HK1226067B

HK1226067B - Pharmaceutical compounds

Info

Publication number: HK1226067B
Application number: HK16114422.1A
Authority: HK
Inventors: J.C.里德
Original assignee: 萨勒姆有限公司
Priority date: 2016-12-20
Filing date: 2013-09-03
Publication date: 2017-09-22

Description

Pharmaceutical compounds

The present invention relates to compounds that inhibit or modulate the activity of JAK kinases, particularly TYK2 kinase, and to the use of such compounds in the treatment or prevention of disease states or conditions mediated by such kinases.

Background

Protein kinases constitute a large family of structurally related enzymes that are responsible for controlling a wide variety of signaling processes within cells (Hardie and Hanks (1995) The Protein Kinase products book.I and II, academic Press, San Diego, Calif.). Kinases can be divided into families based on the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine/threonine, lipids, etc.). Sequence motifs that roughly correspond to each kinase family have been identified (e.g., Hanks and Hunter, FASEB J., (1995) 9.576-596; Knighton, et al, Science, (1991)253, 407-414; Hiles, et al, Cell, (1992)70, 419-429; Kunz, et al., Cell, (1993)73, 585-596; Garcia-Bustos, et al., EMBO J., (1994)13, 2352-2361).

Protein kinases can be characterized by their regulatory mechanisms. These mechanisms include, for example, autophosphorylation, transphosphorylation by other kinases, protein-protein interactions, protein-lipid interactions, and protein-polynucleotide interactions. Individual protein kinases may be regulated by more than one mechanism.

Kinases regulate many different cellular processes including, but not limited to, proliferation, differentiation, apoptosis, motility, transcription, translation and other signaling processes by adding phosphate groups to target proteins. These phosphorylation events act as molecular on/off switches that can modulate or regulate the biological function of the target protein. Phosphorylation of target proteins occurs in response to various extracellular signals (hormones, neurotransmitters, growth and differentiation factors, etc.), cell cycle events, environmental or nutritional stresses, etc. Suitable protein kinases function in signaling pathways to activate or inactivate (directly or indirectly), for example, metabolic enzymes, regulatory proteins, receptors, cytoskeletal proteins, ion channels or pumps, or transcription factors. Defective control of protein phosphorylation leading to uncontrolled signaling has been implicated in a number of diseases including, for example, inflammation, cancer, allergy/asthma, immune system diseases and conditions, central nervous system diseases and conditions, and angiogenesis.

The janus kinase (JAK) family is a family of intracellular non-receptor tyrosine kinases ranging in size from 120-140kDa, transducing cytokine-mediated signals through the JAK-STAT pathway. The JAK family plays a role in cytokine-dependent regulated proliferation and cellular functions involved in immune responses. Currently, there are four known mammalian JAK family members: JAK1, JAK2, JAK3 and TYK 2. JAK1, JAK2 and TYK2 are ubiquitously expressed, whereas JAK3 is expressed in the myeloid and lymphoid lineages. JAK family members are non-receptor tyrosine kinases that are associated with many hematopoietic cytokines, receptor tyrosine kinases, and cytokines of GPCRs.

Each JAK kinase protein has a kinase domain and a catalytically inactive pseudo-kinase domain. JAK proteins bind to cytokine receptors through their amino-terminal FERM (ribbon-4.1, ezrin, radixin, moesin) domain. Following binding of cytokines to their receptors, JAKs are activated and phosphorylate The receptors, creating docking sites for signaling molecules, particularly members of The Signal Transducer and Activator of Transcription (STAT) family (Yamaoka et al,2004.The Janus kinases (JAKs). Genome Biology 5(12): 253).

In mammals, JAK1, JAK2 and TYK2 are ubiquitously expressed. The role of TYK2 in the biological response to cytokines has been characterized by: mutant human Cell lines resistant to the action of type I Interferon (IFN) were used and it was demonstrated that the reactivity of IFNa could be repaired by genetic complementation of TYK2 (Velazquez et al,1992.Cell 70, 313-322). Further in vitro studies have shown that TYK2 is involved in a variety of roles in both innate and adaptive immunitySignal pathways for other cytokines. However, TYK2^-/-analysis of mice showed that the immune deficiency was not as severely affected as expected (Karaghiosofff et al,2000.Immunity 13, 549-560; Shimoda et al,2000.Immunity 13, 561-671.) surprisingly TYK2 deficient mice showed only reduced reactivity to IFN α/β, whereas signaling was normal for interleukin 6(IL-6) and interleukin 10(IL-10), with both interleukin 6(IL-6) and interleukin 10(IL-10) activating TYK2 in vitro, TYK2 was shown to be essential for IL-12 signaling, the lack of TYK2 resulted in the activation of defective STAT4 and the inability of these mice to differentiate into IFNy-producing Thl cells, consistent with TYK2 in mediating the biological effects of type I IFN and IL-12, TYK2^-/-Mice are more susceptible to viral and bacterial infections.

Only 1 patient described so far had an autosomal recessive TYK2 deficiency (Minegishi et al,2006.Immunity 25,745-755). A homozygous deletion of four base pairs (GCTT at nucleotide 550 in the TYK2 gene) and a subsequent frameshift mutation in the patient's coding DNA introduce an advanced (prematurity) stop codon and result in truncation of the TYK2 protein at amino acid 90. The phenotype of this null mutation in human cells is much more severe than would be expected by studies on murine cells lacking TYK 2. The clinical features shown by patients are reminiscent of primary immunodeficiency hyper IgE syndrome (HIES), including susceptibility to recurrent skin abscesses, allergic dermatitis, elevated serum IgE levels, and a variety of opportunistic infections.

With TYK2^-/-In contrast, the mouse reports were that multiple cytokine signals were found to be impaired, highlighting the non-redundant role of human TYK2 in type I IFN, IL-6, IL-10, IL-12, and IL-23 function. An imbalance in T helper cell differentiation was also observed, with patients' T cells showing extreme diagonal IL-4-producing development of Th2 cells and impaired Th1 differentiation. Indeed, these cytokine signaling defects may be responsible for many of the described clinical manifestations, such as allergic dermatitis and high IgE levels (enhanced Th2), increased incidence of viral infection (IFN deficiency), infection of intracellular bacteria (IL-12/Thl deficiency) andextracellular bacteria (IL-6 and IL-23/Thl7 deficient). Evidence emerging from genome-wide association studies suggests that Single Nucleotide Polymorphisms (SNPs) in the TYK2 gene significantly affect susceptibility to autoimmune disease.

The less efficient TYK2 variant is associated with protection against Systemic Lupus Erythematosus (SLE) (TYK2rs2304256andrs12720270, Sigurdsson et al,2005.am.j.hum.genet.76, 528-537; Graham et al,2007.Rheumatology 46, 927-930; Hellquist et al,2009.j.rheumatol.36, 1631-1638; jarvine et al,2010.exp.dermatol.19,123-131) and Multiple Sclerosis (MS) (rs34536443, banet al,2009.eur.j.hum.genet.17, 1309-1313; meret al,2009. eur.j.imm.18, 502-504), whereas the predicted functionally-acquired mutation increases inflammatory bowel disease (ibd.ibd.56, hudrson.18, 4248-56, 2009, 4248-31).

As a support for the involvement of TYK2 in the immunopathological disease process, it has been shown that b10.d1 mice carrying missense mutations in the pseudokinase domain of TYK2 resulting in the deletion of the encoded TYK2 protein are resistant to autoimmune arthritis (CIA) and Experimental Autoimmune Encephalomyelitis (EAE) (Shaw et al,2003.PNAS 100, 11594-11599; space et al,2009.j. immunol.182, 7776-7783). In addition, recent studies have shown that TYK2^-/-Mice were completely resistant to MOG-induced EAE (Oyamada et al,2009.j. immunol.183, 7539-7546). In these mice, resistance was accompanied by a lack of spinal cord-penetrating CD4T cells, and failure to signal through IL-12R and IL-23R, thus failing to upregulate the encephalitogenic levels of IFNy and IL-17.

The non-receptor tyrosine kinase TYK2 plays a key role in innate and adaptive immunity. The lack of TYK2 expression is reflected in a severe imbalance of attenuated signaling and T helper cell differentiation of a variety of pro-inflammatory cytokines. Furthermore, evidence from genetically related studies supports that TYK2 is a common susceptibility gene for autoimmune disease. Taken together, these reasons suggest TYK2 as a therapeutic target for inflammatory and autoimmune diseases.

The development of several disease states involves the overexpression of TYK2 kinase. For example, patients with progressive pulmonary Sarcoidosis are found to have elevated levels of TYK2 (schischchmanoff et al, sarclodosis vasc. diffuse,2006,23(2), 101-7).

Several JAK family inhibitors have been reported in the literature, which can be used in the medical field (ghorechi et al,2009.Immunol Rev,228: 273-287). It is expected that selective TYK2 inhibitors that inhibit TYK2 more potently than JAK2 may have advantageous therapeutic properties because inhibition of JAK2 may cause anemia (Ghoreschi ea.al, 2009.nature elmunol.4, 356-360).

Although TYK2 inhibitors are well known in the art, there is a need to provide additional TYK2 inhibitors that are more effective at least in pharmaceutically relevant properties, such as activity, in particular selectivity over JAK2 kinase, and ADMET properties. It is therefore an object of the present invention to provide a novel class of compounds as TYK2 inhibitors, which preferably show selectivity over JAK2 and may be effective in the treatment or prevention of diseases associated with TYK 2.

W02012/000970(Cellzome) discloses a series of triazolopyridines as TYK2 kinase inhibitors. W02011/113802(Roche) discloses a series of imidazopyridines as TYK2 kinase inhibitors. W02008/156726, W02009/155156, W02010/005841 and W02010/011375 all disclose the properties of JAK kinases in the name of Merck and their relevance as therapeutic targets.

W02010/055304(Sareum) discloses a family of substituted oxazole carboxamides for use in the prevention or treatment of autoimmune diseases, especially multiple sclerosis. The compounds disclosed in W02010/055304 are described as FLT3 kinase inhibitors. The kinase inhibitory effect of oxazole carboxamide is also disclosed in International patent application W02008/139161 (Sareum).

Summary of The Invention

A subset of the compounds of the type disclosed in W02008/139161 and W02010/055304 have now been found to be particularly potent TYK2 kinase inhibitors and, in addition, demonstrate selectivity for TYK2 over the other three JAK kinases, JAK1, JAK2 and JAK 3. These compounds thus provide a method of treating inflammatory conditions and diseases while exhibiting reduced or no side effects associated with JAK1, JAK2, or JAK3 inhibition.

Thus, in a first embodiment (example 1.0), the invention provides a method of inhibiting TYK2 kinase, the method comprising contacting TYK2 kinase with an effective TYK2 kinase inhibiting amount of a compound having the formula (0):

or a salt or stereoisomer thereof; wherein:

n is 0,1 or 2;

Ar¹selected from phenyl, pyridyl, thienyl and furyl, each optionally substituted with 1,2 or 3 substituents independently selected from halogen, C_1-4Alkyl, hydroxy-C_1-4Alkyl radical, C_1-2alkoxy-C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-2alkoxy-C_1-4-alkoxy, C_2-4Alkenyl radical, C_2-4Alkenyloxy radical, C_2-4Alkynyl, C_2-4Alkynyloxy, cyano, C_1-4Alkanoyl, hydroxy and C_1-4Alkanoyloxy of which C is_1-4Alkyl and C_1-4Alkoxy groups are each optionally substituted with one or more fluorine atoms;

Q¹selected from the group consisting of C (═ O), S (═ O) and SO₂；

A is absent or is NR²；

R¹Is selected from

-hydrogen;

-C optionally substituted by one or more substituents_1-6A non-aromatic hydrocarbon group, the substituent being selected from the group consisting of hydroxy, C_1-2Alkoxy radicalAmino, mono-C_1-4Alkylamino radical, bis-C_1-4Alkylamino, 3-to 7-membered non-aromatic carbocycles and heterocycles containing one or two heteroatom ring members selected from O, N and S, and bridged bicyclic heterocycles of 7 to 9 ring members in which one or two ring members are nitrogen atoms, the carbocycles and heterocycles and bridged bicyclic heterocycles optionally being substituted with one or more hydroxy groups, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkanoyl radical, C_1-4Alkanoyloxy group, C_1-4Alkoxycarbonyl or hydroxy-C_1-3Alkyl substitution; and-3-to 7-membered non-aromatic carbocycles and heterocycles comprising one or two heteroatom ring members selected from O, N and S, and bridged bicyclic heterocycles of 7 to 9 ring members in which one or two ring members are nitrogen atoms, the carbocycles and heterocycles and bridged bicyclic heterocycles optionally being substituted by one or more hydroxy groups, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkanoyl radical, C_1-4Alkanoyloxy group, C_1-4Alkoxycarbonyl, amino-C_1-3Alkyl, mono-C_1-2alkylamino-C_1-3Alkyl, bis-C_1-2alkylamino-C_1-3Alkyl or hydroxy-C_1-3Alkyl substitution;

R²selected from hydrogen and C_1-4An alkyl group; or

NR¹R²Forming a 4-to 7-membered non-aromatic nitrogen-containing heterocyclic ring optionally containing a second heteroatom ring member selected from N and O, said heterocyclic ring optionally substituted with one or more hydroxyl groups, C_1-4Alkyl radical, C_1-4Alkanoyl radical, C_1-4Alkanoyloxy group, C_1-4Alkoxy radical, C_1-4alkoxycarbonylamino-C_1-3Alkyl, mono-C_1-2alkylamino-C_1-3Alkyl, bis-C_1-2alkylamino-C_1-3Alkyl or hydroxy-C_1-3Alkyl substitution.

