-20 ℃ until needed. 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 blotting technique

Cell samples were prepared with 4x sample buffer, injected with a 21 gauge needle and boiled for 5 minutes. Loading the sample to 4-12% Bis- Tris gels (Invitro gen BV, The Netherlands) and placing The gels on an Xcell SureLock^TMRun on Mini-Cell device (Invitrogen) with the solution provided and according to the manufacturer's instructions. The gel was blotted to a place in Xcell SureLock using transfer buffer for Western blotting^TMHybond C Extra in Mini-Cell device^TMMembranes (Amersham Pharmacia Biotech UK Ltd.) were incubated at 30 volts for 1 hour. The blotted membrane was stained with 0.1% ponceau S to visualize the transferred protein, which was then horizontally cut into strips for multiple antibody cultures according to molecular weight standards. These independent strips were used to probe IGF-1R, Akt, MAPK and actin controls, respectively.

The membranes were blocked in PBST + 5% milk solution at room temperature for 1 hour. Then, the membranes were placed in 3ml of primary antibody solution in 4-well plates and the plates were incubated overnight at 4 ℃. The membranes were washed in 5ml PBST, 3 times for 5 minutes each. HRP-conjugated secondary antibody solutions were prepared and 5ml were added to each membrane. These membranes were incubated at room temperature for 1 hour while stirring. The membranes were washed in 5ml PBST, 3 times for 5 minutes each. ECL solutions (SuperSignal ECL, Pierce, Perbio Science UKLtd) were prepared and incubated with the membrane for 1 minute (incubation was performed according to the manufacturer's instructions), then brought into contact with the photosensitive membrane and developed.

The compounds of the examples were found to have IC's of less than 20 μ M in the above assays₅₀。

For example, the following table illustrates the activity of typical compounds of the present invention. Column 2 of the Table shows the IC of the above test (c) resulting from the inhibition of murine fibroblasts (NIH3T3) against IGF-stimulated overexpression of the human IGF-1 receptor₅₀Data:

example No. 2	IC50(μ M) -test (c)
		5	0.13
23	0.11
		35	0.56
38	0.054

Claims (32)

1. A compound of formula (I)

Or a pharmaceutically acceptable salt thereof,

wherein:

R¹represents trifluoromethyl, or (C1-C6) alkyl, (C3-C8) cycloalkyl or (C3-C8) cycloalkyl (C1-C6) alkyl, each of which may be optionally substituted by one or more substituents independently selected from halogen and (C1-C6) alkoxy;

R²represents hydrogen, halogen or trifluoromethyl;

R³represents hydrogen, hydroxy or halogen, or (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C8) cycloalkyl (C1-C6) alkoxy, (C1-C6) alkylcarbonyl, (C3-C8) cycloalkylcarbonyl, (C3-C8) cycloalkyl (C1-C6) alkylcarbonyl, (C1-C6) alkoxycarbonyl, amino, (C1-C6) alkylamino, di- [ (C1-C6) alkyl]Amino, (C3-C8) cycloalkylamino, (C3-C8) cycloalkyl (C1-C6) alkylamino, (C1-C6) alkoxyamino, carbamoyl, (C1-C6) alkylcarbamoyl, di- [ (C1-C6) alkylcarbamoyl]Carbamoyl, -C (O) R^3b、-OR^3b、-SR^3b、-NHR^3b-N [ (C1-C6) alkyl group]R^3b、-S(O)_mR^3aor-N (R)^3c)C(O)R^3aWherein R is^3aRepresents (C1-C6) alkyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl or (C1-C6) alkoxy, m is 0, 1 or 2, R is^3bRepresents a saturated 4-, 5-or 6-membered monocyclic heterocycle comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur and R ^3cRepresents hydrogen or (C1-C6) alkyl,

or R³Represents a 5-to 6-membered saturated monocyclic heterocyclic ring containing at least one ring heteroatom selected from nitrogen, oxygen and sulfur,

or R³Represents a 5-to 6-membered heteroaromatic ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur,

or R³Represents a 2, 7-diazaspiro [3.5 ]]A non-alkyl group,

R³each group or ring of (A) may optionally be substituted with one or more groups independently selected from (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkoxy (C1-C6) alkyl, (C1-C6) alkoxy (C1-C6) alkoxy, halogen, hydroxy, trifluoromethyl, tris- [ (C1-C4) alkyl]Silyl, cyano, amino, (C1-C6) alkylamino, di- [ (C1-C6) alkyl]Amino, (C3-C8) cycloalkylamino, (C3-C6) cycloalkyl (C1-C3) alkylamino, amino (C1-C6) alkyl, (C1-C6) alkylamino (C1-C6) alkyl, di- [ (C1-C6) alkyl]Amino (C1-C6) alkyl, (C3-C8) cycloalkylamino (C1-C6) alkyl, (C3-C6) cycloalkaneAlkyl (C1-C3) alkylamino (C1-C6) alkyl, (C1-C6) alkoxycarbonyl, carbamoyl, (C1-C6) alkylcarbamoyl, di- [ (C1-C6) alkyl]Carbamoyl, (C1-C6) alkylthio, (C1-C6) alkylsulfonyl, (C1-C6) alkylsulfinyl, (C1-C6) alkanoyl, wherein R is ^3aAnd R^3cIs as defined above for alkanoylamino-N (R)^3c)C(O)R^3aOr a 3-, 4-, 5-, 6-or 7-membered saturated monocyclic ring optionally containing at least one heteroatom selected from nitrogen, oxygen and sulfur, any of which substituents may be optionally substituted by one or more (C1-C4) alkyl, hydroxy or cyano groups;

-NQ¹represents an N-linked 5-to 6-membered saturated monocyclic ring comprising one nitrogen heteroatom and optionally one or more additional ring heteroatoms selected from nitrogen, oxygen and sulphur;

