The invention provides a compound of formula (0):

MAPK Signalling and the Role of ERK1/2
The extracellular signal regulated kinases (ERK1/2) are ubiquitously expressed protein serine/threonine kinases that comprise a key component of the mitogen-activated protein kinase (MAPK) signalling pathway. The MAPK pathway is an evolutionary conserved cell signalling pathway that regulates a variety of cellular processes including cell cycle progression, cell migration, cell survival, differentiation, metabolism, proliferation and transcription. The ERK/MAPK signalling pathway responds to the extracellular stimulation of cell-surface receptor tyrosine kinases (RTKs). Upon activation of RTKs, the RAS GTPases (K-RAS, N-RAS and H-RAS) are converted from an inactive GDP-bound state to an active GTP-bound state. Activated RAS phosphorylates and thereby activates RAF (A-RAF, B-RAF and C-RAF), which in turn phosphorylates and activates the dual-specificity kinase MEK (MEK1/2). Subsequently, activated MEK phosphorylates and activates ERK1/2. Upon activation, ERK1/2 activates multiple nuclear and cytoplasmic substrates. There are currently >200 known ERK1/2 substrates, which include transcription factors, kinases, phosphatases and cytoskeletal proteins (Roskoski, Pharmacol. Res. 2012; 66: 105-143).
A number of isozymes of ERK have been identified (ERK1, ERK2, ERK3/4, ERK5, ERK7) but the two most widely studied isozymes are ERK1 and ERK2: see R. Roberts, J. Exp. Pharm., The extracellular signal-regulated kinase (ERK) pathway: a potential therapeutic target in hypertension, 2012: 4, 77-83, and Cargnello et al., Microbiol. & Mol. Biol. Rev., Activation and Function of the MAPKs and Their Substrates, the MAPK-Activated Protein Kinases 2011, 50-83.
Upregulation of ERK1/2 Signalling in Cancer
ERK1/2 activity is commonly upregulated in cancer, as a result of activating mutations within upstream components of the MAPK pathway. Approximately 30% of human cancers contain activating RAS mutations (Roberts and Der, Oncogene. 2007; 26: 3291-3310). K-RAS is the most frequently mutated isoform and is mutated in 22% of all tumours. KRAS mutations are particularly prevalent in pancreatic adenocarcinoma (70-90%), non-small cell carcinoma (10-20%) and colorectal cancer (25-35%) (Neuzillet et al., 2014. Pharmacol. Ther. 141; 160-171). N-RAS and H-RAS mutations occur in 8% and 3% of cancers, respectively (Prior et al., Cancer Res. 2012; 72 (10); 2457-2467). Notably, activating N-RAS mutations have been reported in 15-20% of melanoma cases. Furthermore, activating B-RAF mutations occur in 8% of all tumours and are particularly prevalent in melanoma (50-60%), papillary thyroid cancer (40-60%), colorectal cancer (5-10%) and non-small cell lung cancer (3-5%) (Neuzillet et al., 2014. Pharmacol. Ther. 141; 160-171). In addition to the occurrence of activating RAS and RAF mutations, the MAPK signalling pathway can also be up-regulated in cancer by the over-expression or mutational activation of upstream RTKS such as EGFR (Lynch et al., N Engl J Med. 2004; 350: 2129-2139), HER2 (Stephens et al., Nature. 2004; 431: 525-526) and FGFR (Ahmed et al, Biochim. Biophys. Acta Mol. Cell. Res. 2012; 1823: 850-860).
There are multiple mechanisms by which aberrant ERK1/2 signalling can contribute to cancer progression. Upon activation, ERK1/2 phosphorylates and activates a wide range of transcription factors that are involved in promoting cell proliferation and differentiation, such as c-Fos (Murphy et al., Nat. Cell Biol. 2002: 4 (8):556-64) and ELK-1 (Gille et al., EMBO J. 1995; 14 (5):951-62). In addition, ERK1/2 signalling is known to promote cell cycle progression via multiple mechanisms, including the induction of D-type cyclins and repression of the cyclin-dependent kinase inhibitor p27KIP1 (Kawada et al., Oncogene. 1997; 15: 629-637, Lavoie et al., J. Biol. Chem. 1996; 271: 20608-20616). Furthermore, ERK1/2 signalling can promote cell survival by regulating a range of apoptotic proteins. Examples of such mechanisms include the ERK1/2-dependent repression of the pro-apoptotic BCL-2 family proteins BIM1 and BAD (She et al., J. Biol Chem. 2002; 277: 24039-24048. Ley et al., J. Biol. Chem. 2003; 278: 18811-18816) and the ERK1/2-dependent stabilisation of anti-apoptotic proteins such as MCL-1 (Domina et al., Oncogene. 2004; 23: 5301-5315).
Role of ERK1/2 in MAPK Inhibitor Resistance
A wide range of pre-clinical studies have demonstrated that the inhibition of the MAPK pathway suppresses the growth of cancer cell lines harbouring B-Raf or Ras mutations (Friday & Adjei, Clin. Cancer Res. 2008; 14: 342-346). The RAF inhibitors vemurafenib and dabrafenib, and the MEK inhibitor trametinib are clinically approved for the treatment of BRAF-mutant melanoma. These agents elicit profound anti-tumour responses in the majority of patients, although the duration of response is short-lived, due to the onset of acquired drug resistance (Chapman et al., N. Engl. J. Med. 2011; 364 2507-2516. Hauschild et al., Lancet. 2012; 380: 358-365. Solit and Rosen, N Engl J Med. 2011; 364 (8): 772-774. Flaherty et al., N. Engl. J. Med. 2012; 367: 1694-1703). Multiple mechanisms of acquired B-RAF inhibitor resistance have been identified. These include the upregulation or activation of alternative MEK activators such as C-RAF or COT1 (Villanueva et al, Cancer Cell. 2010; 18:683-95. Johannessen et al., Nature. 2010; 468: 968-72), the upregulation of RTK or NRAS signalling (Nazarian et al., Nature. 2010; 468:973-7), and the onset of MEK activating mutations (Wagle et al., J Clin Oncol. 2011; 29:3085-96). Mechanisms of MEK inhibitor-resistance include the occurrence of MEK mutations that reduce drug binding or enhance intrinsic MEK activity (Emery et al., Proc Natl. Acad. Sci. 2009; 106: 20411-20416. Wang et al., Cancer Res. 2011; 71: 5535-5545), and BRAF or KRAS amplification (Little et al., Biochem Soc. Trans. 2012; 40(1): 73-8). A common feature of RAF or MEK inhibitor resistance mechanisms is the re-activation of ERK1/2 signalling, which drives proliferation and survival of the cells in the presence of inhibitors. Based on this observation, it has been suggested that direct ERK1/2 inhibition may be an effective therapeutic approach to overcoming acquired RAF or MEK inhibitor resistance. There is pre-clinical evidence that the inhibition of ERK1/2 overcomes acquired RAF or MEK inhibitor resistance (Hatzivassiliou et al., Mol Cancer Ther. 2012; 11(5):1143-54. Morris et al., Cancer Discov. 2013; 3 (7):742-50)
Additional Diseases
In addition to oncology, abnormal ERK1/2 signalling has also been reported in other diseases including cardiovascular disease (Muslin, Clin. Sci. 2008; 115: 203-218), Alzheimer's disease (Giovannini et al., Neuroscience. 2008; 153: 618-633), polycystic kidney disease (Omori et al., J Am Soc Nephrol. 2006; 17:1604-1614), Asthma (Duan et al., J Immunol. 2004; 172: 7053-7059) and emphysema (Mercer et al., J. Biol. Chem. 2004; 279: 17690-17696).
The Invention
The present invention provides compounds which are useful in therapy, in particular in the treatment of cancer. The compounds are inhibitors of ERK1/2 kinases and will be useful in the treatment of ERK1/2-mediated conditions.
Accordingly, in a first aspect of the invention (Embodiment 0.1), there is provided a compound of formula (0):

or a pharmaceutically acceptable salt, N-oxide or tautomer thereof; wherein:
n is 1 or 2;
X is CH or N;
Y is selected from CH and C—F;
Z is selected from C—Rz and N;
Rz is selected from hydrogen; halogen; methoxy; and C1-3 alkyl optionally substituted with hydroxy or methoxy;
R1 is selected from:                -(Alk1)t-Cyc1; wherein t is 0 or 1; and Alk1 is a C1-4 straight chain or branched alkylene group optionally substituted with 1 or 2 hydroxy groups; and        C1-6 acyclic hydrocarbon groups which are unsubstituted or substituted with 1, 2 or 3 substituents R5 selected from hydroxy; oxo; fluorine; and cyano; and wherein 1 or 2 but not all of the carbon atoms of the hydrocarbon group can be replaced by O or N;
Cyc1 is a cyclic group selected from (a) 3 to 9 membered non-aromatic monocyclic and bicyclic carbocyclic and heterocyclic groups containing 0, 1, 2, or 3 heteroatom ring members selected from O, N, S, S(O) and S(O)2; (b) 5 to 6 membered monocyclic heteroaryl groups containing 1, 2 or 3 heteroatom ring members of which 1 is N and the others, when present, are selected from O, N and S; and (c) 3 to 7 membered monocyclic carbocyclic groups; wherein each cyclic group (a), (b) and (c) is unsubstituted or substituted with 1, 2 or 3 substituents R6 selected from hydroxy; oxo; fluorine; amino; NH(Hyd1); N(Hyd1)2; O-Hyd1; —C(═O)-Hyd1; —C(═O)—O-Hyd1 and Hyd1; where Hyd1 is a C1-4 non-aromatic hydrocarbon group optionally substituted with one or more substituents selected from fluorine, hydroxyl and methoxy;
R2 is selected from hydrogen; halogen; and C1-3 hydrocarbon groups optionally substituted with one or more fluorine atoms;
R3 is hydrogen or a group L1-R7;
R4 is selected from hydrogen; methoxy; and C1-3 alkyl optionally substituted with hydroxy, amino, mono- or di-C1-2 alkylamino, a cyclic amino group or methoxy; wherein the cyclic amino group is a saturated 4-7 membered heterocyclic group containing a nitrogen ring member and optionally a second heteroatom ring member selected from O, N and S, wherein the cyclic amino group is linked via a nitrogen ring member thereof to the C1-2 alkyl, and wherein the cyclic amino group is optionally substituted with one or two methyl groups; provided that no more than one R4 can be other than hydrogen or methyl;
R4a is selected from hydrogen and a C1-3 alkyl group;
L1 is selected from a bond; Alk2, Alk2-O and Alk2-C(═O) wherein Alk2 is a C1-4 straight chain or branched alkylene group which is optionally substituted with one or more substituents selected from hydroxy, methoxy, amino, methylamino, dimethylamino and fluorine;
R7 is selected from:                hydrogen;        CO2H;        NR8R9;        a carbocyclic or heterocyclic group having from 3 to 12 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R10; and        an acyclic C1-8 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; cyano; carboxy; amino; mono- or di-C1-4 alkylamino; and carbocyclic and heterocyclic groups having from 3 to 12 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R10; wherein one or two but not all of the carbon atoms of the acyclic C1-8 hydrocarbon group may optionally be replaced by O, S, SO, SO2 or NR1;
R3 is selected from hydrogen and a C1-4 hydrocarbon group, the C1-4 hydrocarbon group being optionally substituted with 1-2 substituents selected from hydroxy, amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, and 4-7 membered saturated heterocyclic rings containing 1-2 heteroatom ring members selected from O and N, wherein the mono-C1-4 alkylamino, di-C1-4 alkylamino, and 4-7 membered saturated heterocyclic rings are each optionally substituted with 1-2 hydroxy or C1-3 alkyl substituents;
R9 is selected from:                hydrogen;        a carbocyclic or heterocyclic group having from 3 to 12 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R10; and        an acyclic C1-8 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; cyano; carboxy; amino; mono- or di-C1-4 alkylamino; and carbocyclic and heterocyclic groups having from 3 to 12 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R10; wherein one or two but not all of the carbon atoms of the acyclic C1-8 hydrocarbon group may optionally be replaced by O, S, SO, SO2 or NR11;
or NR8R9 forms a heterocyclic group having from 4 to 12 ring members wherein, in addition to the nitrogen atom of NR8R9, the heterocyclic group optionally contains 1 or 2 further heteroatom ring members selected from O, N and S and oxidised forms of S; and wherein the heterocyclic group is optionally substituted with one or more substituents R10;
R10 is selected from:                halogen; hydroxy; oxo; cyano;        OR12 wherein R12 is C1-6 alkyl or C3-6 cycloalkyl, each being optionally substituted with halogen;        an acyclic C1-8 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; cyano; carboxy; amino; mono- or di-C1-4 alkylamino; and carbocyclic and heterocyclic groups having 3 to 7 ring members of which 0, 1, 2, 3 or 4 are heteroatom ring members selected from N, O and S, wherein the carbocyclic and heterocyclic groups are optionally substituted with one or more substituents R13 selected from hydroxy; halogen; cyano; amino; —NH(Hyd1); —N(Hyd1)2; and —(O)v-Hyd1 where v is 0 or 1; wherein one or two but not all of the carbon atoms of the acyclic C1-8 hydrocarbon group may optionally be replaced by O, S, SO, SO2 or NR11; and        carbocyclic and heterocyclic groups having 3 to 7 ring members of which 0, 1, 2, 3 or 4 are heteroatom ring members selected from N, O and S, wherein the carbocyclic and heterocyclic groups are optionally substituted with one or more substituents R13; and
R11 is selected from hydrogen and a C1-4 hydrocarbon group; provided that the compound is other than 6-benzyl-3-{2-[(2-methylpyrimidin-4-yl)amino]pyridin-4-yl}-7,8-dihydro-1,6-naphthyridin-5(6H)-one and 3-{2-[(2-methylpyrimidin-4-yl)amino]pyridin-4-yl}-7,8-dihydro-1,6-naphthyridin-5(6H)-one and salts and tautomers thereof.
Particular aspects and embodiments of the invention are set out in Embodiments 0.2 to 1.179 below.
0.2 A compound according to Embodiment 0.1 wherein Cyc1 is a cyclic group selected from (a) 3 to 9 membered non-aromatic monocyclic and bicyclic carbocyclic and heterocyclic groups containing 0, 1, 2, or 3 heteroatom ring members selected from O, N, S and S(O)2; (b) 5 to 6 membered monocyclic heteroaryl groups containing 1, 2 or 3 heteroatom ring members of which 1 is N and the others, when present, are selected from O, N and S; and (c) 3 to 7 membered monocyclic carbocyclic groups; wherein each cyclic group (a), (b) and (c) is unsubstituted or substituted with 1, 2 or 3 substituents R6 selected from hydroxy; oxo; fluorine; amino; NH(Hyd1); N(Hyd1)2; O-Hyd1; —C(═O)-Hyd1; —C(═O)—O—Hyd1 and Hyd1; where Hyd1 is a C1-4 non-aromatic hydrocarbon group optionally substituted with one or more substituents selected from fluorine, hydroxyl and methoxy.
0.3 A compound according to Embodiment 0.1 or 0.2 wherein R4a is methyl.
0.4 A compound according to Embodiment 0.1 or 0.2 wherein R4a is hydrogen.
0.5 A compound according to any one of Embodiments 0.1 to 0.4 wherein R10 is selected from:                halogen; hydroxy; oxo; cyano;        OR12 wherein R12 is C1-6 alkyl or C3-6 cycloalkyl, each being optionally substituted with halogen;        an acyclic C1-8 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; cyano; carboxy; amino; mono- or di-C1-4 alkylamino; and carbocyclic and heterocyclic groups having 3 to 7 ring members of which 0, 1, 2, 3 or 4 are heteroatom ring members selected from N, O and S, wherein the carbocyclic and heterocyclic groups are optionally substituted with one or more substituents R13 selected from hydroxy; halogen; cyano and —(O)v-Hyd1 where v is 0 or 1; wherein one or two but not all of the carbon atoms of the acyclic C1-8 hydrocarbon group may optionally be replaced by O, S, SO, SO2 or NR11; and        carbocyclic and heterocyclic groups having 3 to 7 ring members of which 0, 1, 2, 3 or 4 are heteroatom ring members selected from N, O and S, wherein the carbocyclic and heterocyclic groups are optionally substituted with one or more substituents R13.
1.0 A compound of formula (1):