In formula (0), n may be selected from 0 or 1 (example 1.0A), or n may be 0 (example 1.0B) or n may be 1 (example 1.0C).

In a second embodiment (example 1.1), the present invention provides a method of inhibiting TYK2 kinase, the method comprising contacting TYK2 kinase with an effective TYK2 kinase inhibiting amount of a compound of formula (1):

or a salt or stereoisomer thereof; wherein:

Q¹selected from the group consisting of C (═ O), S (═ O) and SO₂；

A is absent or is NR²；

R¹Selected from:

-hydrogen;

-C optionally substituted by one or more substituents_1-6A non-aromatic hydrocarbon group, the substituent being selected from the group consisting of hydroxy, C_1-2Alkoxy, amino, mono-C_1-4Alkylamino radical, bis-C_1-4Alkylamino, 3-to 7-membered non-aromatic carbocycles and heterocycles containing one or two heteroatom ring members selected from O, N and S, and bridged bicyclic heterocycles of 7 to 9 ring members in which one or two ring members are nitrogen atoms, the carbocycles and heterocycles and bridged bicyclic heterocycles optionally being substituted with one or more hydroxy groups, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkanoyl radical, C_1-4Alkanoyloxy group, C_1-4Alkoxycarbonyl or hydroxy-C_1-3Alkyl substitution; and-3-to 7-membered non-aromatic carbocycles and heterocycles comprising one or two heteroatom ring members selected from O, N and S, and bridged bicyclic heterocycles of 7 to 9 ring members in which one or two ring members are nitrogen atoms, the carbocycles and heterocycles and bridged bicyclic heterocycles optionally being substituted by one or more hydroxy groups, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkanoyl radical, C_1-4Alkanoyloxy group, C_1-4Alkoxycarbonyl, amino-C_1-3Alkyl, mono-C_1-2alkylamino-C_1-3Alkyl, bis-C_1-2alkylamino-C_1-3Alkyl or hydroxy-C_1-3Alkyl substitution;

R²selected from hydrogen and C_1-4An alkyl group; or

NR¹R²Forming a 4-to 7-membered non-aromatic nitrogen-containing heterocyclic ring optionally containing a second heteroatom ring member selected from nitrogen and oxygen, the heterocyclic ring optionally substituted with one or more hydroxyl groups, C_1-4Alkyl radical, C_1-4Alkanoyl radical, C_1-4Alkanoyloxy group, C_1-4Alkoxy radical, C_1-4alkoxycarbonylamino-C_1-3Alkyl, mono-C_1-2alkylamino-C_1-3Alkyl, bis-C_1-2alkylamino-C_1-3Alkyl or hydroxy-C_1-3Alkyl substitution.

Particular and preferred aspects and embodiments of the invention are given in examples 1.2 to 2.26 and examples 3.1 to 3.3 below.

1.2 the method of any one of embodiments 1.0 to 1.1, wherein Ar¹Is optionally substituted phenyl.

1.3 the method of any one of embodiments 1.0 to 1.1, wherein Ar¹Is an optionally substituted pyridyl group.

1.4 the method of any one of embodiments 1.0 to 1.1, wherein Ar¹Is an optionally substituted thienyl group.

1.5 the method of any one of embodiments 1.0 to 1.1, wherein Ar¹Is an optionally substituted furyl group.

1.6 the method of any one of embodiments 1.0 to 1.5, wherein Ar¹The optional substituents are independently selected from: halogen, C_1-4Alkyl, hydroxy-C_1-4Alkyl radical, C_1-2alkoxy-C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-2alkoxy-C_1-4-alkoxy, C_2-4Alkenyl radical, C_2-4Alkenyloxy radical, C_2-4Alkynyl, C_2-4Alkynyloxy, cyano, C_1-4Alkanoyl, hydroxy and C_1-4Alkanoyloxy of which C is_1-4Alkyl and C_1-4The alkoxy groups are each optionally substituted with one or more fluorine atoms.

1.7 the process of embodiment 1.6, wherein Ar¹The optional substituents are independently selected from: halogen, C_1-3Alkyl, hydroxy-C_1-3Alkyl radical, C_1-2alkoxy-C_1-3Alkyl radical, C_1-3Alkoxy radical, C_1-2alkoxy-C_1-3Alkoxy, cyano, C_1-3Alkanoyl and C_1-3Alkanoyloxy of which C is_1-3Alkyl and C_1-3The alkoxy groups are each optionally substituted with one or more fluorine atoms.

1.8 the process of embodiment 1.7, wherein Ar¹The optional substituents are independently selected from: fluorine, chlorine, bromine, C_1-3Alkyl, hydroxy-C_1-3Alkyl, methoxy-C_1-3Alkyl radical, C_1-3-alkoxy, methoxy-C_1-3Alkoxy, cyano, C_1-3Alkanoyl and C_1-3Alkanoyloxy of which C is_1-3Alkyl and C_1-3The alkoxy groups are each optionally substituted with one or more fluorine atoms.

1.9 the process of embodiment 1.8, wherein Ar¹The optional substituents are independently selected from fluorine,Chlorine, bromine, methyl, ethyl, isopropyl, hydroxymethyl, hydroxyethyl, methoxyethyl, methoxy, ethoxy, isopropoxy, methoxyethoxy, cyano, acetyl, acetoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, and difluoromethoxy.

1.10 the process of embodiment 1.9, wherein Ar¹The optional substituents are independently selected from fluoro, chloro, methyl, ethyl, isopropyl, hydroxymethyl, methoxy, ethoxy, isopropoxy, cyano, acetyl, acetoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, and difluoromethoxy.

1.11 the process of embodiment 1.10, wherein Ar¹The optional substituents are independently selected from fluoro, chloro, methyl, ethyl, methoxy, cyano, acetyl and trifluoromethyl.

1.12 the method of embodiment 1.11, wherein Ar¹The optional substituents are independently selected from fluorine and chlorine.

1.13 the method of embodiment 1.12 wherein each substituent is fluorine.

1.14 the method of any one of embodiments 1.1 to 1.13, wherein Ar¹Unsubstituted or substituted by 1,2 or 3 substituents.

1.15 the method of embodiment 1.14, wherein Ar¹Are not substituted.

1.16 the method of embodiment 1.14, wherein Ar¹There are 1 substituent.

1.17 the method of embodiment 1.14, wherein Ar¹There are 2 substituents.

1.18 the process of embodiment 1.14, wherein Ar¹There are 3 substituents.

1.19 the method of embodiment 1.14, wherein Ar¹Unsubstituted or substituted by 1 or 2 substituents.

1.20 the method of any one of embodiments 1.0 to 1.1, 1.2, and 1.6 to 1.17, wherein Ar¹Is unsubstituted phenyl or 2-monosubstituted, 3-monosubstituted, 4-monosubstituted, 2, 3-disubstituted, 2, 4-disubstituted, 2,5 disubstituted or 2,6 disubstituted phenyl.

1.21 the method of embodiment 1.20, wherein Ar¹Selected from the group consisting of unsubstituted phenyl, 2-fluorophenyl, 2-hydroxyphenyl, 2-methoxyphenyl, 2-methylphenyl, 3-fluorophenyl, 3-methoxyphenyl, 2, 6-difluorophenyl, 2-fluoro-3-methoxyphenyl, 2-fluoro-5-methoxyphenyl, 2-chloro-6-methoxyphenyl, 2-fluoro-6-methoxyphenyl, 2, 6-dichlorophenyl, 2-chloro-6-fluorophenyl, and 5-fluoro-2-methoxyphenyl.

1.22 the method of embodiment 1.21, wherein Ar¹Selected from the group consisting of 2, 6-difluorophenyl, 2-chloro-6-fluorophenyl, and 2, 6-dichlorophenyl.

1.23 the method of embodiment 1.22, wherein Ar¹Is 2, 6-difluorophenyl.

1.23A the method of embodiment 1.22, wherein Ar¹Is 2-chloro-6-fluorophenyl.

1.23B the method of embodiment 1.22, wherein Ar¹Is 2, 6-dichlorophenyl.

1.24 the method of any one of embodiments 1.0 through 1.23B, wherein Q¹Is C (═ O).

1.25 the method of any one of embodiments 1.0 through 1.23B, wherein Q¹Is S (═ O).

1.26 the method of any one of embodiments 1.0 through 1.23B, wherein Q¹Is SO₂。

1.27 the method of any one of embodiments 1.0 to 1.26, wherein A is absent (i.e., group R)¹And Q¹Directly connected together)

1.28 the method of any one of embodiments 1.0 through 1.23BWherein A is absent, and Q¹Is S0₂。

1.29 the method of any one of embodiments 1.0 to 1.26, wherein A is NR²。

1.30 the method of any one of embodiments 1.0 to 1.29, wherein R¹Selected from:

-hydrogen;

-C optionally substituted by one or more substituents_1-6A saturated hydrocarbon group, the substituent being selected from: hydroxy, C_1-2Alkoxy, amino, mono-C_1-4Alkylamino radical, bis-C_1-4Alkylamino, a 3-to 6-membered saturated carbocyclic ring and a 4-to 7-membered heterocyclic ring containing one or two heteroatom ring members selected from O, N and S, and a bridged bicyclic heterocyclic ring of 7-to 9 ring members in which one or two ring members are nitrogen atoms, the carbocyclic and heterocyclic rings and the bridged bicyclic heterocyclic ring being optionally substituted with one or more hydroxy, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkanoyl radical, C_1-4Alkanoyloxy group, C_1-4Alkoxycarbonyl, amino-C_1-3Alkyl, mono-C_1-2alkylamino-C_1-3Alkyl, bis-C_1-2alkylamino-C_1-3Alkyl or hydroxy-C_1-3Alkyl substitution; and

-a 3 to 6 membered saturated carbocyclic ring and a 4 to 7 membered heterocyclic ring containing one or two heteroatom ring members selected from O, N and S, and a bridged bicyclic heterocyclic ring of 7 to 9 ring members in which one or two ring members are nitrogen atoms, the carbocyclic and heterocyclic rings and the bridged bicyclic heterocyclic ring being optionally substituted by one or more of hydroxy, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkanoyl radical, C_1-4Alkanoyloxy group, C_1-4Alkoxycarbonyl, amino-C_1-3Alkyl, mono-C_1-2alkylamino-C_1-3Alkyl, bis-C_1-2alkylamino-C_1-3Alkyl or hydroxy-C_1-3Alkyl substitution;

when R is²When present, R²Selected from hydrogen and C_1-4Alkyl radical(ii) a Or

NR¹R²Forming a 4-to 7-membered saturated nitrogen-containing heterocyclic ring optionally containing a second heteroatom ring member selected from nitrogen and oxygen, the heterocyclic ring optionally being substituted with one or more hydroxy groups, C_1-4Alkyl radical, C_1-4Alkanoyl radical, C_1-4Alkanoyloxy group, C_1-4Alkoxy radical, C_1-4Alkoxycarbonyl or hydroxy-C_1-3Alkyl substitution.