Q²represents a 5-to 6-membered heteroaromatic ring containing at least one ring heteroatom selected from nitrogen, oxygen and sulfur, which ring is substituted by Q³Substituted and optionally substituted on any available ring atom with one or more substituents independently selected from (C1-C6) alkyl or (C1-C6) alkoxy (each of which may be optionally substituted with one or more substituents independently selected from halogen, amino, hydroxy and trifluoromethyl), halogen, nitro, cyano, -NR, and mixtures thereof⁴R⁵Carboxy, hydroxy, (C2-C6) alkenyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl, (C1-C4) alkoxycarbonyl, (C1-C4) alkylcarbonyl, (C1-C4) alkylcarbonylamino, phenylcarbonyl, -S (O)_p(C1-C4) alkyl, -C (O) NR⁶R⁷and-SO₂NR⁸R⁹Wherein R is substituted with a further substituent of ⁴、R⁵、R⁶、R⁷、R⁸And R⁹Each independently represents hydrogen or (C1-C6) alkyl, or R when taken together with the nitrogen atom to which they are attached⁴And R⁵Or R⁶And R⁷Or R⁸And R⁹Each independently may form a saturated heterocyclic ring and p is 0, 1 or 2;

Q³represents (C1-C6) alkyl, (C3-C6) cycloalkyl or (C3-C6) cycloalkyl (C1-C6) alkyl or may comprise at least oneA saturated or unsaturated 5-to 6-membered monocyclic ring having a ring heteroatom selected from nitrogen, oxygen and sulfur, and wherein Q³Optionally substituted with one or more substituents independently selected from (C1-C6) alkyl or (C1-C6) alkoxy, each of which may be optionally substituted with one or more substituents independently selected from halogen, amino, hydroxy and trifluoromethyl, halogen, nitro, cyano, -NR¹⁰R¹¹Carboxy, hydroxy, (C2-C6) alkenyl, (C3-C8) cycloalkyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkylcarbonyl, (C1-C6) alkylcarbonylamino, phenylcarbonyl, -S (O)_n(C1-C6) alkyl, -C (O) NR¹²R¹³and-SO₂NR¹⁴R¹⁵Wherein R is substituted by a substituent of (1)¹⁰、R¹¹、R¹²、R¹³、R¹⁴And R¹⁵Each independently represents hydrogen or (C1-C6) alkyl, or R when taken together with the nitrogen atom to which they are attached¹⁰And R¹¹Or R¹²And R¹³Or R¹⁴And R¹⁵Each independently may form a saturated heterocyclic ring and n is 0, 1 or 2;

and wherein any saturated monocyclic ring optionally bears 1 or 2 oxo or thioxo substituents.

2. The compound of claim 1, wherein:

R¹represents trifluoromethyl, or (C1-C6) alkyl, (C3-C8) cycloalkyl or (C3-C8) cycloalkyl (C1-C6) alkyl, each of which may be optionally substituted by one or more substituents independently selected from halogen and (C1-C6) alkoxy;

R²represents hydrogen, halogen or trifluoromethyl;

R³represents hydrogen or halogen, or (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C8) cycloalkyl (C1-C6) alkoxy, (C1-C6) alkylcarbonyl, (C3-C8) cycloalkylcarbonyl, (C3-C8) cycloalkyl (C1-C6) alkylcarbonyl, (C1-C6) alkoxycarbonyl, amino, (C1-C6) alkylamino, di- [ (C1-C6) alkyl]Amino, (C3-C8) cycloalkylamino, (C3-C8) cycloalkyl (C1-C6) alkylamino, (C1)-C6) alkoxyamino, carbamoyl, (C2-C6) alkanoylamino, -C (O) R^3b、-OR^3b、-SR^3b、-NHR^3b-N [ (C1-C6) alkyl group]R^3bor-S (O)_mR^3aWherein R is^3aRepresents (C1-C6) alkyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl or (C1-C6) alkoxy, m is 0, 1 or 2, and R^3bRepresents a 5-to 6-membered saturated monocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur,

or R³Represents a 5-to 6-membered saturated monocyclic heterocyclic ring containing at least one ring heteroatom selected from nitrogen, oxygen and sulfur,

R³Each group or ring of (A) may optionally be substituted with one or more groups independently selected from (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkoxy (C1-C6) alkoxy, halogen, hydroxy, trifluoromethyl, cyano, amino, (C1-C6) alkylamino, di- [ (C1-C6) alkyl]Amino, (C3-C8) cycloalkylamino, (C3-C6) cycloalkyl (C1-C3) alkylamino, (C1-C6) alkoxycarbonyl, carbamoyl, (C1-C6) alkylcarbamoyl, di- [ (C1-C6) alkylcarbamoyl]Carbamoyl, (C1-C6) alkylthio, (C1-C6) alkylsulfonyl, (C1-C6) alkylsulfinyl, (C1-6) alkanoylamino or a substituent of a 4-, 5-, 6-or 7-membered saturated monocyclic ring which may optionally contain one or more heteroatoms selected from nitrogen, oxygen and sulfur;

-NQ¹represents an N-linked 5-to 6-membered saturated monocyclic ring comprising one nitrogen heteroatom and optionally one or more additional ring heteroatoms selected from nitrogen, oxygen and sulphur;

Q²represents a 5-to 6-membered heteroaromatic ring containing at least one ring heteroatom selected from nitrogen, oxygen and sulfur, which ring is substituted by Q³Substituted and optionally substituted on any available ring atom with one or more substituents independently selected from (C1-C6) alkyl or (C1-C6) alkoxy (each of which may be optionally substituted with one or more substituents independently selected from halogen, amino, hydroxy and trifluoromethyl), halogen, nitro, cyano, -NR, and mixtures thereof ⁴R⁵Carboxyl, hydroxyl, (C2-C6) alkenyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl, (C1-C4) alkoxycarbonyl, (C1-C4) alkylcarbonyl, (C1)-C4) Alkylcarbonylamino, phenylcarbonyl, -S (O)_p(C1-C4) alkyl, -C (O) NR⁶R⁷and-SO₂NR⁸R⁹Wherein R is substituted by a substituent of (1)⁴、R⁵、R⁶、R⁷、R⁸And R⁹Each independently represents hydrogen or (C1-C6) alkyl, or R when taken together with the nitrogen atom to which they are attached⁴And R⁵Or R⁶And R⁷Or R⁸And R⁹Each independently may form a saturated heterocyclic ring and p is 0, 1 or 2;

