Protein kinase inhibitor benzolactam compound

Abstract

The present invention provides a compound of formula (0): or a pharmaceutically acceptable salt, N-oxide or tautomer thereof. The compound is an inhibitor of ERK1 / 2 kinase and will be used for the treatment of ERK1 / 2-mediated diseases. Accordingly, the compound is used for treatment, especially for the treatment of cancer.

Description

[0001] Divisional application

[0002] This application is a divisional application of the application with the application number 2016800611464, the filing date of October 20, 2016, and the title of "Protein kinase inhibitor benzolactam compound". Technical field

[0003] The present invention relates to novel benzolactam compounds, pharmaceutical compositions comprising said compounds, and the use of said compounds in the treatment of diseases such as cancer. Background art

[0004] MAPK Signaling and the Role of ERK1 / 2

[0005] Extracellular signal-regulated kinases (ERK1 / 2) are widely expressed protein serine / threonine kinases and comprise key components of the mitogen-activated protein kinase (MAPK) signaling pathway. The MAPK pathway is an evolutionarily conserved cellular signaling pathway that regulates various cellular processes, including cell cycle progression, cell migration, cell survival, differentiation, metabolism, proliferation, and transcription. The ERK / MAPK signaling pathway responds to extracellular stimuli of cell surface receptor tyrosine kinases (RTKs). When RTKs are activated, the small GTPases (K-Ras, N-Ras, and H-Ras) are converted from the inactive GDP-bound state to the active GTP-bound state. Activated Ras is phosphorylated, thereby activating Raf (A-Raf, B-Raf, and C-Raf), which in turn phosphorylate and activate the dual-specificity kinase MEK (MEK1 / 2). Then, activated MEK is phosphorylated and activates ERK1 / 2. After activation, ERK1 / 2 activates a variety of nuclear and cytoplasmic substrates. There are currently >200 known ERK1 / 2 substrates, including transcription factors, kinases, phosphatases, and cytoskeletal proteins (Roskoski, Pharmacol. Res. 2012; 66: 105-143).

[0006] Multiple ERK isoforms (ERK1, ERK2, ERK3 / 4, ERK5, ERK7) have been identified, but the two most widely studied isoforms 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.

[0007] Upregulation of ERK1 / 2 Signaling in Cancer

[0008] Due to activating mutations in upstream components of the MAPK pathway, the activity of ERK1 / 2 is typically upregulated in cancer. Approximately 30% of human cancers contain activating PAS mutations (Roberts and Der, Oncogene. 2007; 26: 3291-3310). K-PAS is the most common mutant subtype, mutated in 22% of tumors. KRAS mutations are particularly prevalent in pancreatic cancer (70-90%), non-small cell carcinoma (10-20%), and colorectal cancer (25-35%) (Neuzillet et al., 2014. Pharmacol. Ther. 141; 160-171). N-PAS mutations and H-PAS mutations occur in 8% and 3% of cancers, respectively (Prior et al., Cancer Res. 2012; 72(10);. Notably, 15-20% of melanoma cases have been reported to have activating N-RAS mutations. In addition, 8% of all tumors have activating B-RAF mutations, which 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 activating RAS and RAF mutations, the MAPK signaling pathway is also upregulated in cancer by overexpression or mutation 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).

[0009] There are multiple mechanisms by which aberrant ERK1 / 2 signaling promotes cancer progression. Upon activation, ERK1 / 2 is phosphorylated and activates a wide range of transcription factors 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, it is well known that ERK1 / 2 signaling promotes cell cycle progression through multiple mechanisms, including induction of cyclin D and inhibition of the cyclin-dependent kinase inhibitor p27 KIP1(Kawada et al., Oncogene. 1997; 15: 629-637, Lavoie et al., J. Biol. Chem. 1996; 271: 20608-20616). In addition, ERK1 / 2 signaling can promote cell survival by regulating a series of apoptotic proteins. Examples of such mechanisms include ERK1 / 2-dependent inhibition 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 ERK1 / 2-dependent stabilization of anti-apoptotic proteins such as MCL-1 (Domina et al., Oncogene. 2004; 23: 5301-5315).

[0010] The Role of ERK1 / 2 in MAPK Inhibitor Resistance

[0011] Extensive preclinical studies have shown that inhibition of the MAPK pathway inhibits the growth of cancer cell lines containing 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 have all been clinically approved for the treatment of BRAF-mutant melanoma. These agents elicit profound anti-tumor responses in most patients, although the response duration is short due to the development of acquired drug resistance (Chapman et al., N. Engl. J. Med. 2011; 364: 2507-2516. Hauschild et al., Lancet. 2012; 380: 358-365. Solit & 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 mechanisms include 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), upregulation of RTK or NRAS signaling (Nazarian et al., Nature. 2010; 468: 973-7), and the occurrence of MEK activating mutations (Wagle et al., J Clin Oncol. 2011; 29: 3085-96). Mechanisms of MEK inhibitor resistance include the emergence of MEK mutations, reduced drug binding, or enhanced intrinsic MEK activity (Emery et al., Proc Natl Acad Sci. 2009; 106: 20411-20416. Wang et al., Cancer Res. 2011; 71: 5535-5545), 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 reactivation of ERK1 / 2 signaling, which drives cell proliferation and survival in the presence of the inhibitor. Based on this observation, it has been shown that direct ERK1 / 2 inhibition may be an effective therapeutic approach to overcome acquired RAF or MEK inhibitor resistance.Preclinical evidence has shown that inhibition of ERK1 / 2 overcomes acquired resistance to RAF or MEK inhibitors (Hatzivassiliou et al., Mol Cancer Ther. 2012; 11(5):1143 - 54. Morris et al., Cancer Discov. 2013; 3(7):742 - 50).

[0012] Other Diseases

[0013] In addition to tumors, abnormal ERK1 / 2 signaling has been reported in other diseases, including cardiovascular diseases (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). Summary of the Invention

[0014] The present invention provides compounds for the treatment, in particular for the treatment of cancer. The compounds are inhibitors of the ERK1 / 2 kinase and are used for the treatment of ERK1 / 2 - mediated conditions.

[0015] Accordingly, a first aspect (Example 0.1) of the present invention provides a compound of formula (0):

[0016]

[0017] or a pharmaceutically acceptable salt, N - oxide or tautomer thereof; wherein:

[0018] n is 1 or 2;

[0019] X is CH or N;

[0020] Y is selected from CH and C - F;

[0021] Z is selected from C - R z and N;

[0022] R z is selected from hydrogen; halogen; methoxy; and C 1-3 alkyl, said C 1-3The alkyl group is optionally substituted by a hydroxyl group or a methoxy group;

[0023] R 1 is selected from:

[0024] --(Alk 1 ) t -Cyc 1 ; where t is 0 or 1; and Alk 1 is a straight-chain or branched alkylene group, optionally substituted by one or two hydroxyl groups; and 1-4

[0025]

[0026] - an unsubstituted or C 5 1-6 acyclic hydrocarbon group substituted by 1, 2 or 3 substituents R 5 selected from hydroxyl, oxygen, fluorine and cyano; where 1 or 2 carbon atoms but not all carbon atoms of the hydrocarbon group may be replaced by O or N;

[0027] Cyc 1 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, where one heteroatom ring member is N and the other heteroatom ring members (if any) are selected from O, N and S; and (c) 3- to 7-membered monocyclic carbocyclic groups; where each of the cyclic groups (a), (b) and (c) is an unsubstituted or C 6 group substituted by 1, 2 or 3 substituents R 6 selected from hydroxyl, oxygen, fluorine, amino, NH(Hyd 1 )、N(Hyd 1 ) 2 、O-Hyd 1 、-C(=O)-Hyd 1 、-C(=O)-O-Hyd 1 and Hyd 1 ; where Hyd 1 is a C 1-4 non-aromatic group, optionally substituted by one or more substituents selected from fluorine, hydroxyl and methoxy;

[0027] R 2 is selected from hydrogen, halogen; and a C 1-3 hydrocarbon group optionally substituted by one or more fluorine atoms;

[0028] R 3 is hydrogen or L 1 -R 7 Group;

[0029] R 4 selected from hydrogen; methoxy; and optionally hydroxy, amino, mono- or di-C 1-2 Alkylamino (mono- or di-C 1- 2 alkylamino), cyclic amino or methoxy substituted C 1-3 wherein the cyclic amino group is a saturated 4-7 membered heterocyclic group comprising a ring member nitrogen and a second heteroatom ring member optionally selected from O, N and S, wherein the cyclic amino group is connected to C 1-2 alkyl, and wherein the cyclic amino group is optionally substituted by one or two methyl groups; provided that no more than one R 4 Not hydrogen or methyl;

[0030] R 4a Selected from hydrogen and C 1-3 alkyl;

[0031] L 1 Select from bond, Alk 2 , Alk 2 -O and Alk 2 -C(=O), where Alk 2 It is C 1-4 A straight or branched alkylene group, optionally substituted with one or more substituents selected from hydroxy, methoxy, amino, methylamino, dimethylamino and fluorine;

[0032] R 7 Selected from:

[0033] ·hydrogen;

[0034] ·CO 2 H;

[0035] NR 8 R 9 ;

[0036] A carbocyclic or heterocyclic group having 3 to 12 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidized forms of S, the carbocyclic or heterocyclic group being optionally substituted by one or more substituents R 10 Replace; and

[0037] Non-cyclic C 1-8 A hydrocarbon group, optionally substituted by one or more substituents selected from hydroxy, oxygen, halogen, cyano, carboxyl, amino, mono- or di-C1-4 an alkylamino group; and a carbocyclic and heterocyclic group having 3 to 12 ring members, wherein 0, 1, 2 or 3 ring members are heteroatom ring members selected from O, N and S and the oxidized forms of S, and the carbocyclic or heterocyclic group is optionally substituted with one or more substituents R 10 substituted; wherein for the acyclic C 1-8 one or two but not all carbon atoms of the hydrocarbon group may optionally be substituted with O, S, SO, SO 2 or NR 11 substituted;

[0038] R 8 is selected from hydrogen and C 1-4 hydrocarbon group, and the C 1-4 hydrocarbon group is optionally substituted with 1-2 substituents selected from hydroxyl, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino, and a 4-7 membered saturated heterocycle containing 1-2 heteroatom ring members selected from O and N, wherein the mono-C 1-4 alkylamino, di-C 1-4 alkylamino and each of the 4-7 membered saturated heterocycles is optionally substituted with 1-2 hydroxyl or C 1-3 alkyl substituents;

[0039] R 9 is selected from:

[0040] · hydrogen;

[0041] · a carbocyclic or heterocyclic group having 3 to 12 ring members, wherein 0, 1, 2 or 3 ring members are heteroatom ring members selected from O, N, S and the oxidized forms of S, and the carbocyclic or heterocyclic group is optionally substituted with one or more substituents R 10 substituted; and

[0042] · an acyclic C 1-8 hydrocarbon group, optionally substituted with one or more substituents selected from hydroxyl, oxygen, halogen, cyano, carboxyl, amino, mono- or di-C 1-4 alkylamino; and a carbocyclic and heterocyclic group having 3 to 12 ring members, wherein 0, 1, 2 or 3 ring members are heteroatom ring members selected from O, N and S and the oxidized forms of S, and the carbocyclic or heterocyclic group is optionally substituted with one or more substituents R 10 substituted; wherein for the acyclic C 1-8 one or two but not all carbon atoms of the hydrocarbon group may optionally be substituted with O, S, SO, SO 2 or NR 11 substituted;

[0043] or NR 8 R 9Form a heterocyclic group having 4 to 12 ring members; wherein, in addition to the nitrogen atom of NR 8 R 9 , the heterocyclic group optionally further contains 1 or 2 heteroatom ring members selected from O, N, S, and the oxidized forms of S; and wherein the heterocyclic group is optionally substituted by one or more substituents R 10 ;

[0044] R 10 is selected from:

[0045] · halogen; hydroxy; oxygen; cyano;

[0046] · OR 12 , wherein R 12 is C 1-6 alkyl or C 3-6 cycloalkyl, each optionally substituted by halogen;

[0047] · acyclic C 1-8 hydrocarbyl, optionally substituted by one or more substituents selected from hydroxy, oxygen, halogen, cyano, carboxy, amino, mono- or di-C 1-4 alkylamino; and carbocyclic and heterocyclic groups having 3 to 7 ring members, wherein 0, 1, 2, 3, or 4 ring members are heteroatom ring members selected from N, O, and S, wherein the carbocyclic or heterocyclic group is optionally substituted by one or more substituents R 13 R 13 is selected from hydroxy, halogen, cyano, amino, -NH(Hyd 1 ), -N(Hyd 1 ) 2 and -(O) v -Hyd 1 , where v is 0 or 1; wherein one or two but not all carbon atoms of the acyclic C 1-8 hydrocarbyl may optionally be substituted by O, S, SO, SO 2 or NR 11 ; and

[0048] · carbocyclic and heterocyclic groups having 3 to 7 ring members, wherein 0, 1, 2, 3, or 4 ring members are heteroatom ring members selected from N, O, and S, wherein the carbocyclic and heterocyclic groups are optionally substituted by one or more substituents R 13 ; and

[0049] R 11 is selected from hydrogen and C 1-4 hydrocarbyl;

[0050] Provided that the compound is not 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, their salts and tautomers.

[0051] Specific aspects and embodiments of the present invention are given in the following Examples 0.2 to 1.179.

[0052] 0.2 The compound according to Example 0.1, wherein Cyc 1 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, wherein one heteroatom ring member is N and the other heteroatom ring members (if any) are selected from O, N and S; and (c) 3- to 7-membered monocyclic carbocyclic groups; wherein each of the cyclic groups (a), (b) and (c) is an unsubstituted or substituted group by 1, 2 or 3 substituents R 6 substituted groups, R 6 selected from hydroxy, oxygen, fluorine, amino, NH(Hyd 1 ), N(Hyd 1 ) 2 , O-Hyd 1 , -C(=O)-Hyd 1 , -C(=O)-O-Hyd 1 and Hyd 1 ; wherein Hyd 1 is a C 1-4 non-aromatic group, optionally substituted by one or more substituents selected from fluorine, hydroxy and methoxy.

[0053] 0.3 The compound according to Example 0.1 or 0.2, wherein R 4a is methyl.

[0054] 0.4 The compound according to Example 0.1 or 0.2, wherein R 4a is hydrogen.

[0055] 0.5 The compound according to any one of Examples 0.1 to 0.4, wherein R 10 is selected from:

[0056] · halogen; hydroxy; oxygen; cyano;

[0057] · OR 12, wherein R 12 is C 1-6 alkyl or C 3-6 cycloalkyl, each optionally substituted by halogen;

[0058] · An acyclic C 1-8 hydrocarbyl group, optionally substituted by one or more substituents selected from hydroxy, oxygen, halogen, cyano, carboxy, amino, mono- or di-C 1-4 alkylamino; and carbocyclic and heterocyclic groups having 3 to 7 ring members, wherein 0, 1, 2, 3 or 4 ring members are heteroatom ring members selected from N, O and S, wherein said carbocyclic and heterocyclic groups are optionally substituted by one or more substituents R 13 substituted, R 13 selected from hydroxy, halogen, cyano and -(O) v -Hyd 1 , where v is 0 or 1; wherein one or two but not all carbon atoms of the acyclic C 1-8 hydrocarbyl group may optionally be substituted by O, S, SO, SO 2 or NR 11 substituted; and

[0059] · Carbocyclic and heterocyclic groups having 3 to 7 ring members, wherein 0, 1, 2, 3 or 4 ring members are heteroatom ring members selected from N, O and S, wherein said carbocyclic and heterocyclic groups are optionally substituted by one or more substituents R 13 substituted.

[0060] 1.0 A compound of formula (1):

[0061]

[0062] or a pharmaceutically acceptable salt thereof or a tautomer thereof; wherein:

[0063] n is 1 or 2;

[0064] X is CH or N;

[0065] Y is selected from CH and C-F;

[0066] Z is selected from C-R z and N;

[0067] R z is selected from hydrogen; halogen; methoxy; and C 1-3 alkyl, said C 1-3 alkyl optionally substituted by hydroxy or methoxy; R 1 is selected from:

[0068] --(Alk 1 ) t -Cyc 1; wherein t is 0 or 1; Alk 1 is C 1-4 a straight-chain or branched alkylene group, optionally substituted by one or two hydroxyl groups; and

[0069] -C 1-6 an acyclic hydrocarbon group which is unsubstituted or substituted by one, two or three substituents R 5 wherein R 5 is selected from hydroxyl, oxygen, fluorine and cyano; wherein one or two but not all carbon atoms of the hydrocarbon group may be replaced by O or N;

[0070] Cyc 1 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, wherein one heteroatom ring member is N and the other heteroatom ring members (if any) are selected from O, N and S; and (c) 3- to 7-membered monocyclic carbocyclic groups; wherein each of the cyclic groups (a), (b) and (c) is an unsubstituted or substituted group with one, two or three substituents R 6 wherein R 6 is selected from hydroxyl, oxygen, fluorine, amino, NH(Hyd 1 ), N(Hyd 1 ), 2 O-Hyd 1 -C(=O)-Hyd 1 -C(=O)-O-Hyd 1 and Hyd 1 ; wherein Hyd 1 is C 1-4 a non-aromatic hydrocarbon group, optionally substituted by one or more substituents selected from fluorine, hydroxyl and methoxy; R 2 is selected from hydrogen, halogen; and C 1-3 a hydrocarbon group, said C 1-3 hydrocarbon group optionally substituted by one

[0071] or more fluorine atoms;

[0072] R 3 is hydrogen or an L 1 -R 7 group;

[0073] R 4 is selected from hydrogen; methoxy; and C 1-3 an alkyl group, said C 1-3 alkyl group optionally substituted by hydroxyl, amino, mono- or di-C 1-2substituted with an alkylamino, cycloamino or methoxy group; wherein the cycloamino group is a saturated 4- to 7-membered heterocyclic group containing a ring member nitrogen and a second heteroatom ring member optionally selected from O, N and S, wherein the cycloamino group is attached to C through its ring member nitrogen 1-2 alkyl group, and wherein the cycloamino group is optionally substituted with 1 or 2 methyl groups; provided that no more than 1 R 4 is hydrogen or methyl;

[0074] L 1 is selected from a single bond, Alk 2 、Alk 2 -O and Alk 2 -C(=O), wherein Alk 2 is a C 1-4 straight-chain or branched-chain alkylene group, optionally substituted with one or more substituents selected from hydroxyl, methoxy, amino, methylamino, dimethylamino and fluorine;

[0075] R 7 is selected from:

[0076] · hydrogen;

[0077] · CO 2 H;

[0078] · NR 8 R 9 ;

[0079] · a carbocyclic or heterocyclic group having 3 to 12 ring members, wherein 0, 1, 2 or 3 ring members are heteroatom ring members selected from O, N, S and the oxidized form of S, and the carbocyclic or heterocyclic group is optionally substituted with one or more substituents R 10 substituted; and

[0080] · an acyclic C 1-8 hydrocarbon group, optionally substituted with one or more substituents selected from hydroxyl, oxygen, halogen, cyano, carboxyl, amino, mono- or di-C 1-4 alkylamino and carbocyclic and heterocyclic groups having 3 to 12 ring members, wherein 0, 1, 2 or 3 ring members are heteroatom ring members selected from O, N, S and the oxidized form of S, and the carbocyclic or heterocyclic group is optionally substituted with 1 or more substituents R 10 substituted; wherein 1 or 2 but not all carbon atoms of the acyclic C 1-8 hydrocarbon group may optionally be substituted with O, S, SO, SO 2 or NR 11 substituted:

[0081] R 8 is selected from hydrogen and C 1-4 hydrocarbon group, the C 1-4The alkyl group is optionally substituted by 1 or 2 substituents selected from hydroxyl, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino, and a 4- to 7-membered saturated heterocycle containing 1 or 2 heteroatom ring members selected from O and N, wherein mono-C 1-4 alkylamino, di-C 1-4 alkylamino, and the 4- to 7-membered saturated heterocycle are optionally substituted by 1 or 2 hydroxyl groups or C 1-3 alkyl substituents;

[0082] R 9 is selected from:

[0083] · hydrogen;

[0084] · a carbocyclic or heterocyclic group having 3 to 12 ring members, wherein 0, 1, 2, or 3 ring members are heteroatom ring members selected from O, N, S, and the oxidized forms of S, and the carbocyclic or heterocyclic group is optionally substituted by one or more substituents R 10 ; and

[0085] · an acyclic C 1-8 hydrocarbon group, optionally substituted by one or more substituents selected from hydroxyl, oxygen, halogen, cyano, carboxyl, amino, mono- or di-C 1-4 alkylamino; and a carbocyclic and heterocyclic group having 3 to 12 ring members, wherein 0, 1, 2, or 3 ring members are heteroatom ring members selected from O, N, S, and the oxidized forms of S, and the carbocyclic or heterocyclic group is optionally substituted by one or more substituents R 10 ; wherein one or 2 but not all carbon atoms of the acyclic C 1-8 hydrocarbon group can optionally be substituted by O, S, SO, SO 2 or NR 11 ;

[0086] or NR 8 R 9 forms a heterocyclic group having 4 to 12 ring members; wherein, in addition to the nitrogen atom of NR 8 R 9 the heterocyclic group optionally further contains 1 or 2 heteroatom ring members selected from O, N, S, and the oxidized forms of S; and wherein the heterocyclic group is optionally substituted by one or more substituents R 10 ;

[0087] R 10 is selected from:

[0088] · halogen; hydroxyl; oxygen; cyano;

[0089] · OR 12 wherein R 12 is C1-6 alkyl or C 3-6 cycloalkyl, each optionally substituted by halogen;

[0090] · acyclic C 1-8 hydrocarbyl, optionally substituted by one or more substituents selected from hydroxy, oxygen, halogen, cyano, carboxy, amino, mono- or di-C 1-4 alkylamino, and carbocyclic and heterocyclic groups having 3 to 7 ring members, wherein 0, 1, 2, 3 or 4 ring members are heteroatom ring members selected from N, O and S, wherein said carbocyclic and heterocyclic groups are optionally substituted by one or more substituents R 13 substituted, R 13 selected from hydroxy, halogen, cyano and -(O) v -Hyd 1 , where v is 0 or 1; wherein one or two but not all carbon atoms of the acyclic C 1-8 hydrocarbyl may optionally be substituted by O, S, SO, SO 2 or NR 11 substituted; and

[0091] · carbocyclic and heterocyclic groups having 3 to 7 ring members, wherein 0, 1, 2, 3 or 4 ring members are heteroatom ring members selected from N, O and S, wherein said carbocyclic or heterocyclic group is optionally substituted by one or more substituents R 13 substituted; and

[0092] R 11 selected from hydrogen and C 1-4 hydrocarbyl;

[0093] Provided that the compound is not 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, their salts and tautomers.