or a pharmaceutically acceptable salt or tautomer thereof; wherein:
n is 1 or 2;
X is CH or N;
Y is selected from CH and C—F;
Z is selected from C—Rz and N;
Rz is selected from hydrogen; halogen; methoxy; and C1-3 alkyl optionally substituted with hydroxy or methoxy;
R1 is selected from:                -(Alk1)t-Cyc1; wherein t is 0 or 1; and Alk1 is a C1-4 straight chain or branched alkylene group optionally substituted with 1 or 2 hydroxy groups; and        C1-6 acyclic hydrocarbon groups which are unsubstituted or substituted with 1, 2 or 3 substituents R5 selected from hydroxy; oxo; fluorine; and cyano; and wherein 1 or 2 but not all of the carbon atoms of the hydrocarbon group can be replaced by O or N;
Cyc1 is a cyclic group selected from (a) 3 to 9 membered non-aromatic monocyclic and bicyclic carbocyclic and heterocyclic groups containing 0, 1, 2, or 3 heteroatom ring members selected from O, N, S and S(O)2; (b) 5 to 6 membered monocyclic heteroaryl groups containing 1, 2 or 3 heteroatom ring members of which 1 is N and the others, when present, are selected from O, N and S; and (c) 3 to 7 membered monocyclic carbocyclic groups; wherein each cyclic group (a), (b) and (c) is unsubstituted or substituted with 1, 2 or 3 substituents R6 selected from hydroxy; oxo; fluorine; amino; NH(Hyd1); N(Hyd1)2; O-Hyd1; —C(═O)-Hyd1; —C(═O)—O-Hyd1 and Hyd1;                where Hyd1 is a C1-4 non-aromatic hydrocarbon group optionally substituted with one or more substituents selected from fluorine, hydroxyl and methoxy;
R2 is selected from hydrogen; halogen; and C1-3 hydrocarbon groups optionally substituted with one or more fluorine atoms;
R3 is hydrogen or a group L-R7;
R4 is selected from hydrogen; methoxy; and C1-3 alkyl optionally substituted with hydroxy, amino, mono- or di-C1-2 alkylamino, a cyclic amino group or methoxy; wherein the cyclic amino group is a saturated 4-7 membered heterocyclic group containing a nitrogen ring member and optionally a second heteroatom ring member selected from O, N and S, wherein the cyclic amino group is linked via a nitrogen ring member thereof to the C1-2 alkyl, and wherein the cyclic amino group is optionally substituted with one or two methyl groups; provided that no more than one R4 can be other than hydrogen or methyl;
L1 is selected from a bond; Alk2, Alk2-O and Alk2-C(═O) wherein Alk2 is a C1-4 straight chain or branched alkylene group which is optionally substituted with one or more substituents selected from hydroxy, methoxy, amino, methylamino, dimethylamino and fluorine;
R7 is selected from:                hydrogen;        CO2H;        NR8R9;        a carbocyclic or heterocyclic group having from 3 to 12 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R10; and        an acyclic C1-8 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; cyano; carboxy; amino; mono- or di-C1-4 alkylamino; and carbocyclic and heterocyclic groups having from 3 to 12 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R10; wherein one or two but not all of the carbon atoms of the acyclic C1-8 hydrocarbon group may optionally be replaced by O, S, SO, SO2 or NR1;
R3 is selected from hydrogen and a C1-4 hydrocarbon group, the C1-4 hydrocarbon group being optionally substituted with 1-2 substituents selected from hydroxy, amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, and 4-7 membered saturated heterocyclic rings containing 1-2 heteroatom ring members selected from O and N, wherein the mono-C1-4 alkylamino, di-C1-4 alkylamino, and 4-7 membered saturated heterocyclic rings are each optionally substituted with 1-2 hydroxy or C1-3 alkyl substituents;
R9 is selected from:                hydrogen;        a carbocyclic or heterocyclic group having from 3 to 12 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R10; and        an acyclic C1-8 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; cyano; carboxy; amino; mono- or di-C1-4 alkylamino; and carbocyclic and heterocyclic groups having from 3 to 12 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R10; wherein one or two but not all of the carbon atoms of the acyclic C1-8 hydrocarbon group may optionally be replaced by O, S, SO, SO2 or NR1;
or NR8R9 forms a heterocyclic group having from 4 to 12 ring members wherein, in addition to the nitrogen atom of NR8R9, the heterocyclic group optionally contains 1 or 2 further heteroatom ring members selected from O, N and S and oxidised forms of S; and wherein the heterocyclic group is optionally substituted with one or more substituents R10;
R10 is selected from:                halogen; hydroxy; oxo; cyano;        OR12 wherein R12 is C1-6 alkyl or C3-6 cycloalkyl, each being optionally substituted with halogen;        an acyclic C1-8 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; cyano; carboxy; amino; mono- or di-C1-4 alkylamino; and carbocyclic and heterocyclic groups having 3 to 7 ring members of which 0, 1, 2, 3 or 4 are heteroatom ring members selected from N, O and S, wherein the carbocyclic and heterocyclic groups are optionally substituted with one or more substituents R13 selected from hydroxy; halogen; cyano; and —(O)v-Hyd1 where v is 0 or 1; wherein one or two but not all of the carbon atoms of the acyclic C1-8 hydrocarbon group may optionally be replaced by O, S, SO, SO2 or NR11; and        carbocyclic and heterocyclic groups having 3 to 7 ring members of which 0, 1, 2, 3 or 4 are heteroatom ring members selected from N, O and S, wherein the carbocyclic and heterocyclic groups are optionally substituted with one or more substituents R13; and
R11 is selected from hydrogen and a C1-4 hydrocarbon group; provided that the compound is other than 6-benzyl-3-{2-[(2-methylpyrimidin-4-yl)amino]pyridin-4-yl}-7,8-dihydro-1,6-naphthyridin-5(6H)-one and 3-{2-[(2-methylpyrimidin-4-yl)amino]pyridin-4-yl}-7,8-dihydro-1,6-naphthyridin-5(6H)-one and salts and tautomers thereof.
1.01 A compound according to any one of Embodiments 0.1 to 1.0 wherein R1 is selected from:                -(Alk1)t-Cyc1; wherein t is 0 or 1; and Alk1 is a C1-4 straight chain or branched alkylene group optionally substituted with 1 or 2 hydroxy groups; and        C1-6 acyclic hydrocarbon groups which are unsubstituted or substituted with 1, 2 or 3 substituents R5 selected from hydroxy; oxo; and fluorine; and wherein 1 or 2 but not all of the carbon atoms of the hydrocarbon group can be replaced by 0 or N;
1.02 A compound according to any one of Embodiments 0.1 to 1.01 wherein R6 is selected from hydroxy; oxo; fluorine; O-Hyd1; —C(═O)-Hyd1; —C(═O)—O-Hyd1 and Hyd1; where Hyd1 is a C1-4 non-aromatic hydrocarbon group optionally substituted with one or more substituents selected from fluorine, hydroxyl and methoxy.
1.03 A compound according to any one of Embodiments 0.1 to 1.02 wherein R3 is selected from hydrogen and a C1-4 hydrocarbon group optionally substituted with hydroxy.
1.04 A compound according to any one of Embodiments 0.1 to 1.03 wherein, when R10 is selected from:                halogen; hydroxy; oxo; cyano;        OR12 wherein R12 is C1-6 alkyl or C3-6 cycloalkyl, each being optionally substituted with halogen;        an acyclic C1-8 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; cyano; carboxy; amino; mono- or di-C1-4 alkylamino; and carbocyclic and heterocyclic groups having 3 to 6 ring members of which 0, 1 or 2 are heteroatom ring members selected from N, O and S, wherein the carbocyclic and heterocyclic groups are optionally substituted with one or more substituents R13 selected from hydroxy; halogen; cyano; and —(O)v-Hyd1 where v is 0 or 1; wherein one or two but not all of the carbon atoms of the acyclic C1-8 hydrocarbon group may optionally be replaced by O, S, SO, SO2 or NR11; and        carbocyclic and heterocyclic groups having 3 to 6 ring members of which 0, 1, 2 or 3 are heteroatom ring members selected from N, O and S, wherein the carbocyclic and heterocyclic groups are optionally substituted with one or more substituents R13; and R11 is selected from hydrogen and a C1-4 hydrocarbon group.
1.05 A compound according to Embodiment 1.04 wherein, when R10 is selected from:                halogen; hydroxy; oxo; cyano;        OR12 wherein R12 is C1-6 alkyl or C3-6 cycloalkyl, each being optionally substituted with halogen;        an acyclic C1-8 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; cyano; carboxy; amino; mono- or di-C1-4 alkylamino; and carbocyclic and heterocyclic groups having 3 to 6 ring members of which 0, 1 or 2 are heteroatom ring members selected from N, O and S, wherein the carbocyclic and heterocyclic groups are optionally substituted with one or more substituents R13 selected from hydroxy; halogen; cyano; and —(O)v-Hyd1 where v is 0 or 1; wherein one or two but not all of the carbon atoms of the acyclic C1-8 hydrocarbon group may optionally be replaced by O, S, SO, SO2 or NR11; and        carbocyclic and heterocyclic groups having 3 to 6 ring members of which 0, 1 or 2 are heteroatom ring members selected from N, O and S, wherein the carbocyclic and heterocyclic groups are optionally substituted with one or more substituents R13; and
R11 is selected from hydrogen and a C1-4 hydrocarbon group.
1.06 A compound according to any one of Embodiments 0.1 to 1.05 wherein, when Z is C—Rz, Rz is selected from hydrogen; halogen; methoxy; and C1-3 alkyl optionally substituted with hydroxyl.
1.1 A compound of formula (1):

or a pharmaceutically acceptable salt or tautomer thereof; wherein:
n is 1 or 2;
X is CH or N;
Y is selected from CH and C—F;
Z is selected from C—Rz and N;
Rz is selected from hydrogen; halogen; and C1-3 alkyl optionally substituted with hydroxy or methoxy;
R1 is selected from:                -(Alk1)t-Cyc1; wherein t is 0 or 1; and Alk1 is a C1-4 straight chain or branched alkylene group optionally substituted with 1 or 2 hydroxy groups; and        C1-6 acyclic hydrocarbon groups which are unsubstituted or substituted with 1, 2 or 3 substituents R5 selected from hydroxy; oxo; fluorine; and wherein 1 or 2 but not all of the carbon atoms of the hydrocarbon group can be replaced by 0 or N;
Cyc1 is a cyclic group selected from (a) 3 to 9 membered non-aromatic monocyclic and bicyclic carbocyclic and heterocyclic groups containing 0, 1, 2, or 3 heteroatom ring members selected from O, N, S and S(O)2; (b) 5 to 6 membered monocyclic heteroaryl groups containing 1, 2 or 3 heteroatom ring members of which 1 is N and the others, when present, are selected from O, N and S; and (c) 3 to 7 membered monocyclic carbocyclic groups; wherein each cyclic group (a), (b) and (c) is unsubstituted or substituted with 1, 2 or 3 substituents R6 selected from hydroxy; oxo; fluorine; O-Hyd1; —C(═O)-Hyd1; —C(═O)—O-Hyd1 and Hyd1; where Hyd1 is a C1-4 non-aromatic hydrocarbon group optionally substituted with one or more substituents selected from fluorine, hydroxyl and methoxy;
R2 is selected from hydrogen; halogen; and C1-3 hydrocarbon groups optionally substituted with one or more fluorine atoms;
R3 is hydrogen or a group L1-R7;
R4 is selected from hydrogen and C1-2 alkyl optionally substituted with hydroxy, amino, mono- or di-C1-2 alkylamino, a cyclic amino group or methoxy; wherein the cyclic amino group is a saturated 4-7 membered heterocyclic group containing a nitrogen ring member and optionally a second heteroatom ring member selected from O, N and S, wherein the cyclic amino group is linked via a nitrogen ring member thereof to the C1-2 alkyl, and wherein the cyclic amino group is optionally substituted with one or two methyl groups; provided that no more than one R4 can be other than hydrogen or methyl;
L1 is selected from a bond; Alk2, Alk2-O and Alk2-C(═O) wherein Alk2 is a C1-4 straight chain or branched alkylene group which is optionally substituted with one or more substituents selected from hydroxy, methoxy, amino, methylamino, dimethylamino and fluorine;
R7 is selected from:                hydrogen;        CO2H;        NR8R9;        a carbocyclic or heterocyclic group having from 3 to 12 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R10; and        an acyclic C1-8 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; cyano; carboxy; amino; mono- or di-C1-4 alkylamino; and carbocyclic and heterocyclic groups having from 3 to 12 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R10; wherein one or two but not all of the carbon atoms of the acyclic C1-8 hydrocarbon group may optionally be replaced by O, S, SO, SO2 or NR11;        R3 is selected from hydrogen and a C1-4 hydrocarbon group optionally substituted with hydroxy;
R9 is selected from:                hydrogen;        a carbocyclic or heterocyclic group having from 3 to 12 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R10; and        an acyclic C1-8 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; cyano; carboxy; amino; mono- or di-C1-4 alkylamino; and carbocyclic and heterocyclic groups having from 3 to 12 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R10; wherein one or two but not all of the carbon atoms of the acyclic C1-8 hydrocarbon group may optionally be replaced by O, S, SO, SO2 or NR11;        or NR8R9 forms a heterocyclic group having from 4 to 12 ring members wherein, in addition to the nitrogen atom of NR8R9, the heterocyclic group optionally contains 1 or 2 further heteroatom ring members selected from O, N and S and oxidised forms of S; and wherein the heterocyclic group is optionally substituted with one or more substituents R10;
R10 is selected from:                halogen; hydroxy; oxo; cyano;        OR12 wherein R12 is C1-6 alkyl or C3-6 cycloalkyl, each being optionally substituted with halogen;        an acyclic C1-8 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; cyano; carboxy; amino; mono- or di-C1-4 alkylamino; and carbocyclic and heterocyclic groups having 3 to 6 ring members of which 0, 1 or 2 are heteroatom ring members selected from N, O and S, wherein the carbocyclic and heterocyclic groups are optionally substituted with one or more substituents R13 selected from hydroxy; halogen; cyano; and —(O)v-Hyd1 where v is 0 or 1; wherein one or two but not all of the carbon atoms of the acyclic C1-8 hydrocarbon group may optionally be replaced by O, S, SO, SO2 or NR11; and        carbocyclic and heterocyclic groups having 3 to 6 ring members of which 0, 1 or 2 are heteroatom ring members selected from N, O and S, wherein the carbocyclic and heterocyclic groups are optionally substituted with one or more substituents R13; and
R11 is selected from hydrogen and a C1-4 hydrocarbon group; provided that the compound is other than 6-benzyl-3-{2-[(2-methylpyrimidin-4-yl)amino]pyridin-4-yl}-7,8-dihydro-1,6-naphthyridin-5(6H)-one and 3-{2-[(2-methylpyrimidin-4-yl)amino]pyridin-4-yl}-7,8-dihydro-1,6-naphthyridin-5(6H)-one and salts and tautomers thereof.
1.2 A compound according to any one of Embodiments 0.1 to 1.1 wherein X is N.
1.2A A compound according to any one of Embodiments 0.1 to 1.1 wherein X is CH.
1.3 A compound according to any one of Embodiments 0.1 to 1.2 wherein Y is CH.
1.4 A compound according to any one of Embodiments 0.1 to 1.1 having the general formula (2):

or a pharmaceutically acceptable salt or tautomer thereof; wherein R1, R2, R3, R4, Z and n are as defined in any one of Embodiment 0.1 to 1.1.
1.5 A compound according to any one of Embodiments 0.1 to 1.4 wherein n is 1.
1.6 A compound according to any one of Embodiments 0.1 to 1.4 wherein n is 2.
1.7 A compound according to any one of Embodiments 0.1 to 1.1 having the general formula (3):

or a pharmaceutically acceptable salt or tautomer thereof; wherein R1, R2, R3, R4 and Z are as defined in any one of Embodiments 0.1 to 1.1.
1.7A A compound according to Embodiment 1.7 wherein the compound has the structure (3A):

1.7B A compound according to Embodiment 1.7 wherein the compound has the structure (3B):