Q³represents (C1-C6) alkyl, (C3-C6) cycloalkyl or (C3-C6) cycloalkyl (C1-C6) alkyl or a saturated or unsaturated 5-to 6-membered monocyclic ring which may contain at least one ring heteroatom selected from nitrogen, oxygen and sulfur, and wherein Q³Optionally substituted with one or more substituents independently selected from (C1-C6) alkyl or (C1-C6) alkoxy, each of which may be optionally substituted with one or more substituents independently selected from halogen, amino, hydroxy and trifluoromethyl, halogen, nitro, cyano, -NR¹⁰R¹¹Carboxy, hydroxy, (C2-C6) alkenyl, (C3-C8) cycloalkyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkylcarbonyl, (C1-C6) alkylcarbonylamino, phenylcarbonyl, -S (O)_n(C1-C6) alkyl, -C (O) NR ¹²R¹³and-SO₂NR¹⁴R¹⁵Wherein R is substituted by a substituent of (1)¹⁰、R¹¹、R¹²、R¹³、R¹⁴And R¹⁵Each independently represents hydrogen or (C1-C6) alkyl, or R when taken together with the nitrogen atom to which they are attached¹⁰And R¹¹Or R¹²And R¹³Or R¹⁴And R¹⁵Each independently may form a saturated heterocyclic ring and n is 0, 1 or 2.

3. The compound 1 of claim 1, wherein:

R¹represents trifluoromethyl, or (C1-C6) alkyl, (C3-C8) cycloalkyl or (C3-C8) cycloalkyl (C1-C6) alkyl, each of which is optionally substituted by halogen or (C1-C6) alkoxy;

R²represents hydrogen, halogen or trifluoromethyl;

R³represents hydrogen or (C1-C6) alkyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkylcarbonyl, (C3-C8) cycloalkylcarbonyl,

(C3-C8) cycloalkyl (C1-C6) alkylcarbonyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkylamino, (C3-C8) cycloalkylamino, (C3-C8) cycloalkyl (C1-C6) alkylamino, (C1-C6) alkoxyamino or-S (O)_mR^3aEach of which may be optionally substituted with at least one substituent selected from (C1-C6) alkoxy, (C1-C6) alkoxy (C1-C6) alkoxy, halo, hydroxy, trifluoromethyl, or a 4-to 7-membered saturated monocyclic ring which may optionally contain one or more heteroatoms selected from nitrogen, oxygen and sulfur, wherein R is ^3aRepresents (C1-C6) alkyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl or (C1-C6) alkoxy, and m is 0, 1 or 2;

-NQ¹represents an N-linked 5-to 6-membered saturated monocyclic ring comprising one nitrogen heteroatom and optionally one or more additional ring heteroatoms selected from nitrogen, oxygen and sulphur;

Q²represents a 5-to 6-membered heteroaromatic ring containing at least one ring heteroatom selected from nitrogen, oxygen and sulfur, which ring is substituted by Q³Substituted and optionally substituted on any available ring atom by one or more substituents which may be the same or different selected from (C1-C6) alkyl or (C1-C6) alkoxy, each of which may be optionally substituted by at least one substituent selected from halogen, amino, hydroxy and trifluoromethyl, halogen, nitro, cyano, -NR⁴R⁵Carboxy, hydroxy, (C2-C6) alkenyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl, (C1-C4) alkoxycarbonyl, (C1-C4) alkylcarbonyl, (C1-C4) alkylcarbonylamino, phenylcarbonyl, -S (O)_p(C1-C4) alkyl, -C (O) NR⁶R⁷and-SO₂NR⁸R⁹Wherein R is substituted with a further substituent of⁴、R⁵、R⁶、R⁷、R⁸And R⁹Each independently represents hydrogen or (C1-C6) alkyl, or R when taken together with the nitrogen atom to which they are attached⁴And R⁵Or R⁶And R⁷Or R⁸And R⁹Each independently may form a saturated heterocyclic ring and p is 0, 1 or 2;

Q³Represents (C1-C6) alkyl, (C3-C6) cycloalkyl or (C3-C6) cycloalkyl (C1-C6) alkyl or a saturated or unsaturated 5-to 6-membered monocyclic ring which may contain at least one ring heteroatom selected from nitrogen, oxygen and sulfur, and wherein Q³Optionally substituted with at least one substituent selected from (C1-C6) alkyl or (C1-C6) alkoxy, each of which may be optionally substituted with at least one substituent selected from halogen, amino, hydroxy and trifluoromethyl, halogen, nitro, -cyano, -NR¹⁰R¹¹Carboxy, hydroxy, (C2-C6) alkenyl, (C3-C8) cycloalkyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkylcarbonyl, (C1-C6) alkylcarbonylamino, phenylcarbonyl, -S (O)_n(C1-C6) alkyl, -C (O) NR¹²R¹³and-SO₂NR¹⁴R¹⁵Wherein R is substituted by a substituent of (1)¹⁰、R¹¹、R¹²、R¹³、R¹⁴And R¹⁵Each independently represents hydrogen or (C1-C6) alkyl, or R when taken together with the nitrogen atom to which they are attached¹⁰And R¹¹Or R¹²And R¹³Or R¹⁴And R¹⁵Each independently may form a saturated heterocyclic ring and n is 0, 1 or 2.