[0094] 1.01 A compound according to any one of Examples 0.1 to 1.0, wherein R 1 is selected from:

[0095] --(Alk 1 ) t -Cyc 1 ; where t is 0 or 1; and Alk 1 is a C 1-4 straight-chain or branched-chain alkylene, optionally substituted by one or two hydroxy groups; and

[0096] -C 1-6A non-cyclic hydrocarbon group, unsubstituted or substituted by 1, 2 or 3 substituents R selected from hydroxy, oxygen and fluorine, and wherein 1 or 2 but not all of the carbon atoms of said hydrocarbon group may be substituted by O or N; 1.02 The compound according to any one of Examples 0.1 to 1.01, wherein R 5 is selected from hydroxy, oxygen, fluorine, O-Hyd 6 , -C(=O)-Hyd 1 , -C(=O)-O-Hyd 1 and Hyd 1 ; wherein Hyd 1 is a C 1 non-aromatic hydrocarbon group, optionally substituted by one or more substituents selected from fluorine, hydroxy and methoxy. 1-4

[0097] 1.03 The compound according to any one of Examples 0.1 to 1.02, wherein R 8 is selected from hydrogen and a C 1-4 hydrocarbon group optionally substituted by hydroxy.

[0098] 1.04 The compound according to any one of Examples 0.1 to 1.03, wherein R 10 is selected from:

[0099] · halogen; hydroxy; oxygen; cyano;

[0100] · OR 12 , wherein R 12 is an alkyl C 1-6 or a cycloalkyl C 3-6 , each optionally substituted by halogen;

[0101] · a non-cyclic C 1-8 hydrocarbon group, optionally substituted by one or more substituents selected from hydroxy, oxygen, halogen, cyano, carboxy, amino, mono- or di-C 1-4 alkylamino, and carbocyclic and heterocyclic groups having 3 to 6 ring members, wherein 0, 1 or 2 of the ring members are heteroatom ring members selected from N, O and S, wherein said carbocyclic and heterocyclic groups are optionally substituted by one or more substituents R 13 , R 13 is selected from hydroxy, halogen, cyano and -(O) v -Hyd 1 , where v is 0 or 1; wherein 1 or 2 but not all of the carbon atoms of said non-cyclic C 1-8 hydrocarbon group may optionally be substituted by O, S, SO, SO 2 or NR 11 ; and

[0102] ​·Carbocyclic and heterocyclic groups having 3 to 6 ring members, wherein 0, 1, 2 or 3 ring members are heteroatom ring members selected from N, O and S, and wherein said carbocyclic or heterocyclic group is optionally substituted with one or more substituents R 13 substituted; and

[0103] R 11 is selected from hydrogen and C 1-4 hydrocarbyl.

[0104] 1.05 The compound according to embodiment 1.04, wherein R 10 is selected from:[[]]

[0105] · halogen; hydroxy; oxygen; cyano;

[0106] · OR 12 wherein R 12 is C 1-6 alkyl or C 3-6 cycloalkyl, each optionally substituted with halogen;

[0107] · acyclic C 1-8 hydrocarbyl, optionally substituted with one or more substituents selected from hydroxy, oxygen, halogen, cyano, carboxy, amino, mono- or di-C 1-4 alkylamino and carbocyclic and heterocyclic groups having 3 to 6 ring members, wherein 0, 1 or 2 ring members are heteroatom ring members selected from N, O and S, and wherein said carbocyclic and heterocyclic groups are optionally substituted with one or more substituents R 13 substituted, R 13 is selected from hydroxy, halogen, cyano and -(O) v -Hyd 1 where v is 0 or 1; wherein one or two but not all carbon atoms of the acyclic C 1-8 hydrocarbyl may optionally be substituted with O, S, SO, SO 2 or NR 11 substituted; and

[0108] · carbocyclic and heterocyclic groups having 3 to 6 ring members, wherein 0, 1 or 2 ring members are heteroatom ring members selected from N, O and S, and wherein said carbocyclic or heterocyclic group is optionally substituted with one or more substituents R 13 substituted; and

[0109] R 11 is selected from hydrogen and C 1-4 hydrocarbyl.

[0110] 1.06 The compound according to any one of embodiments 0.1 to 1.05, wherein Z is C-R z wherein R z is selected from hydrogen, halogen, methoxy and C optionally substituted with hydroxy1-3 Alkyl

[0111] 1. A compound of formula (1):

[0112]

[0113] or a pharmaceutically acceptable salt thereof or a tautomer thereof; wherein:

[0114] n is 1 or 2;

[0115] X is CH or N;

[0116] Y is selected from CH and C-F;

[0117] Z is selected from C-R z and N;

[0118] R z is selected from hydrogen; halogen;; and C 1-3 alkyl, said C 1-3 alkyl is optionally substituted with hydroxy or methoxy;

[0119] R 1 is selected from:

[0120] --(Alk 1 ) t -Cyc 1 ; where t is 0 or 1; and Alk 1 is a C 1-4 straight or branched chain alkylene, optionally substituted with 1 or 2 hydroxy groups; and

[0121] -C 1-6 acyclic hydrocarbon group, which is unsubstituted or substituted with 1, 2 or 3 substituents R 5 substituted, R 5 is selected from hydroxy, oxygen and fluorine; and where 1 or 2 but not all carbon atoms of said hydrocarbon group may be replaced by O or N;

[0122] Cyc 1 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, where 1 heteroatom ring member is N and the other heteroatom ring members (if any) are selected from O, N and S; and (c) 3- to 7-membered monocyclic carbocyclic groups; where each of the cyclic groups (a), (b) and (c) is unsubstituted or substituted with 1, 2 or 3 substituents R 6 substituted, R 6 is selected from hydroxy, oxygen, fluorine, O-Hyd 1, -C(=O)-Hyd 1 , -C(=O)-O-Hyd 1 and Hyd 1 ; where Hyd 1 is a C 1-4 non-aromatic group, optionally substituted by one or more substituents selected from fluorine, hydroxy and methoxy;

[0123] R 2 is selected from hydrogen; halogen; and C 1-3 hydrocarbyl, said C 1-3 hydrocarbyl optionally substituted by one or more fluorine atoms;

[0124] R 3 is hydrogen or the group L 1 -R 7 ;

[0125] R 4 is selected from hydrogen and C 1-2 alkyl, said C 1-2 alkyl optionally substituted by hydroxy, amino, mono- or di-C 1-2 alkylamino, cycloamino or methoxy; wherein said cycloamino is a saturated 4-7 membered heterocyclic group containing a ring member nitrogen and an optional second heteroatom ring member selected from O, N and S, wherein said cycloamino is linked to C 1-2 alkyl through its ring member nitrogen, and wherein said cycloamino is optionally substituted by 1 or 2 methyl groups; provided that no more than 1 R 4 is not hydrogen or methyl;

[0126] L 1 is selected from a single bond, Alk 2 , Alk 2 -O and Alk 2 -C(=O), where Alk 2 is a C 1-4 straight or branched chain alkylene, optionally substituted by one or more substituents selected from hydroxy, methoxy, amino, methylamino, dimethylamino and fluorine;

[0127] R 7 is selected from:

[0128] · hydrogen;

[0129] · CO 2 H;

[0130] · NR 8 R 9 ;

[0131] · A carbocyclic or heterocyclic group having 3 to 12 ring members, wherein 0, 1, 2 or 3 ring members are heteroatom ring members selected from O, N, S and the oxidized forms of S, and the carbocyclic or heterocyclic group is optionally substituted by one or more substituents R 10 substituted; and

[0132] · An acyclic C 1-8 hydrocarbyl group, optionally substituted by one or more substituents selected from hydroxy, oxygen, halogen, cyano, carboxyl, amino, mono- or di-C 1-4 alkylamino, and carbocyclic and heterocyclic groups having 3 to 12 ring members, wherein 0, 1, 2 or 3 ring members are heteroatom ring members selected from O, N, S and the oxidized forms of S, and the carbocyclic or heterocyclic group is optionally substituted by one or more substituents R 10 substituted; wherein one or two but not all of the carbon 1-8 atoms of the acyclic C 2 hydrocarbyl group may optionally be substituted by O, S, SO, SO 11 or NR

[0133] R 8 is selected from hydrogen and C 1-4 hydrocarbyl optionally substituted by hydroxy;

[0134] R 9 is selected from:

[0135] · Hydrogen;

[0136] · A carbocyclic or heterocyclic group having 3 to 12 ring members, wherein 0, 1, 2 or 3 ring members are heteroatom ring members selected from O, N, S and the oxidized forms of S, and the carbocyclic or heterocyclic group is optionally substituted by one or more substituents R 10 substituted; and

[0137] · An acyclic C 1-8 hydrocarbyl group, optionally substituted by one or more substituents selected from hydroxy, oxygen, halogen, cyano, carboxyl, amino, mono- or di-C 1-4 alkylamino, and carbocyclic and heterocyclic groups having 3 to 12 ring members, wherein 0, 1, 2 or 3 ring members are heteroatom ring members selected from O, N, S and the oxidized forms of S, and the carbocyclic or heterocyclic group is optionally substituted by one or more substituents R 10 substituted; wherein one or two but not all of the carbon 1-8 atoms of the acyclic C 2 hydrocarbyl group may optionally be substituted by O, S, SO, SO 11 or NR

[0138] Or NR 8 R 9Form a heterocyclic group having 4 to 12 ring members, wherein, in addition to the nitrogen atom of NR 8 R 9 , the heterocyclic group optionally further contains 1 or 2 heteroatom ring members selected from O, N, S and the oxidized forms of S; and wherein the heterocyclic group is optionally substituted by one or more substituents R 10 ;

[0139] R 10 is selected from:

[0140] · halogen; hydroxy; oxygen; cyano;

[0141] · OR 12 , wherein R 12 is C 1-6 alkyl or C 3-6 cycloalkyl, each optionally substituted by halogen;

[0142] · acyclic C 1-8 hydrocarbyl, optionally substituted by one or more substituents selected from hydroxy, oxygen, halogen, cyano, carboxy, amino, mono- or di-C 1-4 alkylamino, and carbocyclic and heterocyclic groups having 3 to 6 ring members, wherein 0, 1 or 2 ring members are heteroatom ring members selected from N, O and S, wherein the carbocyclic and heterocyclic groups are optionally substituted by one or more substituents R 13 ; R 13 is selected from hydroxy, halogen, cyano and -(O) v -Hyd 1 , where v is 0 or 1; wherein one or two but not all carbon atoms of the acyclic C 1-8 hydrocarbyl may optionally be substituted by O, S, SO, SO 2 or NR 11 ; and

[0143] · carbocyclic and heterocyclic groups having 3 to 6 ring members, wherein 0, 1 or 2 ring members are heteroatom ring members selected from N, O and S, wherein the carbocyclic and heterocyclic groups are optionally substituted by one or more substituents R 13 ; and

[0144] R 11 is selected from hydrogen and C 1-4 hydrocarbyl;

[0145] Provided that the compound is not 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, their salts and tautomers.

[0146] 1.2 The compound according to any one of Examples 0.1 to 1.1, wherein X is N.

[0147] 1.2A The compound according to any one of Examples 0.1 to 1.1, wherein X is CH.

[0148] 1.3 The compound according to any one of Examples 0.1 to 1.2, wherein Y is CH.

[0149] 1.4 The compound according to any one of Examples 0.1 to 1.1, the compound having the general formula (2):

[0150]

[0151] or a pharmaceutically acceptable salt or tautomer thereof; wherein R 1 , R 2 , R 3 , R 4 , Z and n are as defined in any one of Examples 0.1 to 1.1.

[0152] 1.5 The compound according to any one of Examples 0.1 to 1.4, wherein n is 1.

[0153] 1.6 The compound according to any one of Examples 0.1 to 1.4, wherein n is 2.

[0154] 1.7 The compound according to any one of Examples 0.1 to 1.1, having the general formula (3):

[0155]

[0156] or a pharmaceutically acceptable salt or tautomer thereof; wherein R 1 , R 2 , R 3 , R 4 and Z are as defined in any one of Examples 0.1 to 1.1.

[0157] 1.7A The compound according to Example 1.7, wherein the compound has the structure (3A):

[0158]

[0159] 1.7B A compound according to Embodiment 1.7, wherein the compound has the structure (3B):

[0160]

[0161] 1.8 A compound according to any one of Embodiments 0.1 to 1.7, wherein R 1 Selected from:

[0162] --(Alk 1 ) t -Cyc 1 ; where t is 0 or 1; and Alk 1 It is C 1-2 a straight or branched chain alkylene group, optionally substituted with 1 or 2 hydroxyl groups; and

[0163] -C 1-6 Acyclic hydrocarbon group, which is unsubstituted or substituted by 1, 2 or 3 substituents R selected from hydroxyl, oxygen, fluorine 5 Substituted, and wherein 1 or 2 but not all carbon atoms of the hydrocarbon group may be substituted by O or N;

[0164] 1.9 A compound according to any one of Embodiments 0.1 to 1.7, wherein R 1 Selected from:

[0165] --(Alk 1 ) r Cyc 1 ; where t is 0; and

[0166] -C 1-6 Acyclic hydrocarbon group, which is unsubstituted or substituted by 1, 2 or 3 substituents R selected from hydroxyl, oxygen, fluorine 5 Substituted, and wherein 1 or 2 but not all carbon atoms of the hydrocarbon group may be substituted by O or N.

[0167] 1.10 A compound according to any one of Embodiments 0.1 to 1.7, wherein R 1 Selected from:

[0168] --(Alk 1 ) t -Cyc 1 ; where t is 0; and

[0169] - unsubstituted or substituted with 1 or 2 hydroxy substituents C 1-6 A non-cyclic hydrocarbon group; wherein one but not all carbon atoms of the hydrocarbon group may be substituted by O.

[0170] 1.11 A compound according to any one of Embodiments 0.1 to 1.7, wherein R 1 Selected from:

[0171] --(Alk 1 ) t -Cyc 1 ; where t is 0; and

[0172] - unsubstituted or substituted with 1 or 2 hydroxy substituents C 3-6 A non-cyclic hydrocarbon group; wherein one but not all carbon atoms of the hydrocarbon group may be substituted by O.

[0173] 1.12 A compound according to any one of Embodiments 0.1 to 1.7, wherein R 1 Selected from:

[0174] --(Alk 1 ) t -Cyc 1 ; where t is 0; and

[0175] - unsubstituted or substituted with 1 or 2 hydroxy substituents C 3-5 A non-cyclic hydrocarbon group; and wherein one but not all carbon atoms of the hydrocarbon group may be substituted with O.

[0176] 1.13 A compound according to any one of Embodiments 0.1 to 1.7, wherein R 1 is selected from unsubstituted or substituted by 1, 2 or 3 substituents R selected from hydroxyl, oxygen, fluorine 5 Substituted C 1-6 Acyclic hydrocarbon groups; wherein 1 or 2 carbon atoms but not all carbon atoms in the hydrocarbon group may be substituted by O or N.

[0177] 1.14 A compound according to Embodiment 1.13 wherein R 1 is selected from unsubstituted or substituted by 1, 2 or 3 substituents R selected from hydroxy, oxygen, fluorine 5 Substituted C 2-6 Acyclic hydrocarbon groups; wherein 1 or 2 carbon atoms but not all carbon atoms in the hydrocarbon group may be substituted by O or N.

[0178] 1.15 A compound according to Embodiment 1.14 wherein R 1 is selected from unsubstituted or substituted by 1, 2 or 3 substituents R selected from hydroxy, oxygen, fluorine 5 Substituted C 3-6 Acyclic hydrocarbon groups; wherein 1 or 2 carbon atoms but not all carbon atoms in the hydrocarbon group may be substituted by O or N.

[0179] 1.16 A compound according to Embodiment 1.15 wherein R1 selected from unsubstituted or substituted by 1, 2 or 3 substituents R selected from hydroxy, oxygen, fluorine 5 substituted C 3-5 acyclic hydrocarbon radical; wherein 1 or 2 but not all carbon atoms in said hydrocarbon radical may be replaced by O or N.

[0180] 1.17 The compound according to any one of Examples 1.16, wherein R 1 selected from unsubstituted or substituted by 1, 2 or 3 substituents R selected from hydroxy, oxygen, fluorine 5 substituted C 3-4 acyclic hydrocarbon radical; wherein 1 or 2 but not all carbon atoms in said hydrocarbon radical may be replaced by O or N.

[0181] 1.17A The compound according to any one of Examples 1.8, 1.9, 1.13, 1.14, 1.15, 1.16 and 1.17, wherein R 1 contains 0, 1 or 2 substituents R 5 .

[0182] 1.17B The compound according to any one of Examples 1.8, 1.9, 1.13, 1.14, 1.15, 1.16 and 1.17, wherein R 1 contains 0 substituents R 5 .

[0183] 1.17B The compound according to any one of Examples 1.8, 1.9, 1.13, 1.14, 1.15, 1.16 and 1.17, wherein R 1 contains 1 substituent R 5 .

[0184] 1.17C The compound according to any one of Examples 1.8, 1.9, 1.13, 1.14, 1.15, 1.16 and 1.17, wherein R 1 contains 2 substituents R 5 .

[0185] 1.18 The compound according to any one of Examples 0.1 to 1.17A, wherein when R 1 consists of an unsubstituted or substituted hydrocarbon radical or includes an unsubstituted or substituted hydrocarbon radical, said hydrocarbon radical is selected from unsubstituted or substituted alkyl and alkenyl.