1.8 A compound according to any one of Embodiments 0.1 to 1.7 wherein R1 is selected from:                -(Alk1)t-Cyc1; wherein t is 0 or 1; and Alk1 is a C1-2 straight chain or branched alkylene group optionally substituted with 1 or 2 hydroxy groups; and        C1-6 acyclic hydrocarbon groups which are unsubstituted or substituted with 1, 2 or 3 substituents R5 selected from hydroxy; oxo; fluorine; and wherein 1 or 2 but not all of the carbon atoms of the hydrocarbon group can be replaced by O or N.
1.9 A compound according to any one of Embodiments 0.1 to 1.7 wherein R1 is selected from:                -(Alk1)t-Cyc1; wherein t is 0; and        C1-6 acyclic hydrocarbon groups which are unsubstituted or substituted with 1, 2 or 3 substituents R5 selected from hydroxy; oxo; fluorine; and wherein 1 or 2 but not all of the carbon atoms of the hydrocarbon group can be replaced by O or N.
1.10 A compound according to any one of Embodiments 0.1 to 1.7 wherein R1 is selected from:                -(Alk1)t-Cyc1; wherein t is 0; and        C1-6 acyclic hydrocarbon groups which are unsubstituted or substituted with 1 or 2 hydroxy substituents; and wherein 1 but not all of the carbon atoms of the hydrocarbon group can be replaced by O.
1.11 A compound according to any one of Embodiments 0.1 to 1.7 wherein R1 is selected from:                -(Alk1)t-Cyc1; wherein t is 0; and        C3-6 acyclic hydrocarbon groups which are unsubstituted or substituted with 1 or 2 hydroxy substituents; and wherein 1 but not all of the carbon atoms of the hydrocarbon group can be replaced by O.
1.12 A compound according to any one of Embodiments 0.1 to 1.7 wherein R1 is selected from:                -(Alk1)t-Cyc1; wherein t is 0; and        C3-5 acyclic hydrocarbon groups which are unsubstituted or substituted with 1 or 2 hydroxy substituents; and wherein 1 but not all of the carbon atoms of the hydrocarbon group can be replaced by O.
1.13 A compound according to any one of Embodiments 0.1 to 1.7 wherein R1 is selected from C1-6 acyclic hydrocarbon groups which are unsubstituted or substituted with 1, 2 or 3 substituents R5 selected from hydroxy; oxo; fluorine; and wherein 1 or 2 but not all of the carbon atoms of the hydrocarbon group can be replaced by O or N.
1.14 A compound according to Embodiment 1.13 wherein R1 is selected from C2-6 acyclic hydrocarbon groups which are unsubstituted or substituted with 1, 2 or 3 substituents R5 selected from hydroxy; oxo; fluorine; and wherein 1 or 2 but not all of the carbon atoms of the hydrocarbon group can be replaced by O or N.
1.15 A compound according to Embodiment 1.14 wherein R1 is selected from C3-6 acyclic hydrocarbon groups which are unsubstituted or substituted with 1, 2 or 3 substituents R5 selected from hydroxy; oxo; fluorine; and wherein 1 or 2 but not all of the carbon atoms of the hydrocarbon group can be replaced by O or N.
1.16 A compound according to Embodiment 1.15 wherein R1 is selected from C3-5 acyclic hydrocarbon groups which are unsubstituted or substituted with 1, 2 or 3 substituents R5 selected from hydroxy; oxo; fluorine; and wherein 1 or 2 but not all of the carbon atoms of the hydrocarbon group can be replaced by O or N.
1.17 A compound according to Embodiment 1.16 wherein R1 is selected from C3-4 acyclic hydrocarbon groups which are unsubstituted or substituted with 1, 2 or 3 substituents R5 selected from hydroxy; oxo; fluorine; and wherein 1 or 2 but not all of the carbon atoms of the hydrocarbon group can be replaced by O or N.
1.17A A compound according to any one of Embodiments 1.8, 1.9, 1.13, 1.14, 1.15, 1.16 and 1.17 wherein there are 0, 1 or 2 substituents R5 present in R1.
1.17B A compound according to any one of Embodiments 1.8, 1.9, 1.13, 1.14, 1.15, 1.16 and 1.17 wherein there are 0 substituents R5 present in R1.
1.17B A compound according to any one of Embodiments 1.8, 1.9, 1.13, 1.14, 1.15, 1.16 and 1.17 wherein there is 1 substituent R5 present in R1.
1.17C A compound according to any one of Embodiments 1.8, 1.9, 1.13, 1.14, 1.15, 1.16 and 1.17 wherein there are 2 substituents R5 present in R1.
1.18 A compound according to any one of Embodiments 0.1 to 1.17A wherein, when R1 consists of or comprises an unsubstituted or substituted hydrocarbon group, the hydrocarbon group is selected from unsubstituted or substituted alkyl and alkenyl groups.
1.19 A compound according to Embodiment 1.18 wherein the hydrocarbon group is selected from unsubstituted or substituted alkyl groups.
1.20 A compound according to anyone of Embodiments 1.13 to 1.19 wherein the acyclic hydrocarbon groups are unsubstituted or substituted with 1 or 2 substituents R5 selected from hydroxy; oxo; fluorine; and wherein 1 or 2 but not all of the carbon atoms of the hydrocarbon group can be replaced by O or N.
1.21 A compound according to Embodiment 1.20 wherein the acyclic hydrocarbon groups are unsubstituted or substituted with 1 or 2 substituents R5 selected from hydroxy; oxo; and fluorine; and wherein 1 but not all of the carbon atoms of the hydrocarbon group can be replaced by O.
1.22 A compound according to Embodiment 1.21 wherein the acyclic hydrocarbon groups are unsubstituted or substituted with 1 or 2 substituents R5 selected from hydroxy; and wherein 1 but not all of the carbon atoms of the hydrocarbon group can be replaced by O.
1.23 A compound according to any one of Embodiments 0.1 to 1.7 wherein R1 is selected from Cyc1; isopropyl; tert-butyl; 1,3-dihydroxy-prop-2-yl; 2,3-dihydroxy-prop-1-yl and 2-methoxyethyl.
1.24 A compound according to any one of Embodiments 0.1 to 1.7 wherein R1 is selected from -(Alk1)t-Cyc1; wherein t is 0 or 1; and Alk1 is a C1-4 straight chain or branched alkylene group optionally substituted with 1 or 2 hydroxy groups.
1.25 A compound according to Embodiment 1.24 wherein R1 is selected from -(Alk1)t-Cyc1; wherein t is 0 or 1; and Alk1 is a CH2, CH(CH3) or CH2CH2 group.
1.26 A compound according to Embodiment 1.25 wherein t is 0 and therefore R1 is Cyc1.
1.26A A compound according to any one of Embodiments 0.1 to 1.7 wherein t is 0 and therefore R1 is Cyc1.
1.27 A compound according to any one of Embodiments 0.1 to 1.12 and 1.23 to 1.26 wherein Cyc1 is a cyclic group selected from:
(a-i) 3 to 9 membered monocyclic and bicyclic non-aromatic carbocyclic groups (e.g. cycloalkyl groups);
(a-ii) 4 to 9 membered non-aromatic (e.g. saturated) monocyclic and bicyclic heterocyclic groups containing 1 or 2 heteroatom ring members selected from O, N, S and S(O)2;
(b) 5 to 6 membered monocyclic heteroaryl groups containing 1 or 2 heteroatom ring members of which 1 is N and the others, when present, are selected from O, N and S; and
(c) phenyl groups;
wherein each cyclic group (a-i), (a-ii), (b) and (c) is unsubstituted or substituted with 1, 2 or 3 substituents R6 selected from hydroxy; oxo; fluorine; O-Hyd1; —C(═O)-Hyd1; —C(═O)—O-Hyd1 and Hyd1; where Hyd1 is a C1-4 non-aromatic hydrocarbon group optionally substituted with one or more substituents selected from fluorine, hydroxyl and methoxy.
1.27A A compound according to any one of Embodiments 0.1 to 1.12 and 1.23 to 1.26 wherein Cyc1 is a cyclic group selected from:
(a-i) 3 to 9 membered monocyclic and bicyclic non-aromatic carbocyclic groups (e.g. cycloalkyl groups);
(a-ii) 4 to 9 membered non-aromatic (e.g. saturated) monocyclic and bicyclic heterocyclic groups containing 1 or 2 heteroatom ring members selected from O, N, S and S(O)2;
(b) 5 to 6 membered monocyclic heteroaryl groups containing 1, 2 or 3 heteroatom ring members of which 1 is N and the others, when present, are selected from O, N and S; and
(c) phenyl groups;
wherein each cyclic group (a-i), (a-ii), (b) and (c) is unsubstituted or substituted with 1, 2 or 3 substituents R6 selected from hydroxy; oxo; fluorine; N(Hyd1)2; O-Hyd1; —C(═O)-Hyd1; —C(═O)—O—Hyd1 and Hyd1; where Hyd1 is a C1-4 non-aromatic hydrocarbon group optionally substituted with one or more substituents selected from fluorine, hydroxyl and methoxy.
1.27B A compound according to any one of Embodiments 0.1 to 1.12 and 1.23 to 1.26 wherein Cyc1 is a cyclic group selected from:
(a-i) 3 to 9 membered monocyclic and bicyclic non-aromatic carbocyclic groups (e.g. cycloalkyl groups);
(a-ii) 4 to 9 membered non-aromatic (e.g. saturated) monocyclic and bicyclic heterocyclic groups containing 1 or 2 heteroatom ring members selected from O, N, S and S(O)2;
(b) 5 to 6 membered monocyclic heteroaryl groups containing 1, 2 or 3 heteroatom ring members of which 1 is N and the others, when present, are selected from O, N and S; and
(c) phenyl groups;
wherein each cyclic group (a-i), (a-ii), (b) and (c) is unsubstituted or substituted with 1, 2 or 3 substituents R6 selected from hydroxy; oxo; fluorine; N(Hyd1)2; O-Hyd1; —C(═O)-Hyd1; —C(═O)—O—Hyd1 and Hyd1; where Hyd1 is a C1-4 non-aromatic hydrocarbon group optionally substituted with one or more substituents selected from fluorine, hydroxyl and methoxy.
1.27C A compound according to any one of Embodiments 0.1 to 1.12 and 1.23 to 1.26 wherein Cyc1 is a cyclic group selected from:
(a-i) 3-, 4-, 5-, or 6-membered monocyclic non-aromatic carbocyclic groups (e.g. C3-6 cycloalkyl groups);
(a-ii) 4-, 5-, 6-, or 7-membered non-aromatic (e.g. saturated) monocyclic and 7-membered bicyclic heterocyclic groups containing 1 or 2 heteroatom ring members selected from O, N, S and S(O)2;
(b) 5- or 6-membered monocyclic heteroaryl groups containing 1, 2 or 3 heteroatom ring members of which 1 is N and the others, when present, are selected from O, N and S; and
(c) phenyl groups;
wherein each cyclic group (a-i), (a-ii), (b) and (c) is unsubstituted or substituted with 1, 2 or 3 substituents R6 selected from hydroxy; oxo; fluorine; N(Hyd1)2; O-Hyd1; —C(═O)-Hyd1; —C(═O)—O—Hyd1 and Hyd1; where Hyd1 is a C1-4 non-aromatic hydrocarbon group optionally substituted with one or more substituents selected from fluorine, hydroxyl and methoxy.
1.27D A compound according to any one of Embodiments 0.1 to 1.12 and 1.23 to 1.26 wherein Cyc1 is a cyclic group selected from:
(a-i) 3-, 4-, 5-, or 6-membered monocyclic non-aromatic carbocyclic groups (e.g. C3-6 cycloalkyl groups) unsubstituted or substituted with 1, 2 or 3 substituents R6 selected from hydroxy; oxo; fluorine; N(Hyd1)2 (e.g. —NMe2); O-Hyd1 (e.g. methoxy); —C(═O)-Hyd1 (e.g. —C(═O)-methyl); —C(═O)—O-Hyd1 (e.g. —C(═O)—O—tBu) and Hyd1 (e.g. methyl, iso-propyl); where Hyd1 is a C1-4 non-aromatic hydrocarbon group optionally substituted with one or more substituents selected from hydroxyl;
(a-ii) 4-, 5-, 6-, or 7-membered non-aromatic (e.g. saturated) monocyclic and 7-membered bicyclic heterocyclic groups containing 1 or 2 heteroatom ring members selected from O, N, S and S(O)2 unsubstituted or substituted with 1, 2 or 3 substituents R6 selected from oxo; O-Hyd1 (e.g. methoxy); and Hyd1 (e.g. methyl, ethyl); where Hyd1 is a C1-4 non-aromatic hydrocarbon group;
(b) 5- or 6-membered monocyclic heteroaryl groups containing 1, 2 or 3 heteroatom ring members of which 1 is N and the others, when present, are selected from O, N and S; and
(c) unsubstituted phenyl groups.
1.28 A compound according to Embodiment 1.27 wherein Cyc1 is a cyclic group selected from:
(a-i) 3 to 7 membered monocyclic non-aromatic carbocyclic groups (e.g. cycloalkyl groups);
(a-ii) 4 to 7 membered non-aromatic (e.g. saturated) monocyclic heterocyclic groups and 7 to 9 membered bicyclic heterocyclic groups, wherein the heterocyclic groups contain 1 or 2 heteroatom ring members selected from O, N, S and S(O)2;
(b) 5 to 6 membered monocyclic heteroaryl groups containing 1 or 2 heteroatom ring members of which 1 is N and the others, when present, are selected from O, N and S; and
(c) phenyl groups;
wherein each cyclic group (a-i), (a-ii), (b) and (c) is unsubstituted or substituted with 1, 2 or 3 substituents R6 selected from hydroxy; oxo; fluorine; O-Hyd1; —C(═O)-Hyd1; —C(═O)—O-Hyd1 and Hyd1; where Hyd1 is a C1-4 non-aromatic hydrocarbon group optionally substituted with one or more substituents selected from fluorine, hydroxyl and methoxy.
1.28A A compound according to any one of Embodiments 0.1 to 1.12 and 1.23 to 1.26 wherein Cyc1 is a cyclic group selected from:
(a-ii) 4 to 7 membered non-aromatic (e.g. saturated) monocyclic heterocyclic groups, wherein the heterocyclic groups contain 1 or 2 heteroatom ring members selected from O, N, S and S(O)2; and
(b) 5 to 6 membered monocyclic heteroaryl groups containing 1, 2 or 3 heteroatom ring members of which 1 is N and the others, when present, are selected from O, N and S;
wherein each cyclic group (a-ii) and (b) is unsubstituted or substituted with 1, 2 or 3 substituents R6 selected from hydroxy; oxo; fluorine; O-Hyd1; —C(═O)-Hyd1; —C(═O)—O-Hyd1 and Hyd1; where Hyd1 is a C1-4 non-aromatic hydrocarbon group optionally substituted with one or more substituents selected from fluorine, hydroxyl and methoxy.
1.28B A compound according to Embodiment 1.28A wherein Cyc1 is a cyclic group selected from:
(a-ii) 4 to 7 membered saturated monocyclic heterocyclic groups, wherein the heterocyclic groups contain 1 oxygen heteroatom ring member; and
(b) 5 to 6 membered monocyclic heteroaryl groups containing 1 or 2 nitrogen heteroatom ring members and optionally a further heteroatom ring member selected from O, N, and S;
wherein each cyclic group (a-ii) and (b) is unsubstituted or substituted with 1, 2 or 3 substituents R6 selected from hydroxy; oxo; fluorine; O-Hyd1; —C(═O)-Hyd1; —C(═O)—O-Hyd1 and Hyd1; where Hyd1 is a C1-4 non-aromatic hydrocarbon group optionally substituted with one or more substituents selected from fluorine, hydroxyl and methoxy.
1.28C A compound according to Embodiment 1.28B wherein Cyc1 is a cyclic group selected from:
(a-ii) 5 to 6 membered saturated monocyclic heterocyclic groups, wherein the heterocyclic groups contain 1 oxygen heteroatom ring member;
(b-i) 5 membered monocyclic heteroaryl groups containing 2 or 3 nitrogen heteroatom ring members; and
(b-ii) 6 membered monocyclic heteroaryl groups containing 1 or 2 nitrogen heteroatom ring members;
wherein each cyclic group (a-ii), (b-i) and (b-ii) is unsubstituted or substituted with 1, 2 or 3 substituents R6 selected from hydroxy; oxo; fluorine; O-Hyd1; —C(═O)-Hyd1; —C(═O)—O-Hyd1 and Hyd1; where Hyd1 is a C1-4 non-aromatic hydrocarbon group optionally substituted with one or more substituents selected from fluorine, hydroxyl and methoxy.
1.28D A compound according to Embodiment 1.28B wherein Cyc1 is a cyclic group selected from:
(a-ii) 4 to 7 membered saturated monocyclic heterocyclic groups, wherein the heterocyclic groups contain 1 oxygen heteroatom ring member; wherein each cyclic group (a-ii) is unsubstituted or substituted with 1, 2 or 3 substituents R6 selected from hydroxy; oxo; fluorine; O-Hyd1; —C(═O)-Hyd1; —C(═O)—O-Hyd1 and Hyd1; where Hyd1 is a C1-4 non-aromatic hydrocarbon group optionally substituted with one or more substituents selected from fluorine, hydroxyl and methoxy.
1.28E A compound according to Embodiment 1.28D wherein Cyc1 is a cyclic group selected from:
(a-ii) 4 to 7 membered saturated monocyclic heterocyclic groups, wherein the heterocyclic groups contain 1 oxygen heteroatom ring member; wherein each cyclic group (a-ii) and (b) is unsubstituted or substituted with 1, 2 or 3 substituents R6 selected from oxo; fluorine; and Hyd1; where Hyd1 is a C1-4 non-aromatic hydrocarbon group optionally substituted with one or more substituents selected from fluorine, hydroxyl and methoxy.
1.28F A compound according to Embodiment 1.28B wherein Cyc1 is a cyclic group selected from:
(b) 5 to 6 membered monocyclic heteroaryl groups containing 1 or 2 nitrogen heteroatom ring members and optionally a further heteroatom ring member selected from O, N, and S;