4. A compound according to any preceding claim, wherein R is¹Represents (C1-C4) alkyl or (C3-C6) cycloalkyl.

5. A compound according to any preceding claim, wherein R is²Represents hydrogen or halogen.

6. The compound of claim 5, wherein R ²Represents halogen.

7. A compound according to any preceding claim, wherein R is³Represents hydrogen, hydroxy or halogen, or (C1-C6)Alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C8) cycloalkyl (C1-C6) alkoxy, (C1-C6) alkylcarbonyl, (C1-C6) alkoxycarbonyl, amino, (C1-C6) alkylamino, di- [ (C1-C6) alkyl]Amino, (C3-C8) cycloalkylamino, (C3-C8) cycloalkyl (C1-C6) alkylamino, (C1-C6) alkoxyamino, carbamoyl, (C1-C6) alkylcarbamoyl, di- [ (C1-C6) alkylcarbamoyl]Carbamoyl, -C (O) R^3b、-OR^3b、-NHR^3b-N [ (C1-C6) alkyl group]R^3b、-S(O)_mR^3aor-N (R)^3c)C(O)R^3aWherein R is^3aRepresents (C1-C6) alkyl or (C1-C6) alkoxy, m is 0, 1 or 2, R is^3bRepresents a saturated 4-, 5-or 6-membered monocyclic heterocycle comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur and R^3cRepresents hydrogen or (C1-C6) alkyl, or R³Represents a 5-to 6-membered saturated monocyclic heterocycle containing at least one ring heteroatom selected from nitrogen, oxygen and sulfur, or R³Represents a 5-to 6-membered heteroaromatic ring containing at least one ring heteroatom selected from nitrogen, oxygen and sulfur, or R³Represents a 2, 7-diazaspiro [3.5 ]]Nonyl radical, R ³Each group or ring of (A) may optionally be substituted with one or more groups independently selected from (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkoxy (C1-C6) alkyl, (C1-C6) alkoxy (C1-C6) alkoxy, halogen, hydroxy, trifluoromethyl, tris- [ (C1-C4) alkyl]Silyl, cyano, amino, (C1-C6) alkylamino, di- [ (C1-C6) alkyl]Amino, amino (C1-C6) alkyl, (C1-C6) alkylamino (C1-C6) alkyl, di- [ (C1-C6) alkyl]Amino (C1-C6) alkyl, (C1-C6) alkoxycarbonyl, carbamoyl, (C1-C6) alkylcarbamoyl, di- [ (C1-C6) alkyl]Carbamoyl, (C1-C6) alkylthio, (C1-C6) alkylsulfonyl, (C1-C6) alkylsulfinyl, (C1-C6) alkanoyl, wherein R is^3aAnd R^3calkanoylamino-N (R) as defined in claim 1^3c)C(O)R^3aOr 3-, 4-, 5-, 6-or 7-membered saturated monocyclic ring which optionally contains one or more heteroatoms selected from nitrogen, oxygen and sulfur, any of which substituents may optionally be substituted with one or more(C1-C4) alkyl, hydroxy, or cyano, and wherein any saturated monocyclic ring optionally bears 1 or 2 oxo or thioxo substituents.

8. A compound according to any preceding claim, wherein R is ³Represents hydrogen or halogen, or (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkoxy, (C1-C6) alkylcarbonyl, (C1-C6) alkoxycarbonyl, amino, (C1-C6) alkylamino, di- [ (C1-C6) alkyl]Amino, carbamoyl, -C (O) R^3b、-OR^3b、-SR^3b、-NHR^3b-N [ (C1-C6) alkyl group]R^3bor-S (O)_mR^3aWherein R is^3aAnd R^3bAs defined in claim 1, in accordance with claim 1,

or R³Represents a 5-or 6-membered saturated monocyclic heterocyclic ring containing at least one ring heteroatom selected from nitrogen, oxygen and sulfur,

each ring or group may be optionally substituted by one or more substituents as defined in claim 1.

9. A compound according to any preceding claim, wherein R is³Represents hydrogen or (C1-C4) alkyl, (C1-C3) alkoxy or (C3-C5) cycloalkyl,

or R³Represents a 5-to 6-membered saturated monocyclic heterocyclic ring containing at least one ring heteroatom selected from nitrogen and oxygen,

each group or ring may be optionally substituted with one or more substituents independently selected from hydroxy and (C1-C3) alkoxy.

10. A compound according to any preceding claim, wherein R is³Represents hydrogen.

11. A compound according to any preceding claim, wherein NQ¹Denotes a 5-to 6-membered saturated monocyclic ring comprising one nitrogen heteroatom and optionally at least one further ring heteroatom which may be the same or different selected from nitrogen, oxygen and sulphur.

12. The compound of claim 11, wherein NQ¹Is pyrrolidinyl or piperidinyl.

13. A compound according to any preceding claim, wherein Q is²Denotes a 5-to 6-membered heteroaromatic ring which contains one or two ring heteroatoms which may be identical or different, selected from nitrogen and oxygen, which ring may be substituted by Q³Substituted and optionally substituted with at least one substituent independently selected from (C1-C6) alkyl, (C1-C6) alkoxy, halogen, and (C3-C8) cycloalkyl.

14. The compound of claim 13, wherein the heteroaromatic ring is selected from the group consisting of isoxazolyl and tetrazolyl.

15. The compound of claim 14, wherein the heteroaromatic ring is isoxazolyl.

16. A compound according to any preceding claim, wherein Q is³Represents (C1-C6) alkyl, (C3-C8) cycloalkyl or an optionally substituted, saturated or unsaturated, 5-to 6-membered monocyclic ring optionally containing at least one ring heteroatom selected from nitrogen, oxygen and sulfur.

17. The compound of claim 16, wherein Q³Represents (C1-C4) alkyl or (C3-C6) cycloalkyl or an optionally substituted 5-to 6-membered unsaturated monocyclic ring containing one or two ring heteroatoms which may be the same or different, selected from nitrogen, oxygen and sulfur.