[0186] 1.19 The compound according to Example 1.18, wherein said hydrocarbon radical is selected from unsubstituted or substituted alkyl.

[0187] 1.20 A compound according to any one of embodiments 1.13 to 1.19, wherein the acyclic hydrocarbon group is unsubstituted or substituted with 1 or 2 substituents R selected from hydroxy, oxygen, and fluorine; and 1 or 2 but not all carbon atoms in the hydrocarbon group may be substituted with O or N. 5 Substituted; where 1 or 2 carbon atoms in the hydrocarbon group but not all carbon atoms may be substituted with O or N.

[0188] 1.21 A compound according to embodiment 1.20, wherein the acyclic hydrocarbon group is unsubstituted or substituted with 1 or 2 substituents R selected from hydroxy, oxygen, and fluorine; and 1 carbon atom in the hydrocarbon group but not all carbon atoms may be substituted with O. 5 Substituted; where 1 carbon atom in the hydrocarbon group but not all carbon atoms may be substituted with O.

[0189] 1.22 A compound according to embodiment 1.21, wherein the acyclic hydrocarbon group is unsubstituted or substituted with 1 or 2 substituents R selected from hydroxy; and 1 carbon atom in the hydrocarbon group but not all carbon atoms may be substituted with O. 5 Substituted; where 1 carbon atom in the hydrocarbon group but not all carbon atoms may be substituted with O.

[0190] 1.23 A compound according to any one of embodiments 0.1 to 1.7, wherein R 1 Is selected from Cyc 1 , isopropyl, tert - butyl, 1,3 - dihydroxy - propan - 2 - yl, 2,3 - dihydroxy - propan - 1 - yl, and 2 - methoxyethyl.

[0191] 1.24 A compound according to any one of embodiments 0.1 to 1.7, wherein R 1 Is selected from -(Alk 1 ) t Cyc 1 ; where t is 0 or 1; Alk 1 Is a C 1-4 Straight - chain or branched - chain alkylene group, optionally substituted with 1 or 2 hydroxy groups.

[0192] 1.25 A compound according to embodiment 1.24, wherein R 1 Is selected from -(Alk 1 ) t Cyc 1 ; where t is 0 or 1; Alk 1 Is CH 2 , CH(CH 3 ) or CH 2 CH 2 Groups.

[0193] 1.26 A compound according to embodiment 1.25, wherein t is 0, and thus, R 1 Is Cyc 1 .

[0194] 1.26A The compound according to any one of embodiments 0.1 to 1.7, wherein t is 0, and thus, R 1 is Cyc 1 .

[0195] 1.27 The compound according to any one of embodiments 0.1 to 1.12 and 1.23 to 1.26, wherein Cyc 1 is a cyclic group selected from:

[0196] (a-i) 3- to 9-membered monocyclic and bicyclic non-aromatic carbocyclic groups (e.g., cycloalkyl);

[0197] (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 ;

[0198] (b) 5- to 6-membered monocyclic heteroaryl groups containing 1 or 2 heteroatom ring members, wherein 1 heteroatom ring member is N and the other heteroatom ring members (if any) are selected from O, N, and S; and

[0199] (c) phenyl;

[0200] wherein each of the cyclic groups (a-i), (a-ii), (b), and (c) is an unsubstituted group or is substituted with 1, 2, or 3 substituents R 6 substituted, R 6 is selected from hydroxy, oxygen, fluorine, O-Hyd 1 , -C(=O)-Hyd 1 , -C(=O)-O-Hyd 1 and Hyd 1 ; wherein Hyd 1 is C 1-4 a non-aromatic group optionally substituted with one or more substituents selected from fluorine, hydroxy, and methoxy.

[0201] 1.27A The compound according to any one of embodiments 0.1 to 1.12 and 1.23 to 1.26, wherein Cyc 1 is a cyclic group selected from:

[0202] (a-i) 3- to 9-membered monocyclic and bicyclic non-aromatic carbocyclic groups (e.g., cycloalkyl);

[0203] (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 ;

[0204] (b) A 5- to 6-membered monocyclic heteroaryl group containing 1, 2, or 3 heteroatom ring members, where 1 heteroatom ring member is N and the other heteroatom ring members (if any) are selected from O, N, and S; and

[0205] (c) Phenyl;

[0206] where each of the cyclic groups (a-i), (a-ii), (b), and (c) is an unsubstituted group or is substituted by 1, 2, or 3 substituents R 6 substituted, R 6 selected from hydroxy, oxygen, fluorine, N(Hyd 1 ) 2 , O-Hyd 1 , -C(=O)-Hyd 1 , -C(=O)-O-Hyd 1 and Hyd 1 ; where Hyd 1 is a C 1-4 non-aromatic group, optionally substituted by one or more substituents selected from fluorine, hydroxy, and methoxy.

[0207] 1.27B A compound according to any one of Examples 0.1 to 1.12 and 1.23 to 1.26, where Cyc 1 is a cyclic group selected from:

[0208] (a-i) A 3- to 9-membered monocyclic and bicyclic non-aromatic carbocyclic group (e.g., cycloalkyl);

[0209] (a-ii) A 4- to 9-membered non-aromatic (e.g., saturated) monocyclic and bicyclic heterocyclic group containing 1 or 2 heteroatom ring members selected from O, N, S, and S(O) 2 ;

[0210] (b) A 5- to 6-membered monocyclic heteroaryl group containing 1, 2, or 3 heteroatom ring members, where 1 heteroatom ring member is N and the other heteroatom ring members (if any) are selected from O, N, and S; and

[0211] (c) Phenyl;

[0212] where each of the cyclic groups (a-i), (a-ii), (b), and (c) is an unsubstituted group or is substituted by 1, 2, or 3 substituents R 6 substituted, R 6 selected from hydroxy, oxygen, fluorine, N(Hyd 1 ) 2 , O-Hyd 1 , -C(=O)-Hyd 1 , -C(=O)-O-Hyd 1 and Hyd 1; wherein Hyd 1 is a C 1-4 non-aromatic group, optionally substituted with one or more substituents selected from fluorine, hydroxy and methoxy.

[0213] 1.27C A compound according to any one of Examples 0.1 to 1.12 and 1.23 to 1.26, wherein Cyc 1 is a cyclic group selected from:

[0214] (a-i) A 3-, 4-, 5- or 6-membered monocyclic non-aromatic carbocyclic group (e.g., C 3-6 cycloalkyl);

[0215] (a-ii) A 4-, 5-, 6- or 7-membered non-aromatic (e.g., saturated) monocyclic and 7-membered bicyclic heterocyclic group containing 1 or 2 heteroatom ring members selected from O, N, S and S(O) 2 ;

[0216] (b) A 5- or 6-membered monocyclic heteroaryl group containing 1, 2 or 3 heteroatom ring members, wherein 1 heteroatom ring member is N and the other heteroatom ring members (if any) are selected from O, N and S; and

[0217] (c) Phenyl;

[0218] wherein each of the cyclic groups (a-i), (a-ii), (b) and (c) is an unsubstituted group or is substituted with 1, 2 or 3 substituents R 6 substituted, R 6 is selected from hydroxy, oxygen, fluorine, N(Hyd 1 ) 2 , O-Hyd 1 , -C(=O)-Hyd 1 , -C(=O)-O-Hyd 1 and Hyd 1 ; wherein Hyd 1 is a C 1-4 non-aromatic group, optionally substituted with one or more substituents selected from fluorine, hydroxy and methoxy.

[0219] 1.27D A compound according to any one of Examples 0.1 to 1.12 and 1.23 to 1.26, wherein Cyc 1 is a cyclic group selected from:

[0220] (a-i) A 3-, 4-, 5- or 6-membered monocyclic non-aromatic carbocyclic group (e.g., C 3-6 cycloalkyl), which is unsubstituted or substituted with 1, 2 or 3 substituents R 6 substituted, R 6 is selected from hydroxy, oxygen, fluorine, N(Hyd1 ) 2 (e.g., -NMe 2 ), O-Hyd 1 (e.g., methoxy), -C(=O)-Hyd 1 (e.g., -C(=O)-methyl), -C(=O)-O-Hyd 1 (e.g., -C(=O)-O- t Bu) and Hyd 1 (e.g., methyl, isopropyl); where Hyd 1 is a C 1-4 non-aromatic hydrocarbon group, optionally substituted with one or more substituents selected from hydroxyl;

[0221] (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 and which is unsubstituted or substituted with 1, 2 or 3 substituents R 6 where R 6 is selected from oxygen, O-Hyd 1 (e.g., methoxy), and Hyd 1 (e.g., methyl, ethyl); where Hyd 1 is a C 1-4 non-aromatic hydrocarbon group;

[0222] (b) a 5- or 6-membered monocyclic heteroaryl, containing 1, 2 or 3 heteroatom ring members, where 1 heteroatom ring member is N and the other heteroatom ring members (if any) are selected from O, N and S; and

[0223] (c) an unsubstituted phenyl.

[0224] 1.28 The compound according to embodiment 1.27, where Cyc 1 is a cyclic group selected from: (a-i) a 3- to 7-membered monocyclic non-aromatic carbocyclic group (e.g., cycloalkyl);

[0225] (a-ii) a 4- to 7-membered non-aromatic (e.g., saturated) monocyclic heterocyclic group and a 7- to 9-membered bicyclic heterocyclic group, where the heterocyclic group contains 1 or 2 heteroatom ring members selected from O, N, S and S(O) 2 ;

[0226] (b) a 5- to 6-membered monocyclic heteroaryl, containing 1 or 2 heteroatom ring members, where 1 heteroatom ring member is N and the other heteroatom ring members (if any) are selected from O, N and S; and

[0227] (c) phenyl;

[0228] wherein each of the cyclic groups (a-i), (a-ii), (b), and (c) is an unsubstituted group or is substituted with 1, 2, or 3 substituents R 6 substituted, R 6 is selected from hydroxy, oxygen, fluorine, O-Hyd 1 , -C(=O)-Hyd 1 , -C(=O)-O-Hyd 1 and Hyd 1 ; wherein Hyd 1 is a C 1-4 non-aromatic hydrocarbon group, optionally substituted with one or more substituents selected from fluorine, hydroxy, and methoxy.

[0229] 1.28A A compound according to any one of Examples 0.1 to 1.12 and 1.23 to 1.26, wherein Cyc 1 is a cyclic group selected from:

[0230] (a-ii) a 4- to 7-membered non-aromatic (e.g., saturated) monocyclic heterocyclic group, wherein the heterocyclic group contains 1 or 2 heteroatom ring members selected from O, N, S, and S(O) 2 ; and

[0231] (b) a 5- to 6-membered monocyclic heteroaryl group containing 1, 2, or 3 heteroatom ring members, wherein 1 heteroatom ring member is N and the other heteroatom ring members (if any) are selected from O, N, and S;

[0232] wherein each of the cyclic groups (a-ii) and (b) is an unsubstituted group or is substituted with 1, 2, or 3 substituents R 6 substituted, R 6 is selected from hydroxy, oxygen, fluorine, O-Hyd 1 , -C(=O)-Hyd 1 , -C(=O)-O-Hyd 1 and Hyd 1 ; wherein Hyd 1 is a C 1-4 non-aromatic hydrocarbon group, optionally substituted with one or more substituents selected from fluorine, hydroxy, and methoxy.

[0233] 1.28B A compound according to Example 1.28A, wherein Cyc 1 is a cyclic group selected from:

[0234] (a-ii) a 4- to 7-membered saturated monocyclic heterocyclic group, wherein the heterocyclic group contains 1 oxygen heteroatom ring member; and (b) a 5- to 6-membered monocyclic heteroaryl group containing 1 or 2 nitrogen heteroatom ring members, and optionally another heteroatom ring member selected from O, N, and S;

[0235] wherein each cyclic group (a-ii) and (b) is an unsubstituted group or is substituted by 1, 2, or 3 substituents R 6 substituted, R 6 is selected from the group consisting of hydroxyl, oxygen, fluorine, O-Hyd 1 , -C(=O)-Hyd 1 , -C(=O)-O-Hyd 1 and Hyd 1 ; wherein Hyd 1 is a C 1-4 non-aromatic hydrocarbon group, optionally substituted by one or more substituents selected from the group consisting of fluorine, hydroxyl, and methoxy.

[0236] 1.28C A compound according to Example 1.28B, wherein Cyc 1 is a cyclic group selected from:

[0237] (a-ii) a 5- to 6-membered saturated monocyclic heterocyclic group, wherein said heterocyclic group contains 1 oxygen heteroatom ring member;

[0238] (b-i) a 5-membered monocyclic heteroaryl group containing 2 or 3 nitrogen heteroatom ring members; and

[0239] (b-ii) a 6-membered monocyclic heteroaryl group containing 1 or 2 nitrogen heteroatom ring members;

[0240] wherein each cyclic group (a-ii), (b-i), and (b-ii) is an unsubstituted group or a group substituted by 1, 2, or 3 substituents R 6 substituted, R 6 is selected from the group consisting of hydroxyl, oxygen, fluorine, O-Hyd 1 , -C(=O)-Hyd 1 , -C(=O)-O-Hyd 1 and Hyd 1 ; wherein Hyd 1 is a C 1-4 non-aromatic hydrocarbon group, optionally substituted by one or more substituents selected from the group consisting of fluorine, hydroxyl, and methoxy.

[0241] 1.28D A compound according to Example 1.28B, wherein Cyc 1 is a cyclic group selected from:

[0242] (a-ii) a 4- to 7-membered saturated monocyclic heterocyclic group, wherein said heterocyclic group contains 1 oxygen heteroatom ring member; wherein each cyclic group (a-ii) is unsubstituted or substituted by 1, 2, or 3 substituents R 6 substituted, R 6 is selected from the group consisting of hydroxyl, oxygen, fluorine, O-Hyd 1 , -C(=O)-Hyd 1, -C(=O)-O-Hyd 1 and Hyd 1 ; wherein Hyd 1 is a C 1-4 non-aromatic hydrocarbon group, optionally substituted with one or more substituents selected from fluorine, hydroxyl, and methoxy.

[0243] 1.28E The compound according to Example 1.28D, wherein Cyc 1 is a cyclic group selected from:

[0244] (a-ii) a 4- to 7-membered saturated monocyclic heterocyclic group, wherein the heterocyclic group contains one oxa-atom ring member; wherein each cyclic group (a-ii) and (b) is unsubstituted or substituted with 1, 2, or 3 substituents R 6 substituted, R 6 is selected from oxygen, fluorine, and Hyd 1 ; wherein Hyd 1 is a C 1-4 non-aromatic hydrocarbon group, optionally substituted with one or more substituents selected from fluorine, hydroxyl, and methoxy.

[0245] 1.28F The compound according to Example 1.28B, wherein Cyc 1 is a cyclic group selected from:

[0246] (b) a 5- to 6-membered monocyclic heteroaryl group containing 1 or 2 nitrogen hetero-atom ring members, and optionally another hetero-atom ring member selected from O, N, and S;

[0247] wherein each cyclic group (b) is an unsubstituted group or is substituted with 1, 2, or 3 substituents R 6 substituted, R 6 is selected from fluorine, O-Hyd 1 and Hyd 1 ; wherein Hyd 1 is a C 1-4 non-aromatic hydrocarbon group, optionally substituted with one or more substituents selected from fluorine, hydroxyl, and methoxy.

[0248] 1.28G The compound according to Example 1.28B, wherein Cyc 1 is a cyclic group selected from:

[0249] (b) a 6-membered monocyclic heteroaryl group containing 1 or 2 nitrogen hetero-atom ring members;

[0250] wherein each cyclic group (b) is an unsubstituted group or is substituted with 1, 2, or 3 substituents R 6 substituted, R 6 is selected from hydroxyl, oxygen, fluorine, O-Hyd 1 , -C(=O)-Hyd1 , -C(=O)-O-Hyd 1 and Hyd 1 ; wherein Hyd 1 is a C 1-4 non-aromatic hydrocarbon group, optionally substituted with one or more substituents selected from fluorine, hydroxy and methoxy.

[0251] 1.28H The compound according to Example 1.28G, wherein Cyc 1 is a cyclic group selected from:

[0252] (b) a 6-membered monocyclic heteroaryl group containing 1 or 2 nitrogen heteroatom ring members;

[0253] wherein each cyclic group (b) is an unsubstituted group or is substituted with 1, 2 or 3 substituents R 6 substituted, R 6 is selected from O-Hyd 1 and Hyd 1 ; wherein Hyd 1 is a C 1-4 non-aromatic hydrocarbon group, optionally substituted with one or more substituents selected from fluorine, hydroxy and methoxy.

[0254] 1.29 The compound according to Example 1.28, wherein Cyc 1 is a cyclic group selected from:

[0255] (a-i) a 3- to 7-membered monocyclic non-aromatic carbocyclic group (e.g., cycloalkyl), which is unsubstituted or substituted as defined in Example 1.27.

[0256] 1.30 The compound according to Example 1.29, wherein Cyc 1 is a cyclic group selected from:

[0257] (a-i) a 4- to 6-membered monocyclic non-aromatic carbocyclic group (e.g., cycloalkyl), which is unsubstituted or substituted as defined in Example 1.27.

[0258] 1.31 The compound according to Example 1.30, wherein the 4- to 6-membered monocyclic non-aromatic carbocyclic group is an unsubstituted or substituted 4- to 6-membered cycloalkyl as defined in Example 1.27.

[0259] 1.32 The compound according to Example 1.30, wherein the 4- to 6-membered cycloalkyl is selected from unsubstituted or substituted cyclobutyl and cyclohexyl as defined in Example 1.27.

[0260] 1.32A The compound according to any one of Examples 0.1 to 1.12 and 1.23 to 1.32, wherein R 1There are 0, 1 or 2 substituents R 6 .

[0261] 1.32B A compound according to any one of Examples 0.1 to 1.12 and 1.23 to 1.32, wherein R 1 has 0 substituents R 6 .

[0262] 1.32C A compound according to any one of Examples 0.1 to 1.12 and 1.23 to 1.32, wherein R 1 has 1 substituent R 6 .

[0263] 1.32D A compound according to any one of Examples 0.1 to 1.12 and 1.23 to 1.32, wherein R 1 has 2 substituents R 6 .

[0264] 1.33 A compound according to any one of Examples 1.28 to 1.32, wherein the carbocyclic group is an unsubstituted group or a carbocyclic group substituted with 1 or 2 substituents R selected from hydroxy, oxygen, fluorine, O-Hyd 1 and Hyd 1 . 6 substituted carbocyclic group.

[0265] 1.34 A compound according to Example 1.33, wherein the carbocyclic group is an unsubstituted group or a carbocyclic group substituted with 1 or 2 substituents R selected from hydroxy, methoxy and methyl 6 substituted carbocyclic group; for example, wherein the carbocyclic group is an unsubstituted group or substituted with 1 substituent R selected from hydroxy and methoxy 6 substituted.

[0266] 1.35 A compound according to Example 1.27, wherein Cyc 1 is a cyclic group selected from:

[0267] (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 group contains 1 or 2 heteroatom ring members selected from O, N, S and S(O) 2 and the heterocyclic group is unsubstituted or substituted as defined in Example 1.27.

[0268] 1.36 A compound according to Example 1.35, wherein Cyc 1 is a cyclic group selected from:

[0269] (a-ii) A 4- to 7-membered non-aromatic (e.g., saturated) monocyclic heterocyclic group, wherein said heterocyclic group contains 1 or 2 heteroatom ring members selected from O, N, S, and S(O) 2 and said heterocyclic group is unsubstituted or substituted as defined in Example 1.27 or Example 1.28.

[0270] 1.36A The compound according to Example 1.36, wherein Cyc 1 is a cyclic group selected from:

[0271] (a-ii) A 4- to 7-membered saturated monocyclic heterocyclic group, wherein said heterocyclic group contains 1 or 2 heteroatom ring members selected from O and N, and is unsubstituted or substituted as defined in Example 1.27 or Example 1.28.