1.31 the method of embodiment 1.30, wherein R¹Selected from:

-hydrogen;

-C optionally substituted by one or more substituents_1-4Alkyl, the substituent is selected from hydroxyl and C_1-3Alkoxy, amino, mono-C_1-3Alkylamino radical, bis-C_1-3Alkylamino, a 3-to 5-membered saturated carbocyclic ring and a 4-to 6-membered heterocyclic ring containing one or two heteroatom ring members selected from O, N and S, the carbocyclic and heterocyclic rings optionally being substituted with one or more of hydroxy, C_1-3Alkyl radical, C_1-3Alkoxy radical, C_1-3Alkanoyl radical, C_1-3Alkanoyloxy group, C_1-3Alkoxycarbonyl or hydroxy-C_1-3Alkyl substitution; and

-a 3-to 5-membered saturated carbocyclic ring and a 4-to 6-membered heterocyclic ring containing one or two heteroatom ring members selected from O, N and S, the carbocyclic and heterocyclic rings being optionally substituted by one or more of hydroxy, C_1-3Alkyl radical, C_1-3Alkoxy radical, C_1-3Alkanoyl radical, C_1-3Alkanoyloxy group, C_1-4Alkoxycarbonyl or hydroxy-C_1-3Alkyl substitution;

when R is²When present, R²Selected from hydrogen and C_1-2An alkyl group; or

NR¹R²Forming a 4-to 7-membered saturated nitrogen-containing heterocyclic ring optionally containing a second heteroatom ring member selected from nitrogen and oxygen, the heterocyclic ring optionally being substituted with one or more hydroxy groups, C_1-3Alkyl radical, C_1-3An alkanoyl group,C_1-3Alkanoyloxy group, C_1-3Alkoxy radical, C_1-4Alkoxycarbonyl or hydroxy-C_1-3Alkyl substitution.

1.31 the method of embodiment 1.30, wherein R¹Selected from:

-hydrogen;

-C optionally substituted by one or more substituents_1-4Alkyl, said substituents being selected from hydroxy, amino, mono-C_1-3Alkylamino and bis-C_1-3An alkylamino group; and

-a 5-to 6-membered nitrogen containing heterocyclic ring optionally substituted with one or more C and optionally containing a second heteroatom ring member selected from N and O_1-3Alkyl or hydroxy-C_1-3Alkyl substitution;

when R is²When present, R²Selected from hydrogen and C_1-2An alkyl group; or

NR¹R²Forming a 5-to 6-membered heterocyclic ring containing a nitrogen atom, optionally containing a second ring member selected from N and O, optionally substituted with one or more C_1-3Alkyl or hydroxy-C_1-3Alkyl substitution.

1.32 the method of embodiment 1.31, wherein R¹Selected from:

-hydrogen;

-C optionally substituted by one or more substituents_1-4Alkyl, said substituents being selected from the group consisting of hydroxy, amino and mono-C_1-3An alkylamino group; and

-a 5 to 6-membered heterocyclic ring selected from pyrrolidine, piperidine, piperazine and morpholine, optionally substituted by one or more C_1-3Alkyl or hydroxy-C_1-3Alkyl substitution;

when R is²When present, R²Selected from hydrogen and C_1-2An alkyl group; or

NR¹R²Form 5 to 6 membered heterocycle selected from pyrrolidine, piperidine, piperazine, and morpholine, optionally substituted with one or more C_1-3Alkyl or hydroxy-C_1-3Alkyl substitution.

1.33 the method of embodiment 1.32, wherein R¹Selected from:

-hydrogen;

-C optionally substituted by one or more substituents_1-3An alkyl group, the substituents being selected from the group consisting of hydroxy, amino and methylamino; and

when R is²When present, R²Selected from hydrogen and C_1-2An alkyl group; or

NR¹R²Form 5 to 6-membered heterocycle selected from pyrrolidine, piperidine, piperazine, and morpholine, optionally substituted with one or more C_1-3Alkyl or hydroxy-C_1-3Alkyl substitution.

1.34 the method of embodiment 1.33, wherein R¹Selected from:

-hydrogen;

-C optionally substituted by one or more substituents_1-3An alkyl group, the substituent being selected from the group consisting of a hydroxyl group, an amino group and a methylamino group; and

-a 5 to 6-membered heterocyclic ring selected from pyrrolidine and piperidine, which heterocyclic ring is optionally substituted by methyl;

when R is²When present, R²Selected from hydrogen and methyl; or

NR¹R²Forming a 5 to 6-membered heterocyclic ring selected from pyrrolidine and morpholine, which heterocyclic ring is optionally substituted with hydroxymethyl.

1.35 the method of embodiment 1.34 wherein Q¹-A-R¹Groups AA to AR selected from the following table:

wherein the point of attachment to the phenyl group is indicated by an asterisk.

1.36 the method of embodiment 1.35, wherein Q¹-A-R¹Is a group AA.

1.37 the process of embodiment 1.0 or 1.1 wherein the compound of structural formula (0) or (1) is selected from:

2- (2, 6-difluorophenyl) -5- (4- (methylsulfonyl) phenylamino) oxazole-4-carboxamide;

2- (2, 6-difluorophenyl) -5- (4-sulfamoylanilino) oxazole-4-carboxamide;

2- (2, 6-difluorophenyl) -5- (4- (N, N-dimethylsulfamoyl) anilino) oxazole-4-carboxamide;

2- (2, 6-difluorophenyl) -5- (4- (N' -methylsulfamoyl) anilino) oxazole-4-carboxamide;

2- (2, 6-difluorophenyl) -5- (4- (dimethylcarbamoyl) anilino) oxazole-4-carboxamide;

5- (4- ((3-aminopropyl) carbamoyl) phenylamino) -2- (2, 6-difluorophenyl) oxazole-4-carboxamide;

(R) -2- (2, 6-difluorophenyl) -5- (4- (piperidin-3-ylcarbamoyl) phenylamino) oxazole-4-carboxamide;

(S) -2- (2, 6-difluorophenyl) -5- (4- (piperidin-3-ylcarbamoyl) phenylamino) oxazole-4-carboxamide;

2- (2, 6-difluorophenyl) -5- (4- (morpholine-4-carbonyl) phenylamino) oxazole-4-carboxamide;

5- (4- ((2- (methylamino) ethyl) carbamoyl) phenylamino) -2- (2, 6-difluorophenyl) oxazole-4-carboxamide;

5- (4- ((3- (methylamino) propyl) carbamoyl) phenylamino) -2- (2, 6-difluorophenyl) oxazole-4-carboxamide;

(R) -2- (2, 6-difluorophenyl) -5- (4- (pyrrolidin-3-ylcarbamoyl) phenylamino) oxazole-4-carboxamide;

(S) -2- (2, 6-difluorophenyl) -5- (4- (pyrrolidin-3-ylcarbamoyl) phenylamino) oxazole-4-carboxamide;

(R) -2- (2, 6-difluorophenyl) -5- (4- (2- (hydroxymethyl) pyrrolidine-1-carbonyl) phenylamino) oxazole-4-carboxamide;

5- (4- ((2-hydroxyethyl) carbamoyl) phenylamino) -2- (2, 6-difluorophenyl) oxazole-4-carboxamide;

5- (4- ((3-hydroxypropyl) carbamoyl) phenylamino) -2- (2, 6-difluorophenyl) oxazole-4-carboxamide;

2- (2, 6-difluorophenyl) -5- (4- (piperidin-4-ylcarbamoyl) phenylamino) oxazole-4-carboxamide; and

5- (4- ((1-methylpiperidin-4-yl) carbamoyl) phenylamino) -2- (2, 6-difluorophenyl) oxazole-4-carboxamide;

and salts thereof.

In another aspect, the invention provides a group of novel compounds in structural formula (0) of example 1.0. The novel compounds of the invention are as defined in examples 1.38 to 1.96.

1.38A compound of the formula (2)

Or a salt or stereoisomer thereof; wherein:

R⁷selected from chlorine and fluorine;

R³、R⁴、R⁵and R⁶Each is independently selected from hydrogen, fluorine and chlorine;

n is 0,1 or 2;

Q¹selected from the group consisting of C (═ O), S (═ O) and SO₂；

A is absent or is NR²；

R¹Selected from:

-hydrogen;

-C optionally substituted by one or more substituents_1-6A non-aromatic hydrocarbon group, the substituent being selected from the group consisting of hydroxy, C_1-2Alkoxy, amino, mono-C_1-4Alkylamino radical, bis-C_1-4Alkylamino, a 3-to 7-membered non-aromatic carbocyclic ring and a heterocyclic ring containing one or two heteroatom ring members selected from O, N and S, and a bridged bicyclic heterocyclic ring of 7 to 9 ring members in which one or two ring members are nitrogen atoms, the carbocyclic and heterocyclic rings and the bridged bicyclic heterocyclic ring being optionally substituted by one or more hydroxy groups, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkanoyl radical, C_1-4Alkanoyloxy group, C_1-4Alkoxycarbonyl or hydroxy-C_1-3Alkyl substitution; and

-a 3-to 7-membered non-aromatic carbocyclic and heterocyclic ring containing one or two heteroatom ring members selected from O, N and S, and a bridged bicyclic heterocyclic ring of 7 to 9 ring members in which one or two ring members are nitrogen atoms, the carbocyclic and heterocyclic rings and the bridged bicyclic heterocyclic ring optionally being substituted by one or more hydroxy groups, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkanoyl radical, C_1-4Alkanoyloxy group, C_1-4Alkoxycarbonyl, amino-C_1-3Alkyl, mono-C_1-2alkylamino-C_1-3Alkyl, bis-C_1-2alkylamino-C_1-3Alkyl or hydroxy-C_1-3Alkyl substitution;

R²selected from hydrogen and C_1-4An alkyl group; or

NR¹R²Forming a 4-to 7-membered non-aromatic nitrogen-containing heterocyclic ring which may optionally contain a second heteroatom ring member selected from nitrogen and oxygen, the heterocyclic ring optionally being substituted with one or more hydroxyl groups, C_1-4Alkyl radical, C_1-4Alkanoyl radical, C_1-4Alkanoyloxy group, C_1-4Alkoxy radical, C_1-4alkoxycarbonylamino-C_1-3Alkyl, mono-C_1-2alkylamino-C_1-3Alkyl, bis-C_1-2alkylamino-C_1-3Alkyl or hydroxy-C_1-3Alkyl substitution;

the precondition is that:

(i)R³to R⁶No more than 2 of which are not hydrogen; and

(ii) when R is⁷And R⁶When both are fluorine, then R³To R⁵Is chlorine or fluorine and/or R¹-A-Q¹Selected from the group consisting of sulfonyl and isopropylsulfonyl.

1.38A Compounds according to example 1.38, when R⁷And R⁶While being fluorine, then R³To R⁵One of which is chlorine or fluorine.

1.39A compound according to embodiment 1.38 or embodiment 1.38A, wherein R⁷Is chlorine.

1.40 the compound of embodiment 1.39, wherein R⁷Is chlorine, R⁶Is fluorine.

1.41A compound according to embodiment 1.39, wherein R⁷And R⁶Are all chlorine.

1.42 the compound of any one of embodiments 1.38-1.41, wherein R³And R⁵At least one of which is hydrogen.

1.43 Compounds according to embodiment 1.42, wherein R³And R⁵Are all hydrogen.

1.44 according to the examples1.38 to 1.43, wherein R⁴Is hydrogen.

1.45 Compounds according to any one of embodiments 1.38 to 1.43, wherein R⁴Is fluorine.

1.46 the compound according to any one of embodiments 1.38 to 1.43, wherein R⁴Is chlorine.