wherein each cyclic group (b) is unsubstituted or substituted with 1, 2 or 3 substituents R6 selected from fluorine; O-Hyd1; and Hyd1; where Hyd1 is a C1-4 non-aromatic hydrocarbon group optionally substituted with one or more substituents selected from fluorine, hydroxyl and methoxy.
1.28G A compound according to Embodiment 1.28B wherein Cyc1 is a cyclic group selected from:
(b) 6 membered monocyclic heteroaryl groups containing 1 or 2 nitrogen heteroatom ring members;
wherein each cyclic group (b) is unsubstituted or substituted with 1, 2 or 3 substituents R6 selected from hydroxy; oxo; fluorine; O-Hyd1; —C(═O)-Hyd1; —C(═O)—O-Hyd1 and Hyd1; where Hyd1 is a C1-4 non-aromatic hydrocarbon group optionally substituted with one or more substituents selected from fluorine, hydroxyl and methoxy.
1.28H A compound according to Embodiment 1.28G wherein Cyc1 is a cyclic group selected from:
(b) 6 membered monocyclic heteroaryl groups containing 1 or 2 nitrogen heteroatom ring members;
wherein each cyclic group (b) is unsubstituted or substituted with 1, 2 or 3 substituents R6 selected from O-Hyd1; and Hyd1; where Hyd1 is a C1-4 non-aromatic hydrocarbon group optionally substituted with one or more substituents selected from fluorine, hydroxyl and methoxy.
1.29 A compound according to Embodiment 1.28 wherein Cyc1 is a cyclic group selected from:
(a-i) 3 to 7 membered monocyclic non-aromatic carbocyclic groups (e.g. cycloalkyl groups) which are unsubstituted or substituted as defined in Embodiment 1.27.
1.30 A compound according to Embodiment 1.29 wherein Cyc1 is a cyclic group selected from:
(a-i) 4 to 6 membered monocyclic non-aromatic carbocyclic groups (e.g. cycloalkyl groups) which are unsubstituted or substituted as defined in Embodiment 1.27.
1.31 A compound according to Embodiment 1.30 wherein the 4 to 6 membered monocyclic non-aromatic carbocyclic group is a 4 to 6 membered cycloalkyl group which is unsubstituted or substituted as defined in Embodiment 1.27.
1.32 A compound according to Embodiment 1.30 wherein the 4 to 6 membered cycloalkyl group is selected from cyclobutyl and cyclohexyl groups which are unsubstituted or substituted as defined in Embodiment 1.27.
1.32A A compound according to any one of Embodiments 0.1 to 1.12 and 1.23 to 1.32 wherein 0, 1 or 2 substituents R6 are present in R1.
1.32B A compound according to any one of Embodiments 0.1 to 1.12 and 1.23 to 1.32 wherein 0 substituents R6 are present in R1.
1.32C A compound according to any one of Embodiments 0.1 to 1.12 and 1.23 to 1.32 wherein 1 substituent R6 is present in R1.
1.32D A compound according to any one of Embodiments 0.1 to 1.12 and 1.23 to 1.32 wherein 2 substituents R6 are present in R1.
1.33 A compound according to any one of Embodiments 1.28 to 1.32 wherein the carbocyclic groups are unsubstituted or substituted with 1 or 2 substituents R6 selected from hydroxy; oxo; fluorine; O-Hyd1; and Hyd1.
1.34 A compound according to Embodiment 1.33 wherein the carbocyclic groups are unsubstituted or substituted with 1 or 2 substituents R6 selected from hydroxy; methoxy; and methyl; for example wherein the carbocyclic groups are unsubstituted or substituted with 1 substituent R6 selected from hydroxy and methoxy.
1.35 A compound according to Embodiment 1.27 wherein Cyc1 is a cyclic group selected from:
(a-ii) 4 to 7 membered non-aromatic (e.g. saturated) monocyclic heterocyclic groups and 7 to 9 membered bicyclic heterocyclic groups, wherein the heterocyclic groups contain 1 or 2 heteroatom ring members selected from O, N, S and S(O)2 and are unsubstituted or substituted as defined in Embodiment 1.27.
1.36 A compound according to Embodiment 1.35 wherein Cyc1 is a cyclic group selected from:
(a-ii) 4 to 7 membered non-aromatic (e.g. saturated) monocyclic heterocyclic groups wherein the heterocyclic groups contain 1 or 2 heteroatom ring members selected from O, N, S and S(O)2 and are unsubstituted or substituted as defined in Embodiment 1.27 or Embodiment 1.28.
1.36A A compound according to Embodiment 1.36 wherein Cyc1 is a cyclic group selected from:
(a-ii) 4 to 7 membered saturated monocyclic heterocyclic groups wherein the heterocyclic groups contain 1 or 2 heteroatom ring members selected from O and N and are unsubstituted or substituted as defined in Embodiment 1.27 or Embodiment 1.28.
1.36B A compound according to Embodiment 1.36 wherein Cyc1 is a cyclic group selected from:
(a-ii) 4 to 7 membered saturated monocyclic heterocyclic groups wherein the heterocyclic groups contain 1 heteroatom ring member selected from O and N and are unsubstituted or substituted as defined in Embodiment 1.27 or Embodiment 1.28.
1.36C A compound according to Embodiment 1.36 wherein Cyc1 is a cyclic group selected from oxetane, tetrahydrofuran, oxan, oxaspiro[3.3]heptane, azetidine, pyrrolidine and piperidine groups.
1.37 A compound according to Embodiment 1.36 wherein Cyc1 is a cyclic group selected from:
(a-ii) 4 to 6 membered non-aromatic (e.g. saturated) monocyclic heterocyclic groups wherein the heterocyclic groups contain 1 or 2 heteroatom ring members selected from O, N, S and S(O)2 and are unsubstituted or substituted as defined in Embodiment 1.27.
1.38 A compound according to Embodiment 1.37 wherein Cyc1 is a cyclic group selected from:
(a-ii) 4 to 6 membered saturated non-aromatic monocyclic heterocyclic groups wherein the heterocyclic groups contain 1 or 2 heteroatom ring members selected from O, N and S and are unsubstituted or substituted as defined in Embodiment 1.27.
1.39 A compound according to Embodiment 1.38 wherein Cyc1 is a cyclic group selected from:
(a-ii) 4 to 6 membered saturated non-aromatic monocyclic heterocyclic groups wherein the heterocyclic groups contain 1 heteroatom ring member selected from O and N and are unsubstituted or substituted as defined in Embodiment 1.27.
1.40 A compound according to Embodiment 1.39 wherein Cyc1 is a cyclic group selected from oxetane, tetrahydrofuran, oxan, azetidine, pyrrolidine and piperidine groups, each of which is unsubstituted or substituted as defined in Embodiment 1.27.
1.41 A compound according to Embodiment 1.40 wherein Cyc1 is a cyclic group selected from oxetane, tetrahydrofuran, oxan, azetidine and piperidine groups, each of which is unsubstituted or substituted as defined in Embodiment 1.27.
1.42 A compound according to Embodiment 1.40 wherein Cyc1 is an oxan group which is unsubstituted or substituted as defined in Embodiment 1.27.
1.43 A compound according to any one of Embodiments 1.36 to 1.42 wherein the heterocyclic groups are unsubstituted or substituted with with 1 or 2 substituents R6 selected from hydroxy; oxo; fluorine; O-Hyd1; —C(═O)-Hyd1 and Hyd1; where Hyd1 is a C1-4 non-aromatic hydrocarbon group (e.g. an alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkylalkyl group) optionally substituted with one or more substituents selected from fluorine, hydroxyl and methoxy.
1.44 A compound according to Embodiment 1.43 wherein the heterocyclic groups are unsubstituted or substituted with with 1 or 2 substituents R6 selected from hydroxy; fluorine; O-Hyd1; —C(═O)-Hyd1; —C(═O)—O-Hyd1 and Hyd1; where Hyd1 is a saturated C1-4 hydrocarbon group (e.g. an alkyl, cycloalkyl or cycloalkylalkyl group).
1.45 A compound according to Embodiment 1.44 wherein the heterocyclic groups are unsubstituted or substituted with with 1 or 2 substituents R6 selected from —C(═O)-Hyd1; —C(═O)—O-Hyd1 and Hyd1; where Hyd1 is a saturated C1-4 hydrocarbon group (e.g. an alkyl, cycloalkyl or cycloalkylalkyl group).
1.46 A compound according to Embodiment 1.45 wherein the heterocyclic groups are unsubstituted or substituted with with 1 or 2 substituents R6 selected from C1-4 alkyl such as methyl; C1-4 alkanoyl such as acetyl; and C1-4 alkoxycarbonyl such as tert-butoxycarbonyl.
1.47 A compound according to Embodiment 1.46 wherein the heterocyclic groups are unsubstituted or substituted with with 1 or 2 C1-4 alkyl (e.g. methyl) group substituents R6 or by a single substituent selected from C1-4 alkanoyl (e.g. acetyl); and C1-4 alkoxycarbonyl (e.g. tert-butoxycarbonyl).
1.48 A compound according to Embodiment 1.47 wherein the heterocyclic groups are unsubstituted or substituted with with 1 or 2 methyl group substituents R6.
1.49 A compound according to Embodiment 1.47 wherein the heterocyclic groups are unsubstituted.
1.50 A compound according to Embodiment 1.27 wherein Cyc1 is a cyclic group selected from:
(a-ii) 7 to 9 membered bicyclic heterocyclic groups, wherein the heterocyclic groups contain 1 or 2 heteroatom ring members selected from O, N, S and S(O)2 and are unsubstituted or substituted as defined in Embodiment 1.27.
1.51 A compound according to Embodiment 1.50 wherein Cyc1 is a cyclic group selected from:
(a-ii) 7 to 9 membered bicyclic heterocyclic groups, wherein the heterocyclic groups contain 1 heteroatom ring member selected from O and N and are unsubstituted or substituted as defined in Embodiment 1.27.
1.52 A compound according to Embodiment 1.51 wherein Cyc1 is a cyclic group selected from:
(a-ii) 7 to 9 membered bicyclic heterocyclic groups, wherein the heterocyclic groups are bridged bicyclic or spiro-bicyclic groups containing 1 heteroatom ring member selected from O and N and are unsubstituted or substituted as defined in Embodiment 1.27.
1.53 A compound according to Embodiment 1.52 wherein Cyc1 is a 7 to 9 membered bridged bicyclic heterocyclic group containing 1 heteroatom ring member selected from O and N, the heterocyclic group being unsubstituted or substituted as defined in Embodiment 1.27.
1.54 A compound according to Embodiment 1.53 wherein the heterocyclic group is an oxabicyclo[3.2.1]octane group.
1.55 A compound according to Embodiment 1.52 wherein Cyc1 is a 7 to 9 membered spiro-bicyclic heterocyclic group containing 1 heteroatom ring member selected from O and N, the heterocyclic group being unsubstituted or substituted as defined in Embodiment 1.27.
1.56 A compound according to Embodiment 1.55 wherein the heterocyclic group is an oxaspiro[3.3]heptane group.
1.57 A compound according to Embodiment 1.27 wherein Cyc1 is a cyclic group selected from:
(b) 5 to 6 membered monocyclic heteroaryl groups containing 1 or 2 heteroatom ring members of which 1 is N and the others, when present, are selected from O, N and S; and
(c) phenyl groups;
wherein the heteroaryl groups and phenyl groups are unsubstituted or substituted as defined in Embodiment 1.27.
1.58 A compound according to Embodiment 1.57 wherein Cyc1 is a cyclic group selected from:
(b) 5 to 6 membered monocyclic heteroaryl groups containing 1 or 2 heteroatom ring members of which 1 is N and the others, when present, are selected from O, N and S;
wherein the heteroaryl groups are unsubstituted or substituted as defined in Embodiment 1.27.
1.59 A compound according to Embodiment 1.58 wherein the 5 to 6 membered monocyclic heteroaryl groups are selected from pyrazole and pyridine, each being unsubstituted or substituted as defined in Embodiment 1.27.
1.60 A compound according to any one of Embodiments 1.57 to 1.59 wherein the heteroaryl group is unsubstituted or substituted with 1 or 2 substituents R6 selected from hydroxy; O-Hyd1; —C(═O)-Hyd1; —C(═O)—O-Hyd1 and Hyd1; where Hyd1 is a C1-4 non-aromatic hydrocarbon group (e.g. an alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkylalkyl group) optionally substituted with one or more substituents selected from fluorine, hydroxyl and methoxy.
1.61 A compound according to Embodiment 1.60 wherein the heteroaryl group is unsubstituted or substituted with 1 or 2 substituents R6 selected from hydroxy; O-Hyd1; —C(═O)-Hyd1; and Hyd1; where Hyd1 is a saturated C1-4 hydrocarbon group (e.g. an alkyl, cycloalkyl or cycloalkylalkyl group) optionally substituted with one or more substituents selected from hydroxyl and methoxy.
1.62 A compound according to Embodiment 1.61 wherein the heteroaryl group is unsubstituted or substituted with 1 or 2 substituents R6 selected from O-Hyd1; and Hyd1; where Hyd1 is a saturated C1-4 hydrocarbon group (e.g. an alkyl, cycloalkyl or cycloalkylalkyl group).
1.63 A compound according to Embodiment 1.61 wherein the heteroaryl group is unsubstituted or substituted with 1 or 2 substituents R6 selected from Hyd1; where Hyd1 is a saturated C1-4 hydrocarbon group (e.g. an alkyl, cycloalkyl or cycloalkylalkyl group).
1.64 A compound according to Embodiment 1.61 wherein the heteroaryl group is unsubstituted or substituted with 1 or 2 C1-4 alkyl (e.g. methyl) group substituents R6.
1.65 A compound according to Embodiment 1.27 wherein Cyc1 is a cyclic group selected from:
(c) phenyl groups;
wherein the phenyl groups are unsubstituted or substituted as defined in Embodiment 1.27.
1.66 A compound according to Embodiment 1.65 wherein the phenyl groups are unsubstituted.
1.67 A compound according to any one of Embodiments 0.1 to 1.13, 1.23 to 1.32, 1.35 to 1.41, 1.50 to 1.59 and 1.65 wherein 0, 1 or 2 substituents R6 are present and are selected from hydroxy; oxo; fluorine; O-Hyd1; —C(═O)-Hyd1; —C(═O)—O-Hyd1 and Hyd1; where Hyd1 is a C1-4 non-aromatic hydrocarbon group (e.g. an alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkylalkyl group) optionally substituted with one or more substituents selected from fluorine, hydroxyl and methoxy.
1.67A A compound according to any one of Embodiments 0.1 to 1.13, 1.23 to 1.32, 1.35 to 1.41, 1.50 to 1.59 and 1.65 wherein 0, 1 or 2 substituents R6 are present and are selected from hydroxy; oxo; fluorine; amino; NH(Hyd1); N(Hyd1)2; O-Hyd1; —C(═O)-Hyd1; —C(═O)—O-Hyd1 and Hyd1; where Hyd1 is a C1-4 non-aromatic hydrocarbon group optionally substituted with one or more substituents selected from fluorine, hydroxyl and methoxy.
1.67B A compound according to any one of Embodiments 0.1 to 1.13, 1.23 to 1.32, 1.35 to 1.41, 1.50 to 1.59 and 1.65 wherein 0, 1 or 2 substituents R6 are present and are selected from hydroxy; oxo; fluorine; N(Hyd1)2 (e.g. —NMe2); O-Hyd1 (e.g. methoxy); —C(═O)-Hyd1 (e.g. —C(═O)-methyl); —C(═O)—O-Hyd1 (e.g. —C(═O)—O—tBu) and Hyd1 (e.g. methyl, ethyl, iso-propyl); where Hyd1 is a C1-4 non-aromatic hydrocarbon group optionally substituted with one or more substituents selected from fluorine, hydroxyl and methoxy.
1.68 A compound according to Embodiment 1.67 wherein 0, 1 or 2 substituents R6 are present and selected from hydroxy; fluorine; O-Hyd1; —C(═O)-Hyd1; —C(═O)—O-Hyd1 and Hyd1; where Hyd1 is a C1-4 non-aromatic hydrocarbon group (e.g. an alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkylalkyl group) optionally substituted with one or more substituents selected from fluorine, hydroxyl and methoxy.
1.69 A compound according to Embodiment 1.68 wherein 0, 1 or 2 substituents R6 are present and selected from hydroxy; O-Hyd1; —C(═O)-Hyd1; —C(═O)—O-Hyd1 and Hyd1; where Hyd1 is a C1-4 non-aromatic hydrocarbon group (e.g. an alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkylalkyl group) optionally substituted with one or more substituents selected from hydroxyl and methoxy.
1.70 A compound according to Embodiment 1.69 wherein 0, 1 or 2 substituents R6 are present and selected from hydroxy; O-Hyd1; —C(═O)-Hyd1; —C(═O)—O-Hyd1 and Hyd1; where Hyd1 is a saturated C1-4 hydrocarbon group (e.g. an alkyl, cycloalkyl or cycloalkylalkyl group) optionally substituted with one or more substituents selected from hydroxyl and methoxy.
1.71 A compound according to Embodiment 1.70 wherein 0, 1 or 2 substituents R6 are present and selected from hydroxy; O-Hyd1; —C(═O)-Hyd1; —C(═O)—O-Hyd1 and Hyd1; where Hyd1 is a saturated C1-4 hydrocarbon group (e.g. a saturated C1-3 hydrocarbon group such as an alkyl or cyclopropyl group).
1.72 A compound according to Embodiment 1.71 wherein 0, 1 or 2 substituents R6 are present and selected from hydroxy; methyl; methoxy; acetyl; and tert-butoxycarbonyl.
1.73 A compound according to any one of Embodiments 1.7, 1.42 to 1.49 and 1.67 to 1.72 having the general formula (4):