[0272] 1.36B The compound according to Example 1.36, wherein Cyc 1 is a cyclic group selected from:

[0273] (a-ii) A 4- to 7-membered saturated monocyclic heterocyclic group, wherein said heterocyclic group contains 1 heteroatom ring member selected from O and N, and said heterocyclic group is unsubstituted or substituted as defined in Example 1.27 or Example 1.28.

[0274] 1.36C A compound according to Example 1.36, wherein Cyc 1 is a cyclic group selected from oxetane, tetrahydrofuranyl, oxan, oxaspiro[3.3]heptanyl, azetidinyl, pyrrolidinyl, and piperidinyl.

[0275] 1.37 The compound according to Example 1.36, wherein Cyc 1 is a cyclic group selected from:

[0276] (a-ii) A 4- to 6-membered non-aromatic (e.g., saturated) monocyclic heterocyclic group, wherein said heterocyclic group contains 1 or 2 heteroatom ring members selected from O, N, S, and S(O) 2 and said heterocyclic group is unsubstituted or substituted as defined in Example 1.27.

[0277] 1.38 The compound according to Example 1.37, wherein Cyc 1 is a cyclic group selected from:

[0278] (a-ii) A 4- to 6-membered saturated non-aromatic monocyclic heterocyclic group, wherein said heterocyclic group contains 1 or 2 heteroatom ring members selected from O, N, and S, and said heterocyclic group is unsubstituted or substituted as defined in Example 1.27.

[0279] 1.39 The compound according to embodiment 1.38, wherein Cyc 1 is a cyclic group selected from:

[0280] (a-ii) A 4- to 6-membered saturated non-aromatic monocyclic heterocyclic group, wherein the heterocyclic group contains 1 heteroatom ring member selected from O and N, and the heterocyclic group is unsubstituted or substituted as defined in embodiment 1.27.

[0281] 1.40 The compound according to embodiment 1.39, wherein Cyc 1 is a cyclic group selected from oxetanyl, tetrahydrofuranyl, oxanyl, azetidinyl, pyrrolidinyl, and piperidinyl, wherein these groups are unsubstituted or substituted as defined in embodiment 1.27.

[0282] 1.41 The compound according to embodiment 1.40, wherein Cyc 1 is a cyclic group selected from oxetanyl, tetrahydrofuranyl, oxanyl, azetidinyl, and piperidinyl, and each of these groups is unsubstituted or substituted as defined in embodiment 1.27.

[0283] 1.42 The compound according to embodiment 1.40, wherein Cyc 1 is an unsubstituted or substituted oxanyl as defined in embodiment 1.27.

[0284] 1.43 The compound according to any one of embodiments 1.36 to 1.42, wherein the heterocyclic group is unsubstituted or substituted by 1 or 2 substituents R 1 selected from hydroxy, oxygen, fluorine, O-Hyd 1 , -C(=O)-Hyd 1 , and Hyd 6 ; wherein Hyd 1 is a C 1-4 non-aromatic hydrocarbon group (such as alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkylalkyl), optionally substituted by 1 or more substituents selected from fluorine, hydroxy, and methoxy.

[0285] 1.44 The compound according to embodiment 1.43, wherein the heterocyclic group is unsubstituted or substituted by 1 or 2 substituents R 1 selected from hydroxy, fluorine, O-Hyd 1 , -C(=O)-Hyd 1 , -C(=O)-O-Hyd 1 , and Hyd 6 ; wherein Hyd 1 is a saturated C 1-4 hydrocarbon group (such as alkyl, cycloalkyl, or cycloalkylalkyl).

[0286] 1.45 A compound according to Embodiment 1.44 wherein the heterocyclic group is unsubstituted or substituted with 1 or 2 selected from -C(=O)-Hyd 1 、-C(=O)-O-Hyd 1 and Hyd 1 The substituent R 6 Replacement; among them Hyd 1 It is saturated C 1-4 A hydrocarbon group (such as an alkyl group, a cycloalkyl group or a cycloalkylalkyl group).

[0287] 1.46 A compound according to Embodiment 1.45 wherein the heterocyclic group is unsubstituted or substituted by 1 or 2 groups selected from C 1-4 Alkyl (such as methyl), C 1-4 Alkanoyl (such as acetyl) and C 1-4 Substituents R of alkoxycarbonyl (such as tert-butoxycarbonyl) 6 Substituted groups.

[0288] 1.47 A compound according to Embodiment 1.46 wherein the heterocyclic group is unsubstituted or substituted with 1 or 2 C 1-4 Alkyl (such as methyl) substituent R 6 Or choose C 1-4 Alkanoyl (such as acetyl) and C 1-4 Alkoxycarbonyl (eg tert-butoxycarbonyl) is substituted with a single substituent.

[0289] 1.48 A compound according to Embodiment 1.47 wherein the heterocyclic group is unsubstituted or substituted by 1 or 2 methyl groups R 6 Substituted groups.

[0290] 1.49 A compound according to Embodiment 1.47 wherein the heterocyclic group is unsubstituted.

[0291] 1.50 A compound according to Embodiment 1.27 wherein Cyc 1 is a cyclic group selected from:

[0292] (a-ii) a 7- to 9-membered bicyclic heterocyclic group, wherein the heterocyclic group contains 1 or 2 atoms selected from O, N, S and S(O) 2 wherein the heterocyclic group is unsubstituted or substituted as defined in Embodiment 1.27.

[0293] 1.51 A compound according to Embodiment 1.50 wherein Cyc 1 is a cyclic group selected from:

[0294] (a-ii) A 7- to 9-membered bicyclic heterocyclic group, wherein the heterocyclic group contains 1 heteroatom ring member selected from O and N, and the heterocyclic group is an unsubstituted or substituted group as defined in Example 1.27.

[0295] 1.52 The compound according to Example 1.51, wherein Cyc 1 is a cyclic group selected from:

[0296] (a-ii) A 7- to 9-membered bicyclic heterocyclic group, wherein the heterocyclic group is a bridged bicyclic or spiro-bicyclic group containing 1 heteroatom ring member selected from O and N, and the heterocyclic group is an unsubstituted or substituted group as defined in Example 1.27.

[0297] 1.53 The compound according to Example 1.52, wherein Cyc 1 is a 7- to 9-membered bridged bicyclic heterocyclic group containing 1 heteroatom ring member selected from O and N, and the heterocyclic group is an unsubstituted or substituted group as defined in Example 1.27.

[0298] 1.54 The compound according to Example 1.53, wherein the heterocyclic group is an oxabicyclo[3.2.1]octyl group.

[0299] 1.55 The compound according to Example 1.52, wherein Cyc 1 is a 7- to 9-membered spiro bicyclic heterocyclic group containing 1 heteroatom ring member selected from O and N, and the heterocyclic group is an unsubstituted or substituted group as defined in Example 1.27.

[0300] 1.56 The compound according to Example 1.55, wherein the heterocyclic group is an oxaspiro[3.3]heptyl group.

[0301] 1.57 The compound according to Example 1.27, wherein Cyc 1 is a cyclic group selected from:

[0302] (b) A 5- to 6-membered monocyclic heteroaryl containing 1 or 2 heteroatom ring members, wherein 1 heteroatom ring member is N and the other heteroatom ring member (if any) is selected from O, N, and S; and

[0303] (c) Phenyl;

[0304] wherein the heteroaryl and phenyl are unsubstituted groups or substituted groups as defined in Example 1.27.

[0305] 1.58 The compound according to Example 1.57, wherein Cyc 1 is a cyclic group selected from:

[0306] (b) a 5- to 6-membered monocyclic heteroaryl group containing 1 or 2 heteroatom ring members, 1 of which is N and the other heteroatom ring members (if present) are selected from O, N and S; wherein the heteroaryl group is unsubstituted or substituted as defined in Embodiment 1.27.

[0307] 1.59 A compound according to Embodiment 1.58 wherein the 5- to 6-membered monocyclic heteroaryl is selected from unsubstituted pyrazole and pyridine or substituted pyrazole and pyridine as defined in Embodiment 1.27.

[0308] 1.60 A compound according to any one of Embodiments 1.57 to 1.59 wherein the heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from hydroxy, O-Hyd 1 、-C(=O)-Hyd 1 、-C(=O)-O-Hyd 1 and Hyd 1 The substituent R 6 Substituted groups; wherein Hyd 1 It is C 1-4 The non-aromatic hydrocarbon group (eg, alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkylalkyl) is optionally substituted with one or more substituents selected from fluorine, hydroxy and methoxy.

[0309] 1.61 A compound according to Embodiment 1.60 wherein the heteroaryl is unsubstituted or substituted with 1 or 2 groups selected from hydroxy, O-Hyd 1 、-C(=O)-Hyd 1 and Hyd 1 The substituent R 6 Substituted groups; wherein Hyd 1 It is saturated C 1-4 The hydrocarbon group (eg, alkyl, cycloalkyl or cycloalkylalkyl) is optionally substituted with one or more substituents selected from hydroxy and methoxy.

[0310] 1.62 A compound according to Embodiment 1.61 wherein the heteroaryl is unsubstituted or substituted with 1 or 2 moieties selected from O-Hyd 1 and Hyd 1 The substituent R 6 Substituted groups; wherein Hyd 1 It is saturated C 1-4 A hydrocarbon group (eg, an alkyl group, a cycloalkyl group, or a cycloalkylalkyl group).

[0311] 1.63 A compound according to Embodiment 1.61 wherein the heteroaryl is unsubstituted or substituted with 1 or 2 selected from Hyd 1 The substituent R 6 Substituted groups; wherein Hyd1 is a saturated C 1-4 hydrocarbyl group (such as an alkyl group, a cycloalkyl group or a cycloalkylalkyl group).

[0312] 1.64 The compound according to embodiment 1.61, wherein the heteroaryl group is an unsubstituted group or is substituted with 1 or 2 C 1-4 alkyl (such as methyl) substituents R 6 substituted group.

[0313] 1.65 The compound according to embodiment 1.27, wherein Cyc 1 is a cyclic group selected from:

[0314] (c) phenyl;

[0315] wherein the phenyl group is an unsubstituted group or a substituted group as defined in embodiment 1.27.

[0316] 1.66 The compound according to embodiment 1.65, wherein the phenyl group is an unsubstituted group.

[0317] 1.67 The 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 there are 0, 1 or 2 substituents R 6 , the substituent R 6 is selected from hydroxy, oxygen, fluorine, O-Hyd 1 , -C(=O)-Hyd 1 , -C(=O)-O-Hyd 1 and Hyd 1 ; wherein Hyd 1 is a C 1-4 non-aromatic hydrocarbyl group (such as an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group or a cycloalkylalkyl group), optionally substituted with 1 or more substituents selected from fluorine, hydroxy and methoxy.

[0318] 1.67A The 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 there are 0, 1 or 2 substituents R 6 , the substituent R 6 is selected from hydroxy, oxygen, fluorine, amino, NH(Hyd 1 ), N(Hyd 1 ) 2 , O-Hyd 1 , -C(=O)-Hyd 1 , -C(=O)-O-Hyd 1 and Hyd 1 ; wherein Hyd1 is C 1-4 a non-aromatic hydrocarbon group, optionally substituted with one or more substituents selected from fluorine, hydroxyl, and methoxy.

[0319] 1.67B The compound according to any one of Examples 0.1 to 1.13, 1.23 to 1.32, 1.35 to 1.41, 1.50 to 1.59, and 1.65, wherein there are 0, 1, or 2 substituents R 6 , and the substituent R 6 is selected from hydroxyl, oxygen, fluorine, N(Hyd 1 ), 2 (such as -NMe2), O-Hyd 1 (such as methoxy), -C(=O)-Hyd 1 (such as -C(=O)-methyl), -C(=O)-O-Hyd 1 (such as -C(=O)-O-tBu), and Hyd 1 (such as methyl, ethyl, isopropyl); wherein Hyd 1 is C 1-4 a non-aromatic hydrocarbon group, optionally substituted with one or more substituents selected from fluorine, hydroxyl, and methoxy.

[0320] 1.68 The compound according to Example 1.67, wherein there are 0, 1, or 2 substituents R 6 , and the substituent R 6 is selected from hydroxyl, fluorine, O-Hyd 1 , -C(=O)-Hyd 1 , -C(=O)-O-Hyd 1 , and Hyd 1 ; wherein Hyd 1 is C 1-4 a non-aromatic hydrocarbon group (such as alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkylalkyl), optionally substituted with one or more substituents selected from fluorine, hydroxyl, and methoxy.

[0321] 1.69 The compound according to Example 1.68, wherein there are 0, 1, or 2 substituents R 6 , and the substituent R 6 is selected from hydroxyl, O-Hyd 1 , -C(=O)-Hyd 1 , -C(=O)-O-Hyd 1 , and Hyd 1 ; wherein Hyd 1 is C 1-4 a non-aromatic hydrocarbon group (such as alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkylalkyl), optionally substituted with one or more substituents selected from hydroxyl and methoxy.

[0322] 1.70 The compound according to embodiment 1.69, wherein there are 0, 1 or 2 substituents R 6 , and the substituent R 6 is selected from hydroxy, O-Hyd 1 , -C(=O)-Hyd 1 , -C(=O)-O-Hyd 1 and Hyd 1 ; wherein Hyd 1 is a saturated C 1-4 hydrocarbon group (such as an alkyl group, a cycloalkyl group or a cycloalkylalkyl group), optionally substituted by one or more substituents selected from hydroxy and methoxy.

[0323] 1.71 The compound according to embodiment 1.70, wherein there are 0, 1 or 2 substituents R 6 , and the substituent R 6 is selected from hydroxy, O-Hyd 1 , -C(=O)-Hyd 1 , -C(=O)-O-Hyd 1 and Hyd 1 ; wherein Hyd 1 is a saturated C 1-4 hydrocarbon group (such as a saturated C 1-3 hydrocarbon group, such as an alkyl group or a cyclopropyl group).

[0324] 1.72 The compound according to embodiment 1.71, wherein there are 0, 1 or 2 substituents R 6 , and the substituent R 6 is selected from hydroxy, methyl, methoxy, acetyl and tert-butoxycarbonyl.

[0325] 1.73 The compound according to any one of embodiments 1.7, 1.42 to 1.49 and 1.67 to 1.72, which has the general formula (4):

[0326]

[0327] or a pharmaceutically acceptable salt thereof or a tautomer thereof; wherein: R 1 , R 2 , R 3 , R 4 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.

[0328] 1.73A The compound according to embodiment 1.73, having the structure (4A):

[0329]

[0330] 1.73B The compound according to Embodiment 1.73 has the structure (4B):

[0331]

[0332] 1.74 The compound according to any one of Embodiments 1.73 to 1.73B, wherein v is 0, 1, or 2.

[0333] 1.75 The compound according to any one of Embodiments 1.73 to 1.73B, wherein v is 0 or 1.

[0334] 1.76 The compound according to any one of Embodiments 1.73 to 1.73B, wherein v is 0.

[0335] 1.77 The compound according to any one of Embodiments 1.73 to 1.73B, wherein v is 1.

[0336] 1.78 The compound according to any one of Embodiments 1.73 to 1.73B, wherein v is 2.

[0337] 1.79 The compound according to any one of Embodiments 1.73 to 1.73B, wherein v is 3.

[0338] 1.80 The compound according to any one of Embodiments 0.1 to 1.79, wherein R 1 is selected from the AA to ACY groups in Table 1 below, where the * marks the point of attachment of the N atom.

[0339] 1.80A The compound according to any one of Embodiments 0.1 to 1.79, wherein R 1 is selected from the AA to ABI groups in Table 1 below, where the * marks the point of attachment of the N atom.

[0340] Table 1

[0341]

[0342]

[0343]

[0344]

[0345]

[0346]

[0347] 1.81 The compound according to Embodiment 1.80A, wherein R1 Groups AA, AE, AF, AG, and AY selected from Table 1.

[0348] 1.81A The compound according to Example 1.80A, wherein R 1 Groups AA, AE, AF, AG, AY, AAC, AAF, and ABI selected from Table 1.

[0349] 1.81B The compound according to Example 1.80, wherein R 1 Groups AA, ABJ, and ABK selected from Table 1.

[0350] 1.82 The compound according to Example 1.81, wherein R 1 is Group AA in Table 1.

[0351] 1.82A The compound according to Example 1.81A, wherein R 1 is Group ABI in Table 1.

[0352] 1.82B The compound according to Example 1.81B, wherein R 1 is Group ABJ in Table 1.

[0353] 1.82C The compound according to Example 1.81B, wherein R 1 is Group ABK in Table 1.

[0354] 1.83 The compound according to any one of Examples 0.1 to 1.82, wherein R 2 is selected from hydrogen, fluorine, chlorine, and C 1-3 hydrocarbyl, and the C 1-3 hydrocarbyl is optionally substituted with one or more fluorine atoms.

[0355] 1.83A The compound according to any one of Examples 0.1 to 1.82, wherein R 2 is selected from hydrogen, fluorine, chlorine, bromine, and C 1-3 hydrocarbyl, and the C 1-3 hydrocarbyl is optionally substituted with one or more fluorine atoms.

[0356] 1.84 The compound according to Example 1.83, wherein R 2 is selected from hydrogen, fluorine, chlorine, C 1-3 alkyl, C2-3 alkenyl, cyclopropyl, and trifluoromethyl.

[0357] 1.84A The compound according to Example 1.83, wherein R 2 is selected from hydrogen, fluorine, chlorine, bromine, C 1-3 alkyl, C2-3 alkenyl, cyclopropyl, and trifluoromethyl.

[0358] 1.85 The compound according to embodiment 1.84, wherein R 2 is selected from hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl, vinyl, isopropenyl, cyclopropyl, and trifluoromethyl.

[0359] 1.85A The compound according to embodiment 1.84A, wherein R 2 is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, vinyl, isopropenyl, cyclopropyl, and trifluoromethyl.

[0360] 1.86 The compound according to embodiment 1.84, wherein R 2 is selected from fluorine, chlorine, ethyl, isopropyl, vinyl, isopropenyl, cyclopropyl, and trifluoromethyl.

[0361] 1.86A The compound according to embodiment 1.84A, wherein R 2 is selected from fluorine, chlorine, bromine, ethyl, isopropyl, vinyl, isopropenyl, cyclopropyl, and trifluoromethyl.

[0362] 1.87 The compound according to embodiment 1.84, wherein R 2 is selected from chlorine, isopropyl, vinyl, isopropenyl, and cyclopropyl.

[0363] 1.87A The compound according to embodiment 1.84A, wherein R 2 is selected from chlorine, bromine, isopropyl, vinyl, isopropenyl, and cyclopropyl.

[0364] 1.88 The compound according to embodiment 1.84, wherein R 2 is chlorine.

[0365] 1.88A The compound according to embodiment 1.84A, wherein R 2 is bromine.

[0366] 1.89 The compound according to embodiment 1.88, having the general formula (5):

[0367]

[0368] or a pharmaceutically acceptable salt thereof or a tautomer thereof.

[0369] 1.89A The compound according to embodiment 1.89, having the structure (5A):

[0370]

[0371] 1.89B The compound according to embodiment 1.89, having the following structure (5B):

[0372]

[0373] 1.90 The compound according to any one of embodiments 0.1 to 1.89B, wherein Z is CR Z .

[0374] 1.91 The compound according to embodiment 1.90, wherein R z is selected from hydrogen, fluorine, chlorine, methyl, hydroxymethyl and methoxymethyl.

[0375] 1.92 The compound according to embodiment 1.91, wherein R z is selected from hydrogen and fluorine.

[0376] 1.93 The compound according to embodiment 1.92, wherein R z is hydrogen.

[0377] 1.94 The compound according to any one of embodiments 0.1 to 1.89, wherein Z is N.

[0378] 1.95 The compound according to any one of embodiments 0.1 to 1.94, wherein R 4 is selected from hydrogen and C 1-2 alkyl, and the C 1-2 alkyl is optionally substituted with hydroxyl, amino, methylamino, dimethylamino, cyclic amino or methoxy; wherein the cyclic amino is selected from azetidine, pyrrolidine, piperidine, piperazine, N-methyl-piperazine, morpholine and thiomorpholine.