1.47 Compounds according to any one of embodiments 1.38 to 1.46, wherein Q¹Is C (═ O).

1.48 Compounds according to any one of embodiments 1.38 to 1.46, wherein Q¹Is S (═ O).

1.49A compound according to any one of embodiments 1.38 to 1.46, wherein Q¹Is SO₂。

1.50 Compounds according to any one of embodiments 1.38 to 1.49, wherein A is absent (i.e. group R)¹And Q²Directly connected together)

1.51 Compounds according to example 1.50, wherein A is absent, Q¹Is SO₂。

1.52 Compounds according to any one of embodiments 1.38 to 1.49, wherein A is NR²。

1.53 the compound of any one of embodiments 1.38 to 1.52 wherein:

R¹selected from:

-hydrogen;

-C optionally substituted by one or more substituents_1-6Saturated hydrocarbon radical, the substituent is selected from hydroxyl and C_1-2Alkoxy, amino, mono-C_1-4Alkylamino radical, bis-C_1-4Alkylamino, a 3-to 6-membered saturated carbocyclic ring and a 4-to 7-membered heterocyclic ring containing one or two heteroatom ring members selected from O, N and S, and a 7-to 9 ring member bridged bicyclic heterocyclic ring in which one or two ring members are nitrogen atomsThe carbocycle and heterocycle and the bridged bicyclic heterocycle may optionally be substituted with one or more hydroxy groups, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkanoyl radical, C_1-4Alkanoyloxy group, C_1-4Alkoxycarbonyl, amino-C_1-3Alkyl, mono-C_1-2alkylamino-C_1-3Alkyl, bis-C_1-2alkylamino-C_1-3Alkyl or hydroxy-C_1-3Alkyl substitution; and

-a 3-to 6-membered saturated carbocyclic ring and a 4-to 7-membered heterocyclic ring containing one or two heteroatom ring members selected from O, N and S, and a bridged bicyclic heterocyclic ring of 7 to 9 ring members in which one or two ring members are nitrogen atoms, the carbocyclic and heterocyclic rings and the bridged bicyclic heterocyclic ring being optionally substituted by one or more hydroxy groups, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkanoyl radical, C_1-4Alkanoyloxy group, C_1-4Alkoxycarbonyl, amino-C_1-3Alkyl, mono-C_1-2alkylamino-C_1-3Alkyl, bis-C_1-2alkylamino-C_1-3Alkyl or hydroxy-C_1-3Alkyl substitution;

when R is²When present, R²Selected from hydrogen and C_1-4An alkyl group; or

NR¹R²Forming a 4-to 7-membered saturated nitrogen-containing heterocyclic ring, optionally containing a second heteroatom ring member selected from nitrogen and oxygen, the heterocyclic ring optionally being substituted with one or more hydroxy groups, C_1-4Alkyl radical, C_1-4Alkanoyl radical, C_1-4Alkanoyloxy group, C_1-4Alkoxy radical, C_1-4Alkoxycarbonyl or hydroxy-C_1-3Alkyl substitution.

1.54 the compound of embodiment 1.53 wherein:

R¹selected from:

-hydrogen;

-C optionally substituted by one or more substituents_1-4Alkyl, the substituent is selected from hydroxyl and C_1-3Alkoxy, amino, mono-C_1-3Alkylamino radical, bis-C_1-3Alkylamino, a 3-to 5-membered saturated carbocyclic ring and a 4-to 6-membered heterocyclic ring containing one or two heteroatom ring members selected from O, N and S, the carbocyclic and heterocyclic rings optionally being substituted with one or more hydroxy groups, C_1-3Alkyl radical, C_1-3Alkoxy radical, C_1-3Alkanoyl radical, C_1-3Alkanoyloxy group, C_1-3Alkoxycarbonyl, or hydroxy-C_1-3Alkyl substitution; and

-a 3-to 5-membered saturated carbocyclic ring and a 4-to 6-membered non-aromatic heterocyclic ring containing one or two heteroatom ring members selected from O, N and S, the carbocyclic and heterocyclic rings being optionally substituted by one or more of hydroxy, C_1-3Alkyl radical, C_1-3Alkoxy radical, C_1-3Alkanoyl radical, C_1-3Alkanoyloxy group, C_1-4Alkoxycarbonyl or hydroxy-C_1-3Alkyl substitution;

when R is²When present, R²Selected from hydrogen or C_1-2An alkyl group; or

NR¹R²Forming a 4-to 7-membered saturated nitrogen-containing heterocyclic ring, optionally containing a second heteroatom ring member selected from nitrogen and oxygen, the heterocyclic ring optionally being substituted with one or more hydroxy groups, C_1-3Alkyl radical, C_1-3Alkanoyl radical, C_1-3Alkanoyloxy group, C_1-3Alkoxy radical, C_1-4Alkoxycarbonyl or hydroxy-C_1-3Alkyl substitution.

A compound according to embodiment 1.54 wherein:

R¹selected from:

-hydrogen;

-a 5 to 6-membered non-aromatic nitrogen-containing heterocycle optionally comprising a second ring member selected from N and O, the heterocycle optionally substituted with one or more C_1-3Alkyl or hydroxy-C_1-3Alkyl substitution;

when R is²When present, R²Selected from hydrogen and C_1-2An alkyl group; or

NR¹R²Forming a 5-to 6-membered nitrogen-containing heterocyclic ring, optionally containing a second ring member selected from N and O, optionally substituted with one or more C_1-3Alkyl or hydroxy-C_1-3Alkyl substitution;

1.56 the compound of embodiment 1.55 wherein:

R¹selected from:

-hydrogen;

-a 5-6 membered non-aromatic heterocycle selected from pyrrolidine, piperidine, piperazine and morpholine, optionally substituted by one or more C_1-3Alkyl or hydroxy-C_1-3Alkyl substitution;

when R is²When present, R²Selected from hydrogen and C_1-2An alkyl group; or

NR¹R²Forming a 5 to 6-membered heterocyclic ring selected from pyrrolidine, piperidine, piperazine and morpholine, which heterocyclic ring may optionally be substituted by one or more C_1-3Alkyl or hydroxy-C_1-3Alkyl substitution.

1.57A compound according to embodiment 1.56 wherein:

R¹selected from:

-hydrogen;

when R is²When present, R²Selected from hydrogen and C_1-2An alkyl group; or

NR¹R²Forming a 5 to 6 membered heterocyclic ring selected from pyrrolidine, piperidine, piperazine and morpholine, which heterocyclic ring may optionally be substituted by one or more C_1-3Alkyl or hydroxy-C_1-3Alkyl substitution.

1.58 the compound of embodiment 1.57 wherein:

R¹selected from:

-hydrogen;

when R is²When present, R²Selected from hydrogen and methyl; or

NR¹R²Forming a 5 to 6 membered heterocyclic ring selected from pyrrolidine and morpholine, which heterocyclic ring is optionally substituted with hydroxymethyl.

1.59 Compounds according to any one of embodiments 1.38 to 1.52, wherein R¹Selected from:

-hydrogen; and

-C optionally substituted by one or more substituents_1-6A non-aromatic hydrocarbon group, the substituent being selected from the group consisting of hydroxy, C_1-2Alkoxy, amino, mono-C_1-4Alkylamino, bis-C_1-4Alkylamino, a 3-to 7-membered non-aromatic carbocyclic ring and a heterocyclic ring containing one or two heteroatom ring members selected from O, N and S, and one orA bridged bicyclic heterocycle of 7 to 9 ring members with two ring members being nitrogen atoms, the carbocycle and heterocycle and the bridged bis-heterocyclyl being optionally substituted by one or more hydroxy groups, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkanoyl radical, C_1-4Alkanoyloxy group, C_1-4Alkoxycarbonyl or hydroxy-C_1-3And (4) alkyl substitution.

1.60 Compounds according to any one of embodiments 1.38 to 1.52, wherein R¹Selected from:

-hydrogen; and

-C optionally substituted by one or more substituents_1-4Alkyl, the substituent is selected from hydroxyl and C_1-3Alkoxy, amino, mono-C_1-3Alkylamino, bis-C_1-3Alkylamino, a 3-to 5-membered saturated carbocyclic ring and a 4-to 6-membered heterocyclic ring containing one or two heteroatom ring members selected from O, N and S, the carbocyclic and heterocyclic rings optionally being substituted with one or more hydroxy groups, C_1-3Alkyl radical, C_1-3Alkoxy radical, C_1-3Alkanoyl radical, C_1-3Alkanoyloxy group, C_1-3Alkoxycarbonyl or hydroxy-C_1-3Alkyl substitution.

1.61 Compounds according to any one of embodiments 1.38 to 1.52, wherein R¹Selected from:

-hydrogen; and

-C optionally substituted by one or more substituents_1-4Alkyl, said substituents being selected from hydroxy, amino, mono-C_1-3Alkylamino and bis-C_1-3An alkylamino group.

1.62 Compounds according to any one of embodiments 1.38 to 1.52, wherein R¹Selected from:

-hydrogen; and

-C optionally substituted by one or more substituents_1-4Alkyl, said substituents being selected from the group consisting of hydroxy, amino and mono-C_1-3An alkylamino group.

1.63 Compounds according to any one of embodiments 1.38 to 1.52, wherein R¹Selected from:

-hydrogen; and

-C optionally substituted by one or more substituents_1-3An alkyl group, said substituent being selected from the group consisting of a hydroxyl group, an amino group and a methylamino group.

1.64A compound according to embodiment 1.63, wherein R¹Is C_1-3An alkyl group.

1.65 Compounds according to embodiment 1.64, wherein R¹Selected from methyl, ethyl and isopropyl.

1.66A compound according to embodiment 1.65, wherein R¹Is methyl.

1.67 Compounds according to embodiment 1.65, wherein R¹Is ethyl.

1.68A compound according to embodiment 1.65, wherein R¹Is isopropyl.

1.69 Compounds according to embodiment 1.63, wherein R¹Is C_1-3An alkyl group, which alkyl group may optionally be substituted with one or more substituents selected from the group consisting of hydroxy, amino and methylamino.

1.70A compound according to embodiment 1.69, wherein R¹Is C_2-3An alkyl group substituted with one or more substituents selected from the group consisting of a hydroxyl group, an amino group and a methylamino group.

1.71A compound according to embodiment 1.70, wherein R¹Selected from the group consisting of 3-aminopropyl, 3-methylaminopropyl, 2-methylaminoethyl, 3-hydroxypropyl and 2-hydroxyethyl.

1.73A compound according to example 1.63, wherein R¹Is hydrogen.

1.74 Compounds according to any one of embodiments 1.38 to 1.52, wherein R¹Selected from 3-to 6-membered saturated carbocyclic rings and containing oneA 4-to 7-membered heterocyclic ring of one or two heteroatom ring members selected from O, N and S, and a bridged bicyclic heterocyclic ring of 7 to 9 ring members in which one or two ring members are nitrogen atoms, the carbocyclic and heterocyclic rings and the bridged bicyclic heterocyclic ring being optionally substituted by one or more hydroxy groups, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkanoyl radical, C_1-4Alkanoyloxy group, C_1-4Alkoxycarbonyl, amino-C_1-3Alkyl, mono-C_1-2alkylamino-C_1-3Alkyl, bis-C_1-2alkylamino-C_1-3Alkyl or hydroxy-C_1-3Alkyl substitution.

1.75 the compound according to any one of embodiments 1.38 to 1.52, wherein R¹Selected from 3-to 5-membered saturated carbocyclic rings and 4-to 6-membered non-aromatic heterocyclic rings containing one or two heteroatom ring members selected from O, N and S, the carbocyclic and heterocyclic rings optionally being substituted by one or more hydroxy groups, C_1-3Alkyl radical, C_1-3Alkoxy radical, C_1-3Alkanoyl radical, C_1-3Alkanoyloxy group, C_1-4Alkoxycarbonyl or hydroxy-C_1-3Alkyl substitution.

1.76 the compound according to any one of embodiments 1.38 to 1.52, wherein R¹Selected from 5 to 6-membered non-aromatic nitrogen-containing heterocycles optionally comprising a second ring member selected from nitrogen and oxygen, optionally substituted with one or more C_1-3Alkyl or hydroxy-C_1-3Alkyl substitution.

1.77 the compound of any one of embodiments 1.38 to 1.52, wherein R¹Is a 5-or 6-membered non-aromatic heterocyclic ring selected from pyrrolidine, piperidine, piperazine and morpholine, optionally substituted by one or more C_1-3Alkyl or hydroxy-C_1-3Alkyl substitution.

1.78 Compounds according to embodiment 1.57, wherein R¹Is a 5 to 6-membered heterocyclic ring selected from pyrrolidine and piperidine, which heterocyclic ring is optionally substituted by methyl.

1.79A compound according to any one of embodiments 1.38 to 1.49, wherein AIs NR²，NR¹R²Forming a 4-to 7-membered saturated nitrogen-containing heterocyclic ring optionally containing a second heteroatom ring member selected from nitrogen and oxygen, the heterocyclic ring optionally substituted with one or more hydroxyl groups, C_1-4Alkyl radical, C_1-4Alkanoyl radical, C_1-4Alkanoyloxy group, C_1-4Alkoxy radical, C_1-4Alkoxycarbonyl or hydroxy-C_1-3Alkyl substitution.

1.80 Compounds according to any one of embodiments 1.38 to 1.49, wherein A is NR²And NR is¹R²Forming a 4-to 7-membered saturated nitrogen-containing heterocyclic ring optionally containing a second heteroatom ring member selected from nitrogen and oxygen, the heterocyclic ring optionally substituted with one or more hydroxyl groups, C_1-3Alkyl radical, C_1-3Alkanoyl radical, C_1-3Alkanoyloxy group, C_1-3Alkoxy radical, C_1-4Alkoxycarbonyl or hydroxy-C_1-3Alkyl substitution.