18. The compound of claim 16 or 17, wherein Q³Represents an optionally substituted 5-to 6-membered unsaturated monocyclic ring comprising one or two ring heteroatoms which may be the same or different, selected from nitrogen, oxygen and sulphur.

19. The compound of claim 18, wherein Q³Represents thiazolyl, pyrazinyl, pyrimidinyl or pyridyl.

20. The compound of claim 1, wherein R¹Represents (C1-C4) alkyl or (C3-C6) cycloalkyl; r²Represents halogen; r³Represents hydrogen; -NQ¹Represents a 5-or 6-membered saturated monocyclic ring comprising one nitrogen heteroatom and optionally at least one further ring heteroatom selected from nitrogen, oxygen and sulphur; q²Represents a substituted 5-to 6-membered heteroaromatic ring containing one or two ring heteroatoms which may be the same or different selected from nitrogen and oxygen; and Q³Represents (C1-C4) alkyl or (C3-C6) cycloalkyl or an optionally substituted 5-to 6-membered unsaturated monocyclic ring containing one or two ring heteroatoms which may be the same or different, selected from nitrogen, oxygen and sulfur.

21. The compound of claim 20, wherein-NQ¹Represents pyrrolidinyl or piperidinyl; q²Represents isoxazolyl or tetrazolyl; and Q³Represents methyl, cyclopropyl, thiazolyl, tetrahydrofuryl, pyrazinyl, thiazolyl, pyrimidinyl or pyridyl.

22. A compound according to claim 20 or 21, wherein-NQ¹Represents a pyrrolidinyl group; q²Represents an isoxazolyl group; and Q³Represents thiazolyl, pyrazinyl, pyrimidinyl or pyridyl.

23. A compound according to claim 20 or 21, wherein-NQ¹Represents pyrrolidinyl or piperidinyl; q²Represents an isoxazolyl group; and Q³Represents methyl, cyclopropyl, thiazolyl or pyridyl.

24. A compound of formula (I) as claimed in claim 1 selected from one or more of the following:

5-chloro-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] 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-1H-pyrazol-3-ylamino) pyrimidine;

5-chloro-2- [2- (3-cyclopropylisoxazol-5-yl ] pyrrolidin-1-yl ] -4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine;

5-chloro-2- [2- (3-cyclopropylisoxazol-5-yl ] pyrrolidin-1-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

5-chloro-2- [2- (3-methylisoxazol-5-yl ] pyrrolidin-1-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

5-chloro-2- {2- [3- (thiazol-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) 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- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine;

5-chloro-2- {2- [3- (pyridin-3-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

5-chloro-2- {2- [3- (pyridin-3-yl) 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-cyclopropylisoxazol-5-yl) pyrrolidin-1-yl ] -6-methoxymethyl-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine;

5-chloro-2- (2- (3- (pyridin-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-1H-pyrazol-3-ylamino) pyrimidine;

5-chloro-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2- (3- { tetrahydrofuran-3-yl } isoxazol-5-yl ] pyrrolidin-1-yl ] -pyrimidine;

6-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine;

5-chloro-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] piperidin-1-yl } pyrimidine;

5-chloro-2- {2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

5-fluoro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -pyrimidine;

4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -5-fluoro-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine;

s-5-chloro-2- {2- [ 3-methylisoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine;

4- (5-methyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine;

4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine;

4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -6-methyl-2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

4- (5-methyl-1H-pyrazol-3-ylamino) -6-methyl-2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -6-methyl-2- [2- (3-methylisoxazol-5-yl) pyrrolidin-1-yl ] pyrimidine;

6-ethyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

6- (3-methoxypropyl) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl ] pyrimidine;

6-methoxymethyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -6-methoxymethyl-2- [2- {3- (pyridin-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- (pyridin-3-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

4- (5-methyl-1H-pyrazol-3-ylamino) -6- (pent-3-en-1-yl) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

4- (5-methyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -6-trifluoromethylpyrimidine;

4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -6-trifluoromethylpyrimidine;

S-6-ethyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-5-chloro-2- {2- [3- (thiazol-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-5-chloro-2- {2- [3- (pyridin-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- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-5-chloro-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-5-chloro-2- {2- [3- (2-methoxypyridin-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- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

6- (3-pyrrolidin-1-ylpropyl) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

6-methoxycarbonyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine;

6- (2-hydroxyethylcarbamoyl) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine;

4- (5-methyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -6- (pyrrolidin-1-ylcarbonyl) pyrimidine;

6-methoxy-4- (5-methyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-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-ethylpiperazinyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine;

6-N-methylpiperazinyl (piperazyl) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

6-morpholino-4- (5-methyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine;

6- (3- (N, N-dimethylamino) propyn-1-yl) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- (2- (3- (pyridin-2-yl) isoxazol-5-yl) pyrrolidin-1-yl) pyrimidine;

6-methylamino-4- (5-methyl-1H-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- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine;

6-methoxycarbonyl-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

6- (N-methylcarbamoyl) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

6-morpholinocarbonyl-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

6- (N- (2-methoxyethyl) carbamoyl) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

6- (N-hydroxycarbamoyl) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

6-carbamoyl-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6-methoxycarbonyl-2- {2- [3- (pyridin-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- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

S-6- [ N- (2-methoxyethyl) -N-methylcarbamoyl ] -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6- [ N- (2- (acetylamino) ethyl) carbamoyl ] -2- {2- [3- (pyridin-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- (pyridin-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- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6- [ N- (4-hydroxybutyl) carbamoyl ] -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6- [ N- ((2R) -2, 3-dihydroxypropyl) carbamoyl ] -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6- [ N- (carbamoylmethyl) carbamoyl ] -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