[0379] 1.96 The compound according to embodiment 1.95, wherein R 4 is selected from hydrogen, methyl, -CH 2 OH, -CH 2 NH 2 , -(CH 2 ) 2 OH, -(CH 2 ) 2 OCH 3 and -(CH 2 ) 2 NH 2 .

[0380] 1.97 The compound according to embodiment 1.95, wherein R 4 is selected from hydrogen, methyl, -CH 2 OH and -(CH 2 ) 2 OH.

[0381] 1.98 The compound according to embodiment 1.97, wherein R 4 is hydrogen.

[0382] 1.99 The compound according to embodiment 1.97, wherein R 4 is methyl.

[0383] 1.100 The compound according to embodiment 1.97, wherein R 4 is -CH 2 OH.

[0384] 1.101 The compound according to any one of embodiments 0.1 to 1.100, wherein R 3 is hydrogen.

[0385] 1.102 The compound according to any one of embodiments 0.1 to 1.100, wherein R 3 is the group L 1 -R 7 ; L 1 is selected from a single bond, Alk 2 , Alk 2 -O and Alk 2 -C(=O), wherein Alk 2 is a C 1-4 straight or branched alkylene group, optionally substituted by one or more hydroxyl or fluorine substituents.

[0386] 1.103 The compound according to embodiment 1.102, wherein L 1 is a single bond.

[0387] 1.104 The compound according to embodiment 1.102, wherein L 1 is an Alk 2 group.

[0388] 1.105 The compound according to embodiment 1.102, wherein L 1 is an Alk 2 -O group.

[0389] 1.106 The compound according to embodiment 1.102, wherein L 1 is Alk 2 -C(=O).

[0390] 1.106A The compound according to any one of embodiments 0.1 to 1.102 and 1.104 to 1.106, wherein Alk 2 is selected from C 1-4 straight or branched alkylene group, optionally substituted by one or more hydroxyl substituents.

[0391] 1.107 The compound according to any one of embodiments 0.1 to 1.102 and 1.104 to 1.106, wherein Alk 2Selected from C 1-4 A linear or branched alkylene group.

[0392] 1.107A The compound according to embodiment 1.106A, wherein Alk 2 Selected from C 1-3 A linear or branched alkylene group, optionally substituted with one or more hydroxyl substituents.

[0393] 1.108 The compound according to embodiment 1.107, wherein Alk 2 Selected from C 1-3 A linear or branched alkylene group.

[0394] 1.108A The compound according to embodiment 1.107A, wherein Alk 2 Selected from CH 2 、CH(CH 3 )、CH(CH 2 OH) and CH(CH 2 CH 3 ).

[0395] 1.109 The compound according to embodiment 1.108, wherein Alk 2 Selected from CH 2 、CH 2 CH 2 、CH(CH 3 ) and C(CH 3 ) 2 .

[0396] 1.109A The compound according to embodiment 1.109, wherein Alk 2 Selected from CH 2 and CH(CH 3 ).

[0397] 1.110 The compound according to embodiment 1.109, wherein Alk 2 is CH 2 .

[0398] 1.110A The compound according to embodiment 1.109, wherein Alk 2 is CH(CH 3 ).

[0399] 1.110B The compound according to embodiment 1.108A, wherein Alk 2 is CH(CH 2 OH).

[0400] 1.111 The compound according to any one of embodiments 1.106 to 1.110 has the following general formula (6):

[0401]

[0402] or a pharmaceutically acceptable salt or tautomer thereof.

[0403] 1.111A The compound according to Example 1.111 has the following structure (6A):

[0404]

[0405] 1.111B The compound according to Example 1.111 has the following structure (6B):

[0406]

[0407] 1.112 The compound according to Example 1.111 has the following general formula (7):

[0408]

[0409] or a pharmaceutically acceptable salt or tautomer thereof.

[0410] 1.112A The compound according to Example 1.112 has the following structural formula (7A):

[0411]

[0412] 1.112B The compound according to Example 1.112 has the following structural formula (7B):

[0413]

[0414] 1.112C The compound according to any one of Examples 1.111 to 1.112B, wherein the following moiety:

[0415]

[0416] has the structure:

[0417]

[0418] wherein Alk 2a is the residue of Alk 2

[0419] 1.112D The compound according to any one of Examples 1.111 to 1.112B, wherein the following moiety:

[0420] ​

[0421] Has a structure:

[0422]

[0423] Wherein Alk 2a Is Alk 2 Residue of.

[0424] 1.112E A compound according to Example 1.112C or 1.112D, wherein Alk 2a Is selected from hydrogen and C 1-3 Alkyl, said C 1-3 Alkyl is optionally substituted with a hydroxyl group.

[0425] 1.112F A compound according to Example 1.112E, wherein Alk 2a Is selected from hydrogen and methyl.

[0426] 1.112G A compound according to Example 1.112F, wherein Alk 2a Is hydrogen.

[0427] 1.112H A compound according to Example 1.112E, wherein Alk 2a Is methyl.

[0428] 1.113 A compound according to any one of Examples 0.1 to 1.100 and 1.102 to 1.112H, wherein R 7 Is selected from:

[0429] · NR 8 R 9 ;

[0430] · A carbocyclic or heterocyclic group having 3 to 12 ring members, wherein 0, 1, 2 or 3 ring members are heteroatom ring members selected from O, N, S and the oxidized forms of S, wherein the carbocyclic or heterocyclic group is connected to L through its carbocyclic members, and wherein the carbocyclic or heterocyclic group is optionally substituted with one or more substituents R 1 Connected, and wherein the carbocyclic or heterocyclic group is optionally substituted with one or more substituents R 10 Substituted; and

[0431] · A non-cyclic C 1-8 Hydrocarbyl, optionally substituted with one or more substituents selected from hydroxyl, oxygen, halogen, cyano, carboxyl, amino, mono- or di-C 1-4 Alkylamino, and carbocyclic and heterocyclic groups having 3 to 12 ring members, wherein 0, 1, 2 or 3 ring members of the carbocyclic or heterocyclic group are heteroatom ring members selected from O, N, S, the oxidized forms of S, and the carbocyclic or heterocyclic group is optionally substituted with one or more substituents R 10 Substituted; wherein the non-cyclic C 1-8One or two but not all carbon atoms of the hydrocarbyl group may optionally be replaced by O, S, SO, SO 2 or NR 11 substituted.

[0432] 1.114 The compound according to embodiment 1.113, wherein R 7 is a carbocyclic or heterocyclic group having 3 to 12 ring members, wherein 0, 1, 2 or 3 ring members are heteroatom ring members selected from O, N, S and the oxidized forms of S, wherein the carbocyclic or heterocyclic group is connected to L through its carbocyclic members 1 and wherein the carbocyclic or heterocyclic group is optionally substituted by one or more substituents R 10 substituted.

[0433] 1.115 The compound according to embodiment 1.114, wherein R 7 is a monocyclic carbocyclic or heterocyclic group having 3 to 7 ring members, wherein 0, 1, 2 or 3 ring members are heteroatom ring members selected from O, N, S and the oxidized forms of S, wherein the carbocyclic or heterocyclic group is connected to L through its carbocyclic members 1 and wherein the carbocyclic or heterocyclic group is optionally substituted by one or more substituents R 10 substituted.

[0434] 1.116 The compound according to embodiment 1.115, wherein R 7 is a monocyclic carbocyclic or heterocyclic group selected from:

[0435] · C 3-6 cycloalkyl;

[0436] · phenyl;

[0437] · a 4- to 7-membered non-aromatic heterocyclic group containing 1, 2 or 3 heteroatom ring members selected from O, N, S and the oxidized forms of S; and

[0438] · a 5-6-membered heteroaryl group containing 1, 2 or 3 heteroatom ring members selected from O, N and S;

[0439] each of the monocyclic carbocyclic and heterocyclic groups is optionally substituted by one or more substituents R 10 substituted.

[0440] 1.117 The compound according to embodiment 1.116, wherein R 7 is a monocyclic carbocyclic or heterocyclic group selected from:

[0441] · C 3-6 cycloalkyl;

[0442] · phenyl;

[0443] · A 4- to 7-membered non-aromatic heterocyclic group containing 1, 2 or 3 heteroatom ring members selected from O, N, S and the oxidized form of S; and

[0444] · A 5- to 6-membered heteroaryl group containing 1, 2 or 3 heteroatom ring members selected from O, N and S;

[0445] Each of the monocyclic carbocyclic and heterocyclic groups is optionally substituted by one or more substituents R 10 Substituted.

[0446] 1.118 The compound according to embodiment 1.117, wherein R 7 is a monocyclic carbocyclic or heterocyclic group selected from:

[0447] · C 3-6 Cycloalkyl;

[0448] · A 4- to 6-membered non-aromatic heterocyclic group containing 1, 2 or 3 heteroatom ring members selected from O, N, S and the oxidized form of S; and

[0449] · A 5-membered heteroaryl group containing 1, 2 or 3 heteroatom ring members selected from O, N and S;

[0450] Each of the monocyclic carbocyclic and heterocyclic groups is optionally substituted by one or more substituents R 10 Substituted.

[0451] 1.119 The compound according to embodiment 1.118, wherein R 7 is a monocyclic carbocyclic or heterocyclic group selected from:

[0452] · C 3-5 Cycloalkyl;

[0453] · A 4- to 6-membered non-aromatic heterocyclic group containing 1, 2 or 3 heteroatom ring members selected from O, N, S and the oxidized form of S; and

[0454] · A 5-membered heteroaryl group containing 1, 2 or 3 heteroatom ring members selected from O and N;

[0455] Each of the monocyclic carbocyclic and heterocyclic groups is optionally substituted by one or more substituents R 10 Substituted.

[0456] 1.120 The compound according to embodiment 1.119, wherein R 7 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 is optionally substituted by one or more substituents R 10 Substituted.

[0457] 1.121 The compound according to embodiment 1.113, wherein R 7 is an acyclic C 1-8 hydrocarbyl group, optionally substituted with one or more substituents selected from hydroxy, oxygen, halogen, cyano, carboxy, amino, mono- or di-C 1-4 alkylamino, and carbocyclic and heterocyclic groups having 3 to 12 ring members, wherein 0, 1, 2 or 3 ring members of the carbocyclic and heterocyclic groups are heteroatom ring members selected from O, N, S and the oxidized forms of S, and the carbocyclic or heterocyclic group is optionally substituted with one or more substituents R 10 ; wherein one or two but not all carbon atoms of the acyclic C 1-8 hydrocarbyl group may optionally be substituted with O, S, SO, SO 2 or NR 11 .

[0458] 1.122 The compound according to embodiment 1.121, wherein R 7 is an acyclic C 1-4 hydrocarbyl group, optionally substituted with one or more substituents selected from hydroxy, oxygen, halogen, amino, mono- or di-C 1-4 alkylamino, and carbocyclic and heterocyclic groups having 3 to 7 ring members, wherein 0, 1, 2 or 3 ring members of the carbocyclic and heterocyclic groups are heteroatom ring members selected from O, N, S and the oxidized forms of S, and the carbocyclic or heterocyclic group is optionally substituted with one or more substituents R 10 ; wherein one but not all carbon atoms of the acyclic C 1-4 hydrocarbyl group may optionally be substituted with O, S, SO, SO 2 or NR 11 .

[0459] 1.123 The compound according to embodiment 1.122, wherein R 7 is an acyclic C 1-4 hydrocarbyl group, optionally substituted with one or more substituents selected from hydroxy, oxygen, fluorine, amino, mono- or di-C 1-4 alkylamino, and carbocyclic and heterocyclic groups having 3 to 7 ring members, wherein 0, 1, 2 or 3 ring members of the carbocyclic and heterocyclic groups are heteroatom ring members selected from O, N, S and the oxidized forms of S, and the carbocyclic or heterocyclic group is optionally substituted with one or more substituents R 10 ; wherein one but not all carbon atoms of the acyclic C 1-4 hydrocarbyl group may optionally be substituted with O or NR 11 .

[0460] 1.124 The compound according to embodiment 1.123, wherein R 7 is an acyclic C1-4 A hydrocarbyl group, optionally substituted with one or more substituents selected from hydroxy, amino, mono- or di-C 1-4 alkylamino, and carbocyclic and heterocyclic groups having 3 to 6 ring members, wherein 0, 1, 2 or 3 ring members of the carbocyclic and heterocyclic groups are heteroatom ring members selected from O and N, and the carbocyclic or heterocyclic group is optionally substituted with one or more substituents R 10 ; wherein one but not all of the carbon atoms of the acyclic C 1-4 hydrocarbyl group may optionally be substituted with O or NR 11 .

[0461] 1.125 The compound according to embodiment 1.123, wherein R 7 is an acyclic C 1-4 hydrocarbyl group; wherein one but not all of the carbon atoms of the acyclic C 1-4 hydrocarbyl group may optionally be substituted with O.

[0462] 1.126 The compound according to embodiment 1.113, wherein R 7 is an NR 8 R 9 group.

[0463] 1.127 The compound according to embodiment 1.126, wherein R 8 is selected from hydrogen, C 1-4 alkyl, cyclobutyl, cyclopropylmethyl and hydroxy-C 2-4 -alkyl.

[0464] 1.128 The compound according to embodiment 1.127, wherein R 8 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, hydroxyethyl and hydroxypropyl.

[0465] 1.129 The compound according to embodiment 1.128, wherein R 8 is selected from hydrogen, methyl, ethyl and hydroxyethyl.

[0466] 1.130 The compound according to embodiment 1.129, wherein R 8 is selected from hydrogen and methyl.

[0467] 1.131 The compound according to embodiment 1.130, wherein R 8 is hydrogen.

[0468] 1.132 The compound according to embodiment 1.130, wherein R 8 is methyl.

[0469] 1.133 The compound according to any one of embodiments 1.126 to 1.131, wherein R9 Selected from:

[0470] · hydrogen;

[0471] · a carbocyclic or heterocyclic group having 3 to 10 ring members, wherein 0, 1 or 2 ring members are heteroatom ring members selected from O, N, S and the oxidized forms of S, and the carbocyclic or heterocyclic group is optionally substituted by one or more substituents R 10 substituted; and

[0472] · an acyclic C 1-8 hydrocarbyl group, optionally substituted by one or more substituents selected from hydroxy, oxygen, halogen, carboxyl, amino, mono- or di-C 1-4 alkylamino and carbocyclic and heterocyclic groups having 3 to 10 ring members, wherein 0, 1 or 2 ring members of the carbocyclic and heterocyclic groups are heteroatom ring members selected from O, N, S, the oxidized forms of S, and the carbocyclic or heterocyclic group is optionally substituted by one or more substituents R 10 substituted; wherein one or two but not all carbon atoms of the acyclic C 1-8 hydrocarbyl group may optionally be substituted by O, S, SO 2 or NR 11 substituted.

[0473] 1.133A The compound according to embodiment 1.133, wherein R 9 is an acyclic C 1-8 hydrocarbyl group, optionally substituted by one or more substituents selected from hydroxy and carbocyclic and heterocyclic groups having 3 to 10 ring members, wherein 0, 1 or 2 ring members of the carbocyclic and heterocyclic groups are heteroatom ring members selected from O, N, S and the oxidized forms of S, and the carbocyclic or heterocyclic group is optionally substituted by one or more substituents R 10 substituted; wherein one or two but not all carbon atoms of the acyclic C 1-8 hydrocarbyl group may optionally be substituted by O, S, SO 2 or NR 11 substituted.

[0474] 1.133B The compound according to embodiment 1.133A, wherein R 9 is an acyclic C 1-8 hydrocarbyl group, optionally substituted by one or more substituents selected from hydroxy and carbocyclic and heterocyclic groups having 3 to 10 ring members, wherein 0, 1 or 2 ring members of the carbocyclic and heterocyclic groups are heteroatom ring members selected from O, N, S and the oxidized forms of S, and the carbocyclic or heterocyclic group is optionally substituted by one or more substituents R 10 substituted.

[0475] 1.133C The compound according to embodiment 1.133B, wherein R9 is an acyclic C 1-3 hydrocarbyl group, optionally substituted with one or more substituents selected from hydroxy and carbocyclic and heterocyclic groups having 3 to 10 ring members, wherein 0, 1 or 2 ring members of said carbocyclic and heterocyclic groups are heteroatom ring members selected from O, N, S and the oxidized forms of S, and said carbocyclic or heterocyclic group is optionally substituted with one or more substituents R 10 .

[0476] 1.134 The compound according to embodiment 1.131 or embodiment 1.132, wherein R 9 is selected from:

[0477] · hydrogen;

[0478] · a carbocyclic or heterocyclic group having 3 to 10 ring members, wherein 0, 1 or 2 ring members are heteroatom ring members selected from O and N, and said carbocyclic or heterocyclic group is optionally substituted with one or more substituents R 10 ; and

[0479] · an acyclic C 1-8 hydrocarbyl group, optionally substituted with one or more substituents selected from hydroxy, oxygen, halogen, carboxyl, amino, mono- or di-C 1-4 alkylamino and carbocyclic and heterocyclic groups having 3 to 10 ring members, wherein 0 or 1 ring member of said carbocyclic and heterocyclic groups is a heteroatom ring member selected from O and N, and said carbocyclic or heterocyclic group is optionally substituted with one or more substituents R 10 ; wherein one or two but not all carbon atoms of the acyclic C 1-8 hydrocarbyl group may optionally be substituted with O, S, SO 2 or NR 11 .

[0480] 1.135 The compound according to embodiment 1.134, wherein R 9 is selected from:

[0481] · hydrogen;

[0482] · a carbocyclic group having 3 to 10 ring members, said carbocyclic group being optionally substituted with one or more substituents R 10 ; and

[0483] · a heterocyclic group having 4 to 10 ring members, wherein 1 or 2 ring members are heteroatom ring members selected from O and N, and said heterocyclic group is optionally substituted with one or more substituents R 10 ; and

[0484] · an acyclic C 1-8An alkyl group, optionally substituted with one or more substituents selected from the group consisting of hydroxyl, oxygen, halogen, carboxyl, amino, mono- or di-C 1-4 alkylamino; and carbocyclic and heterocyclic groups having 3 to 10 ring members, wherein 0 or 1 ring member of said carbocyclic and heterocyclic groups is a heteroatom ring member selected from O and N, and said carbocyclic or heterocyclic group is optionally substituted with one or more substituents R 10 wherein one or two but not all of the carbon atoms of said acyclic C 1-8 hydrocarbon group may optionally be substituted with O, S, SO 2 or NR 11 substituted.

[0485] 1.136 The compound according to embodiment 1.135, wherein R 9 is selected from:

[0486] · hydrogen;

[0487] · a carbocyclic group having 3 to 10 ring members, said carbocyclic group being optionally substituted with one or more substituents R 10 substituted;

[0488] · a heterocyclic group having 4 to 10 ring members, wherein 1 or 2 ring members are heteroatom ring members selected from O and N, and said heterocyclic group is optionally substituted with one or more substituents R 10 substituted; and

[0489] · an acyclic C 1-8 hydrocarbon group, optionally substituted with one or more substituents selected from the group consisting of hydroxyl, oxygen, halogen, carboxyl, amino, mono- or di-C 1-4 alkylamino; and carbocyclic and heterocyclic groups having 3 to 10 ring members, wherein 0 or 1 ring member of said carbocyclic and heterocyclic groups is a heteroatom ring member selected from O and N, and said carbocyclic or heterocyclic group is optionally substituted with one or more substituents R 10 substituted; wherein one or two but not all of the carbon atoms of said acyclic C 1-8 hydrocarbon group may optionally be substituted with O, S, SO 2 or NR 11 substituted.