1.81 Compounds according to any one of embodiments 1.38 to 1.49, wherein A is NR²，NR¹R²Forming a 5-to 6-membered nitrogen-containing heterocyclic ring optionally containing a second ring member selected from N and O, optionally substituted with one or more C_1-3Alkyl or hydroxy-C_1-3Alkyl substitution.

1.82 Compounds according to any one of embodiments 1.38 to 1.49, wherein A is NR²，NR¹R²Forming a 5 to 6-membered heterocyclic ring selected from pyrrolidine, piperidine, piperazine and morpholine, which heterocyclic ring may optionally be substituted by one or more C_1-3Alkyl or hydroxy-C_1-3Alkyl substitution.

1.83 Compounds according to any one of embodiments 1.38 to 1.49, wherein A is NR²，NR¹R²Forming a 5 to 6-membered heterocyclic ring selected from pyrrolidine and morpholine, which heterocyclic ring is optionally substituted with hydroxymethyl.

1.84 the compound of any one of embodiments 1.38 to 1.49 and 1.52 to 1.78, wherein R²Selected from hydrogen and methyl.

1.85 Compounds according to any one of embodiments 1.38 to 1.49 and 1.52 to 1.78, wherein R²Is hydrogen.

1.86 Compounds according to any one of embodiments 1.38 to 1.49 and 1.52 to 1.78, wherein R²Is methyl.

1.87 compounds according to any one of embodiments 1.38 to 1.46, wherein Q¹-A-R¹Selected from the groups AA to AT in the following table:

1.88A compound according to embodiment 1.87, wherein Q¹-A-R¹Selected from the groups AA, AG, AH, AI, AR, AS and AT.

1.89A compound according to embodiment 1.88, wherein Q¹-A-R¹Selected from the groups AA, AS and AT.

1.90A compound according to embodiment 1.89, wherein Q¹-A-R¹Is a group AA.

1.91 Compounds according to embodiment 1.88, wherein Q¹-A-R¹Selected from the groups AG, AH, AI and AR.

1.92 the compound according to any one of embodiments 1.38 to 1.91, wherein n is selected from 0 and 1.

A compound according to embodiment 1.92 wherein n is 0.

A compound according to embodiment 1.92 wherein n is 1.

1.95 Compounds according to embodiment 1.94, wherein the fluorine atom is bound to the phenyl ring Q¹Ortho to the radical.

A compound according to embodiment 1.38 wherein the compound of structural formula (2) is selected from:

2- (2, 6-dichloro-phenyl) -5- (4-methanesulfonyl-phenylamino) -oxazole-4-carboxylic acid amide;

2- (2-chloro-6-fluoro-phenyl) -5- (4-methanesulfonyl-phenylamino) -oxazole-4-carboxylic acid amide;

5- (4-methanesulfonyl-phenylamino) -2- (2,4, 6-trifluoro-phenyl) -oxazole-4-carboxylic acid amide;

2- (2, 5-difluoro-phenyl) -5- (4-methanesulfonyl-phenylamino) -oxazole-4-carboxylic acid amide;

(S)2- (2-chloro-6-fluoro-phenyl) -5- [4- (piperidin-3-ylcarbamoyl) -phenylamino ] -oxazole-4-carboxylic acid amide;

(R)2- (2-chloro-6-fluoro-phenyl) -5- [4- (piperidin-3-ylcarbamoyl) -phenylamino ] -oxazole-4-carboxylic acid amide;

2- (2-chloro-6-fluoro-phenyl) -5- [4- (morpholine-4-carbonyl) -phenylamino ] oxazole-4-carboxylic acid amide;

2- (2-chloro-6-fluoro-phenyl) -5- [4- (1-methyl-piperidin-4-ylcarbamoyl) -phenylamino ] -oxazole-4-carboxylic acid amide;

(S)2- (2, 6-dichloro-phenyl) -5- [4- (piperidin-3-ylcarbamoyl) -phenylamino ] -oxazole-4-carboxylic acid amide;

(R) -2- (2, 6-dichloro-phenyl) -5- [4- (piperidin-3-ylcarbamoyl) -phenylamino ] -oxazole-4-carboxylic acid amide;

2- (2, 6-dichloro-phenyl) -5- [4- (morpholine-4-carbonyl) -phenylamino ] -oxazole-4-carboxylic acid amide;

2- (2, 6-dichloro-phenyl) -5- [4- (1-methyl-piperidin-4-ylcarbamoyl) -phenylamino ] -oxazole-4-carboxylic acid amide;

2- (2, 6-difluoro-phenyl) -5- (4-ethanesulfonyl-phenylamino) -oxazole-4-carboxylic acid amide;

2- (2, 6-difluoro-phenyl) -5- (4-methanesulfonyl-phenylamino) -oxazole-4-carboxylic acid amide; and

2- (2, 6-difluoro-phenyl) -5- [ 4-propane-2-sulfonyl) -phenylamino ] -oxazole-4-carboxylic acid amide;

and salts and stereoisomers thereof.

A compound according to any one of embodiments 1.0 to 1.37, or 1.38 to 1.96, wherein the compound of structural formula (0), (1) or (2) is in the form of a salt.

1.98 the method or compound of embodiment 1.97, wherein the salt is an acid addition salt.

1.99 the method or compound of embodiment 1.97 or embodiment 1.98 wherein the acid addition salt is a pharmaceutically acceptable salt.

A compound according to any one of embodiments 1.0 to 1.37, or 1.38 to 1.96, wherein the compound of structural formula (0), (1) or (2) is in the form of the free base.

Definition of

The following references to structural formula (1) include structural formulae (0) and (2) as well as structural formula (1) unless the context indicates otherwise.

The term "non-aromatic hydrocarbon radical", e.g. "C_1-6Non-aromatic hydrocarbyl "as used herein means that the structural group consists of carbon and hydrogen, but has no aromatic character.

Unless otherwise specified, non-aromatic hydrocarbon groups may be acyclic or cyclic, and may be saturated or unsaturated. Thus, the term encompasses alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkene groups, and combinations thereof.

Wherein the specified non-aromatic hydrocarbon group may be substituted; i.e. the hydrogen atom may be substituted by another atom or functional group.

Reference to "non-aromatic carbocyclic and heterocyclic" herein refers to saturated and unsaturated ring systems, as long as any such unsaturated ring system does not have aromatic character.

The term "bridged bicyclic heterocycle" refers herein to a non-aromatic heterocyclic ring system in which the two rings share more than two atoms, as can be seen, for example, in Advanced Organic Chemistry, by Jerry March,4th Edition, wiley inter science, pages131-133,1992. The bridged bicyclic system may be, for example, a [3.2.1] bicyclic system such as an 8-aza-bicyclo [3.2.1] octan-3-yl group or a [2.2.2] bicyclic system such as a quinuclidin-3-yl group.

Salt (salt)

The compounds of formulae (0), (1) and (2) may exist in the form of salts.

The salts (as defined in examples 1.97 to 1.99) are typically acid addition salts.

Such salts can be synthesized from the parent compound by conventional chemical methods, such as those described in pharmaceutical salts: Properties, Selection, and Use, P.Heinrich Stahl (Editor), Camile G.Wermuth (Editor), ISBN:3-90639-026-8, Hardcover,388pages, August 2002. In general, these salts can be prepared by reacting the free base of the compound with an acid in water or an organic solvent or a mixture of both; typically, a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile is used.

acid addition salts (as defined in example 1.98) may be prepared from various acids (inorganic and organic) examples of acid addition salts include salts formed from acids selected from the group consisting of acetic acid, 2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid (such as L-ascorbic acid), L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, butyric acid, (+) camphoric acid, camphor-sulfonic acid, (+) - (1S) -camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1, 2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethylsulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, glucuronic acid (such as D-glucuronic acid), glutamic acid (such as L-glutamic acid), α -ketonic acid, glycolic acid, hippurric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, isethionic acid, (+) -L-lactic acid, (+) -DL-lactic acid, tartaric acid, malic acid, (+) -malic acid, (-) -malic acid, salicylic acid, tartaric acid, malic acid, tartaric acid.

Salt forms of the compounds of the invention are typically Pharmaceutically Acceptable Salts, examples of which are discussed in Berge et al, 1977, "pharmaceutical Acceptable Salts," j.pharm.sci., vol.66, pp.1-19. However, salts that are not pharmaceutically acceptable may also be prepared in intermediate form and may then be converted into pharmaceutically acceptable salts. Such non-pharmaceutically acceptable salt forms may be useful, for example, in the purification or isolation of the compounds of the invention, which are also part of the invention.

Isotope of carbon monoxide

The compounds of the invention as defined in any one of examples 1.0 to 1.100 may contain one or more isotopic substitutions, and reference to a particular element includes within its scope all isotopes of the element. For example, reference to hydrogen is included within the scope thereof¹H、²H (D) and³h (T). Also, references to carbon and oxygen include within their scope¹²C、¹³C and¹⁴c and¹⁶o and¹⁸O。

in a similar manner, reference to a particular functional group also includes isotopic variations within its scope, unless the context indicates otherwise.

For example, reference to an alkyl group such as ethyl also encompasses variants in which one or more hydrogen atoms on the group are in the form of deuterium or a tritium isotope, e.g., five hydrogen atoms in the ethyl group are each in the form of isotopic deuterium (deuterated ethyl).

The isotope may be radioactive or non-radioactive. In one embodiment of the present invention (example 1.101), none of the compounds of any one of examples 1.0 to 1.100 comprises a radioactive isotope. Such compounds are the first choice for therapeutic use. In another example (example 1.102), however, the compound of any one of examples 1.0 to 1.100 may comprise one or more radioisotopes. Compounds containing such radioisotopes may be useful in diagnostic settings.

Solvates

A compound of formula (0), (1) or (2) as defined in any one of examples 1.0 to 1.102 may form a solvate.

Preferred solvates are those formed by incorporating non-toxic pharmaceutically acceptable solvent (hereinafter referred to as dissolution solvent) molecules into the solid state structure (e.g., crystal structure) of the compounds of the present invention. Examples of such solvents include water, alcohols (such as ethanol, isopropanol, and butanol), and dimethyl sulfoxide. Solvates may be prepared by recrystallisation of a compound of the invention from a solvent or a mixture of solvents comprising a dissolved solvent. Whether a solvate has formed, in a given case, can be determined by analysis of the crystals of the compound using standard accepted techniques, such as thermogravimetric analysis (TGE), Differential Scanning Calorimetry (DSC), and x-ray crystal diffraction.

The solvate may be a stoichiometric or non-stoichiometric solvate.

Particularly preferred solvates are hydrates, examples of which include hemihydrate, monohydrate and dihydrate.

Thus, in further examples 1.103 and 1.104, the present invention provides:

a compound or method according to any one of embodiments 1.0 to 1.102 wherein the compound of structural formula (0), (1) or (2) is in the form of a solvate.

A method or compound according to embodiment 1.103 wherein the solvate is a hydrate.

For a more detailed discussion of solvates and methods for making and characterizing them, see Bryn et al, Solid-State Chemistry of Drugs, Second Edition, published IN SSCI, Inc of West Lafayette, IN, USA,1999, ISBN 0-967-06710-3.

Alternatively, in addition to being present as a hydrate, the compounds of the present invention may also be anhydrous. Thus, in another embodiment (example 1.105), the compound of formula (1) as defined in any one of examples 1.0 to 1.102 is present in anhydrous form.

Inhibition of TYK2 kinase and therapeutic uses resulting therefrom

In examples 1.0 to 1.37 there is provided a method of inhibiting TYK2 kinase, the method comprising contacting TYK2 kinase with an effective TYK2 kinase inhibiting amount of a compound of formula (0) or formula (1).

Inhibition of TYK2 kinase may occur in vitro or in vivo.

Accordingly, the present invention provides:

2.1 the method of any one of embodiments 1.0 to 1.37 and 1.97 to 1.105, wherein the inhibition of TYK2 kinase occurs in vitro.

2.2 the method of any one of embodiments 1.1 to 1.37 and 1.97 to 1.105, wherein the inhibition of TYK2 kinase occurs in vivo.

The novel compounds of examples 1.38 to 1.105 can also be used for inhibiting TYK2 kinase. Accordingly, the present invention further provides:

2.3 a method of inhibiting TYK2 kinase, the method comprising contacting a compound of formula (2) as defined in any one of examples 1.38 to 1.105 or a salt or stereoisomer thereof in an amount effective to inhibit the TYK2 kinase and TYK2 kinase.