or a pharmaceutically acceptable salt or tautomer thereof; wherein R1, R2, R3, R4 and Z are as defined in any one of Embodiments 1.0, 1.7, 1.42 to 1.49 and 1.67 to 1.72; and v is 0, 1, 2 or 3.
1.73A A compound according to Embodiment 1.73 having the structure (4A):

1.73B A compound according to Embodiment 1.73 having the structure (4B):

1.74 A compound according to any one of Embodiments 1.73 to 1.73B wherein v is 0, 1 or 2.
1.75 A compound according to any one of Embodiments 1.73 to 1.73B wherein v is 0 or 1.
1.76 A compound according to any one of Embodiments 1.73 to 1.731B wherein v is 0.
1.77 A compound according to any one of Embodiments 1.73 to 1.731B wherein v is 1.
1.78 A compound according to any one of Embodiments 1.73 to 1.731B wherein v is 2.
1.79 A compound according to any one of Embodiments 1.73 to 1.731B wherein v is 3.
1.80 A compound according to any one of Embodiments 0.1 to 1.79 wherein R1 is selected from groups AA to ACY in Table 1 below, where * marks the point of connection to the N atom.
1.80A A compound according to any one of Embodiments 0.1 to 1.79 wherein R1 is selected from groups AA to ABI in Table 1 below, where * marks the point of connection to the Na tom.
TABLE 1
1.81 A compound according to Embodiment 1.80A wherein R1 is selected from groups AA, AE, AF, AG and AY in Table 1.
1.81A A compound according to Embodiment 1.80A wherein R1 is selected from groups AA, AE, AF, AG, AY, AAC, AAF and ABI in Table 1.
1.81 BA compound according to Embodiment 1.80 wherein R1 is selected from groups AA, ABJ and ABK in Table 1.
1.82 A compound according to Embodiment 1.81 wherein R1 is group AA in Table 1.
1.82A A compound according to Embodiment 1.81A wherein R1 is group ABI in Table 1.
1.82B A compound according to Embodiment 1.81B wherein R1 is group ABJ in Table 1.
1.82C A compound according to Embodiment 1.81B wherein R1 is group ABK in Table 1.
1.83 A compound according to any one of Embodiments 0.1 to 1.82 wherein R2 is selected from hydrogen; fluorine; chlorine; and C1-3 hydrocarbon groups optionally substituted with one or more fluorine atoms.
1.83A A compound according to any one of Embodiments 0.1 to 1.82 wherein R2 is selected from hydrogen; fluorine; chlorine; bromine; and C1-3 hydrocarbon groups optionally substituted with one or more fluorine atoms.
1.84 A compound according to Embodiment 1.83 wherein R2 is selected from hydrogen; fluorine; chlorine; C1-3 alkyl; C2-3 alkenyl; cyclopropyl; and trifluoromethyl.
1.84A A compound according to Embodiment 1.83 wherein R2 is selected from hydrogen; fluorine; chlorine; bromine; C1-3 alkyl; C2-3 alkenyl; cyclopropyl; and trifluoromethyl.
1.85 A compound according to Embodiment 1.84 wherein R2 is selected from hydrogen; fluorine; chlorine; methyl; ethyl; isopropyl; vinyl; isopropenyl; cyclopropyl; and trifluoromethyl.
1.85A A compound according to Embodiment 1.84A wherein R2 is selected from hydrogen; fluorine; chlorine; bromine; methyl; ethyl; isopropyl; vinyl; isopropenyl; cyclopropyl; and trifluoromethyl.
1.86 A compound according to Embodiment 1.84 wherein R2 is selected from fluorine; chlorine; ethyl; isopropyl; vinyl; isopropenyl; cyclopropyl; and trifluoromethyl.
1.86A A compound according to Embodiment 1.84A wherein R2 is selected from fluorine; chlorine; bromine; ethyl; isopropyl; vinyl; isopropenyl; cyclopropyl; and trifluoromethyl.
1.87 A compound according to Embodiment 1.84 wherein R2 is selected from chlorine; isopropyl; vinyl; isopropenyl; and cyclopropyl.
1.87A A compound according to Embodiment 1.84A wherein R2 is selected from chlorine; bromine; isopropyl; vinyl; isopropenyl; and cyclopropyl.
1.88 A compound according to Embodiment 1.84 wherein R2 is chlorine.
1.88A A compound according to Embodiment 1.84A wherein R2 is bromine.
1.89 A compound according to Embodiment 1.88 having the general formula (5):

or a pharmaceutically acceptable salt or tautomer thereof.
1.89A A compound according to Embodiment 1.89 having the structure (5A):

1.89B A compound according to Embodiment 1.89 having the structure (5B):

1.90 A compound according to any one of Embodiments 0.1 to 1.89B wherein Z is CRz.
1.91 A compound according to Embodiment 1.90 wherein Rz is selected from hydrogen, fluorine, chlorine, methyl, hydroxymethyl and methoxymethyl.
1.92 A compound according to Embodiment 1.91 wherein Rz is selected from hydrogen and fluorine.
1.93 A compound according to Embodiment 1.92 wherein Rz is hydrogen.
1.94 A compound according to any one of Embodiments 0.1 to 1.89 wherein Z is N.
1.95 A compound according to any one of Embodiments 0.1 to 1.94 wherein R4 is selected from hydrogen and C1-2 alkyl optionally substituted with hydroxy, amino, methylamino, dimethylamino, a cyclic amino group or methoxy; wherein the cyclic amino group is selected from azetidine, pyrrolidine, piperidine, piperazine, N-methyl-piperazine, morpholine and thiomorpholine.
1.96 A compound according to Embodiment 1.95 wherein R4 is selected from hydrogen, methyl, —CH2OH, —CH2NH2; —(CH2)2OH; —(CH2)2OCH3; and —(CH2)2NH2.
1.97 A compound according to Embodiment 1.95 wherein R4 is selected from hydrogen, methyl, —CH2OH and —(CH2)2OH.
1.98 A compound according to Embodiment 1.97 wherein R4 is hydrogen.
1.99 A compound according to Embodiment 1.97 wherein wherein R4 is methyl.
1.100 A compound according to Embodiment 1.97 wherein R4 is —CH2OH.
1.101 A compound according to any one of Embodiments 0.1 to 1.100 wherein R3 is hydrogen.
1.102 A compound according to any one of Embodiments 0.1 to 1.100 wherein R3 is a group L1-R7; and L1 is selected from a bond; Alk2, Alk2-O and Alk2-C(═O) wherein Alk2 is a C1-4 straight chain or branched alkylene group which is optionally substituted with one or more hydroxy or fluorine substituents.
1.103 A compound according to Embodiment 1.102 wherein L1 is a bond.
1.104 A compound according to Embodiment 1.102 wherein L1 is a group Alk2.
1.105 A compound according to Embodiment 1.102 wherein L1 is a group Alk2-.
1.106 A compound according to Embodiment 1.102 wherein L is Alk2-C(═O).
1.106A A compound according to any one of Embodiments 0.1 to 1.102 and 1.104 to 1.106 wherein Alk2 is selected from a C1-4 straight chain or branched alkylene group optionally substituted with one or more hydroxyl substituents.
1.107 A compound according to any one of Embodiments 0.1 to 1.102 and 1.104 to 1.106 wherein Alk2 is selected from a C1-4 straight chain or branched alkylene group.
1.107A A compound according to Embodiment 1.106A wherein Alk2 is selected from a C1-3 straight or branched alkylene group optionally substituted with one or more hydroxyl substituents.
1.108 A compound according to Embodiment 1.107 wherein Alk2 is selected from a C1-3 straight chain or branched alkylene group.
1.108A A compound according to Embodiment 1.107A wherein Alk2 is selected from CH2, CH(CH3), CH(CH2OH) and CH(CH2CH3), 1.109 A compound according to Embodiment 1.108 wherein Alk2 is selected from CH2, CH2CH2, CH(CH3) and C(CH3)2.
1.109A A compound according to Embodiment 1.109 wherein Alk2 is selected from CH2 and CH(CH3).
1.110 A compound according to Embodiment 1.109 wherein Alk2 is CH2.
1.110A A compound according to Embodiment 1.109 wherein Alk2 is CH(CH3).
1.110B A compound according to Embodiment 1.108A wherein Alk2 is CH(CH2OH).
1.111 A compound according to any one of Embodiments 1.106 to 1.110 having the general formula (6):

or a pharmaceutically acceptable salt or tautomer thereof.
1.111A A compound according to Embodiment 1.111 having the structure (6A):

1.111B A compound according to Embodiment 1.111 having the structure (6B):

1.112 A compound according to Embodiment 1.111 having the general formula (7):

or a pharmaceutically acceptable salt or tautomer thereof.
1.112A A compound according to Embodiment 1.112 having the formula (7A):

1.112B A compound according to Embodiment 1.112 having the formula (7B):

1.112C A compound according to any one of Embodiments 1.111 to 1.112B wherein the moiety:
has the structure:
where Alk2a ia the residue of Alk2.
1.112D A compound according to any one of Embodiments 1.111 to 1.112B wherein the moiety:
has the structure:
where Alk2a ia the residue of Alk2.
1.112E A compound according to Embodiment 1.112C or 1.112D wherein Alk2a is selected from hydrogen and C1-3 alkyl optionally substituted with hydroxy.
1.112F A compound according to Embodiment 1.112E wherein Alk2a is selected from hydrogen and methyl.
1.112G A compound according to Embodiment 1.112F wherein Alk2a is hydrogen.
1.112H A compound according to Embodiment 1.112E wherein Alk2a is methyl.
1.113 A compound according to any one of Embodiments 0.1 to 1.100 and 1.102 to 1.112H wherein R7 is selected from:                NR8R9;        a carbocyclic or heterocyclic group having from 3 to 12 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidised forms of S, wherein the carbocyclic or heterocyclic group is attached through a carbon ring member thereof to L1, and wherein the carbocyclic or heterocyclic group is optionally substituted with one or more substituents R10; and        an acyclic C1-3 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; cyano; carboxy; amino; mono- or di-C1-4 alkylamino; and carbocyclic and heterocyclic groups having from 3 to 12 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R10; wherein one or two but not all of the carbon atoms of the acyclic C1-3 hydrocarbon group may optionally be replaced by O, S, SO, SO2 or NR11.
1.114 A compound according to Embodiment 1.113 wherein R7 is a carbocyclic or heterocyclic group having from 3 to 12 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidised forms of S, wherein the carbocyclic or heterocyclic group is attached through a carbon ring member thereof to L1, and wherein the carbocyclic or heterocyclic group is optionally substituted with one or more substituents R10.
1.115 A compound according to Embodiment 1.114 wherein R7 is a monocyclic carbocyclic or heterocyclic group having from 3 to 7 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidised forms of S, wherein the carbocyclic or heterocyclic group is attached through a carbon ring member thereof to L1, and wherein the carbocyclic or heterocyclic group is optionally substituted with one or more substituents R10.
1.116 A compound according to Embodiment 1.115 wherein R7 is a monocyclic carbocyclic or heterocyclic group selected from:                C3-6 cycloalkyl groups;        phenyl groups;        4-7 membered non-aromatic heterocyclic groups containing 1, 2 or 3 heteroatom ring members selected from O, N and S and oxidised forms of S; and        5-6 membered heteroaryl groups containing 1, 2 or 3 heteroatom ring members selected from O, N and S;        each of the monocyclic carbocyclic and heterocyclic groups being optionally substituted with one or more substituents R10.
1.117 A compound according to Embodiment 1.116 wherein R7 is a monocyclic carbocyclic or heterocyclic group selected from:                C3-6 cycloalkyl groups;        phenyl groups;        4-7 membered non-aromatic heterocyclic groups containing 1, 2 or 3 heteroatom ring members selected from O, N and S and oxidised forms of S; and        5-6 membered heteroaryl groups containing 1, 2 or 3 heteroatom ring members selected from O, N and S;        each of the monocyclic carbocyclic and heterocyclic groups being optionally substituted with one or more substituents R10.
1.118 A compound according to Embodiment 1.117 wherein R7 is a monocyclic carbocyclic or heterocyclic group selected from:                C3-6 cycloalkyl groups;        4-6 membered non-aromatic heterocyclic groups containing 1, 2 or 3 heteroatom ring members selected from O, N and S and oxidised forms of S; and        5 membered heteroaryl groups containing 1, 2 or 3 heteroatom ring members selected from O, N and S;        each of the monocyclic carbocyclic and heterocyclic groups being optionally substituted with one or more substituents R10.
1.119 A compound according to Embodiment 1.118 wherein R7 is a monocyclic carbocyclic or heterocyclic group selected from:                C3-5 cycloalkyl groups;        4-6 membered non-aromatic heterocyclic groups containing 1, 2 or 3 heteroatom ring members selected from O, N and S and oxidised forms of S; and        5 membered heteroaryl groups containing 1, 2 or 3 heteroatom ring members selected from O and N;        each of the monocyclic carbocyclic and heterocyclic groups being optionally substituted with one or more substituents R10.
1.120 A compound according to Embodiment 1.119 wherein R7 is a monocyclic carbocyclic or heterocyclic group selected from cyclopropyl; cyclopentane; oxetane; tetrahydrofuran; pyrrolidine; pyrrolidone; piperidone; isoxazole; oxadiazole and triazole; each of the monocyclic carbocyclic and heterocyclic groups being optionally substituted with one or more substituents R10.
1.121 A compound according to Embodiment 1.113 wherein R7 is an acyclic C1-3 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; cyano; carboxy; amino; mono- or di-C1-4 alkylamino; and carbocyclic and heterocyclic groups having from 3 to 12 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R10; wherein one or two but not all of the carbon atoms of the acyclic C1-3 hydrocarbon group may optionally be replaced by O, S, SO, SO2 or NR11.
1.122 A compound according to Embodiment 1.121 wherein R7 is an acyclic C1-4 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; amino; mono- or di-C1-4 alkylamino; and carbocyclic and heterocyclic groups having from 3 to 7 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R10; wherein one but not all of the carbon atoms of the acyclic C1-4 hydrocarbon group may optionally be replaced by O, S, SO, SO2 or NR11.
1.123 A compound according to Embodiment 1.122 wherein R7 is an acyclic C1-4 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; oxo; fluorine; amino; mono- or di-C1-4 alkylamino; and carbocyclic and heterocyclic groups having from 3 to 7 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R10; wherein one but not all of the carbon atoms of the acyclic C1-4 hydrocarbon group may optionally be replaced by O or NR11.
1.124 A compound according to Embodiment 1.123 wherein R1 is an acyclic C1-4 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; amino; mono- or di-C1-4 alkylamino; and carbocyclic and heterocyclic groups having from 3 to 6 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O and N, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R10; wherein one but not all of the carbon atoms of the acyclic C1-4 hydrocarbon group may optionally be replaced by O or NR11.
1.125 A compound according to Embodiment 1.123 wherein R7 is an acyclic C1-4 hydrocarbon group; wherein one but not all of the carbon atoms of the acyclic C1-4 hydrocarbon group may optionally be replaced by O.
1.126 A compound according to Embodiment 1.113 wherein R7 is a group NR8R9.
1.127 A compound according to Embodiment 1.1.26 wherein R3 is selected from hydrogen; C1-4 alkyl; cyclobutyl; cyclopropylmethyl and hydroxy-C2-4-alkyl.
1.128 A compound according to Embodiment 1.127 wherein R3 is selected from hydrogen; methyl; ethyl; propyl; isopropyl; cyclopropyl; hydroxyethyl; and hydroxypropyl.
1.129 A compound according to Embodiment 1.128 wherein R8 is selected from hydrogen; methyl; ethyl; and hydroxyethyl.
1.130 A compound according to Embodiment 1.129 wherein R8 is selected from hydrogen and methyl.
1.131 A compound according to Embodiment 1.130 wherein R8 is hydrogen.
1.132 A compound according to Embodiment 1.130 wherein R8 is methyl.
1.133 A compound according to anyone of Embodiments 1.126 to 1.131 wherein R9 is selected from:                hydrogen;        a carbocyclic or heterocyclic group having from 3 to 10 ring members, of which 0, 1 or 2 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R10; and        an acyclic C1-3 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; carboxy; amino; mono- or di-C1-4 alkylamino; and        carbocyclic and heterocyclic groups having from 3 to 10 ring members, of which 0, 1 or 2 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R1; wherein one or two but not all of the carbon atoms of the acyclic C1-8 hydrocarbon group may optionally be replaced by 0, S, SO2 or NR11.
1.133A A compound according to Embodiment 1.133 wherein R9 is an acyclic C1-8 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; and carbocyclic and heterocyclic groups having from 3 to 10 ring members, of which 0, 1 or 2 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R10;
wherein one or two but not all of the carbon atoms of the acyclic C1-3 hydrocarbon group may optionally be replaced by 0, S, SO2 or NR11.
1.133B A compound according to Embodiment 1.133A wherein R9 is an acyclic C1-8 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; and carbocyclic and heterocyclic groups having from 3 to 10 ring members, of which 0, 1 or 2 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R10.
1.133C A compound according to Embodiment 1.133B wherein R9 is an acyclic C1-3 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; and carbocyclic and heterocyclic groups having from 3 to 10 ring members, of which 0, 1 or 2 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R10.
1.134 A compound according to Embodiment 1.131 or Embodiment 1.132 wherein R9 is selected from:                hydrogen;        a carbocyclic or heterocyclic group having from 3 to 10 ring members, of which 0, 1 or 2 are heteroatom ring members selected from O and N, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R10; and        an acyclic C1-3 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; carboxy; amino; mono- or di-C1-4 alkylamino; and carbocyclic and heterocyclic groups having from 3 to 10 ring members, of which 0 or 1 are heteroatom ring members selected from O and N, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R10; wherein one or two but not all of the carbon atoms of the acyclic C1-8 hydrocarbon group may optionally be replaced by O, S, SO2 or NR11.
1.135 A compound according to Embodiment 1.134 wherein R9 is selected from:                hydrogen;        a carbocyclic group having from 3 to 10 ring members, the carbocyclic group being optionally substituted with one or more substituents R10; and        a heterocyclic group having from 4 to 10 ring members, of which 1 or 2 are heteroatom ring members selected from O and N, the heterocyclic group being optionally substituted with one or more substituents R10; and        an acyclic C1-8 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; carboxy; amino; mono- or di-C1-4 alkylamino; and carbocyclic and heterocyclic groups having from 3 to 10 ring members, of which 0 or 1 are heteroatom ring members selected from O and N, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R10; wherein one or two but not all of the carbon atoms of the acyclic C1-8 hydrocarbon group may optionally be replaced by 0, S, SO2 or NR11.
1.136 A compound according to Embodiment 1.135 wherein R9 is selected from:                hydrogen;        a carbocyclic group having from 3 to 10 ring members, the carbocyclic group being optionally substituted with one or more substituents R10;        a heterocyclic group having from 4 to 10 ring members, of which 1 or 2 are heteroatom ring members selected from O and N, the heterocyclic group being optionally substituted with one or more substituents R10; and        an acyclic C1-8 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; carboxy; amino; mono- or di-C1-4 alkylamino; and carbocyclic and heterocyclic groups having from 3 to 10 ring members, of which 0 or 1 are heteroatom ring members selected from O and N, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R10; wherein one or two but not all of the carbon atoms of the acyclic C1-8 hydrocarbon group may optionally be replaced by O, S, SO2 or NR11.
1.137 A compound according to Embodiment 1.136 wherein R9 is selected from:                hydrogen;        a monocyclic carbocyclic group having from 3 to 6 ring members, the monocyclic carbocyclic group being optionally substituted with one or more substituents R10;        a bicyclic carbocyclic group having from 7 to 10 ring members, the bicyclic carbocyclic group being optionally substituted with one or more substituents R10;        a monocyclic heterocyclic group having from 4 to 7 ring members, of which 1 is a heteroatom ring member selected from O and N, the heterocyclic group being optionally substituted with one or more substituents R10; and        an acyclic C1-8 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; amino; mono- or di-C1-4 alkylamino; and carbocyclic and heterocyclic groups having from 3 to 10 ring members, of which 0 or 1 are heteroatom ring members selected from O and N, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R10; wherein one or two but not all of the carbon atoms of the acyclic C1-8 hydrocarbon group may optionally be replaced by O, S, SO2 or NR11.
1.138 A compound according to Embodiment 1.137 wherein R9 is selected from:                hydrogen;        a monocyclic non-aromatic carbocyclic group having from 3 to 6 ring members, the monocyclic non-aromatic carbocyclic group being optionally substituted with one or more substituents R10;        a bicyclic carbocyclic group having from 7 to 10 ring members, the bicyclic carbocyclic group being non-aromatic or containing no more than one aromatic ring; the bicyclic carbocyclic group being optionally substituted with one or more substituents R10;        a monocyclic heterocyclic group having from 4 to 7 ring members, of which 1 is a heteroatom ring member selected from O and N, the heterocyclic group being optionally substituted with one or more substituents R10; and        an acyclic C1-8 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; amino; mono- or di-C1-4 alkylamino; and carbocyclic and heterocyclic groups having from 3 to 10 ring members, of which 0 or 1 are heteroatom ring members selected from O and N, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R10; wherein one or two but not all of the carbon atoms of the acyclic C1-8 hydrocarbon group may optionally be replaced by O, S, SO2 or NR11.
1.138A A compound according to Embodiment 1.138 wherein R9 is an acyclic C1-8 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; and carbocyclic and heterocyclic groups having from 3 to 10 ring members, of which 0 or 1 are heteroatom ring members selected from O and N, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R10; wherein one or two but not all of the carbon atoms of the acyclic C1-3 hydrocarbon group may optionally be replaced by O, S, SO2 or NR11.
1.138B A compound according to Embodiment 1.138A wherein R9 is an acyclic C1-3 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; and carbocyclic and heterocyclic groups having from 3 to 10 ring members, of which 0 or 1 are heteroatom ring members selected from O and N, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R10.
1.138C A compound according to Embodiment 1.138B wherein R9 is an acyclic C1-3 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; and carbocyclic and heterocyclic groups having from 3 to 10 ring members, of which 0 or 1 are heteroatom ring members selected from O and N, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R10.
1.139 A compound according to Embodiment 1.138 wherein R9 is selected from:                hydrogen;        a monocyclic saturated carbocyclic group having from 3 to 6 ring members, the monocyclic saturated carbocyclic group being optionally substituted with one or more substituents R10;        a bicyclic carbocyclic group having from 9 or 10 ring members, the bicyclic carbocyclic group containing an aromatic ring and a non-aromatic ring; the bicyclic carbocyclic group being optionally substituted with one or more substituents R10;        a monocyclic heterocyclic group having from 4 to 6 ring members, of which 1 is a heteroatom ring member selected from 0, the heterocyclic group being optionally substituted with one or more substituents R10; and        an acyclic saturated C1-3 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; halogen; amino; mono- or di-C1-4 alkylamino; phenyl; and monocyclic heterocyclic groups having from 4 to 6 ring members, of which 1 is a heteroatom ring member selected from O and N, the phenyl or heterocyclic group being optionally substituted with one or more substituents R10; wherein one but not all of the carbon atoms of the acyclic C1-3 hydrocarbon group may optionally be replaced by 0, S, SO2 or NR11.
1.139A A compound according to Embodiment 1.139 wherein R9 is an acyclic saturated C1-3 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; phenyl; and monocyclic heterocyclic groups having from 4 to 6 ring members, of which 1 is a heteroatom ring member selected from O and N, the phenyl or heterocyclic group being optionally substituted with one or more substituents R10; wherein one but not all of the carbon atoms of the acyclic C1-8 hydrocarbon group may optionally be replaced by O, S, SO2 or NR11.
1.139B A compound according to Embodiment 1.139A wherein R9 is an acyclic saturated C1-3 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; phenyl; and monocyclic heterocyclic groups having from 4 to 6 ring members, of which 1 is a heteroatom ring member selected from O and N, the phenyl or heterocyclic group being optionally substituted with one or more substituents R10.
1.139C A compound according to Embodiment 1.139B wherein R9 is an acyclic saturated C1-3 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; phenyl; and pyridyl, the phenyl or pyridyl group being optionally substituted with one or more substituents R10.
1.139D A compound according to Embodiment 1.139C wherein R9 is an acyclic saturated C1-3 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; and phenyl, the phenyl group being optionally substituted with one or more substituents R10.
1.139E A compound according to Embodiment 1.139C wherein R9 is an acyclic saturated C1-3 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; and phenyl, the phenyl group being optionally substituted with one or more substituents R10 wherein R10 is selected from: fluorine; chlorine; hydroxy; oxo; cyano; and OR12 wherein R12 is methyl, ethyl, propyl, iso-propyl or cyclopropyl, each being optionally substituted with fluorine.
1.139F A compound according to Embodiment 1.139C wherein R9 is an acyclic saturated C1-3 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; and phenyl, the phenyl group being optionally substituted with one or two substituents R10 wherein R10 is selected from: fluorine and OR12 wherein R12 is methyl, ethyl, propyl, iso-propyl or cyclopropyl, each being optionally substituted with fluorine.
1.139G A compound according to Embodiment 1.139C wherein R9 is an acyclic saturated C1-3 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; and phenyl, the phenyl group being optionally substituted with one or two substituents R10 wherein R10 is selected from: fluorine and OR12 wherein R12 is methyl, ethyl, propyl, iso-propyl or cyclopropyl, each being unsubstituted.
1.139H A compound according to Embodiment 1.139C wherein R9 is an acyclic saturated C1-3 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; and phenyl, the phenyl group being optionally substituted with one or two substituents R10 wherein R10 is selected from: fluorine and OR12 wherein R12 is unsubstituted methyl.
1.139J A compound according to any one of Embodiments 1.133 to 1.139H wherein R9 is an acyclic saturated hydrocarbon group substituted with a carbocyclic or heterocyclic group and optionally a hydroxyl group, wherein the acyclic saturated hydrocarbon group has the structure:

wherein R15 is C1-3 alkyl or hydroxy-C1-3 alkyl; "a" denotes the point of attachment to the carbocyclic or heterocyclic group and "b" denotes the point of attachment to the nitrogen atom of NR8R9.
1.139K A compound according to any one of Embodiments 1.133 to 1.139H wherein R9 is an acyclic saturated hydrocarbon group substituted with a carbocyclic or heterocyclic group and optionally a hydroxyl group, wherein the acyclic saturated hydrocarbon group has the structure:

wherein R15 is C1-3 alkyl or hydroxy-C1-3 alkyl; "a" denotes the point of attachment to the carbocyclic or heterocyclic group and "b" denotes the point of attachment to the nitrogen atom of NR8R9.
1.140 A compound according to Embodiment 1.139 wherein R9 is selected from:                hydrogen;        cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups each being optionally substituted with one or more substituents R10;        indane and tetrahydronaphathalene, each being optionally substituted with one or more substituents R10;        oxetane and oxanyl, each being optionally substituted with one or more substituents R10; and        an acyclic saturated C1-6 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; halogen; amino; mono- or di-C1-4 alkylamino; phenyl; and oxetane; the phenyl or oxetane group being optionally substituted with one or more substituents R10.
1.140A A compound according to any one of Embodiments 0.1 to 1.132 wherein R9 is selected from groups HA to SX in Table 3 below, where * marks the point of connection to the N atom.

1.140B A compound according to Embodiment 1.140A wherein R9 is selected from groups IH, KQ, NG and NP in Table 3, where * marks the point of connection to the N atom.
1.140C A compound according to Embodiment 1.140A wherein R9 is selected from groups SV, SW and SX in Table 3, where * marks the point of connection to the N atom.
1.140D A compound according to Embodiment 1.140B wherein R9 is group NG in Table 3, where * marks the point of connection to the N atom.
1.140E A compound according to Embodiment 1.140B wherein R9 is group SW in Table 3, where * marks the point of connection to the N atom.
1.141 A compound according to Embodiment 1.126 wherein NR8R9 forms a heterocyclic group having from 4 to 12 ring members wherein, in addition to the nitrogen atom of NR8R9, the heterocyclic group optionally contains 1 or 2 further heteroatom ring members selected from O, N and S and oxidised forms of S; and wherein the heterocyclic group is optionally substituted with one or more substituents R10.
1.142 A compound according to Embodiment 1.141 wherein NR8R9 forms a heterocyclic group having from 4 to 11 ring members wherein, in addition to the nitrogen atom of NR8R9, the heterocyclic group optionally contains 1 or 2 further heteroatom ring members selected from O and N; and wherein the heterocyclic group is optionally substituted with one or more substituents R10.
1.143 A compound according to Embodiment 1.142 wherein NR8R9 forms a heterocyclic group selected from:                monocyclic heterocyclic groups having from 4 to 7 ring members wherein, in addition to the nitrogen atom of NR8R9, the heterocyclic group optionally contains 1 or 2 further heteroatom ring members selected from O and N; and wherein the heterocyclic group is optionally substituted with one or more substituents R10;        non-aromatic bicyclic heterocyclic groups having from 7 to 10 ring members wherein, in addition to the nitrogen atom of NR8R9, the heterocyclic group optionally contains 1 or 2 further heteroatom ring members selected from O and N; and wherein the heterocyclic group is optionally substituted with one or more substituents R10; and        bicyclic heterocyclic groups having from 7 to 11 ring members, one ring of the bicyclic heterocyclic group being aromatic and the other ring being non-aromatic; wherein, in addition to the nitrogen atom of NR8R9, the heterocyclic group optionally contains 1 or 2 further heteroatom ring members selected from O and N; and wherein the heterocyclic group is optionally substituted with one or more substituents R10.
1.144 A compound according to Embodiment 1.143 wherein NR8R9 forms a heterocyclic group selected from:                monocyclic heterocyclic groups having from 4 to 7 ring members wherein, in addition to the nitrogen atom of NR8R9, the heterocyclic group optionally contains 1 or 2 further heteroatom ring members selected from O and N; and wherein the heterocyclic group is optionally substituted with one or more substituents R10.
1.145 A compound according to Embodiment 1.143 or Embodiment 1.144 wherein the monocyclic heterocyclic group is non-aromatic.
1.146 A compound according to Embodiment 1.145 wherein the monocyclic heterocyclic group is selected from azetidine, pyrrolidine, piperidine, azepane, morpholine and piperazine, the heterocyclic group being optionally substituted with one or more substituents R10.
1.147 A compound according to Embodiment 1.143 wherein NR8R9 forms a heterocyclic group selected from:                non-aromatic bicyclic heterocyclic groups having from 7 to 10 ring members wherein, in addition to the nitrogen atom of NR8R9, the heterocyclic group optionally contains 1 or 2 further heteroatom ring members selected from O and N; and wherein the heterocyclic group is optionally substituted with one or more substituents R10.
1.148 A compound according to Embodiment 1.147 wherein NR8R9 forms a heterocyclic group selected from:                non-aromatic fused bicyclic, spirobicyclic and bridge bicyclic heterocyclic groups having from 7 to 10 ring members wherein, in addition to the nitrogen atom of NR8R9, the heterocyclic group optionally contains 1 further heteroatom ring members selected from O and N; and wherein the heterocyclic group is optionally substituted with one or more substituents R10.
1.149 A compound according to Embodiment 1.148 wherein NR8R9 forms a heterocyclic group selected from:                non-aromatic fused bicyclic, spirobicyclic and bridge bicyclic heterocyclic groups having from 7 to 10 ring members wherein, in addition to the nitrogen atom of NR8R9, the heterocyclic group optionally contains no further heteroatom ring members; and wherein the heterocyclic group is optionally substituted with one or more substituents R10.
1.150 A compound according to Embodiment 1.149 wherein NR8R9 forms a non-aromatic heterocyclic group selected from 5.5 fused bicyclic heterocyclic rings; 5.6 fused bicyclic heterocyclic rings; spirocyclopropylpiperidine; azabicyclo-heptanes; and azabicyclooctanes; and
wherein the heterocyclic group is optionally substituted with one or more substituents R10.
1.151 A compound according to Embodiment 1.141 wherein NR8R9 forms a heterocyclic group selected from:                fused bicyclic heterocyclic groups having from 7 to 11 ring members, one ring of the fused bicyclic heterocyclic group being aromatic and the other ring being non-aromatic;
wherein, in addition to the nitrogen atom of NR8R9, the heterocyclic group optionally contains 1 or 2 further heteroatom ring members selected from O and N; and wherein the heterocyclic group is optionally substituted with one or more substituents R10.
1.151A A compound according to Embodiment 1.141 wherein NR8R9 forms a heterocyclic group selected from:                fused bicyclic heterocyclic groups having from 7 to 12 ring members, one ring of the fused bicyclic heterocyclic group being aromatic and the other ring being non-aromatic; wherein, in addition to the nitrogen atom of NR8R9, the heterocyclic group optionally contains 1 or 2 further heteroatom ring members selected from O and N; and wherein the heterocyclic group is optionally substituted with one or more substituents R10.
1.152 A compound according to Embodiment 1.151 or Embodiment 1.51A wherein the aromatic ring of the fused bicyclic heterocyclic ring is a 5 or 6 membered ring containing 0, 1 or 2 heteroatom ring members selected from N and O.
1.153 A compound according to Embodiment 1.152 wherein the aromatic ring of the fused bicyclic heterocyclic ring is a 5 or 6 membered ring containing 0, 1 or 2 nitrogen ring members; for example wherein the aromatic ring is selected from benzene, pyrrole, pyridine and pyrimidine rings.
1.154 A compound according to any one of Embodiments 1.151 to 1.153 wherein the non-aromatic ring is selected from 5, 6 and 7-membered rings and bridged bicyclic rings, provided that the total number of ring members in the heterocyclic group does not exceed 11.
1.154 A compound according to any one of Embodiments 1.151 to 1.153 wherein the non-aromatic ring is selected from 5, 6 and 7-membered rings, provided that the total number of ring members in the heterocyclic group does not exceed 11.
1.155 A compound according to any one of Embodiments 1.151 to 1.154 wherein the nitrogen atom of NR8R9 is located in the non-aromatic ring.
1.156 A compound according to any one of Embodiments 1.151 to 1.154 wherein the non-aromatic ring is selected from 5, 6 and 7-membered rings containing a single nitrogen heteroatom ring member and 6- and 7-membered rings containing one nitrogen and one oxygen heteroatom ring member.
1.157 A compound according to Embodiment 1.151 wherein NR8R9 forms a heterocyclic group selected from tetrahydroisoquinoline; tetrahydroquinoline; dihydroindole; dihydroisoindole; tetrahydrobenzazepine; pyrimidinopiperidine; benzomorpholine and benzo-homomorpholine; and wherein the heterocyclic group is optionally substituted with one or more substituents R10.
1.157AA compound according to Embodiment 1.141 wherein NR8R9 forms a heterocyclic group selected from tetrahydroisoquinoline; tetrahydroquinoline; tetrahydronapthyridine; dihydroindole; dihydroisoindole; tetrahydrobenzazepine; pyrimidinopiperidine; benzomorpholine; benzo-homomorpholine; azatricyclododecatrienyl; and tetrahydro-oxopyrimidoazepine wherein the heterocyclic group is optionally substituted with one or more substituents R10.
1.158 A compound according to Embodiment 1.157 wherein NR8R9 forms a heterocyclic group selected from tetrahydroisoquinoline and tetrahydrobenzazepine; and wherein the heterocyclic group is optionally substituted with one or more substituents R10.
1.159 A compound according to Embodiment 1.158 wherein NR8R9 forms a tetrahydroisoquinoline group which is optionally substituted with one or more substituents R10.
1.160 A compound according to Embodiment 1.158 wherein NR8R9 forms a tetrahydrobenzazepine group which is optionally substituted with one or more substituents R10.
1.161 A compound according to anyone of Embodiments 1.126 to 1.160 having the formula (8):

or a pharmaceutically acceptable salt or tautomer thereof, wherein R1, R4, R8, R9, Alk2 and Z are as defined in any of the preceding Embodiments.
1.161A A compound according to Embodiment 1.161 wherein the compound has the structure (8A):

1.161B A compound according to Embodiment 1.161 wherein the compound has the structure (8B):