[0490] 1.137 The compound according to embodiment 1.136, wherein R 9 is selected from:

[0491] · hydrogen;

[0492] · a monocyclic carbocyclic group having 3 to 6 ring members, said monocyclic carbocyclic group being optionally substituted with one or more substituents R 10 substituted;

[0493] · A bicyclic carbocyclic group having 7 to 10 ring members, said bicyclic carbocyclic group being optionally substituted by one or more substituents R 10 substituted;

[0494] · A monocyclic heterocyclic group having 4 to 7 ring members, wherein 1 ring member is a heteroatom ring member selected from O and N, said heterocyclic group being optionally substituted by 1 or more substituents R 10 substituted; and

[0495] · An acyclic C 1-8 hydrocarbyl group, optionally substituted by one or more substituents selected from hydroxy, oxygen, halogen, amino, mono- or di-C 1-4 alkylamino; and a carbocyclic and heterocyclic group having 3 to 10 ring members, wherein 0 or 1 ring member of said carbocyclic and heterocyclic group is a heteroatom ring member selected from O and N, said carbocyclic or heterocyclic group being optionally substituted by 1 or more substituents R 10 wherein 1 or 2 but not all carbon atoms of said acyclic C 1-8 hydrocarbyl group may optionally be substituted by O, S, SO 2 or NR 11 substituted.

[0496] 1.138 The compound according to embodiment 1.137, wherein R 9 is selected from:

[0497] · Hydrogen;

[0498] · A monocyclic non-aromatic carbocyclic group having 3 to 6 ring members, said monocyclic non-aromatic carbocyclic group being optionally substituted by one or more substituents R 10 substituted;

[0499] · A bicyclic carbocyclic group having 7 to 10 ring members, said bicyclic carbocyclic group being non-aromatic or containing no more than 1 aromatic ring, said bicyclic carbocyclic group being optionally substituted by one or more substituents R 10 substituted;

[0500] · A monocyclic heterocyclic group having 4 to 7 ring members, wherein 1 ring member is a heteroatom ring member selected from O and N, said heterocyclic group being optionally substituted by 1 or more substituents R 10 substituted; and

[0501] · An acyclic C 1-8 hydrocarbyl group, optionally substituted by one or more substituents selected from hydroxy, oxygen, halogen, amino, mono- or di-C 1-4 alkylamino; and a carbocyclic and heterocyclic group having 3 to 10 ring members, wherein 0 or 1 ring member of said carbocyclic and heterocyclic group is a heteroatom ring member selected from O and N, said carbocyclic or heterocyclic group being optionally substituted by 1 or more substituents R10 Substituted; wherein one or two but not all carbon atoms of said acyclic C 1-8 hydrocarbyl group may optionally be substituted by O, S, SO 2 or NR 11 Substituted.

[0502] 1.138A The compound according to embodiment 1.138, wherein R 9 is an acyclic C 1-8 hydrocarbyl group, optionally substituted by one or more substituents selected from hydroxyl and carbocyclic and heterocyclic groups having 3 to 10 ring members, wherein 0 or 1 ring member of said carbocyclic and heterocyclic groups is a heteroatom ring member selected from O and N, and said carbocyclic or heterocyclic group is optionally substituted by one or more substituents R 10 Substituted; wherein one or two but not all carbon atoms of said acyclic C 1-8 hydrocarbyl group may optionally be substituted by O, S, SO 2 or NR 11 Substituted.

[0503] 1.138B The compound according to embodiment 1.138A, wherein R 9 is an acyclic C 1-8 hydrocarbyl group, optionally substituted by one or more substituents selected from hydroxyl and carbocyclic and heterocyclic groups having 3 to 10 ring members, wherein 0 or 1 ring member of said carbocyclic and heterocyclic groups is a heteroatom ring member selected from O and N, and said carbocyclic or heterocyclic group is optionally substituted by one or more substituents R 10 Substituted.

[0504] 1.138C The compound according to embodiment 1.138B, wherein R 9 is an acyclic C 1-3 hydrocarbyl group, optionally substituted by one or more substituents selected from hydroxyl and carbocyclic and heterocyclic groups having 3 to 10 ring members, wherein 0 or 1 ring member of said carbocyclic and heterocyclic groups is a heteroatom ring member selected from O and N, and said carbocyclic or heterocyclic group is optionally substituted by one or more substituents R 10 Substituted.

[0505] 1.139 The compound according to embodiment 1.138, wherein R 9 is selected from:

[0506] · Hydrogen;

[0507] · A monocyclic saturated carbocyclic group having 3 to 6 ring members, said monocyclic saturated carbocyclic group being optionally substituted by one or more substituents R 10 Substituted;

[0508] · A bicyclic carbocyclic group having 9 or 10 ring members, said bicyclic carbocyclic group comprising an aromatic ring and a non-aromatic ring, said bicyclic carbocyclic group being optionally substituted by one or more substituents R 10 substituted;

[0509] · A monocyclic heterocyclic group having 4 to 6 ring members, wherein 1 ring member is a heteroatom ring member selected from O, said heterocyclic group being optionally substituted by 1 or more substituents R 10 substituted; and

[0510] · An acyclic saturated C 1-8 hydrocarbyl group, optionally substituted by 1 or more substituents selected from hydroxy, halogen, amino, mono- or di-C 1-4 alkylamino, phenyl, and a monocyclic heterocyclic group having 4 to 6 ring members, wherein 1 ring member of said monocyclic heterocyclic group is a heteroatom ring member selected from O and N, said phenyl or heterocyclic group being optionally substituted by 1 or more substituents R 10 substituted; wherein 1 but not all of the carbon atoms of said acyclic C 1-8 hydrocarbyl group may optionally be substituted by O, S, SO 2 or NR 11 substituted.

[0511] 1.139A The compound according to Example 1.139, wherein R 9 is an acyclic saturated C 1-8 hydrocarbyl group, optionally substituted by 1 or more substituents selected from hydroxy, phenyl, and a monocyclic heterocyclic group having 4 to 6 ring members, wherein 1 ring member of said monocyclic heterocyclic group is a heteroatom ring member selected from O and N, said phenyl or heterocyclic group being optionally substituted by 1 or more substituents R 10 substituted; wherein 1 but not all of the carbon atoms of said acyclic C 1-8 hydrocarbyl group may optionally be substituted by O, S, SO 2 or NR 11 substituted.

[0512] 1.139B The compound according to Example 1.139A, wherein R 9 is an acyclic saturated C 1-3 hydrocarbyl group, optionally substituted by 1 or more substituents selected from hydroxy, phenyl, and a monocyclic heterocyclic group having 4 to 6 ring members, wherein 1 ring member of said monocyclic heterocyclic group is a heteroatom ring member selected from O and N, said phenyl or heterocyclic group being optionally substituted by 1 or more substituents R 10 substituted.

[0513] 1.139C The compound according to Example 1.139B, wherein R 9 is an acyclic saturated C 1-3A hydrocarbyl group, optionally substituted with one or more substituents selected from hydroxy, phenyl, and pyridyl, said phenyl or pyridyl being optionally substituted with one or more substituents R 10 substituted.

[0514] 1.139D The compound according to Example 1.139C, wherein R 9 is an acyclic saturated C 1-3 hydrocarbyl group, optionally substituted with one or more substituents selected from hydroxy and phenyl, said phenyl being optionally substituted with one or more substituents R 10 substituted.

[0515] 1.139E The compound according to Example 1.139C, wherein R 9 is an acyclic saturated C 1-3 hydrocarbyl group, optionally substituted with one or more substituents selected from hydroxy and phenyl, said phenyl being optionally substituted with one or more substituents R 10 substituted, wherein R 10 is selected from: fluorine, chlorine, hydroxy, oxygen, cyano, and OR 12 wherein R 12 is methyl, ethyl, propyl, isopropyl or cyclopropyl, each group being optionally substituted with fluorine.

[0516] 1.139F The compound according to Example 1.139C, wherein R 9 is an acyclic saturated C 1-3 hydrocarbyl group, optionally substituted with one or more substituents selected from hydroxy and phenyl, said phenyl being optionally substituted with one or two substituents R 10 substituted, wherein R 10 is selected from: fluorine and OR 12 wherein R 12 is methyl, ethyl, propyl, isopropyl or cyclopropyl, each group being optionally substituted with fluorine.

[0517] 1.139G The compound according to Example 1.139C, wherein R 9 is an acyclic saturated C 1-3 hydrocarbyl group, optionally substituted with one or more substituents selected from hydroxy and phenyl, said phenyl being optionally substituted with one or two substituents R 10 substituted, wherein R 10 is selected from: fluorine and OR 12 wherein R 12 is methyl, ethyl, propyl, isopropyl or cyclopropyl, each group being an unsubstituted group.

[0518] 1.139H The compound according to Example 1.139C, wherein R 9 is an acyclic saturated C 1-3An alkyl group, optionally substituted with one or more substituents selected from hydroxyl and phenyl, wherein the phenyl is optionally substituted with one or two substituents R 10 substituted, where R 10 is selected from: fluorine and OR 12 , where R 12 is unsubstituted methyl.

[0519] 1.139J A compound according to any one of Examples 1.133 to 1.139H, wherein R 9 is an acyclic saturated hydrocarbon group substituted with a carbocyclic or heterocyclic group and optionally hydroxyl, wherein the acyclic saturated hydrocarbon group has the following structure:

[0520]

[0521] where R 15 is C 1-3 alkyl or hydroxy-C 1-3 alkyl, "a" represents the attachment point of the carbocyclic or heterocyclic group, and "b" represents the attachment point of the nitrogen atom of NR 8 R 9 R.

[0522] 1.139K A compound according to any one of Examples 1.133 to 1.139H, wherein R 9 is an acyclic saturated hydrocarbon group substituted with a carbocyclic or heterocyclic group and optionally hydroxyl, wherein the acyclic saturated hydrocarbon group has the following structure:

[0523]

[0524] where R 15 is C 1-3 alkyl or hydroxy-C 1-3 alkyl, "a" represents the attachment point of the carbocyclic or heterocyclic group, and "b" represents the attachment point of the nitrogen atom of NR 8 R 9 R.

[0525] 1.140 A compound according to Example 1.139, wherein R 9 is selected from:

[0526] · hydrogen;

[0527] · cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, each group optionally substituted with one or more substituents R 10 substituted;

[0528] · indane and tetrahydronaphthalene, each of which is optionally substituted with one or more substituents R 10 substituted;

[0529] · Oxetanyl and oxanyl, optionally substituted by one or more substituents R 10 substituted; and

[0530] · Acyclic saturated C 1-6 hydrocarbyl, optionally substituted by one or more substituents selected from hydroxy, halogen, amino, mono- or di-C 1-4 alkylamino, phenyl and oxetanyl, wherein the phenyl or oxetanyl is optionally substituted by one or more substituents R 10 substituted.

[0531] 1.140A A compound according to any one of Examples 0.1 to 1.132, wherein R 9 is selected from the HA to SX groups in Table 3 below, where the * marks the point of attachment of the N atom.

[0532]

[0533]

[0534]

[0535]

[0536]

[0537]

[0538]

[0539]

[0540]

[0541]

[0542]

[0543] 1.140B A compound according to Example 1.140A, wherein R 9 is selected from: the groups IH, KQ, NG and NP in Table 3, where the * marks the point of attachment of the N atom.

[0544] 1.140C A compound according to Example 1.140A, wherein R 9 is selected from: the groups SV, SW and SX in Table 3, where the * marks the point of attachment of the N atom.

[0545] 1.140D A compound according to Example 1.140B, wherein R9 is the group NG in Table 3, where the * marks the point of attachment of the N atom.

[0546] 1.140E The compound according to Example 1.140B, wherein R 9 is the group SW in Table 3, where the * marks the point of attachment of the N atom.

[0547] 1.141 The compound according to Example 1.126, wherein NR 8 R 9 forms a heterocyclic group having 4 to 12 ring members; wherein, in addition to the nitrogen atom of NR 8 R 9 , the heterocyclic group optionally further contains 1 or 2 heteroatom ring members selected from O, N, S, and the oxidized forms of S; wherein the heterocyclic group is optionally substituted by one or more substituents R 10 substituted.

[0548] 1.142 The compound according to Example 1.141, wherein NR 8 R 9 forms a heterocyclic group having 4 to 11 ring members; wherein, in addition to the nitrogen atom of NR 8 R 9 , the heterocyclic group optionally further contains 1 or 2 heteroatom ring members selected from O and N; wherein the heterocyclic group is optionally substituted by one or more substituents R 10 substituted.

[0549] 1.143 The compound according to Example 1.142, wherein NR 8 R 9 forms a heterocyclic group selected from:

[0550] · a monocyclic heterocyclic group having 4 to 7 ring members, wherein, in addition to the nitrogen atom of NR 8 R 9 , the heterocyclic group optionally further contains 1 or 2 heteroatom ring members selected from O and N; wherein the heterocyclic group is optionally substituted by one or more substituents R 10 substituted;

[0551] · a non-aromatic bicyclic heterocyclic group having 7 to 10 ring members, wherein, in addition to the nitrogen atom of NR 8 R 9 , the heterocyclic group optionally further contains 1 or 2 heteroatom ring members selected from O and N; wherein the heterocyclic group is optionally substituted by one or more substituents R 10 substituted; and

[0552] · A bicyclic heterocyclic group having 7 to 11 ring members, one ring of the bicyclic heterocyclic group being an aromatic ring and the other ring being a non-aromatic ring; wherein, except for the nitrogen atom of NR 8 R 9 , the heterocyclic group optionally further contains 1 or 2 heteroatomic ring members selected from O and N; wherein the heterocyclic group is optionally substituted by one or more substituents R 10 .

[0553] 1.144 The compound according to embodiment 1.143, wherein NR 8 R 9 forms a heterocyclic group, and the heterocyclic group is selected from:

[0554] · A monocyclic heterocyclic group having 4 to 7 ring members, wherein, except for the nitrogen atom of NR 8 R 9 , the heterocyclic group optionally further contains 1 or 2 heteroatomic ring members selected from O and N; wherein the heterocyclic group is optionally substituted by one or more substituents R 10 ;

[0555] 1.145 The compound according to embodiment 1.143 or embodiment 1.144, wherein the monocyclic heterocyclic group is a non-aromatic group.

[0556] 1.146 The compound according to embodiment 1.145, wherein the monocyclic heterocyclic group is selected from azetidine, pyrrolidine, piperidine, azepane, morpholine and piperazine, and the heterocyclic group is optionally substituted by one or more substituents R 10 .

[0557] 1.147 The compound according to embodiment 1.143, wherein NR 8 R 9 forms a heterocyclic group, and the heterocyclic group is selected from:

[0558] · A non-aromatic bicyclic heterocyclic group having 7 to 10 ring members, wherein, except for the nitrogen atom of NR 8 R 9 , the heterocyclic group optionally further contains 1 or 2 heteroatomic ring members selected from O and N; wherein the heterocyclic group is optionally substituted by one or more substituents R 10 .

[0559] 1.148 The compound according to embodiment 1.147, wherein NR 8 R 9 forms a heterocyclic group, and the heterocyclic group is selected from:

[0560] · Non-aromatic fused bicyclic, spirobicyclic, and bridged bicyclic heterocyclic groups having from 7 to 10 ring members, wherein, in addition to the nitrogen atom of NR 8 R 9 the heterocyclic group optionally further contains 1 heteroatom ring member selected from O and N; and wherein the heterocyclic group is optionally substituted by one or more substituents R 10 Substituted.

[0561] 1.149 The compound according to embodiment 1.148, wherein NR 8 R 9 forms a heterocyclic group selected from:

[0562] · Non-aromatic fused bicyclic, spirobicyclic, and bridged bicyclic heterocyclic groups having from 7 to 10 ring members, wherein, in addition to the nitrogen atom of NR 8 R 9 the heterocyclic group optionally does not contain additional heteroatom ring members; and wherein the heterocyclic group is optionally substituted by one or more substituents R 10 Substituted.

[0563] 1.150 The compound according to embodiment 1.149, wherein NR 8 R 9 forms a non-aromatic heterocyclic group selected from 5.5 fused bicyclic heterocycles, 5.6 fused bicyclic heterocycles, spiropropylpiperidine, azabicyclo-heptane, and azabicyclooctane, and wherein the heterocyclic group is optionally substituted by one or more substituents R 10 Substituted.

[0564] 1.151 The compound according to embodiment 1.141, wherein NR 8 R 9 constitutes a heterocyclic group selected from:

[0565] · A fused bicyclic heterocyclic group having from 7 to 11 ring members, one ring of the fused bicyclic heterocyclic group being an aromatic ring and the other ring being a non-aromatic ring; wherein, in addition to the nitrogen atom of NR 8 R 9 the heterocyclic group optionally further contains 1 or 2 heteroatom ring members selected from O and N; and wherein the heterocyclic group is optionally substituted by one or more substituents R 10 Substituted.

[0566] 1.151A The compound according to embodiment 1.141, wherein NR 8 R 9 constitutes a heterocyclic group selected from:

[0567] ·A fused bicyclic heterocyclic group having 7 to 12 ring members, one ring of the fused bicyclic heterocyclic group being an aromatic ring and the other ring being a non-aromatic ring; wherein, except for the nitrogen atom of NR 8 R 9 , the heterocyclic group optionally further contains 1 or 2 heteroatomic ring members selected from O and N; and wherein the heterocyclic group is optionally substituted by one or more substituents R 10 substituted.

[0568] 1.152 The compound according to embodiment 1.151 or embodiment 1.151A, wherein the aromatic ring of the fused bicyclic heterocycle is a 5- or 6-membered ring containing 0, 1 or 2 heteroatomic ring members selected from N and O.

[0569] 1.153 The compound according to embodiment 1.152, wherein the aromatic ring of the fused bicyclic heterocycle is a 5- or 6-membered ring containing 0, 1 or 2 ring member nitrogens, for example, wherein the aromatic ring is selected from benzene ring, pyrrole ring, pyridine ring and pyrimidine ring.

[0570] 1.154 The 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 bicyclics, provided that the total number of ring members of the heterocyclic group does not exceed 11.

[0571] 1.154 The 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 of the heterocyclic group does not exceed 11.

[0572] 1.155 The compound according to any one of embodiments 1.151 to 1.154, wherein the nitrogen atom of NR 8 R 9 is located on the non-aromatic ring.

[0573] 1.156 The 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 heteroatomic ring member and 6- and 7-membered rings containing 1 nitrogen heteroatomic ring member and 1 oxygen heteroatomic ring member.

[0574] 1.157 The compound according to embodiment 1.151, wherein NR 8 R 9 forms a heterocyclic group selected from tetrahydroisoquinoline, tetrahydroquinoline, dihydroindole, dihydroisoindole, tetrahydrobenzazepine, pyrimidinepiperidine, benzomorpholine and benzohomomorpholine, and wherein the heterocyclic group is optionally substituted by one or more substituents R 10 substituted.

[0575] 1.157 A compound according to embodiment 1.141, wherein NR 8 R 9 forms a heterocyclic group selected from tetrahydroisoquinoline, tetrahydroquinoline, tetrahydronaphthyridine, dihydroindole, dihydroisoindole, tetrahydrobenzazepine, pyrimidinepiperidine, benzomorpholine, benzohomomorpholine, azatricyclododecatrienyl, and tetrahydro-oxopyrimidineazepine, wherein said heterocyclic group is optionally substituted with one or more substituents R 10 substituted.

[0576] 1.158 A compound according to embodiment 1.157, wherein NR 8 R 9 forms a heterocyclic group selected from tetrahydroisoquinoline and tetrahydrobenzazepine, and wherein said heterocyclic group is optionally substituted with one or more substituents R 10 substituted.

[0577] 1.159 A compound according to embodiment 1.158, wherein NR 8 R 9 forms a tetrahydroisoquinoline group, which is optionally substituted with one or more substituents R 10 substituted.

[0578] 1.160 A compound according to embodiment 1.158, wherein NR 8 R 9 forms a tetrahydrobenzazepine group, which is optionally substituted with one or more substituents R 10 substituted.

[0579] 1.161 A compound according to any one of embodiments 1.126 to 1.160 has the following general formula (8):

[0580]

[0581] or a pharmaceutically acceptable salt or tautomer thereof, wherein R 1 、R 4 、R 8 、R 9 、Alk 2 and Z are as defined in any of the foregoing embodiments.

[0582] 1.161A A compound according to embodiment 1.161, wherein the compound has structure (8A):

[0583]

[0584] 1.161B A compound according to embodiment 1.161, wherein the compound has structure (8B):

[0585]

[0586] 1.162 The compound according to any one of embodiments 1.126 to 1.160 has the following general formula (9):

[0587]

[0588] or a pharmaceutically acceptable salt or tautomer thereof; wherein R 4 、R 6 、R 8 、R 9 、Alk 2 、Z and v are defined as in any of the foregoing embodiments.