S-6- ((3R) -3-hydroxypyrrolidin-1-ylcarbonyl) -2- {2- [3- (pyridin-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- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6- (N-cyclopropylcarbamoyl) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6- (N-cyclopentylcarbamoyl) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6- (azetidin-1-ylcarbonyl) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6- (N-methylcarbamoyl) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

6- (N-carbamoyl) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

6- [ N- (acetylamino) carbamoyl ] -2- {243- (pyridin-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- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

6-hydroxymethyl-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

6- (morpholinomethyl) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

6- (4-methylpiperazin-1-ylmethyl) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

6- (methylaminomethyl) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

6- (pyrrolidin-1-ylmethyl) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

6-aminomethyl-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6-hydroxymethyl-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6-ethoxymethyl-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

S-6- [ (2-methoxyethoxy) methyl ] -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-5-chloro-2- {2- [3- (pyrazin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6-methyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyrazin-2-yl) isoxazol-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) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine;

s-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -6-methoxy- {2- [3- (pyrazin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine;

6-pyrrolidin-1-yl-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

S-6- (2, 2, 6, 6-tetramethylpiperidin-4-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6-iodo-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

S-E-6- [3- (tert-butoxycarbonylamino) prop-1-en-1-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-vinyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

S-E-6- (3-hydroxyprop-1-en-1-yl) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- [3- (tert-butoxycarbonylamino) propan-1-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- [ 3-aminopropyl-1-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

S-E-6- [ 3-aminopropyl-1-en-1-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

S-6- [ 3-methylaminoprop-1-yn-1-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-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- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- [ 3-hydroxypropan-1-yn-1-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- [2- (trimethylsilyl) ethynyl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-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- (pyridin-2-yl) isoxazol-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- (pyridin-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- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- [2- (ethoxycarbonyl) ethyl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

S-E-6- [2- (methoxycarbonyl) ethen-1-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-ethynyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

6-methoxymethyl-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-methoxymethyl-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-methoxymethyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- [ 3-aminoprop-1-yn-1-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- [2- (N-methylcarbamoyl) ethyl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidin-1-yl ] pyrimidine;

s-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidin-1-yl ] pyrimidine;

S-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidin-1-yl ] pyrimidine;

6- (N-tert-butoxycarbonyl) amino-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

6- (4-aminopiperidin-1-yl) 2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

6- (4- (N-tert-butoxycarbonylamino) piperidin-1-yl) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

6-piperazin-1-yl-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6- {4- [2- (2-hydroxyethoxy) ethyl ] piperazin-1-yl } -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6- (1-formyl-piperazin-4-yl) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6-piperazin-1-yl-2- {2- [3- (pyridin-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- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6- [ (4- (2-hydroxyethyl) piperazin-1-yl) ] -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6- [ (3R) -3-hydroxypyrrolidin-1-yl ] -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6- [ (3R) -3-dimethylamino-pyrrolidin-1-yl ] -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4 (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6- (4-tetrahydropyranylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6-morpholino-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6- (2-methoxyethyl) amino-2- {2- [3- (pyridin-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- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

S-6- ((2R) -2-hydroxypropan-1-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6- [ N- (2-hydroxyethyl) -N-ethylamino ] -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6-dimethylamino-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6-methylamino-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6-chloro-2- {2- [3- (pyrazin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

6-morpholino (mopolino) -2- {2- [3- (pyrazin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

6-chloro-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine;

6- (2-hydroxyethoxy) -2- {2- [3- (pyridin-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-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

6- (4-acetylpiperazin-1-yl) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

6- [2- (tert-butoxycarbonyl) -2, 7-diazaspiro [3.5] non-7-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

6- (2, 7-diazaspiro [3.5] non-7-yl) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- [4- (2-aminoethyl) piperazin-1-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- [4- (3-hydroxypropyl) piperazin-1-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- [4- (2-cyanoethyl) piperazin-1-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- [4- (2-methoxyethyl) piperazin-1-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- (4-acetylpiperazin-1-yl) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-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- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- [2- (2-hydroxyethoxy) ethylamino ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- [2- (acetylamino) ethylamino ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- [ 2-aminoethylamino ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- [ 4-methylcyclohexylamino ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- [ 4-hydroxycyclohexylamino ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- [ cis-3, 4-dihydroxypyrrolidin-1-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyrimidin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

S-6-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (3-methoxypyrazin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-morpholino-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyrimidin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-morpholino-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (3-methoxypyrazin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-morpholino-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (3-hydroxypyrazin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- [ 4-methylpiperazin-1-yl ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- [ cyclobutylamino ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- [ 3-isopropoxyprop-1-ylamino ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-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- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- [2- (dimethylamino) ethylamino ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

S-6- [ (2S) -2-hydroxypropan-1-ylamino ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- [ 2-methylpropan-1-ylamino ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- [ 3-methoxypropylamino ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-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- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- [ 3-ethoxypropylamino ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- [ (2R) -tetrahydrofuran-2-ylmethyl-amino ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- (2-isopropoxyethylamino) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-morpholino-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyrimidin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

S-6-methylamino-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyrimidin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-chloro-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyrimidin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-methyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (3-methoxypyrazin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-methoxy-4- (5-cyclopropyl-1H-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- (pyrimidin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine;

s-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine;

s-4- (5-ethyl-1H-pyrazol-3-ylamino) -5-fluoro-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine;

s-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -5-fluoro-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine;

4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -6-methyl-2- {2- [3- (pyrimidin-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- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine;

6- (3-hydroxypropyl) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine;

s-6- (3-hydroxypropyl) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } pyrimidine;

s-6-propyl-2- {2- [3- (pyridin-2-yl) isoxazol-5-yl ] pyrrolidin-1-yl } -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine;

s-6-chloro-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- (2-hydroxyethoxy) -4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- (2-methoxyethoxy) -4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-morpholino-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-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- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