2.4 the compound according to example 2.3, wherein the inhibition of TYK2 kinase occurs in vitro.

2.5 the compound of example 2.4, wherein the inhibition of TYK2 kinase occurs in vivo.

2.6A compound of structural formula (0), (1) or (2) as defined in any one of embodiments 1.0 to 1.105 for use as an inhibitor of TYK2 kinase.

2.7A compound of formula (2) as defined in any one of embodiments 1.38 to 1.105 for use in medicine (medicine).

Inhibition of TYK2 kinase preferably occurs in vivo as part of a therapeutic treatment of a disease or condition in which TYK2 kinase is implicated.

The methods of the invention are particularly useful for treating a disease or condition selected from the group consisting of inflammatory diseases or conditions, immune diseases or conditions, allergic diseases or disorders, transplant rejection, and graft-versus-host disease. The method is also useful in the treatment of sepsis and septic shock conditions.

Thus, further, the present invention provides:

a method of treating a disease or condition selected from inflammatory diseases or conditions, immune diseases or conditions, allergic diseases or disorders, transplant rejection and graft versus host disease, or selected from sepsis and septic shock in a subject in need thereof, wherein the disease or condition is susceptible to TYK2 inhibition, comprising administering to the subject an effective TYK2 inhibiting amount of a compound of formula (0), (1) or (2) as defined in any one of examples 1.0 to 1.105 or a salt thereof.

2.9 a compound of formula (0), (1) or (2) or a salt thereof as defined in any one of examples 1.0 to 1.105 for use in the treatment of inflammatory diseases or conditions, immune diseases or conditions, allergic diseases or disorders, transplant rejection and graft-versus-host disease; or for the treatment of sepsis or septic shock, wherein the disease or condition is susceptible to TYK2 inhibition.

2.10 use of a compound of formula (0), (1) or (2) or a salt thereof as defined in any one of examples 1.0 to 1.105 for the manufacture of a medicament for the treatment of inflammatory diseases or conditions, immune diseases or conditions, allergic diseases or disorders, transplant rejection and graft versus host disease; or for the treatment of sepsis or septic shock, wherein the disease or condition is susceptible to TYK2 inhibition.

Autoimmune diseases

The TYK2 inhibitory activity of the compounds of structural formulae (0), (1) and (2) is useful for treating autoimmune diseases. Thus, further, the present invention provides:

a method of treating an autoimmune disease in a subject in need thereof, which method comprises administering to the subject an effective TYK2 inhibiting amount of a compound of formula (0), (1) or (2) as defined in any one of examples 1.0 to 1.105 to inhibit TYK2 kinase in the subject, thereby preventing or reducing the extent of inflammatory processes associated with the autoimmune disease.

2.12 a compound of structural formula (0), (1) or (2) as defined in any one of examples 1.0 to 1.105 for use in a method of treating an autoimmune disease in a subject in need thereof, the method comprising administering to the subject an effective TYK 2-inhibiting amount of the compound to inhibit TYK2 kinase in the subject, thereby preventing or reducing the extent of an inflammatory process associated with the autoimmune disease.

2.13 use of a compound of structural formula (0), (1), or (2) as defined in any one of examples 1.0 to 1.105 in the manufacture of a medicament for treating an autoimmune disease in a subject in need thereof by administering to the subject an effective TYK2 inhibiting amount of the compound to inhibit TYK2 kinase in the subject, thereby preventing or reducing the extent of an inflammatory process associated with the autoimmune disease.

2.14 the method, compound or use for use according to any one of embodiments 2.11 to 2.13, wherein the autoimmune disease is multiple sclerosis.

Experimental Autoimmune Encephalomyelitis (EAE) and Theiler murine encephalitis virus-Induced demyelinating disease (TMEV-IDD) are two clinically relevant murine Models of Multiple Sclerosis (MS) (see (i) amine CS: biological disease. the analysis of Autoimmune degeneration: its implementation: edition upper multiple surgery. Lab Invest 1984,50: 608-635; (ii) Steinman L: Assessment to the Experimental analysis of MS and optimizing disease in the analysis of Experimental therapy. neuron 1999,24: 511-514; and (media G. Fuller et al, Mouse model of multiple diagnosis: Experimental Automation and therapy: Molecular analysis: Instrument, analysis and analysis: 102: Molecular analysis: 102, Molecular simulation and Molecular analysis: 102, Molecular model: analysis and pathogen 361, Molecular model: analysis: Molecular analysis: 102, Molecular analysis: 102-361, Molecular analysis: analysis, Molecular analysis.

The usefulness of a compound of structural formula (0), (1) or (2) in the treatment of multiple sclerosis can be demonstrated using any of the above models, in particular the Experimental Autoimmune Encephalomyelitis (EAE) model described in the examples below.

The terms "treatment" and "treatment" as used in the context of multiple sclerosis include any one or more of the following:

■ arrest the progression of the disease;

■ slowing the progression of the disease;

■ ameliorating the progression of the disease;

■ provide symptomatic relief, e.g., by eliminating or reducing the severity of one or more symptoms;

■ prolonging remission;

■ preventing recurrence;

■ reduce the severity of the recurrence, and

■ prevent or slow down the progression from primary relapsing-remitting MS to secondary progressive MS.

Symptoms of multiple sclerosis that may be eliminated or reduced in severity according to the present invention include any one or more symptoms (in any combination) selected from:

■ weakness and/or numbness in one or more extremities;

■ pricking limb;

■ a tight belt-like feel around the torso or limb;

■ tremor of one or more extremities;

■ drag or differential control of one or both legs;

■ spastic or ataxic paresis;

■ paralysis of one or more extremities;

■ hyperreflexia of the tendon;

■ Abdominal wall reflex disappears;

■ Leelmett;

■ retrobulbar or optic neuritis;

■ walking is unstable;

■ equilibrium is problematic;

■ increased muscle fatigue;

■ brainstem symptoms (double vision, dizziness, vomiting);

■ urinary disturbance;

■ hemiplegia;

■ trigeminal neuralgia;

■ other pain syndromes;

■ nystagmus, ataxia;

■ cerebellar ataxia;

■ Trinity of Chake, double vision;

■ bilateral intercouclear ophthalmoplegia;

■ myofibrillar twitching or paralysis of facial muscles;

■ deafness;

■ tinnitus;

■ unshaped auditory hallucinations (due to the intervention of a cochlear implant connection);

■ transient facial anesthesia or trigeminal neuralgia;

■ incontinence of feces and urine;

■ bladder dysfunction stimulation;

■ depression;

■ tired;

■ dementia;

■ posterior cryptomelalgia of waist;

■ pricking limb, burning pain, and pain in affected parts;

■ neurological deficit of sudden attack;

■ dysarthria and ataxia;

■ paroxysmal pain and dysesthesia of limbs;

■ flickering light;

■ paroxysmal pruritus;

■ tonic attacks;

■ change in sensation;

■ visual problems;

■ myasthenia;

■ coordinating dysphasia;

■ cognitive dysfunction;

■ are superheated, and

■ mobility impairment and disability.

Such compounds may be used during remission in a prophylactic sense to prevent or reduce the likelihood or severity of relapse or the compounds may be used to treat patients with relapse. Preferably, the compounds are used in a prophylactic sense.

The compounds of structural formula (0), (1) or (2) or pharmaceutically acceptable salts thereof may be used as monotherapeutic agents or in combination with other therapeutic agents, such as steroids or interferons.

In one general embodiment of the invention, a compound of structural formula (0), (1) or (2), or a pharmaceutically acceptable salt thereof, is used as the sole therapeutic agent.

Use in the treatment of diseases and conditions other than multiple sclerosis

Although the TYK2 inhibitory activity of the compound of structural formula (1) may be useful in the treatment of autoimmune diseases, it may also be well-suited for the treatment of various other inflammatory diseases, as well as immunological and allergic diseases. Accordingly, the present invention also provides:

a method of treating a disease or condition in a subject in need thereof, wherein the disease is not an autoimmune disease, selected from the group consisting of an inflammatory disease or condition, an immune disease or condition, an allergic disease or disorder, transplant rejection and graft versus host disease, wherein the disease or condition is susceptible to TYK2 inhibition, the method comprising administering to the subject an effective TYK2 inhibiting amount of a compound of formula (0), (1) or (2) or a salt thereof as defined in any one of examples 1.0 to 1.105.

A method of treating a disease or condition in a subject in need thereof, wherein the disease or condition is not multiple sclerosis and is selected from the group consisting of an inflammatory disease or condition, an immune disease or condition, an allergic disease or disorder, transplant rejection and graft versus host disease, wherein the disease or condition is susceptible to TYK2 inhibition, the method comprising administering to the subject an effective TYK2 inhibiting amount of a compound of formula (0), (1) or (2) or a salt thereof as defined in any one of examples 1.0 to 1.105.

2.17A method of treating a disease or condition in a subject in need thereof, wherein the disease is selected from any one or more of the following:

(a) skin inflammation due to radiation exposure;

(b) asthma;

(c) allergic inflammation;

(d) chronic inflammation;

(e) inflammatory ophthalmic diseases;

(f) dry eye (DES, also known as keratoconjunctivitis sicca or tear insufficiency syndrome);

(g) uveitis (e.g., chronically progressive or recurrent non-infectious uveitis);

(h) insulin-dependent diabetes mellitus (type I);

(i) hashimoto's thyroiditis;

(j) graves' disease;

(k) cushing's disease;

(l) Addison's disease (affecting the adrenal gland);

(m) chronic active hepatitis (affecting the liver);

(n) polycystic ovary syndrome (PCOS);

(o) celiac disease;

(p) psoriasis;

(q) Inflammatory Bowel Disease (IBD);

(r) ankylosing spondylitis;

(s) rheumatoid arthritis;

(t) systemic lupus erythematosus;

(u) myasthenia gravis;

(v) graft rejection (allograft rejection); and

(w) graft versus host disease (GVDH);

the method comprises administering to the subject an effective TYK2 inhibiting amount of a compound of structural formula (0), (1) or (2) as defined in any one of examples 1.0 to 1.105, or a salt thereof.

2.18A compound of formula (0), (1) or (2) as defined in any one of examples 1.0 to 1.105 for use in a method as defined in any one of examples 2.15, 2.16 and 2.17.

2.19 use of a compound of structural formula (0), (1) or (2) as defined in any one of examples 1.0 to 1.105 in the manufacture of a medicament for use in a method as defined in any one of examples 2.15, 2.16 and 2.17.

in the context of the present invention, an autoimmune disease is a disease that is provoked at least in part by the body's immune response against its own components, such as proteins, lipids or dna, examples of organ-specific autoimmune disorders are insulin-dependent diabetes mellitus (type I) affecting the pancreas, hashimoto's thyroiditis and graves ' disease affecting the thyroid, pernicious anemia affecting the stomach, cushing's disease and edison's disease affecting the adrenal gland, chronic active hepatitis affecting the liver, polycystic ovary syndrome (PCOS), celiac disease, psoriasis, Inflammatory Bowel Disease (IBD) and ankylosing spondylitis.

Rheumatoid Arthritis (RA) is a chronic, progressive, debilitating inflammatory disease that affects approximately 1% of the world population. RA is a symmetric polyarthritis that primarily affects the small joints of the hands and feet. In addition to inflammation in the synovium, joint lining (the invasive anterior aspect of tissue known as the pannus) invades and destroys local joint structures (Firestein 2003, Nature 423: 356-361).

Inflammatory Bowel Disease (IBD) is characterized by a chronic, recurrent intestinal inflammation. IBD is subdivided into the crohn's disease and ulcerative colitis phenotypes. Crohn's disease is most common in the terminal ileum and colon, with transmural and discontinuities. In contrast, in ulcerative colitis, inflammation is continuous and localized to the rectal and colonic mucosa layers. In about 10% of cases limited to the rectum and colon, crohn's disease or ulcerative colitis cannot be classified unambiguously and they are all designated as "indeterminate colitis". Both of these diseases include external intestinal inflammation of the skin, eyes or joints. Neutrophil-induced damage can be prevented by the use of inhibitors of neutrophil migration (Asakura et al,2007, World J. gastroenterol.13(15): 2145-9).

Psoriasis is a chronic inflammatory skin disease that affects approximately 2% of the population. It is characterized by red, scaly skin, common to scalp, elbows and knees, and may be associated with severe arthritis. Lesions are caused by abnormal keratinocyte proliferation and infiltration of inflammatory cells into the dermis and epidermis (Schon et al,2005, New Engl. J. Med.352: 1899-1912).