[0589] 1.162A The compound according to embodiment 1.162, wherein the compound has structure (9A):

[0590]

[0591] 1.162B The compound according to embodiment 1.162, wherein the compound has structure (9B):

[0592]

[0593] 1.162C The compound according to any one of embodiments 1.161 to 1.162B, wherein the following moiety:

[0594]

[0595] has the following structure:

[0596]

[0597] wherein Alk 2a is a residue of Alk 2 。

[0598] 1.162D The compound according to any one of embodiments 1.161 to 1.162B, wherein the following moiety:

[0599]

[0600] has the following structure:

[0601]

[0602] wherein Alk 2a is a residue of Alk 2 。

[0603] 1.163 The compound according to any one of Examples 0.1 to 1.100 and 1.102 to 1.162D, wherein R 10 is selected from:

[0604] · halogen; hydroxy; oxygen; cyano;

[0605] · OR 12 wherein R 12 is C 1-6 alkyl or C 3-6 cycloalkyl, each of which is optionally substituted by halogen;

[0606] · acyclic C 1-8 hydrocarbyl, optionally substituted by one or more substituents selected from hydroxy, oxygen, halogen, cyano, carboxy, amino, mono- or di-C 1-4 alkylamino and carbocyclic and heterocyclic groups having 3 to 6 ring members, wherein 0, 1 or 2 ring members of the carbocyclic and heterocyclic groups are heteroatom ring members selected from N, O and S, wherein the carbocyclic and heterocyclic groups are optionally substituted by one or more substituents R 13 wherein R 13 is selected from hydroxy, halogen, cyano and -(O) v -Hyd 1 wherein v is 0 or 1; wherein one or two but not all carbon atoms of the acyclic C 1-8 hydrocarbyl may optionally be substituted by O, S, SO, SO 2 or NR 11 ; and

[0607] · carbocyclic and heterocyclic groups having 3 to 6 ring members, wherein 0, 1 or 2 ring members of the carbocyclic and heterocyclic groups are heteroatom ring members selected from N, O and S, wherein the carbocyclic and heterocyclic groups are optionally substituted by one or more substituents R 13 ; and

[0608] R 11 is selected from hydrogen and C 1-4 hydrocarbyl.

[0609] 1.164 The compound according to Example 1.163, wherein R 10 is selected from:

[0610] · halogen; hydroxy; oxygen; cyano;

[0611] · OR 12 wherein R 12 is C 1-6 alkyl or C 3-6 cycloalkyl, each of which is optionally substituted by halogen;

[0612] · Acyclic C 1-8 hydrocarbyl (such as alkyl, alkenyl or alkynyl), optionally substituted by one or more substituents selected from hydroxy, oxygen, halogen, cyano, carboxyl, amino, mono- or di-C 1-4 alkylamino, wherein one or two but not all carbon atoms of said acyclic C 1-8 hydrocarbyl may optionally be substituted by O, S, SO, SO 2 or NR 11 ; and

[0613] · Aryl and heteroaryl having 5 or 6 ring members, wherein 0, 1 or 2 ring members are heteroatom ring members selected from N, O and S, wherein said aryl and heteroaryl are optionally substituted by one or more substituents selected from hydroxy, halogen, cyano and -(O) v -Hyd 1 (wherein v is 0 or 1); and

[0614] R 11 is selected from hydrogen and C 1-4 hydrocarbyl (for example, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl or cycloalkyl).

[0615] 1.165 The compound according to embodiment 1.164, wherein R 10 is selected from:

[0616] · Fluorine, chlorine, hydroxy, oxygen, cyano, methoxy, ethoxy, trifluoromethoxy, difluoromethoxy;

[0617] · Acyclic C 1-6 hydrocarbyl (such as alkyl, alkenyl or alkynyl), optionally substituted by one or more substituents selected from hydroxy, oxygen, fluorine, amino, mono- or di-C 1-2 alkylamino, wherein one but not all carbon atoms of said acyclic C 1-6 hydrocarbyl may optionally be substituted by O, SO 2 or NR 11 ; and

[0618] · Aryl and heteroaryl having 5 or 6 ring members, wherein 0, 1 or 2 ring members are heteroatom ring members selected from N, O and S, wherein said aryl and heteroaryl are optionally substituted by one or more substituents selected from hydroxy, fluorine, chlorine and -(O) v -Hyd 1 (wherein v is 0 or 1); and

[0619] R 11 is selected from hydrogen and C 1-2 alkyl.

[0620] 1.166 The compound according to embodiment 1.165, wherein R 10Selected from:

[0621] · Fluorine, chlorine, hydroxyl, oxygen, cyano, methoxy, ethoxy, trifluoromethoxy, difluoromethoxy;

[0622] · C 1-4 hydrocarbyl (such as alkyl, alkenyl, alkynyl, cyclopropyl, methylcyclopropyl or cyclopropylmethyl), optionally substituted by one or more substituents selected from hydroxyl, oxygen, fluorine, amino, mono- or di-C 1-2 alkylamino, wherein one but not all of the carbon atoms of said C 1-4 alkyl may optionally be substituted by O;

[0623] · Phenyl, optionally substituted by one or more substituents selected from hydroxyl, fluorine, chlorine and -(O) v -Hyd 1 (where v is 0 or 1);

[0624] · Heteroaryl having 5 or 6 ring members, wherein 1 or 2 ring members are heteroatom ring members selected from N, O and S, and wherein said heteroaryl is optionally substituted by one or more substituents selected from hydroxyl, fluorine, chlorine and -(O) v -Hyd 1 (where v is 0 or 1).

[0625] 1.167 The compound according to embodiment 1.166, wherein R 10 is selected from:

[0626] · Fluorine, chlorine, hydroxyl, oxygen, cyano, methoxy, ethoxy, trifluoromethoxy, difluoromethoxy;

[0627] · Saturated C 1-4 hydrocarbyl (such as C 1-4 alkyl, cyclopropyl, cyclobutyl, cyclopropylmethyl or methylcyclopropyl), optionally substituted by one or more substituents selected from hydroxyl and fluorine, wherein one but not all of the carbon atoms of said C 1-4 hydrocarbyl may optionally be substituted by O;

[0628] · Phenyl, optionally substituted by one or more substituents selected from hydroxyl, fluorine, chlorine and -(O) v -Hyd 1 (where v is 0 or 1);

[0629] · Heteroaryl having 5 or 6 ring members, wherein 1 or 2 ring members are heteroatom ring members selected from N, O and S, and wherein said heteroaryl is optionally substituted by one or more substituents selected from hydroxyl, fluorine, chlorine and -(O) v -Hyd 1 (where v is 0 or 1).

[0630] 1.168 The compound according to embodiment 1.167, wherein R 10 is selected from:

[0631] · Fluorine, chlorine, hydroxyl, oxygen, cyano, methoxy, ethoxy, trifluoromethoxy, difluoromethoxy;

[0632] · Saturated C 1-4 hydrocarbyl (such as C 1-4 alkyl, cyclopropyl, cyclobutyl, cyclopropylmethyl or methylcyclopropyl), optionally substituted by one or more substituents selected from hydroxyl and fluorine, wherein one but not all of the carbon atoms of the C 1-4 hydrocarbyl may optionally be substituted by O;

[0633] · Phenyl, optionally substituted by one or more substituents selected from hydroxyl, fluorine, chlorine and -(O) v -Hyd 1 (wherein v is 0 or 1);

[0634] · Heteroaryl having 5 ring members, wherein 1 or 2 ring members are heteroatom ring members selected from N, O and S, and wherein the heteroaryl is optionally substituted by one or more substituents selected from -(O) v -Hyd 1 (wherein v is 0).

[0635] 1.169 The compound according to embodiment 1.168, wherein R 10 is selected from oxygen, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, tert-butyl, hydroxymethyl, trifluoromethyl, methoxy, trifluoromethoxy, difluoromethoxy, phenyl and thiazolyl.

[0636] 1.169A The compound according to embodiment 1.163, wherein R 10 is selected from: fluorine, methyl, methoxy and dimethylamino.

[0637] 1.169B The 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 R 7 in R 10 .

[0638] 1.169C The 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 R 7 in R 10 .

[0639] 1.169D The compound according to any one of embodiments 0.1 to 1.100 and 1.102 to 1.169, wherein R7 There are 0, 1 or 2 substituents R 10 .

[0640] 1.169E A compound according to any one of Examples 0.1 to 1.100 and 1.102 to 1.169, wherein R 7 has 1 or 2 substituents R 10 .

[0641] 1.169F A compound according to any one of Examples 0.1 to 1.100 and 1.102 to 1.169, wherein R 7 has 0 substituents R 10 .

[0642] 1.169G A compound according to any one of Examples 0.1 to 1.100 and 1.102 to 1.169, wherein R 7 has 1 substituent R 10 .

[0643] 1.169H A compound according to any one of Examples 0.1 to 1.100 and 1.102 to 1.169, wherein R 7 has 2 substituents R 10 .

[0644] 1.169J A compound of formula (0):

[0645]

[0646] or a pharmaceutically acceptable salt, N-oxide or tautomer thereof; wherein:

[0647] n is 1 or 2;

[0648] X is CH or N;

[0649] Y is selected from CH and C-F;

[0650] Z is selected from C-R z and N;

[0651] R z is selected from hydrogen; fluorine; methoxy; and C 1-2 alkyl, wherein the C 1-2 alkyl is optionally substituted by hydroxy or methoxy;

[0652] R 1 is selected from:

[0653] --(Alk 1 ) t -Cyc 1 ; wherein t is 0 or 1; and Alk1 is methylene; and

[0654] -C 1-6 is an acyclic hydrocarbon group, and said C 1-6 acyclic hydrocarbon group is unsubstituted or substituted with one, two or three substituents R 5 , R 5 is selected from hydroxy, oxygen and cyano; and wherein one but not all carbon atoms of said hydrocarbon group may be replaced by O (for example, forming an alkoxyalkyl group such as methoxyethyl or methoxypropyl);

[0655] Cyc 1 is a cyclic group selected from (a) 3- to 8-membered non-aromatic monocyclic and bicyclic carbocyclic and heterocyclic groups, said carbocyclic and heterocyclic groups containing 0 or 1 heteroatom ring member 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, wherein one heteroatom ring member is N and the other heteroatom ring members (if any) are selected from O, N and S; and (c) phenyl; wherein (a), (b) and (c) are unsubstituted groups or are substituted with 1, 2 or 3 substituents R 6 , R 6 is selected from hydroxy, oxygen, fluorine, amino, N(Hyd 1 ) 2 , O-Hyd 1 , -C(=O)-Hyd 1 , -C(=O)-O-Hyd 1 and Hyd 1 ; wherein Hyd 1 is a C 1-3 non-aromatic group, optionally substituted with one or more substituents selected from fluorine, hydroxy and methoxy;

[0656] R 2 is selected from hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl, ethyl, 1-hydroxyethyl, cyclopropyl, isopropyl, vinyl and allyl;

[0657] R 3 is hydrogen or an L 1 -R 7 group;

[0658] R 4 is selected from hydrogen, methoxy and C 1-3 alkyl, said C 1-3 alkyl is optionally substituted with hydroxy, amino, di-C 1-2 alkylamino or methoxy;

[0659] R 4a is selected from hydrogen and methyl;

[0660] L 1 Selected from single bond, Alk 2 and Alk 2 -C(=O), where Alk 2 is C 1-4 a straight-chain or branched alkylene group, optionally substituted by one or more substituents selected from hydroxyl, methoxy, amino, methylamino, (dimethyl)amino, and fluorine;

[0661] R 7 Selected from:

[0662] · Hydrogen;

[0663] · CO 2 H;

[0664] · NR 8 R 9 ;

[0665] · A heterocyclic group having 5 to 12 ring members, where 1, 2, or 3 ring members are heteroatom ring members selected from O and N, and the carbocyclic or heterocyclic group is optionally substituted by one or more substituents R 10 substituted; and

[0666] · An acyclic C 1-8 hydrocarbyl group, optionally substituted by one or more substituents selected from hydroxyl, oxygen, mono- or di-C 1-4 alkylamino, and carbocyclic and heterocyclic groups having 3 to 10 ring members, where 0, 1, 2, or 3 ring members of the carbocyclic and heterocyclic groups are heteroatom ring members selected from O and N, and the carbocyclic or heterocyclic group is optionally substituted by one or more substituents R 10 substituted; where one but not all of the carbon atoms of the acyclic C 1-8 hydrocarbyl group can optionally be substituted by O or NR 11 substituted (for example, to form C 1-4 alkoxy, such as methoxy or tert-butoxy; or alkoxyalkyl, such as methoxymethyl; or CH 2 O group; or O-CH(CH 3 ) 2 group);

[0667] R 8 Selected from hydrogen, methyl, ethyl, hydroxyethyl, aminoethyl, and (dimethylamino)ethyl;

[0668] R 9 Selected from:

[0669] · Hydrogen;

[0670] ·A carbocyclic or heterocyclic group having 3 to 10 ring members, wherein 0, 1 or 2 ring members of the carbocyclic or heterocyclic group are heteroatom ring members selected from the oxidized forms of O, N and S, and the carbocyclic or heterocyclic group is optionally substituted by one or more substituents R 10 substituted; and

[0671] ·An acyclic C 1-6 hydrocarbyl group, optionally substituted by one or more substituents selected from hydroxy, fluoro, mono- or di-C 1-4 alkylamino and carbocyclic and heterocyclic groups having 3 to 11 ring members, wherein 0, 1, 2 or 3 ring members of the carbocyclic and heterocyclic groups are heteroatom ring members selected from O, N and S, and the carbocyclic or heterocyclic group is optionally substituted by one or more substituents R 10 substituted; wherein one or two but not all carbon atoms of the acyclic C 1-6 hydrocarbyl group may optionally be substituted by O (for example, to form an O-ether linkage between the acyclic hydrocarbyl group and the attached carbocyclic substituent; or to form an alkoxy substituent such as methoxy on the acyclic hydrocarbyl group);

[0672] or NR 8 R 9 forms a heterocyclic group having 5 to 12 ring members; wherein, in addition to the nitrogen atom of NR 8 R 9 the heterocyclic group optionally further contains 1 or 2 heteroatom ring members selected from O and N; and wherein the heterocyclic group is optionally substituted by one or more substituents R 10 substituted;

[0673] R 10 is selected from:

[0674] ·Fluoro, chloro, hydroxy, oxygen, cyano;

[0675] ·OR 12 wherein R 12 is methyl, ethyl, propyl, isopropyl or cyclopropyl, each group optionally substituted by fluoro;

[0676] ·An acyclic C 1-8 hydrocarbyl group, optionally substituted by one or more substituents selected from hydroxy, oxygen, fluoro, amino, dimethylamino and carbocyclic and heterocyclic groups having 3 to 7 ring members, wherein 0, 1, 2, 3 or 4 ring members of the carbocyclic and heterocyclic groups are heteroatom ring members selected from N, O and S, wherein the carbocyclic and heterocyclic groups are optionally substituted by one or more substituents R 13 substituted, R 13 is selected from hydroxy, halogen, -N(Hyd 1 ) 2 and -(O) v-Hyd 1 , where v is 0 or 1; wherein one or two but not all carbon atoms of the acyclic C 1-8 hydrocarbyl group may optionally be substituted by O (e.g., to form an alkoxyalkyl such as methoxymethyl or ethoxymethyl; hydroxyalkoxy such as hydroxyethoxy; or C(=O)O-C 1-4 alkyl group for example), SO 2 (e.g., to form a C 1-3 alkylsulfonyl such as ethylsulfonyl), or NR 11 (such as to form an alkylamino such as methylamino, ethylamino, dimethylamino or methyl(ethyl)amino; or alkylaminoalkyl such as methylaminomethyl or dimethylaminomethyl; or aminoalkoxy such as aminoethoxy or dimethylaminoethoxy; or hydroxyalkylamino such as hydroxyethyl(methyl)amino; or amido such as C(=O)NH); and

[0677] · carbocyclic and heterocyclic groups having 3 to 7 ring members, wherein 0, 1, 2, 3 or 4 ring members are heteroatom ring members selected from N, O and S, and wherein said carbocyclic and heterocyclic groups are optionally substituted by one or more substituents R 13 substituted; and

[0678] R 11 is selected from hydrogen and C 1-4 hydrocarbyl group;

[0679] provided that the compound is not 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, their salts and tautomers.

[0680] 1.170 The compound according to any one of Examples 0.1 to 1.100 or Example 1.169J, wherein R 3 is selected from the BA to GBB groups in Table 2 below, where the * marks the point of attachment of the N atom.

[0681] Table 2

[0682]

[0683]

[0684]

[0685]

[0686]

[0687]

[0688]

[0689]

[0690]

[0691]

[0692] 1.170A A compound according to any one of Examples 0.1 to 1.100, wherein R 3 is selected from groups GBC to GRJ of Table 2A below.

[0693]

[0694]

[0695]

[0696]

[0697] 1.170B A compound according to any one of Examples 0.1 to 1.100 or Example 1.169J, wherein R 3 is selected from groups GBC, GBD, GMH, GNF and GSA of the table below.

[0698]

[0699] 1.171 A compound according to Example 1.170, wherein R 3 is selected from groups BA to GP of Table 2.

[0700] 1.172 A compound according to Example 1.171, wherein R 3 is selected from groups CO, DD, DZ, EC, EF, ES, GM, GN, GO and GP of Table 2.

[0701] 1.172A A compound as defined in any one of Examples 0.1 to 1.172, provided that when n is 2 and X is CH, then Z is C-R z .

[0702] 1.172B A compound as defined in any one of Examples 0.1 to 1.172, provided that when n is 2, then X is N.

[0703] 1.17C A compound as defined in any one of Examples 0.1 to 1.172, provided that when n is 2, Cyc 1 is not 2-methyl-pyrimidin-4-yl.

[0704] 1.172D A compound as defined in any one of Examples 0.1 to 1.172, provided that when n is 2, Cyc 1 is not methyl-pyrimidyl.

[0705] 1.172E A compound as defined in any one of Examples 0.1 to 1.172, provided that when Z is N, then X is N.

[0706] 1.172F A compound according to Example 1.0, having the following structural formula (10):

[0707]

[0708] or a pharmaceutically acceptable salt thereof or a tautomer thereof; wherein,

[0709] R 1 is:

[0710] -tetrahydropyran, or

[0711] -a 6-membered heterocycle selected from pyridine and pyrimidine, optionally substituted with methyl or methoxy;

[0712] R 15 is C 1-3 alkyl or hydroxy-C 1-3 alkyl; and

[0713] Ar 1 is a benzene ring or a pyridine ring, optionally substituted with one or two substituents selected from fluorine, methoxy, dimethylamino, and 4-methylpiperazine.

[0714] 1.172G A compound of formula (11):

[0715]

[0716] or a salt thereof or a tautomer thereof; wherein:

[0717] R 1 is

[0718] -tetrahydropyran, or

[0719] -a 6-membered heterocycle selected from pyridine and pyrimidine, optionally substituted with methyl or methoxy;

[0720] R 15 is C 1-3 alkyl or hydroxy-C 1-3 alkyl;

[0721] Ar 1 is a benzene ring or a pyridine ring, optionally substituted with one or two substituents selected from fluorine, methoxy, dimethylamino, and 4-methylpiperazine;

[0722] R 2 , X, Y, Z, R 4 and R 4a is defined as in any one of Examples 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.

[0723] 1.172H A compound according to Example 1.172F or 1.172G, wherein R 1 is selected from tetrahydropyran, 2-methoxypyridin-4-yl, and 2-methylpyrimidin-4-yl.

[0724] 1.172J A compound according to any one of Examples 1.172F, 1.172G, and 1.172H, wherein R 15 is hydroxymethyl or methyl.

[0725] 1.173 A compound according to Example 1.1, a compound selected from any one of Examples 1 to 196 herein, or a pharmaceutically acceptable salt thereof.

[0726] 1.174 A compound according to Example 1.173, a compound selected from any one 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.