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- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- (2-methoxyethoxy) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-pyrrolidin-1-yl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-methoxymethyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-morpholinocarbonyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-carbamoyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-5-fluoro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

S-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-4- (5-methyl-1H-pyrazol-3-ylamino) -6- (2-hydroxyethoxy) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-4- (5-methyl-1H-pyrazol-3-ylamino) -6- (2- { N- [ 2-hydroxyethyl ] -N-methyl-amino } ethoxy) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-4- (5-methyl-1H-pyrazol-3-ylamino) -6- (2-morpholinoethoxy) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-4- (5-methyl-1H-pyrazol-3-ylamino) -6- (methylthio) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

4- (5-methyl-1H-pyrazol-3-ylamino) -6- (tetrahydrofuran-3-ylmethoxy) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-4- (5-methyl-1H-pyrazol-3-ylamino) -6- (2- (2-hydroxyethoxy) ethoxy) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

4- (5-methyl-1H-pyrazol-3-ylamino) -6- (2-methoxyethoxy) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-4- (5-methyl-1H-pyrazol-3-ylamino) -6- (3-hydroxypropoxy) -2- [2- {3- (pyridin-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- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-4- (5-methyl-1H-pyrazol-3-ylamino) -6- (2-ethoxyethoxy) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-4- (5-methyl-1H-pyrazol-3-ylamino) -6- (3-morpholinopropan-1-yloxy) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-4- (5-methyl-1H-pyrazol-3-ylamino) -6- (3-methoxypropan-1-yloxy) -2- [2- {3- (pyridin-2-yl) 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- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-4- (5-methyl-1H-pyrazol-3-ylamino) -6- [ (2S) -2-methoxypropan-1-yloxy ] -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-4- (5-methyl-1H-pyrazol-3-ylamino) -6- [3- (methylthio) propan-1-yloxy ] -2- [2- {3- (pyridin-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- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

S-4- (5-methyl-1H-pyrazol-3-ylamino) -6- [ (2R) -5-oxopyrrolidin-2-yl) methoxy ] -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-4- (5-methyl-1H-pyrazol-3-ylamino) -6- [2- (imidazolidin-2-one-1-yl) ethoxy ] -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-4- (5-methyl-1H-pyrazol-3-ylamino) -6-ethoxy-2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-4- (5-methyl-1H-pyrazol-3-ylamino) -6-hydroxy-2- [2- {3- (pyridin-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 } pyrrolidin-1-yl ] 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-methyl-1H-pyrazol-3-ylamino) -6- [ (2R) -2-hydroxypropan-1-yloxy ] -2- [2- {3- (pyridin-2-yl) isoxazol-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-yl ] pyrimidine;

s-4- (5-ethyl-1H-pyrazol-3-ylamino) -6-methoxy-2- [2- {3- (pyrazin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] 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-methyl-1H-pyrazol-3-ylamino) -6- (tetrahydropyran-4-yloxy) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-5-fluoro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (thiazol-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-5-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (thiazol-4-yl) isoxazol-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 } pyrrolidin-1-yl ] pyrimidine;

s-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2- {3- (thiazol-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2- {3- (thiazol-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -5-fluoro-2- [2- {3- (thiazol-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (thiazol-2-yl) isoxazol-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-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (thiazol-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] 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) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-methylamino-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (thiazol-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- (4-methylpiperazin-1 yl) -4- (5-methyl-1H-pyrazol-3-ylamino) -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) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6- [3- (methylsulfonyl) propyl-1-oxy ] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -6- (2-methoxyethoxy) -2- [2- {3- (pyrazin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

S-6-methyl-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2- {3- (3-methoxypyrazin-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) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-chloro-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyrimidin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-methoxy-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyrimidin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-ethyl-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyrimidin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-methylamino-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyrimidin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-ethyl-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyrimidin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-cyclopropyl-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyrimidin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-cyclopropyl-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyrimidin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

S-6- (2-methoxyethoxy) -4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyrimidin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-methyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidin-1-yl ] pyrimidine;

s-5-fluoro-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidin-1-yl ] pyrimidine;

s-5-fluoro-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidin-1-yl ] pyrimidine;

s-6- (2-hydroxyethoxy) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidin-1-yl ] pyrimidine;

s-6-chloro-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidin-1-yl ] pyrimidine;

s-6-chloro-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidin-1-yl ] pyrimidine;

s-6- (2-hydroxyethoxy) -4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidin-1-yl ] pyrimidine;

s-5-fluoro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidin-1-yl ] pyrimidine;

S-6- (2-hydroxyethoxy) -4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyridin-3-yl) isoxazol-5-yl ] pyrrolidin-1-yl ] 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-1H-pyrazol-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-methoxypyridin-3-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-methyl-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyrimidin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-methyl-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

s-6-morpholino-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2- {3- (3-hydroxypyrazin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine; and

s-6- (3-methoxypropyl) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- {3- (pyridin-2-yl) isoxazol-5-yl } pyrrolidin-1-yl ] pyrimidine;

and pharmaceutically acceptable salts thereof.

25. A pharmaceutical composition which comprises a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 24, in association with a pharmaceutically-acceptable adjuvant, diluent or carrier.

26. A process for the preparation of a pharmaceutical composition as claimed in claim 25 which comprises mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 24 with a pharmaceutically acceptable adjuvant, diluent or carrier.

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

28. A compound of formula (I) as claimed in any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof for use in modulating insulin-like growth factor 1 receptor activity in a human or animal body.

29. Use of a compound of formula (I) as claimed in any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cancer.

30. Use of a compound of formula (I) according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for modulating insulin-like growth factor 1 receptor activity.

31. A method of treating cancer which comprises administering to a patient a therapeutically effective amount of a compound of formula (I) as claimed in any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof.