1.162 A compound according to anyone of Embodiments 1.126 to 1.160 having the formula (9):

or a pharmaceutically acceptable salt or tautomer thereof, wherein R4, R6, R8, R9, Alk2, Z and v are as defined in any of the preceding Embodiments.
1.162A A compound according to Embodiment 1.162 wherein the compound has the structure (9A):

1.162B A compound according to Embodiment 1.162 wherein the compound has the structure (9B):

1.162C A compound according to any one of Embodiments 1.161 to 1.162B wherein the moiety:
has the structure:
where Alk2a ia the residue of Alk2.
1.162D A compound according to any one of Embodiments 1.161 to 1.162B wherein the moiety:

has the structure:
where Alk2a ia the residue of Alk2.
1.163 A compound according to any one of Embodiments 0.1 to 1.100 and 1.102 to 1.162D wherein R10 is selected from:                halogen; hydroxy; oxo; cyano;        OR12 wherein R12 is C1-6 alkyl or C3-6 cycloalkyl, each being optionally substituted with halogen;        an acyclic C1-8 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; cyano; carboxy; amino; mono- or di-C1-4 alkylamino; and carbocyclic and heterocyclic groups having 3 to 6 ring members of which 0, 1 or 2 are heteroatom ring members selected from N, O and S, wherein the carbocyclic and heterocyclic groups are optionally substituted with one or more substituents R13 selected from hydroxy; halogen; cyano; and —(O)v-Hyd1 where v is 0 or 1; wherein one or two but not all of the carbon atoms of the acyclic C1-8 hydrocarbon group may optionally be replaced by O, S, SO, SO2 or NR11; and        carbocyclic and heterocyclic groups having 3 to 6 ring members of which 0, 1 or 2 are heteroatom ring members selected from N, O and S, wherein the carbocyclic and heterocyclic groups are optionally substituted with one or more substituents R13; and
R11 is selected from hydrogen and a C1-4 hydrocarbon group.
1.164 A compound according to Embodiment 1.163 wherein R10 is selected from:                halogen; hydroxy; oxo; cyano;        OR12 wherein R12 is C1-6 alkyl or C3-6 cycloalkyl, each being optionally substituted with halogen;        an acyclic C1-8 hydrocarbon group (e.g. an alkyl, alkenyl or alkynyl group) optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; cyano; carboxy; amino; mono- or di-C1-4 alkylamino; wherein one or two but not all of the carbon atoms of the acyclic C1-8 hydrocarbon group may optionally be replaced by O, S, SO, SO2 or NR11; and        aryl and heteroaryl groups having 5 or 6 ring members of which 0, 1 or 2 are heteroatom ring members selected from N, O and S, wherein the aryl and heteroaryl groups are optionally substituted with one or more substituents selected from hydroxy; halogen; halogen; cyano; and —(O)v-Hyd1 where v is 0 or 1; and
R11 is selected from hydrogen and a C1-4 hydrocarbon group (e.g. an alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl or cycloalkyl group).
1.165 A compound according to Embodiment 1.164 wherein R10 is selected from:                fluorine; chlorine; hydroxy; oxo; cyano; methoxy; ethoxy; trifluoromethoxy; difluoromethoxy;        an acyclic C1-6 hydrocarbon group (e.g. an alkyl, alkenyl or alkynyl group) optionally substituted with one or more substituents selected from hydroxy; oxo; fluorine; amino; mono- or di-C1-2 alkylamino; wherein one but not all of the carbon atoms of the acyclic C1-6 hydrocarbon group may optionally be replaced by O, SO2 or NR11; and        aryl and heteroaryl groups having 5 or 6 ring members of which 0, 1 or 2 are heteroatom ring members selected from N, O and S, wherein the aryl and heteroaryl groups are optionally substituted with one or more substituents selected from hydroxy; fluorine; chlorine; and —(O)v-Hyd1 where v is 0 or 1; and
R11 is selected from hydrogen and a C1-2 alkyl group.
1.166 A compound according to Embodiment 1.165 wherein R10 is selected from:                fluorine; chlorine; hydroxy; oxo; cyano; methoxy; ethoxy; trifluoromethoxy; difluoromethoxy;        a C1-4 hydrocarbon group (e.g. an alkyl, alkenyl, alkynyl, cyclopropyl, methylcyclopropyl or cyclopropylmethyl group) optionally substituted with one or more substituents selected from hydroxy; oxo; fluorine; amino; mono- or di-C1-2 alkylamino; wherein one but not all of the carbon atoms of the C1-4 alkyl group may optionally be replaced by O;        phenyl optionally substituted with one or more substituents selected from hydroxy; fluorine; chlorine; and —(O)v-Hyd1 where v is 0 or 1;        heteroaryl groups having 5 or 6 ring members of which 1 or 2 are heteroatom ring members selected from N, O and S, wherein the heteroaryl groups are optionally substituted with one or more substituents selected from hydroxy; fluorine; chlorine; and —(O)v-Hyd1 where v is 0 or 1.
1.167 A compound according to Embodiment 1.166 wherein R10 is selected from:                fluorine; chlorine; hydroxy; oxo; cyano; methoxy; ethoxy; trifluoromethoxy; difluoromethoxy;        a saturated C1-4 hydrocarbon group (e.g. C1-4 alkyl, cyclopropyl, cyclobutyl, cyclopropylmethyl or methylcyclopropyl) optionally substituted with one or more substituents selected from hydroxy and fluorine; wherein one but not all of the carbon atoms of the C1-4 hydrocarbon group may optionally be replaced by O;        phenyl optionally substituted with one or more substituents selected from hydroxy; fluorine; chlorine; and —(O)v-Hyd1 where v is 0 or 1;        heteroaryl groups having 5 or 6 ring members of which 1 or 2 are heteroatom ring members selected from N, O and S, wherein the heteroaryl groups are optionally substituted with one or more substituents selected from hydroxy; fluorine; chlorine; and —(O)v-Hyd1 where v is 0 or 1.
1.168 A compound according to Embodiment 1.167 wherein R10 is selected from:                fluorine; chlorine; hydroxy; oxo; cyano; methoxy; ethoxy; trifluoromethoxy; difluoromethoxy;        a saturated C1-4 hydrocarbon group (e.g. C1-4 alkyl, cyclopropyl, cyclobutyl, cyclopropylmethyl or methylcyclopropyl) optionally substituted with one or more substituents selected from hydroxy and fluorine; wherein one but not all of the carbon atoms of the C1-4 hydrocarbon group may optionally be replaced by O;        phenyl optionally substituted with one or more substituents selected from hydroxy; fluorine; chlorine; and —(O)v-Hyd1 where v is 0 or 1;        heteroaryl groups having 5 ring members of which 1 or 2 are heteroatom ring members selected from N, O and S, wherein the heteroaryl groups are optionally substituted with one or more substituents selected from —(O)v-Hyd1 where v is 0.
1.169 A compound according to Embodiment 1.168 wherein R10 is selected from oxo; fluorine; chlorine; cyano; methyl; ethyl; isopropyl; tert-butyl; hydroxymethyl; trifluoromethyl; methoxy; trifluoromethoxy; difluoromethoxy; phenyl; and thiazolyl.
1.169A A compound according to Embodiment 1.163 wherein R10 is selected from fluorine, methyl, methoxy and dimethylamino.
1.169B A compound according to any one of Embodiments 0.1 to 1.100 and 1.102 to 1.169 wherein there are 0, 1, 2, 3 or 4 substituents R10 present in R7.
1.169C A compound according to any one of Embodiments 0.1 to 1.100 and 1.102 to 1.169 wherein there are 0, 1, 2 or 3 substituents R10 present in R7.
1.169D A compound according to any one of Embodiments 0.1 to 1.100 and 1.102 to 1.169 wherein there are 0, 1 or 2 substituents R10 present in R7.
1.169E A compound according to any one of Embodiments 0.1 to 1.100 and 1.102 to 1.169 wherein there are 1 or 2 substituents R10 present in R7.
1.169F A compound according to any one of Embodiments 0.1 to 1.100 and 1.102 to 1.169 wherein there are 0 substituents R10 present in R7.
1.169G A compound according to any one of Embodiments 0.1 to 1.100 and 1.102 to 1.169 wherein there is 1 substituent R10 present in R7.
1.169H A compound according to any one of Embodiments 0.1 to 1.100 and 1.102 to 1.169 wherein there are 2 substituents R10 present in R7.
1.169J A compound of formula (0):

or a pharmaceutically acceptable salt, N-oxide or tautomer thereof; wherein:
n is 1 or 2;
X is CH or N;
Y is selected from CH and C—F;
Z is selected from C—Rz and N;
Rz is selected from hydrogen; fluorine; methoxy; and C1-2 alkyl optionally substituted with hydroxy or methoxy;
R1 is selected from:                -(Alk1)t-Cyc1; wherein t is 0 or 1; and Alk1 is a methylene group; and        C1-6 acyclic hydrocarbon groups which are unsubstituted or substituted with 1, 2 or 3 substituents R5 selected from hydroxy; oxo; and cyano; and wherein 1 but not all of the carbon atoms of the hydrocarbon group can be replaced by O (for example to form an alkoxyalkyl group such as methoxyethyl or methoxypropyl;
Cyc1 is a cyclic group selected from (a) 3 to 8 membered non-aromatic monocyclic and bicyclic carbocyclic and heterocyclic groups containing 0 or 1 heteroatom ring members selected from O, N, S, S(O) and S(O)2; (b) 5 to 6 membered monocyclic heteroaryl groups containing 1, 2 or 3 heteroatom ring members of which 1 is N and the others, when present, are selected from O, N and S; and (c) phenyl; (a), (b) and (c) is unsubstituted or substituted with 1, 2 or 3 substituents R6 selected from hydroxy; oxo; fluorine; amino; N(Hyd1)2; O-Hyd1; —C(═O)-Hyd1; —C(═O)—O-Hyd1 and Hyd1; where Hyd1 is a C1-3 non-aromatic hydrocarbon group optionally substituted with one or more substituents selected from fluorine, hydroxyl and methoxy;
R2 is selected from hydrogen; fluorine, chlorine, bromine, methyl, trifluoromethyl, ethyl, 1-hydroxyethyl, cyclopropyl, iso-propyl, vinyl and allyl groups
R3 is hydrogen or a group L1-R7;
R4 is selected from hydrogen; methoxy; and C1-3 alkyl optionally substituted with hydroxy, amino, di-C1-2 alkylamino, or methoxyl;
R4a is selected from hydrogen and methyl;
L1 is selected from a bond; Alk2 and Alk2-C(═O); wherein Alk2 is a C1-4 straight chain or branched alkylene group which is optionally substituted with one or more substituents selected from hydroxy, methoxy, amino, methylamino, (dimethyl)amino and fluorine;
R7 is selected from:                hydrogen;        CO2H;        NR8R9;        a heterocyclic group having from 5 to 12 ring members, of which 1, 2 or 3 are heteroatom ring members selected from O and N, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R10; and        an acyclic C1-8 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; oxo; mono- or di-C1-4 alkylamino; and carbocyclic and heterocyclic groups having from 3 to 10 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O and N, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R10; wherein one but not all of the carbon atoms of the acyclic C1-8 hydrocarbon group may optionally be replaced by O or NR11 (for example to form a C1-4 alkoxy group such as methoxy or tert-butyloxy; or an alkoxyalkyl group such as methoxymethyl; or a group CH2O; or a group O—CH(CH3)2);
R3 is selected from hydrogen, methyl, ethyl, hydroxyethyl, aminoethyl and (dimethylamino)ethyl;
R9 is selected from:                hydrogen;        a carbocyclic or heterocyclic group having from 3 to 10 ring members, of which 0, 1 or 2 are heteroatom ring members selected from O and N and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R10; and        an acyclic C1-6 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; fluorine; mono- or di-C1-4 alkylamino; and carbocyclic and heterocyclic groups having from 3 to 11 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R10; wherein one or two but not all of the carbon atoms of the acyclic C1-6 hydrocarbon group may optionally be replaced by O (for example to give an O-ether linkage between the acyclic hydrocarbon group and an attached carbocylic group substituent; or to give an alkoxy substituent such as methoxy on the acyclic hydrocarbon group);        or NR8R9 forms a heterocyclic group having from 5 to 12 ring members wherein, in addition to the nitrogen atom of NR8R9, the heterocyclic group optionally contains 1 or 2 further heteroatom ring members selected from O and N; and wherein the heterocyclic group is optionally substituted with one or more substituents R10;
R10 is selected from:                fluorine; chlorine; hydroxy; oxo; cyano;        OR12 wherein R12 is methyl, ethyl, propyl, iso-propyl or cyclopropyl, each being optionally substituted with fluorine;        an acyclic C1-8 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; oxo; fluorine; amino; dimethylamino; and carbocyclic and heterocyclic groups having 3 to 7 ring members of which 0, 1, 2, 3 or 4 are heteroatom ring members selected from N, O and S, wherein the carbocyclic and heterocyclic groups are optionally substituted with one or more substituents R13 selected from hydroxy; halogen; —N(Hyd1)2; and —(O)v-Hyd1 where v is 0 or 1; wherein one or two but not all of the carbon atoms of the acyclic C1-8 hydrocarbon group may optionally be replaced by 0 (for example to give an alkoxy alkyl group such as methoxymethyl or ethoxymethyl; a hydroxyalkoxy group such as hydroxyethoxy; or a group C(═O)O—C1-4 alkyl such as) SO2 (for example to give a C1-3 alkyl sulphonyl group such as ethylsulphonyl), or NR11 (for example to give an alkylamino group such as methylamino, ethylamino, dimethylamino or methyl(ethyl)amino, or an alkylaminoalkyl group such as methylaminomethyl or dimethylaminomethyl; or an aminoalkoxy group such as aminoethoxy or dimethylaminoethoxy; or hydroxalkylamino group such as hydroxyethyl(methyl)amino; or an amide group such as C(═O)NH); and        carbocyclic and heterocyclic groups having 3 to 7 ring members of which 0, 1, 2, 3 or 4 are heteroatom ring members selected from N, O and S, wherein the carbocyclic and heterocyclic groups are optionally substituted with one or more substituents R13; and
R11 is selected from hydrogen and a C1-4 hydrocarbon group;
provided that the compound is other than 6-benzyl-3-{2-[(2-methylpyrimidin-4-yl)amino]pyridin-4-yl}-7,8-dihydro-1,6-naphthyridin-5(6H)-one and 3-{2-[(2-methylpyrimidin-4-yl)amino]pyridin-4-yl}-7,8-dihydro-1,6-naphthyridin-5(6H)-one and salts and tautomers thereof.
1.170 A compound according to any one of Embodiments 0.1 to 1.100 or Embodiment 1.169J wherein R3 is selected from groups BA to GBB in Table 2 below, where * marks the point of connection to the N atom.
TABLE 2
1.170A A compound according to any one of Embodiments 0.1 to 1.100 wherein R3 is selected from groups GEC to GRJ in Table 2A below.
The groupR3 inGroupExample No:GBC701GBD702GBE703GBG705GBH706GBJ707GBI708GBK709GBM711GCQ741GCR742GCS743GCT744GCU745GCV746GCW747GCX748GCY749GCZ750GDA751GDB752GDC753GDD754GDE755GDF756GDG757GDH758GDJ759GDK761GDL762GDM763GDN764GDO765GDP766GDQ767GDR768GDS769GDT770GDU771GDW773GDX774GDY775GDZ776GEA777GEB778GEC779GED780GEE781GEF782GEG783GEH784GEJ785GEI786GHW877GHX878GHY879GHZ880GIA881GIB882GIC883GID884GIE885GIF886GIG887GIH888GIJ889GII890GIK891GIL892GIM893GIN894GIO895GIP896GIQ897GIR898GIS899GIT900GIU901GIV902GIW903GIX904GIY905GIZ906GJA907GJB908GJC909GJD910GJE911GJF912GJG913GJH914GJJ915GJI916GJK917GJL918GJM919GJN920GMZ1010GNA1011GNB1012GNC1013GND1014GNE1015GNF1016GNG1017GNH1018GNJ1019GNI1020GNK1021GNL1022GNM1023GNN1024GNO1025GNP1026GNQ1027GNR1028GNS1029GNT1030GNU1031GNV1032GNW1033GNX1034GNY1035GNZ1036GOA1037GOB1038GOC1039GOD1040GOE1041GOF1042GOG1043GOH1044GOJ1045GOI1046GOK1047GBN712GBO713GBP714GBQ715GBR716GBS717GBT718GBU719GBV720GBW721GBX722GBY723GBZ724GEK787GEL788GEM789GEN790GEO791GEP792GEQ793GER794GES795GET796GEU797GEV798GEW799GEX800GEY801GEZ802GFA803GFB804GFC805GFD806GFF808GFG809GFH810GFJ811GFI812GFK813GFL814GFM815GFN816GFO817GFP818GFQ819GFR820GFS821GFT822GFU823GFV824GFW825GFX826GFY827GFZ828GGA829GGB830GGC831GJO921GJP922GJR924GJS925GJT926GJU927GJV928GJW929GJX930GJY931GJZ932GKA933GKB934GKC935GKD936GKE937GKF938GKG939GKH940GKJ941GKI942GKK943GKL944GKM945GKN946GKO947GKP948GKQ949GKR950GKS951GKT952GKU953GKV954GKW955GKX956GKY957GKZ958GLA959GLB960GLC961GLD962GLE963GLF964GLG965GOL1048GOM1049GON1050GOO1051GOP1052GOQ1053GOR1054GOS1055GOT1056GOU1057GOV1058GOW1059GOX1060GOY1061GOZ1062GPA1063GPB1064GPC1065GPD1066GPE1067GPF1068GPG1069GPH1070GPJ1071GPI1072GPK1073GPL1074GPM1075GPN1076GPO1077GPP1078GPQ1079GPR1080GPS1081GPT1082GPU1083GPV1084GPW1085GCA725GCB726GCC727GOD728GCF730GCG731GCH732GCJ733GC!734GCK735GCM737GCN738GOP740GGD832GGE833GGF834GGG835GGH836GGJ837GGI838GGK839GGL840GGM841GGN842GGO843GGP844GGR846GGS847GGT848GGU849GGV850GGW851GGX852GGY853GGZ854GHA855GHB856GHC857GHD858GHE859GHF860GHG861GHH862GHJ863GHI864GHK865GHL866GHM867GHN868GHO869GHP870GHQ871GHR872GHS873GHT874GHU875GHV876GLH966GLJ967GLI968GLK969GLL970GLM971GLN972GLO973GLP974GLQ975GLR976GLS977GLT978GLU979GLV980GLW981GLX982GLY983GLZ984GMA985GMB986GMC987GMD988GME989GMF990GMG991GMH992GMJ993GMI994GMK995GML996GMM997GMN998GMO999GMP1000GMQ1001GMR1002GMS1003GMT1004GMU1005GMV1006GMW1007GMX1008GMY1009GPX1086GPY1087GPZ1088GQA1089GQB1090GQC1091GQD1092GQE1093GQF1094GQG1095GQH1096GQJ1097GQI1098GQK1099GQL1100GQM1101GQN1102GQO1103GQP1104GQQ1105GQR1106GQS1107GQT1108GQU1109GQV1110GQW1111GQX1112GQY1113GQZ1114GRA1115GRB1116GRC1117GRD1118GRE1119GRF1120GRG1121GRH1122GRJ1123
1.170B A compound according to any one of Embodiments 0.1 to 1.100 or Embodiment 1.169J wherein R3 is selected from groups in GBC, GBD, GMH, GNF and GSA in the table below.