Systemic Lupus Erythematosus (SLE) is a chronic inflammatory disease, resulting from T cell-mediated activation of B cells, which leads to glomerulonephritis and renal failure. Human SLE is characterized by persistent expansion of autoreactive CD4+ memory cells at an early stage (D' Cruz et al,2007, Lancet 369(9561): 587-596).

Transplant rejection (allograft rejection) includes, but is not limited to, acute and chronic allograft rejection, such as that which occurs after transplantation of the kidney, heart, liver, lung, bone marrow, skin and cornea. It is well known that T cells play a central role in the specific immune response of allograft rejection. Hyperacute, acute and chronic organ transplant rejection can be treated. Hyperacute rejection occurs within minutes of transplantation. Acute rejection usually occurs within six to twelve months of transplantation. Where treatment with immunosuppressive agents is employed, hyperacute and acute rejection are generally reversible. Chronic rejection, characterized by a gradual loss of organ function, is a constant concern for transplant recipients because it can occur at any time after transplantation.

Graft versus host disease (GVDH) is a major complication of allogeneic Bone Marrow Transplantation (BMT). GVDH is caused by differences in donor T cell recognition and response to the recipient histocompatibility complex system, resulting in significant morbidity and mortality.

The compounds of structural formulae (0), (1) and (2) may also be useful in the treatment of diseases or conditions characterised by or caused, at least in part, by overexpression (elevated expression) of TYK2 kinase or associated with overexpression (elevated expression) of TYK2 kinase. One disease that has been shown to be associated with elevated levels of TYK2 kinase is pulmonary sarcoidosis.

Pulmonary sarcoidosis is a relatively rare inflammatory disorder of unknown origin, and commonly occurs in adults between 20 and 50 years of age. Pulmonary sarcoidosis is characterized by small lumps or granulomas in the lung that usually heal and disappear on their own. However, for those granulomas that do not heal, the tissue remains inflamed and develops scars, or fibrosis. Pulmonary sarcoidosis progresses to pulmonary fibrosis, distorting the structure of the lungs and interfering with breathing.

Thus, further, the present invention provides:

a method of treating a disease or condition in a subject in need thereof, wherein the disease is characterized by or caused, at least in part, by overexpression (elevated expression) of TYK2 kinase or is associated with overexpression (elevated expression) of TYK2 kinase, which method comprises administering to the subject an effective TYK2 inhibiting amount of a compound of formula (0), (1) or (2), or a salt thereof, as defined in any one of examples 1.0 to 1.105.

2.21A method according to embodiment 2.20, wherein the disease or condition is pulmonary sarcoidosis.

2.22A compound of formula (0), (1) or (2) as defined in any one of examples 1.0 to 1.105 or a salt thereof for use in a method as defined in any one of examples 2.20 or 2.21.

2.23 use of a compound of structural formula (0), (1) or (2) as defined in any one of embodiments 1.0 to 1.105 or a salt thereof in the manufacture of a medicament for use in a method as defined in embodiment 2.20 or 2.21.

Other aspects

In a further aspect (examples 2.24 to 2.26), the present invention provides:

2.24A compound of formula (0), (1) or (2) as defined in any one of examples 1.0 to 1.105 or a salt thereof for use in inhibiting TYK2 kinase.

2.25 a compound of formula (0), (1) or (2) as defined in any one of examples 1.0 to 1.105 or a salt thereof for use in the treatment of a disease or condition selected from: inflammatory diseases or conditions, immunological diseases or conditions, allergic diseases or disorders, transplant rejection and graft-versus-host disease, as defined herein.

2.26 use of a compound of formula (0), (1) or (2) as defined in any one of embodiments 1.0 to 1.105 or a salt thereof for the preparation of a medicament for the treatment of a disease or condition selected from: inflammatory diseases or conditions, immunological diseases or conditions, allergic diseases or disorders, transplant rejection and graft-versus-host disease, as defined herein.

The activity of the compounds of formulae (0), (1) and (2) as TYK2 inhibitors can be measured by the assays set forth in the examples below, and the level of activity exhibited by a given compound can be determined by IC₅₀And (4) value limitation. Preferred compounds of the invention are IC₅₀Compounds with values less than 0.03 μ M.

An advantage of the compounds of structural formulae (0), (1) and (2) as defined herein is that they show selectivity for TYK2 kinase over other kinases of the JAK family. For example, most of the compounds of formulae (0), (1) and (2) exemplified herein are at least ten times selective for TYK2 and JAK2, 3 and at least five times selective for TYK2 relative to JAK 1.

While selectivity for TYK2 is considered advantageous, it is envisaged that in some cases activity against other JAK kinases may be beneficial as well as for TYK 2. Thus, for example, a compound of formula (0), (1) or (2) as defined herein may have an IC for TYK2₅₀Values less than 200 nanomolar (e.g., less than 50 nanomolar) and IC for JAK1, JAK2, and JAK3₅₀A value of less than 500 nanomolar (e.g., less than 200 nanomolar), but wherein activity for TYK2 is greater than for any of JAK1, JAK2, and JAK 3.

Process for the preparation of compounds of formulae (0), (1) and (2)

The compounds of structural formulae (0), (1) and (2) are prepared by the process described in international patent application WO2008/139161 (Sareum): for example, the method described in examples Q-3, Q-14, Q-20, Q-21, Q-22, Q-25, Q-26, Q-27, Q-28, Q-29, Q-50, Q-51, Q-52, Q-53, Q-54, Q-55, Q-57, U-2, U-3, U-4, U-6, U-7, U-8, U-9, U-12, U-13, U-14, U-15, U-16, U-17, U-18, U-19, U-24, U-25, U-26 and U-27, and the like can be used. The preparation of the compounds of formula (2) is also given in the following examples.

Pharmaceutical preparation

While the active compounds may be administered alone, they are preferably presented as pharmaceutical compositions (e.g., formulations) comprising at least one active compound of the invention together with one or more pharmaceutically acceptable adjuvants, such as carriers, adjuvants, diluents, fillers, buffers, stabilizers, preservatives, lubricants or other materials well known in the art, and optionally other therapeutic or prophylactic agents.

The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject (e.g., a human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. Each adjuvant must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation.

The pharmaceutical composition may be in any form suitable for oral, parenteral, topical, intranasal, ophthalmic, otic, rectal, intravaginal or transdermal administration. Where the compositions are intended for parenteral administration, they may be formulated for intravenous, intramuscular, intraperitoneal, subcutaneous administration by injection, infusion or other delivery means or for direct delivery to the target organ or tissue.

Pharmaceutical dosage forms suitable for oral administration include tablets, capsules, caplets, troches, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, wafers or patches and buccal patches.

Pharmaceutical compositions comprising compounds of structural formulae (0), (1) and (2) can be formulated according to known techniques, see, e.g., Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA.

Thus, a tablet composition may comprise a unit dose of the active compound in association with an inert diluent or carrier, such as a sugar or sugar alcohol, e.g. lactose, sucrose, sorbitol or mannitol; and/or diluents of non-sugar origin such as sodium carbonate, calcium phosphate, calcium carbonate, or cellulose or derivatives thereof, such as methyl cellulose, ethyl cellulose, hydroxypropylmethyl cellulose, and starches such as corn starch. Tablets may also contain standard ingredients such as binders and granules (e.g. polyvinylpyrrolidone), disintegrants (e.g. swellable cross-linked polymers such as cross-linked carboxymethylcellulose), lubricants (e.g. stearates), preservatives (e.g. parabens), antioxidants (e.g. BHT), buffers (e.g. phosphate or citrate buffers), and effervescent agents such as citrate/bicarbonate mixtures. Such excipients are well known and need not be discussed in detail herein.

Capsules may be of the hard or soft gelatin variety and may contain the active ingredient in solid, semi-solid or liquid form. Gelatin capsules may be formed from animal gelatin or synthetic or plant derived equivalents.

Solid dosage forms (e.g., tablets, capsules, etc.) may be coated or uncoated, but are typically coated, for example, with a protective film coating (e.g., wax or paint) or a controlled release coating. Coating (e.g. Eudragit)^TMType polymers) can be designed to release the active ingredient at a predetermined location within the gastrointestinal tract. Thus, the coating may be selected to degrade under certain pH conditions in the gastrointestinal tract, thereby selectively releasing the compound in the stomach or ileum or duodenum.

Instead of, or in addition to, a coating, the drug may be present in a solid matrix comprising a controlled release agent, e.g. a slow release agent adapted to selectively release the compound in case of different acidity or basicity in the gastrointestinal tract. Alternatively, the matrix material or the release-retarding coating may be in the form of an erodible polymer (e.g., a maleic anhydride polymer) that is substantially continuously eroded as the dosage form passes through the gastrointestinal tract. As a further alternative, the active compound may be formulated in a delivery system that provides osmotic control of the release of the compound. Osmotic release and other delayed or sustained release formulations can be prepared by methods well known to those skilled in the art.

Topical compositions include ointments, creams, sprays, patches, gels, drops, and implants (e.g., intraocular implants). These compositions can be prepared according to known methods.

Compositions for parenteral administration are typically sterile aqueous or oily solutions or fine suspensions, or may be provided in the form of a finely divided sterile powder for extemporaneous preparation for injection with sterile water.

Compositions for parenteral administration may be formulated for administration in discrete dosage units, or for administration by infusion.

Examples of dosage forms for rectal or intravaginal administration include pessaries or suppositories, which may be formed, for example, from a plastically formable or waxy material containing the active compound.

Compositions for administration by inhalation may be in the form of inhalable powder compositions or liquid or powder sprays and may be administered in standard forms using powder inhalers or aerosol dispensers. Such instruments are known. For administration by inhalation, powdered formulations typically contain the active compound and an inert solid powdered diluent, for example, lactose.

The compounds of the invention will generally be presented in unit dosage form and, therefore, will generally contain sufficient compound to provide the desired level of biological activity. For example, formulations for oral administration may contain from 0.1 mg to 2 g of the active ingredient, more often from 10 mg to 1 g, for example 50mg to 500 mg.

The active compound will be administered to a patient (e.g., a human or animal patient) in need thereof in an amount sufficient to achieve the desired therapeutic effect.

Method of treatment

It is envisaged that the compounds of structural formulae (0), (1) and (2) as defined in any one of examples 1.0 to 1.105 will be useful in the prevention or treatment of inflammatory diseases or conditions, immunological diseases or conditions, allergic diseases or disorders, transplant rejection and graft-versus-host disease. Examples of such disease states and conditions are given above.

The compounds will generally be administered in amounts that are therapeutically or prophylactically useful and generally non-toxic. However, in certain circumstances (e.g., in the case of life-threatening diseases), the benefit of administering a compound of structural formula (0), (1), or (2) may outweigh the adverse effects of any toxic effects or side effects, in which case it may be deemed desirable to administer an amount of the compound associated with a degree of toxicity.

The compounds may be administered chronically to maintain a beneficial therapeutic effect or may be administered only chronically. Alternatively, they may be administered in a pulsed or continuous manner.

The compounds of structural formula (0), (1) or (2) are typically administered to a subject, e.g., a human patient, in need of such administration.

Typical daily dosages of the compounds may be up to 1000 mg/day, for example between 0.01 mg and 10 mg/kg body weight, more usually between 0.025 mg and 5 mg/kg body weight, for example up to 3 mg/kg body weight, and more typically 0.15 mg to 5 mg/kg body weight, although higher or lower dosages may be administered where required.

For example, an initial starting dose of 12.5mg may be administered 2-3 times daily. The dose may be increased by 12.5 mg/day every 3 to 5 days until the maximum tolerated and effective dose for the individual as determined by the physician is reached. Ultimately, the amount of the compound administered will be commensurate with the nature or physiological condition of the disease being treated and the therapeutic effect and with or without adverse side effects of the established dosing regimen, as will be determined by a physician at the discretion of the skilled artisan.

The compounds of structural formulae (0), (1) and (2) may be administered as monotherapeutic agents or they may be administered in combination with one or more other compounds such as steroids or interferons.

Diagnostic method

Prior to administration of the compound of structural formula (0), (1) or (2), the patient may be screened to determine whether the disease or condition that the patient has or may have is susceptible to treatment with a compound having anti-TYK 2 activity.

Thus, in further embodiments (3.1 to 3.6), the invention provides:

3.1 a compound as defined in any one of examples 1.0 to 1.105 herein, or any subgroup or example thereof as defined herein, for use in the treatment or prevention of a disease state or condition susceptible to treatment with a compound having anti-TYK 2 kinase activity in a patient who has been screened for or determined to have, or to be at risk of having, the disease or condition.