32. A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in claim 1, which comprises

(i) Reacting a compound of formula (II) with a compound of formula (III),

wherein L is¹Represents a leaving group (e.g. halogen or sulfonyloxy such as methanesulfonyloxy or toluene-4-sulfonyloxy) and R¹，R²And R³As described in formula (I), except that any functional groups are protected if necessary,

wherein Q¹And Q²As defined in formula (I) except that any functional groups are protected if desired;

or

(ii) Reacting a compound of formula (IV) with a compound of formula (V),

wherein L is²Represents a leaving group (e.g. halogen or sulfonyloxy such as methanesulfonyloxy or toluene-4-sulfonyloxy) and R²、R³、Q¹And Q²As defined in formula (I), except that any functional groups are protected if desired,

wherein R is¹As defined in formula (I) except that any functional groups are protected if desired;

or

(iii) Reacting a compound of formula (VI) with a compound of formula (VII),

wherein Q¹And Q²As described in formula (I), except that any functional groups are protected if necessary,

wherein X represents an oxygen atom and q is 1 or X represents a nitrogen atom and q is 2, R²¹Independently represent (C1-C6) alkyl and R²And R³As defined in formula (I) except that any functional groups are protected if desired;

Or

(iv) Reacting a compound of formula (VIII) with hydrazine,

wherein R is¹，R²，R³，NQ¹And Q²As defined in formula (I) except that any functional groups are protected if desired;

or

(v) For R in the formula³Is (C1-C6) alkoxy, amino, (C1-C6) alkylamino, di- [ (C1-C6) alkyl]Amino, -OR^3b、-SR^3b、-NHR^3b-N [ (C1-C6) alkyl group]R^3bOr wherein m is 0 and R^3aAnd R^3bAre as defined above (and the radical R)³Optionally substituted by at least one group as defined above) -S (O)_mR^3aFor compounds of formula (I), a compound of formula (IX) is reacted with a compound of formula H-Xa, wherein Xa is selected from OR²²、NH₂、NHR²²、N(R²²)₂、NH₂、OR^3b、SR^3b、NHR^3bN [ (C1-C6) alkyl group]R^3bAnd SR^3aWherein R is²²Is optionally substituted (C1-C6) alkyl and R^3aAnd R^3bThe respective definitions are as described above, except that any functional groups are protected if necessary,

wherein L is³Represents a leaving group (e.g. halogen or sulfonyloxy such as methanesulfonyloxy or toluene-4-sulfonyloxy) and R¹、R²、Q¹And Q²As defined in formula (I) except that any functional groups are protected if desired;

or

(vi) For R in the formula³(ii) is an optionally substituted 5-or 6-membered saturated monocyclic heterocycle comprising at least one ring nitrogen and optionally one or more additional heteroatoms selected from nitrogen, oxygen and sulphur, reacting a compound of formula (IX) with a compound of formula (Xb),

Wherein Q⁴Is a 5-or 6-membered saturated monocyclic heterocyclic ring optionally containing one or more heteroatoms selected from nitrogen, oxygen and sulfur in addition to the above nitrogen atom, which ring is optionally substituted by at least one group as defined above, or has an optionally substituted 2, 7-diazaspiro [3.5 ] ring]A nonyl group;

or

(vii) For R in the formula³Is (C2-C6) alkenyl or (C2-C6) alkynyl, and R³(ii) for compounds of formula (I) optionally substituted by at least one group as defined above, reacting a compound of formula (IX) with a compound of formula (Xc) or formula (Xc'),

H-C≡C-R²³ (Xc)

wherein R is²³Selected from hydrogen and optionally substituted (1-4C) alkyl or (C1-C4) alkoxycarbonyl;

or

(viii) For R in the formula³As compounds of formula (I) which are attached to the pyrimidine ring via a carbon atom, compounds of formula (IX) are described with R³Suitably selected from R as defined above³The radicals and M being metal-containing radicals, e.g. ZnBr, B (OH)₂CuCN or SnBu₃Of the formula M-R³Reacting the compound (a);

(ix) for R in the formula³Is (C1-C6) alkoxycarbonyl (and R³Optionally substituted by at least one group as defined above), with a compound of formula (X) wherein (C1-C6) alkyl is optionally substituted by at least one group as defined above and any functional group is protected if desired, a compound of formula H-O- (C1-C6) alkyl,

Wherein R is¹、R²、Q¹And Q²As defined in formula (I) except that any functional groups are protected if desired; or

(x) For R in the formula³Is a 5-membered heteroaromatic ring containing at least one heteroatom selected from nitrogen, oxygen and sulfur (and R³Optionally substituted by at least one group as defined above), with suitable starting materials and suitable dehydrating agents. For example, for wherein R³Compounds of the formula (I) which are 1, 3, 4-oxadiazolyl, the compounds of the formula (XI) are reacted with a suitable dehydrating agent, such as (methoxycarbonylsulfamoyl) triethylammonium hydroxide,

wherein Z represents any suitable R as defined above³And R¹、R²、Q¹And Q²As defined in formula (I) except that any functional groups are protected if desired; or

(xi) For R in the formula³(ii) Compounds of formula (I) which are (C1-C6) alkyl, (C3-C6) alkenyl, (C3-C6) alkynyl or (C1-C6) alkoxy substituted by at least one group as defined above, compounds of formula (XII) are reacted with a compound of formula H-Xa, (Xb), (Xc') or M-R6 as defined above³The compound (a) is reacted with (b),

wherein L is³Represents a leaving group as defined above, W represents an optionally substituted (C1-C6) alkyl, (C3-C6) alkenyl, (C3-C6) alkynyl or (C1-C6) alkoxy group and R ¹、R²、Q¹And Q²As defined in formula (I) except that any functional groups are protected if desired;

and optionally after (i), (ii), (iii), (iv), (v), (vi), (vii), (viii), (ix), (x) or (xi) one or more of the following steps are performed:

conversion of the resulting compound into another compound of the invention

To form a pharmaceutically acceptable salt of said compound.