1.171 A compound according to Embodiment 1.170 wherein R3 is selected from groups BA to GP in Table 2.
1.172 A compound according to Embodiment 1.171 wherein R3 is selected from groups CO, DD, DZ, EC, EF, ES, GM, GN, GO and GP in Table 2.
1.172A A compound as defined in any one of Embodiments 0.1 to 1.172, with the proviso that when n is 2 and X is OCH, then Z is C—Rz.
1.172B A compound as defined in any one of Embodiments 0.1 to 1.172, with the proviso that when n is 2, then X is N.
1.172C A compound as defined in any one of Embodiments 0.1 to 1.172, with the proviso that when n is 2, Cyc1 is other than 2-methyl-pyrimidin-4-yl.
1.172D A compound as defined in any one of Embodiments 0.1 to 1.172, with the proviso that when n is 2, Cyc1 is other than methyl-pyrimidinyl.
1.172E A compound as defined in any one of Embodiments 0.1 to 1.172, with the proviso that when Z is N, then X is N.
1.172F A compound according to Embodiment 1.0 having the formula (10):

or a pharmaceutically acceptable salt or tautomer thereof, wherein,
R1 is                tetrahydropyran; or        a 6-membered heterocyclic ring selected from pyridine and pyrimidine optionally substituted with a methyl or methoxy group;
R15 is C1-3 alkyl or hydroxy-C1-3 alkyl; and
Ar1 is a benzene or pyridine ring optionally substituted with 1 or 2 substituents selected from fluorine, methoxy, dimethylamino and 4-methylpiperazine.
1.172G A compound having the formula (11):

or a salt or tautomer thereof; wherein:
R1 is                tetrahydropyran; or        a 6-membered heterocyclic ring selected from pyridine and pyrimidine optionally substituted with a methyl or methoxy group;
R15 is C1-3 alkyl or hydroxy-C1-3 alkyl;
Ar1 is a benzene or pyridine ring optionally substituted with 1 or 2 substituents selected from fluorine, methoxy, dimethylamino and 4-methylpiperazine;
R2, X, Y, Z, R4 and R4a are as defined in any one of Embodiments 0.1, 0.3, 0.4, 1.01, 1.02, 1.06, 1.2 to 1.3, 1.8 to 1.72, 1.80 to 1.88A and 1.90 to 1.100.
1.172H A compound according to Embodiment 1.172F or 1.172G wherein R1 is selected from tetrahydropyran, 2-methyoxypyridin-4-yl and 2-methylpyrimidin-4-yl.
1.172J A compound according to any one of Embodiments 1.172F, 1.172G and 1.172H wherein R15 is hydroxymethyl or methyl.
1.173 A compound according to Embodiment 1.1 which is selected from the compounds of any of Examples 1 to 196 herein, or a pharmaceutically acceptable salt thereof.
1.174 A compound according to Embodiment 1.173 which is selected from the compounds of any of Examples 2, 3, 4, 7, 11, 16, 19, 21, 22, 25, 27, 34, 35, 38, 40, 42, 48, 55, 59, 67, 72, 74, 76, 79, 80, 82, 84, 85, 86, 87, 93, 94, 95, 96, 101, 103, 137, 141, 151, 152, 188, 192, 193, 194, 195 and 196 herein, or a pharmaceutically acceptable salt thereof.
1.175 A compound according to Embodiment 1.174 which is selected from the compounds of any of Examples 40, 55, 79 and 82 or a pharmaceutically acceptable salt thereof.
1.175A A compound according to Embodiment 1.0 or Embodiment 1.1 which is selected from the compounds of any of Examples 1 to 699 herein, or a pharmaceutically acceptable salt thereof.
1.175B A compound according to Embodiment 0.1 which is selected from the compounds of Examples 2, 3, 4, 7, 11, 16, 19, 21, 22, 25, 27, 34, 35, 38, 40, 42, 48, 55, 59, 67, 72, 74, 76, 79, 80, 82, 84, 85, 86, 87, 93, 94, 95, 96, 101, 103, 137, 141, 151, 152, 188, 192, 193, 194, 195, 196, 197, 201, 207, 209, 210, 214, 219, 221, 230, 232, 234, 235, 239, 240, 241, 242, 244, 260, 261, 262, 263, 264, 265, 266, 271, 280, 282, 283, 284, 287, 289, 290, 291, 292, 294, 303, 316, 317, 318, 319, 321, 322, 323, 324, 325, 326, 327, 328, 333, 334, 335, 336, 337, 341, 342, 344, 345, 346, 347, 348, 349, 351, 352, 354, 355, 356, 357, 358, 359, 360, 365, 367, 369, 370, 371, 372, 381, 383, 384, 385, 386, 389, 390, 391, 392, 393, 395, 396, 397, 398, 399, 400, 401, 402, 406, 415, 421, 422, 423, 425, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 442, 443, 444, 445, 448, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 465, 466, 467, 469, 471, 475, 476, 477, 478, 480, 481, 482, 488, 495, 498, 499, 500, 504, 508, 509, 510, 511, 512, 514, 517, 522, 525, 526, 529, 538, 539, 540, 542, 543, 544, 545, 548, 549, 554, 555, 558, 560, 562, 563, 565, 567, 571, 574, 575, 583, 584, 585, 586, 587, 588, 591, 592, 593, 596, 597, 598, 600, 601, 602, 603, 604, 606, 607, 608, 609, 611, 612, 613, 614, 615, 616, 621, 622, 623, 624, 625, 627, 627, 628, 629, 630, 631, 633, 634, 635, 638, 639, 640, 641, 642, 643, 644, 645, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658, 659, 660, 661, 663, 664, 665, 666, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 681, 682, 683, 684, 685, 686, 687, 688, 689, 690, 692, 693, 694, 696, 697, 698 and 699 herein, or a pharmaceutically acceptable salt thereof.
1.175C A compound according to Embodiment 1.175B which is selected from the compounds of any of Examples 303, 616, 683 and 675 or a pharmaceutically acceptable salt thereof.
1.175D A compound according to Embodiment 1.175B which is selected from the compounds of any of Examples 685, 697, 698 and 699 or a pharmaceutically acceptable salt thereof.
1.175E A compound according to Embodiment 1.0 which is selected from the compounds of Examples 1 to 1134 herein, or a pharmaceutically acceptable salt thereof.
1.175F A compound according to Embodiment 1.0 which is selected from the compounds of Examples 2, 3, 4, 7, 11, 16, 19, 21, 22, 25, 26, 27, 34, 35, 38, 40, 42, 48, 55, 56, 57, 59, 67, 72, 74, 76, 78, 79, 80, 82, 84, 85, 86, 87, 93, 94, 95, 96, 101, 103, 137, 141, 150, 151, 152, 192, 193, 194, 195, 196, 197, 201, 207, 209, 210, 214, 219, 221, 230, 232, 234, 235, 239, 240, 241, 242, 244, 260, 261, 262, 263, 264, 266, 271, 280, 282, 283, 284, 287, 289, 290, 291, 294, 303, 316, 317, 318, 319, 321, 322, 323, 324, 325, 326, 327, 328, 333, 335, 336, 337, 341, 342, 344, 347, 348, 349, 351, 352, 354, 355, 356, 357, 358, 359, 360, 365, 367, 369, 370, 371, 372, 381, 383, 384, 372, 386, 390, 391, 392, 393, 395, 396, 397, 398, 399, 400, 402, 406, 415, 421, 422, 423, 425, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 442, 443, 444, 445, 448, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 465, 466, 469, 471, 475, 476, 477, 478, 480, 481, 482, 488, 495, 498, 499, 500, 504, 509, 510, 511, 512, 514, 517, 522, 525, 526, 529, 538, 540, 542, 543, 545, 548, 549, 554, 555, 558, 560, 563, 565, 567, 571, 574, 575, 583, 588, 591, 593, 596, 597, 598, 600, 601, 602, 603, 604, 606, 608, 609, 612, 613, 614, 615, 616, 621, 623, 624, 625, 626, 627, 628, 629, 630, 631, 633, 634, 635, 639, 640, 641, 642, 643, 644, 650, 651, 652, 653, 654, 656, 657, 658, 660, 661, 663, 665, 666, 669, 671, 672, 673, 674, 675, 676, 677, 678, 681, 683, 684, 685, 686, 687, 688, 689, 692, 693, 694, 696, 697, 698, 699, 703, 705, 707, 708, 711, 712, 713, 715, 716, 717, 719, 720, 721, 722, 727, 728, 730, 732, 735, 737, 738, 740, 742, 743, 746, 747, 753, 754, 756, 757, 759, 763, 765, 767, 768, 769, 774, 776, 777, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 798, 799, 800, 801, 802, 803, 804, 805, 806, 808, 809, 810, 811, 812, 814, 815, 816, 817, 818, 819, 820, 822, 823, 824, 825, 826, 827, 828, 830, 831, 834, 835, 836, 837, 838, 840, 841, 843, 844, 846, 847, 848, 849, 850, 851, 852, 853, 855, 856, 857, 858, 859, 864, 865, 867, 868, 869, 870, 871, 872, 873, 875, 876, 877, 878, 880, 881, 882, 883, 886, 887, 888, 890, 891, 892, 894, 895, 896, 897, 986, 900, 902, 903, 907, 908, 909, 910, 911, 912, 913, 914, 915, 918, 919, 920, 921, 922, 924, 925, 926, 927, 928, 929, 930, 931, 932, 934, 935, 936, 940, 941, 942, 943, 944, 945, 947, 949, 950, 951, 952, 953, 954, 956, 957, 958, 959, 960, 961, 962, 963, 964, 965, 966, 968, 970, 971, 972, 973, 974, 975, 976, 977, 979, 980, 981, 982, 983, 984, 985, 986, 987, 988, 989, 990, 992, 995, 996, 997, 999, 1000, 1001, 1002, 1003, 1004, 1005, 1007, 1008, 1010, 1011, 1014, 1015, 1016, 1017, 1018, 1019, 1020, 1021, 1022, 1023, 1024, 1025, 1026, 1027, 1029, 1030, 1031, 1033, 1034, 1035, 1036, 1038, 1039, 1040, 1041, 1042, 1043, 1044, 1045, 1046, 1047, 1048, 1049, 1050, 1051, 1052, 1053, 1054, 1056, 1057, 1058, 1060, 1061, 1062, 1063, 1064, 1065, 1066, 1067, 1068, 1069, 1070, 1071, 1072, 1073, 1074, 1075, 1076, 1077, 1078, 1079, 1080, 1081, 1083, 1085, 1086, 1087, 1088, 1089, 1092, 1093, 1094, 1095, 1096, 1097, 1098, 1099, 1100, 1101, 1102, 1103, 598, 1105, 1106, 1107, 1108, 1109, 1110, 1111, 1112, 1113, 1114, 1115, 1116, 1117, 1118, 1119, 1120, 1121, 1122, 1123, 1124, 1125, 1126, 1127, 1128, 1129, 1130, 1131, 1132, 1133 and 1134 or a pharmaceutically acceptable salt thereof.
1.175G A compound according to Embodiment 0.1 which is selected from the compounds of Examples 685, 698, 701, 702, 992 and 1016 or a pharmaceutically acceptable salt thereof.
1.175H A compound according to Embodiment 1.175G which is (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl]propanamide:

or a pharmaceutically acceptable salt or tautomer thereof.
1.175J A compound according to Embodiment 1.175H which is (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl]propanamide.
1.175K A compound according to Embodiment 1.175G which is (2R)-2-(6-{5-Chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-2-hydroxy-1-(2-methoxypyridin-4-yl)ethyl]propanamide:

or a pharmaceutically acceptable salt or tautomer thereof.
1.175L A compound according to Embodiment 1.175K which is (2R)-2-(6-{5-Chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-2-hydroxy-1-(2-methoxypyridin-4-yl)ethyl]propanamide.
1.175M A compound according to Embodiment 1.175G which is (R)-2-(6-(5-chloro-2-((2-methoxypyridin-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)-N—((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)propanamide:

or a pharmaceutically acceptable salt or tautomer thereof.
1.175N A compound according to Embodiment 1.175M which is (R)-2-(6-(5-chloro-2-((2-methoxypyridin-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)-N—((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)propanamide.
1.175P A compound according to Embodiment 1.175G which is (R)-2-(6-(5-chloro-2-((2-methylpyrimidin-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)-N—((S)-1-(6-(dimethylamino)pyridin-2-yl)-2-hydroxyethyl)propanamide:

or a pharmaceutically acceptable salt or tautomer thereof.
1.175Q A compound according to Embodiment 1.175P which is (R)-2-(6-(5-chloro-2-((2-methylpyrimidin-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)-N—((S)-1-(6-(dimethylamino)pyridin-2-yl)-2-hydroxyethyl)propanamide.
1.175R A compound according to Embodiment 1.175G which is (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-2-hydroxy-1-[6-(4-methylpiperazin-1-yl)pyridin-2-yl]ethyl]propanamide:

or a pharmaceutically acceptable salt or tautomer thereof.
1.175S A compound according to Embodiment 1.175R which is (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-2-hydroxy-1-[6-(4-methylpiperazin-1-yl)pyridin-2-yl]ethyl]propanamide.
1.175T A compound according to Embodiment 1.175G which is 2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1R)-1-[3-fluoro-5-(4-methylpiperazin-1-yl)phenyl]ethyl]propanamide:

or a pharmaceutically acceptable salt of tautomer thereof.
1.175U A compound according to Embodiment 1.175T which is 2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1R)-1-[3-fluoro-5-(4-methylpiperazin-1-yl)phenyl]ethyl]propanamide.
1.176 A compound according to any one of Embodiments 0.1 to 1.175U which is in the form of a salt.
1.177 A compound according to Embodiment 1.176 wherein the salt is an acid addition salt.
1.178 A compound according to Embodiment 1.176 or Embodiment 1.177 wherein the salt is a pharmaceutically acceptable salt.
1.179 A compound according to any one of Embodiments 0.1 to 1.175U which is in the form of a free base.

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Benzolactam compounds as protein kinase inhibitors

Abstract: or a pharmaceutically acceptable salt, N-oxide or tautomer thereof; wherein:    n is 1 or 2;    X is CH or N;    Y is selected from CH and C—F;    Z is selected from C—Rz and N;    R1 is selected from:            -(Alk1)t-Cyc1; wherein t is 0 or 1;        Optionally substituted C1-6 acyclic hydrocarbon groups            R2 is selected from hydrogen; halogen; and C1-3 hydrocarbon groups optionally substituted with one or more fluorine atoms;    R3 is hydrogen or a group L-R7;    R4 is selected from hydrogen; methoxy; and optionally substituted C1-3 alkyl; and    R4a is selected from hydrogen and a C1-3 alkyl group;    wherein Rz, Alk1, Cyc1, L1 and R7 are defined herein; provided that the compound is other than 6-benzyl-3-{2-[(2-methylpyrimidin-4-yl)amino]pyridin-4-yl}-7,8-dihydro-1,6-naphthyridin-5(6H)-one and 3-{2-[(2-methylpyrimidin-4-yl)amino]pyridin-4-yl}-7,8-dihydro-1,6-naphthyridin-5(6H)-one and salts and tautomers thereof.

Abstract: The compounds are inhibitors of ERK1/2 kinases and will be useful in the treatment of ERK1/2-mediated conditions. The compounds are therefore useful in therapy, in particular in the treatment of cancer.