3.2 use of a compound as defined in any one of examples 1.0 to 1.105 herein or any subgroup or example defined herein for the manufacture of a medicament for the treatment or prevention of a disease state or condition which is susceptible to treatment with a compound having anti-TYK 2 kinase activity in a patient who has been screened for and determined to have or be at risk of having the disease or condition.

A method of diagnosis and treatment of a disease state or condition mediated by TYK2 kinase, which method comprises (i) screening a patient to determine whether the patient has, or is likely to have, a disease or condition which is susceptible to treatment with a compound having activity against the kinase; and (ii) a compound as defined in any one of examples 1.0 to 1.105 herein or any subgroup or example defined herein, in an amount effective to inhibit TYK2 thereafter administered to the patient when indicative of the disease or condition to which the patient is thus susceptible.

A subject (e.g., a patient) may be subjected to a diagnostic test to detect a marker indicative of the presence of a disease or condition involving TYK2, or a marker indicative of susceptibility to the disease or condition. For example, subjects may be screened for genetic markers that indicate a predisposition to develop autoimmune or inflammatory disease.

Genetic markers may include specific alleles or single nucleotide polymorphisms of the TYK2 gene that indicate a predisposition to autoimmune diseases such as multiple sclerosis (see, e.g., Ban et al, European Journal of Human Genetics (2009),17,1309-1313) or inflammatory bowel disease such as crohn's disease (see Sato et al, j. clin. immunol. (2009),29: 815-825). For example, the genetic marker may be a single nucleotide polymorphism in the TYK2 gene, or it may be a haploid containing a single nucleotide polymorphism on the TYK2 gene and a polymorphism on another gene.

Diagnostic tests are typically performed using a biological sample selected from the group consisting of a blood sample, a biopsy specimen, a stool biopsy, saliva, a chromosome analysis, a pleural effusion, an abdominal fluid, or urine.

Methods for identifying genetic markers such as single nucleotide polymorphisms are well known. Examples of suitable methods for identifying these markers are described in Ban et al and Sato et al, above.

Examples of the invention

The invention will now be illustrated with reference to, but not limited to, specific embodiments described in the following examples.

Enzyme inhibition

The compounds of the invention were assayed for their ability to inhibit TYK2 kinase and other JAK kinases.

The substrates and kinases used in the assay are shown in table 2 below.

The kinase assay was performed in Reaction Biology corp, Malvern, Pennsylvania, USA using the following general procedure:

1) in freshly prepared base (base) reaction buffer (20mM Hepes pH 7.5, 10mM MgCl₂，1mMEGTA，0.02％Brij35，0.02mg/ml BSA，0.1mM Na₃VO₄2mM DTT, 1% DMSO) were prepared.

2) Cofactor (1.5mM CaCl)₂16 μ g/mL calmodulin, 2mM MnCl₂) Into the substrate solution above

3) Delivery of the indicated kinase to the substrate solution and gentle mixing

4) Delivery of varying concentrations of test compounds in DMSO into kinase reaction mixtures

5) Will be provided with³³P-ATP (final specific activity 0.01. mu. Ci/. mu.L) was delivered to the reaction mixture to initiate the reaction

6) The kinase reaction was incubated at room temperature for 120 min

7) Reactions were spotted on P81 ion exchange filter paper (Whatman #3698-915)

8) Unbound phosphate was removed by rinsing the filter extensively (extensivevely) in 0.75% phosphoric acid.

9) Determination with Typhoon phosphorimagers³³The P signal (GE Healthcare). IC was determined using a non-linear regression function in Prism (Graphpad software) after subtraction of background from control reactions containing inactive enzyme₅₀The value is obtained.

TABLE 2

Substrate:

AXLtide＝[KKSRGDYMTMQIG]

JAK3tide＝[Ac-GEEEEYFELVKKKK-NH₂]

pEY-polyglulu-Tyr [ GIu: Tyr (4:1), m.w.: 5,000-20,000]

The results are shown in table 3 below.

TABLE 3

The data presented in the above table indicate that the compound of structural formula (1) is a strong inhibitor of TYK2 kinase and shows significant selectivity for TYK2 kinase over other JAK kinases.

On the basis of their activity against TYK2 kinase, the compounds of formula (1) are conceivable as therapeutic agents for the treatment of various inflammatory, immunological and allergic diseases and conditions.

Examples 19 to 33

In table 4 below, the compounds of examples 19 to 33 are novel compounds and are prepared by the following methods or the like. The starting materials and synthetic intermediates used in the procedure are shown in table 5, and the NMR and LCMS properties of the final product are shown in table 6.

TABLE 4

TABLE 5 Synthesis of intermediates and starting materials

General procedure A

Step a-preparation of intermediate Compound (12)

In the reaction scheme, the group R in the formulae (11) and (12)^1’Is a group R as defined herein¹Or a radical R¹In the form of protection of (1).

A solution of palladium acetate (0.025mmol) and (. + -.) -2,2 "-bis (diphenylphosphino) -1, 1" -binaphthalene (0.024mmol) in DMF (7.1 ml) was stirred at room temperature for 3 minutes. Then, compound (10) (0.35mmol), compound (11) (1.40mmol) and tribasic phosphate (tribasic) (0.70mmol) were added, and the resulting mixture was heated by microwave at 180 ℃ for 3 minutes. The reaction was diluted with EtOAc and washed with water. The organic phase was passed through a MP-SH resin cartridge, using MgS0₄Dried and the solvent removed in vacuo. The residue was purified by silica gel column chromatography with a gradient of 10-100% EtOAc-n-hexane to provide compound (12), which can be purified by¹H NMR (DMSO) and LCMS confirm its identity.

Step b-preparation of Compound (2)

A solution of compound (12) (0.09mmol) in concentrated sulfuric acid (1.7mL) was stirred at room temperature for 1.5 hours. The solution was poured into saturated sodium bicarbonate solution for neutralization. The aqueous phase was extracted with EtOAc. The combined organic phases were separated by MgSO₄Drying and removal of the solvent in vacuo to provide compound (2), can be prepared by¹H NMR (DMSO) and LCMS confirm its identity.

General procedure B

Step a-preparation of intermediate Compound (14)

Compound (10) is reacted with compound (13) under the conditions given in step a of general procedure a to give compound (14).

Step b-preparation of intermediate Compound (15)

Compound (14) is hydrolyzed with lithium hydroxide to give carboxylic acid compound (15).

Alternatively, compound (15) can be prepared by the method of step a of example U-1 of WO2008/139161 or an analogous method thereof.

Step c-preparation of intermediate Compound (16)

A solution of compound (15) (0.059mmol), O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (0.059mmol) and diisopropylethylamine (0.117mmol) dissolved in N, N-dimethylformamide (2mL) was addedOf the formula HNR^xR^yThe reaction mixture was stirred at room temperature for 16 hours (0.059 mmol). The reaction mixture was then diluted with EtOAc, washed with 1M HCl, water, and brine. The organic phase is MgSO₄Dried and the solvent removed in vacuo. The residue was purified by preparative HPLC to provide compound (16), whose identity was confirmed by LCMS.

Step d-preparation of Compound (17)

A solution of compound (16) (0.022mmol) dissolved in concentrated sulfuric acid (0.5mL) was stirred at room temperature for 1.5 hours. The solution was poured into saturated sodium bicarbonate solution for neutralization. The aqueous phase was then basified to pH14 using 5M sodium hydroxide and extracted with EtOAc. The combined organic phases were separated by MgSO₄Drying and removal of the solvent in vacuo to afford compound (17), can be obtained by¹H NMR (DMSO) and LCMS confirm its identity. Compounds (17) containing basic nitrogen, such as those prepared from I-11 or I-12, have acid-labile nitrogen protecting groups and are simultaneously protected in the final acid-mediated reaction step.

General procedure B can be used to prepare NR therein^xR^yA compound forming a cyclic amine such as morpholine, piperazine or piperidinyl, or wherein R^xIs hydrogen or a substituent and R^yA compound that is hydrogen or a substituent.

Example 34

Enzyme inhibitory Activity of novel Compounds of structural formula (2)

The novel compounds of structural formula (2) were tested using the TYK2 kinase inhibition assay described above and other JAK kinase inhibition assays. The results are shown in Table 7 below.

The data presented in the above table indicate that the compound of structural formula (2) is a strong inhibitor of TYK2 kinase and shows significant selectivity for TYK2 kinase over other JAK kinases.

Based on its anti-TYK 2 kinase activity, it is contemplated that the compounds of structural formula (2) will be useful as therapeutic agents for the treatment of various inflammatory, immune and allergic diseases and conditions.

Example 35

Pharmaceutical dosage form

(i) Tablet formulation

A tablet composition containing the compound of structural formula (0), (1) or (2) was prepared by mixing 50mg of the compound with 197mg of lactose (BP) as a diluent and 3mg of magnesium stearate as a lubricant and compressing into tablets by a known method.

(ii) Capsule preparation

Capsules were prepared by mixing 100mg of a compound of formula (0), (1) or (2) with 100mg of lactose and filling the resulting mixture into standard opaque hard gelatin capsules.

(iii) Injection I

Parenteral compositions for injection can be prepared by: the compound of formula (0), (1) or (2) (for example in the form of a salt) is dissolved in water containing 10% propylene glycol so that the concentration of active compound is 1.5% by weight. The solution is then filter sterilized, filled into ampoules and sealed.

(iv) Injection II

Parenteral compositions for injection are prepared by: the compound of formula (0), (1) or (2) (e.g. in the form of a salt) (2 mg/mL) and mannitol (50mg/mL) are dissolved in water, the solution is sterile filtered and filled into 1mL sealable vials or ampoules.

(iv) Subcutaneous injection

The subcutaneous administration composition was prepared by: the compound of formula (0), (1) or (2) was mixed with pharmaceutical grade corn oil to a concentration of 5 mg/mL. The composition is sterilized and filled into suitable containers.

Equivalents of

The foregoing examples are provided merely to illustrate the invention and are not to be construed as limiting the scope of the invention. Numerous modifications and variations of the specific embodiments described above and illustrated in the examples will be apparent to those skilled in the art without departing from the principles of the invention. All such modifications and variations are intended to be included herein.

Claims

1. A compound which is an amide of the formula (2):

or a salt or stereoisomer thereof; wherein:

R⁷is chlorine;

R⁶selected from chlorine or fluorine;

R³、R⁴and R⁵All are hydrogen;

n is 0,1 or 2;

Q¹selected from the group consisting of C (═ O), S (═ O) and SO₂；

A is absent or is NR²；

R¹Selected from:

-hydrogen;

-a 5 to 6 membered heterocyclic ring selected from pyrrolidine and piperidine, which heterocyclic ring is optionally substituted by methyl;

when R is²When present, R²Selected from hydrogen and methyl; or

2. The compound of claim 1, wherein R⁷Is chlorine and R⁶Is fluorine.

3. The compound of claim 1, wherein R⁷And R⁶Are all chlorine.

4.The compound of claim 1, wherein Q¹Is C (═ O).

5. The compound of claim 4, wherein A is NR²And NR is¹R²Forming a 5 to 6 membered heterocyclic ring selected from pyrrolidine and morpholine, which heterocyclic ring is optionally substituted with hydroxymethyl.

6. The compound of claim 1, wherein A is absent, Q¹Is SO₂And R is¹Is C_1-3An alkyl group.

7. The compound of claim 1, wherein Q¹-A-R¹Groups selected from AA, AG, AH, AI, AR, AS and AT from the following table:

wherein the point of attachment of the phenyl group is indicated by an asterisk.

8. The compound of claim 1, selected from the group consisting of:

(S) -2- (2-chloro-6-fluoro-phenyl) -5- [4- (piperidin-3-ylcarbamoyl) -phenylamino ] -oxazole-4-carboxylic acid amide;

(R) -2- (2-chloro-6-fluoro-phenyl) -5- [4- (piperidin-3-ylcarbamoyl) -phenylamino ] -oxazole-4-carboxylic acid amide;

2- (2-chloro-6-fluoro-phenyl) -5- [4- (morpholine-4-carbonyl) -phenylamino ] -oxazole-4-carboxylic acid amide;

(S) -2- (2, 6-dichloro-phenyl) -5- [4- (piperidin-3-ylcarbamoyl) -phenylamino ] -oxazole-4-carboxylic acid amide;

and salts and stereoisomers thereof.

9. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 8 and a pharmaceutically acceptable adjuvant.