[0727] 1.175 A compound according to Example 1.174, a compound selected from any one of Examples 40, 55, 79, and 82, or a pharmaceutically acceptable salt thereof.

[0728] 1.175A A compound according to Example 1.0 or Example 1.1, a compound selected from any one of Examples 1 to 699 herein, or a pharmaceutically acceptable salt thereof.

[0729] 1.175B The compound according to Example 0.1, selected from 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,Compounds of 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, or a pharmaceutically acceptable salt thereof.

[0730] 1.175C A compound according to Example 1.175B, selected from the compounds described in any one of Examples 303, 616, 683 and 675, or a pharmaceutically acceptable salt thereof.

[0731] 1.175D A compound according to Example 1.175B, selected from the compounds described in any one of Examples 685, 697, 698 and 699, or a pharmaceutically acceptable salt thereof.

[0732] 1.175E A compound according to Example 1.0, selected from the compounds of Examples 1 to 1134 herein, or a pharmaceutically acceptable salt thereof.

[0733] 1.175F The compound according to Example 1.0, selected from 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、Compounds of 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 The compound according to Example 0.1, being a compound selected from Examples 685, 698, 701, 702, 992 and 1016, or a pharmaceutically acceptable salt thereof.

[0734] 1.175H The compound according to Example 1.175G, said compound being (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:

[0735]

[0736] or a pharmaceutically acceptable salt thereof or a tautomer thereof.

[0737] 1.175J The compound according to Example 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.

[0738] 1.175K The compound according to Example 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:

[0739]

[0740] or a pharmaceutically acceptable salt thereof or a tautomer thereof.

[0741] 1.175L The compound according to Example 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.

[0742] 1.175M The compound according to Example 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:

[0743]

[0744] or a pharmaceutically acceptable salt thereof or a tautomer thereof.

[0745] 1.175N The compound according to Example 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.

[0746] 1.175P The compound according to Example 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:

[0747]

[0748] or a pharmaceutically acceptable salt thereof or a tautomer thereof.

[0749] 1.175Q The compound according to Example 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.

[0750] 1.175R The compound according to Example 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:

[0751]

[0752] or a pharmaceutically acceptable salt thereof or a tautomer thereof.

[0753] 1.175S The compound according to Example 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.

[0754] 1.175T The compound according to Example 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:

[0755]

[0756] or a pharmaceutically acceptable salt or tautomer thereof.

[0757] 1.175U The compound according to Example 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.

[0758] 1.176 The compound according to any one of Examples 0.1 to 1.175U, wherein the compound is in the form of a salt.

[0759] 1.177 The compound according to Example 1.176, wherein the salt is an acid addition salt.

[0760] 1.178 The compound according to Example 1.176 or Example 1.177, wherein the salt is a pharmaceutically acceptable salt.

[0761] 1.179 The compound according to any one of Examples 0.1 to 1.175U, wherein the compound is in the form of a free base.

[0762] Definitions

[0763] Unless the context indicates otherwise, Formula (1) as referred to in all parts of this document (including the uses, methods, and other aspects of the present invention) includes Formula (0) as defined herein and all other sub-formulas (such as Formulas (2), (3), (3A), (3B), (4), (4A), (4B), (5), (5A), (5B), (6), (6A), (6B), (7), (7A), (7B), (8), (8A), (8B), (9), (9A), (9B), (10), and (11)), subgroups, preferences, examples, and instances.

[0764] ERK1 / 2 refers to either or both of the ERK1 and ERK2 isoforms of extracellular signal-regulated kinase (ERK).

[0765] "Potency" is an index of drug activity expressed as the amount required to produce a given intensity of effect. A drug with high potency elicits a greater response at a lower concentration. Potency is proportional to affinity and efficacy. Affinity is the ability of a drug to bind to an enzyme. Efficacy is the relationship between target occupancy and the ability to elicit a response at the molecular, cellular, tissue, or systemic level.

[0766] The term "inhibitor" refers to an enzyme inhibitor, which is a ligand or drug type that blocks or hinders ERK1 / 2-mediated biological reactions. Inhibitors modulate their effects by binding to the active site or to an allosteric site on the enzyme, or they can interact at unique binding sites that are not normally involved in the biological regulation of enzyme activity. Inhibition can be caused directly or indirectly, mediated by any mechanism and at any physiological level. Thus, ligand- or drug-induced inhibition may manifest in functionally different ways in different situations. Depending on the lifetime of the inhibitor-enzyme complex, the inhibitory activity may be reversible or irreversible, and the lifetime of the inhibitor-enzyme complex depends on the binding nature of the inhibitor to the enzyme.

[0767] In the context of a therapeutic condition, i.e., a state, disorder or disease, the term "treatment" as used herein generally involves the management and care, whether for humans or animals (e.g., veterinary applications), in which certain desired therapeutic outcomes are achieved, e.g., inhibition of the progression of the condition, including slowing the rate of development, halting the rate of development, alleviating the condition, reducing or alleviating at least one symptom associated with or caused by the disease being treated and curing the condition. For example, treatment may reduce one or several symptoms of a disorder or completely cure the disorder.

[0768] In the context of a therapeutic condition, i.e., a state, disorder or disease, the term "prevention" (i.e., using a compound as a preventive measure) as used herein generally involves preventing or forestalling, whether for humans or animals (e.g., veterinary applications), in which certain desired preventive outcomes are achieved, e.g., preventing the occurrence of a disease or forestalling the occurrence of a disease. Prevention includes completely and generally blocking all symptoms of a disorder for an indefinite period of time, merely slowing the appearance of one or several symptoms of a disease, or reducing the likelihood of the occurrence of a disease, and does not include alleviating the condition, reducing or alleviating at least one symptom associated with or caused by the disease being treated and curing the condition.

[0769] Preventing or treating a disease state or condition (such as cancer) includes reducing or decreasing, for example, the incidence of cancer within their scope.

[0770] As used herein, the term "mediate", when used in connection with ERK1 / 2 as described herein (and for, e.g., various physiological processes, diseases, states, conditions, treatments, procedures or interventions), is intended to operate restrictively such that the various processes, diseases, states, conditions, treatments and interventions to which the term applies are those in which the protein plays a biological role. When the term applies to a disease, state or condition, the biological role played by the protein may be direct or indirect and may be necessary and / or sufficient for manifestation of symptoms of the disease, state or condition (or its etiology or progression). Thus, protein function (especially abnormal levels of function, e.g., overexpression or underexpression) is not necessarily the proximal cause of the disease, state or condition: rather, we contemplate that mediated diseases, states or conditions include those with multifactorial etiologies and complex processes, where only part of which involves the protein in question. When the term is used in connection with a treatment, prevention or intervention, the role played by the protein may be direct or indirect and may be necessary and / or sufficient for the treatment operation, prevention or intervention outcome. Thus, protein-mediated disease states or conditions include the formation of resistance to any particular cancer drug or treatment.

[0771] Compared to the therapeutic effects when the individual compounds / formulations are administered separately, the combinations of the present invention can produce therapeutically effective effects.

[0772] The term "effective" includes beneficial effects such as additivity, synergy, reduction of side effects, reduction of toxicity, prolongation of disease progression time, prolongation of survival time, sensitization or resensitization of one agent to another, or improvement of response rate. Advantageously, an effective effect may allow reduction of the patient administration dose of each or any component, thereby reducing the toxicity of chemotherapy while achieving and / or maintaining the same therapeutic effect. In the present invention, a "synergistic" effect refers to a therapeutic effect produced by the combination that is greater than the sum of the therapeutic effects when the agents in the combination are administered separately. In the present invention, an "additive" effect refers to a therapeutic effect produced by the combination that is greater than the therapeutic effect of any one of the agents in the combination when administered separately. In the case of solid tumors, the term "response rate" as used in the present invention refers to the degree of reduction in tumor size at a given time point (e.g., 12 weeks). Thus, for example, a 50% response rate refers to a 50% reduction in tumor size. A "clinical response" herein refers to a response rate equal to or greater than 50%. A "partial response" is defined herein as a response rate less than 50%, provided that the response rate is greater than 0%.

[0773] As used herein, the term "combination", when applied to two or more compounds and / or reagents, for example, refers to a material in which two or more reagents are combined. In the present invention, the terms "combined" and "combination" are interpreted accordingly.

[0774] The association of two or more compounds / reagents in a combination may be physical or non - physical. Examples of physically associated combinations of compounds / reagents include:

[0775] · A composition (e.g., a unitary formulation) that includes two or more compounds / reagents in a mixture (e.g., in the same unit dose);

[0776] · A composition that includes a material in which two or more compounds / reagents are chemically / physicochemically linked (e.g., cross - linked, molecular aggregation, or bound to a common vehicle moiety);

[0777] · A composition that includes a material in which two or more compounds / reagents are chemically / physicochemically co - packaged (e.g., on or within lipid vesicles, particles (such as microparticles or nanoparticles), or emulsion droplets);

[0778] · A drug kit, drug pack, or patient pack in which two or more compounds / reagents are co - packaged or co - presented (e.g., as part of a series of unit doses);

[0779] Examples of non - physically associated combinations of compounds / reagents include:

[0780] · A material that includes at least one of two or more compounds / reagents (e.g., a non - unitary formulation) and instructions for immediately combining the at least one compound to form a physical combination of the two or more compounds / reagents;

[0781] · A material that includes at least one of two or more compounds / reagents (e.g., a non - unitary formulation) and instructions for treating with a combination of the two or more compounds / reagents;

[0782] · A material that includes at least one of two or more compounds / reagents and instructions for administering to a population of patients who have already received other compounds / reagents of the two or more compounds / reagents;

[0783] · A material that includes at least one of two or more compounds / reagents, the quantity or form of which is specifically adapted for use in combination with other compounds / reagents of the two or more compounds / reagents.

[0784] As used herein, the term "combination therapy" refers to a therapy that includes the use of a combination of two or more compounds / reagents (as defined above). Thus, in this application, "combination therapy", "combination", and the compounds / reagents using "combination" may refer to the compounds / reagents administered as part of the same overall treatment regimen. Thus, the doses of each of the two or more compounds / reagents may be different: each compound / reagent may be administered simultaneously or at different times. Thus, it should be understood that the compounds / reagents in the combination may be administered in the same pharmaceutical formulation (e.g., together) or sequentially (e.g., before or after) or simultaneously in different pharmaceutical formulations (i.e., separately). Administration simultaneously in the same formulation is administration as a single preparation, while administration simultaneously in different pharmaceutical formulations is administration as a non-single preparation. The doses of each of the two or more compounds / reagents in a combination therapy may also be different with respect to the route of administration.

[0785] As used herein, the term "pharmaceutical kit" defines a series of one or more unit doses of a pharmaceutical composition and a measuring means (such as a measuring device) and / or a means of administration (such as an inhaler or syringe), optionally all contained within the same outer package. In a pharmaceutical kit containing a combination of two or more compounds / reagents, a single compound / reagent may be a single or non-single preparation. The unit dose may be contained in a blister pack. The pharmaceutical kit may optionally further include instructions for use.

[0786] As used herein, the term "pharmaceutical pack" defines a series of one or more unit doses of a pharmaceutical composition, optionally contained within the same outer package. In a pharmaceutical pack containing a combination of two or more compounds / reagents, a single compound / reagent may be a single or non-single preparation. The unit dose may be contained in a blister pack. The pharmaceutical pack may optionally further include instructions for use.

[0787] As used herein, the term "optionally substituted by..." means that it may or may not be substituted by a substituent defined herein.

[0788] As used herein, the prefix "C x-y " (where x and y are integers) refers to the number of carbon atoms in a given group. Thus, C 1-6 alkyl contains 1 to 6 carbon atoms, C 3-6 cycloalkyl contains 3 to 6 carbon atoms, C 1-4 alkoxy contains 1 to 4 carbon atoms, etc.

[0789] As used herein, the term "halo" or "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0790] As used herein, the term "oxo" refers to the group ═O.

[0791] Unless otherwise specified by the context, the term "amino" refers to the group -NH 2 .

[0792] In the definition of the compound of formula (0) above and hereinafter, unless otherwise stated, the term "hydrocarbon" (such as the hydrocarbon in "hydrocarbyl") is a generic term that includes aliphatic, alicyclic and aromatic groups, having an all-carbon backbone and consisting of carbon atoms and hydrogen atoms. Each hydrogen in a compound (such as in a hydrocarbyl group, an alkyl group or where hydrogen is mentioned) includes all isotopes of hydrogen, especially 1 H and 2 H (deuterium).

[0793] As defined herein, in some cases, one or more carbon atoms constituting the carbon backbone may be replaced by a specified atom or atomic group. For example, in some embodiments of the present invention as defined herein, in an acyclic hydrocarbyl group (e.g., a C 1-8 hydrocarbyl group or a C 1-6 hydrocarbyl group), 1 or 2 but not all carbon atoms of the hydrocarbyl group may be replaced by O or N, or by the atom or group O, S, SO, SO 2 or NR 11 . Examples of groups in which 1 or 2 carbon atoms in a hydrocarbyl group are replaced by the above-defined alternative atoms or groups include ethers (e.g., alkoxy or alkoxy-alkyl) and thioethers (C replaced by O or S), sulfones and sulfoxides (C replaced by SO or SO 2 ), amines (C replaced by N or NR 11 ), esters (one C in the C═C moiety is replaced by O and the other C is replaced by O), thioesters (one C in the C═C moiety is replaced by O and the other C is replaced by S), amides (one C in the C═C moiety is replaced by O and the other C is replaced by NR 11 ), and nitriles (one C in the C═C moiety is replaced by N) groups. However, in one embodiment, no carbon atoms are replaced by O or N, or by the atom or group O, S, SO, SO 2 or NR 11 .

[0794] For example, when R 1 is optionally substituted by an acyclic hydrocarbyl group in which 1 but not all carbon atoms in the hydrocarbyl group can be replaced by O, examples of such a group R 1 include alkoxyalkyl, such as methoxyethyl or methoxypropyl. In a subgroup of compounds of each of Examples 0.1 to 1.179, no carbon atoms in the acyclic hydrocarbyl group R 1 are so substituted by other atoms or groups.

[0795] When R 7 is selected from optionally substituted acyclic C 1-8 hydrocarbyl, where one but not all of the carbon atoms of the acyclic hydrocarbyl are optionally substituted with O, examples of such substitution are those that constitute C 1-4 alkoxy, such as methoxy or tert-butoxy; or constitute alkoxyalkyl, such as methoxymethyl; or constitute the group CH 2 O; or constitute the group O-CH(CH 3 ) 2 ) In the subgroup compounds of each of Examples 0.1 to 1.179, in the acyclic hydrocarbyl R 7 , no carbon atom is subject to such substitution by other atoms or groups.

[0796] When R 9 is an optionally substituted acyclic hydrocarbyl, where one or two but not all of the carbon atoms of the acyclic C 1-6 hydrocarbyl are optionally substituted with O, examples of such substitution include those that constitute an O-ether linkage between the acyclic hydrocarbyl and the attached carbocyclic substituent; or those that provide an alkoxy substituent, such as methoxy on the acyclic hydrocarbyl. In the subgroup compounds of each of Examples 0.1 to 1.179, in the acyclic hydrocarbyl R 9 , no carbon atom is subject to such substitution by other atoms or groups.

[0797] When R 10 is an optionally substituted acyclic hydrocarbyl, where one or two but not all of the carbon atoms of the acyclic C 1-8 hydrocarbyl can be substituted with O, SO 2 or NR 11 , examples of such substitution are those that constitute alkoxyalkyl (such as methoxymethyl or ethoxymethyl), hydroxyalkoxy (such as hydroxyethoxy), C(=O)O-C 1-4 alkyl, C 1-3 alkylsulfonyl (such as ethylsulfonyl), alkylamino (such as methylamino, ethylamino, dimethylamino or methyl(ethyl)amino), alkylaminoalkyl (such as methylaminomethyl or dimethylaminomethyl), aminoalkoxy (such as aminoethoxy or dimethylaminoethoxy), hydroxyalkylamino (such as hydroxyethyl(methyl)amino) and amido (such as C(=O)NH). In the subgroup compounds of each of Examples 0.1 to 1.179, in the acyclic hydrocarbyl R 10 , no carbon atom is subject to such substitution by other atoms or groups.

[0798] Examples of hydrocarbyl groups include alkyl, cycloalkyl, cycloalkenyl, carbocyclic aryl, alkenyl, alkynyl, cycloalkylalkyl, cycloalkenylalkyl, and carbocyclic aralkyl, aralkenyl, and aralkynyl. Such groups may be unsubstituted groups or, when indicated, groups substituted with one or more substituents defined herein. Unless otherwise stated, the examples and preferred examples given below apply to each hydrocarbyl substituent or hydrocarbyl-containing substituent mentioned in the definition of each substituent of the compound of formula (0).

[0799] Specific examples of non-aromatic hydrocarbyl groups are saturated groups such as alkyl, cycloalkyl, alkylcycloalkyl, and cycloalkylalkyl.

[0800] Generally by way of example, unless otherwise stated, a hydrocarbyl group may have up to 8 carbon atoms. Within the subset of hydrocarbyl groups having 1 to 8 carbon atoms, specific examples are C 1-6 hydrocarbyl groups such as C 1-4 hydrocarbyl groups (e.g., C 1-3 hydrocarbyl groups or C 1-2 hydrocarbyl groups), and specific examples are any single value or combined values selected from C 1 、C 2 、C 3 、C 4 、C 5 、C 6 、C 7 and C 8 hydrocarbyl groups.

[0801] The term "alkyl" includes straight-chain and branched-chain alkyls. Examples of alkyls include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl, and n-hexyl and their isomers. Within the subset of alkyls having 1 to 8 carbon atoms, specific examples are C 1-6 alkyls such as C 1-4 alkyls (C 1-3 alkyls or C 1-2 alkyls).

[0802] As used herein, the term "cycloalkyl" refers to a saturated monocyclic hydrocarbon ring. Examples of cycloalkyls are those derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane. Within the subset of cycloalkyls, cycloalkyls have 3 to 8 carbon atoms, and specific examples are C 3-6 cycloalkyls.

[0803] As a group or part of a group, the term "alkenyl" refers to a linear or branched hydrocarbyl group containing one or more carbon-carbon double bonds. Examples of alkenyls include, but are not limited to, vinyl (ethylene), 1-propenyl, 2-propenyl (allyl), isopropenyl, butenyl, buta-1,4-dienyl, pentenyl, and hexenyl. Within the subset of alkenyls, alkenyls will have 2 to 8 carbon atoms, and specific examples are C2-6 Alkenyl, such as C 2-4 alkenyl.

[0804] The term "cycloalkenyl" refers to a monocyclic hydrocarbon ring having a carbon-carbon double bond.

[0805] Examples of cycloalkenyl include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, and cyclohexenyl. In a subset of cycloalkenyl, cycloalkenyl has 3 to 8 carbon atoms, and specific examples are C 3-6 cycloalkenyl.

[0806] As a group or part of a group, the term "alkynyl" refers to a linear or branched hydrocarbon group containing a carbon-carbon triple bond. Examples of alkynyl include, but are not limited to, ethynyl and 2-propynyl (propargyl). Within a subset of alkynyl, alkynyl has 2 to 8 carbon atoms, and specific examples are C 2-6 alkynyl, such as C 2-4 alkynyl.

[0807] As used herein, the term "alkylene" (e.g., C 1-4 straight-chain or branched alkylene) refers to an alkanediyl, i.e., a divalent saturated acyclic straight-chain or branched hydrocarbon group. Examples of straight-chain alkylene include methylene (CH 2 ), ethylene (CH 2 CH 2 ), and propylene (CH 2 CH 2 CH 2 ). Examples of branched alkylene include CH(CH 3 ), CH 2 CH(CH 3 )CH 2 , and CH 2 (CH 3 )CH 2 CH 2 .

[0808] If indicated, the alkylene may be substituted with one or more substituents.

[0809] Examples of carbocyclic aryl include substituted and unsubstituted phenyl.

[0810] Examples of cycloalkylalkyl, cycloalkenylalkyl, carbocyclic aralkyl, aralkenyl, and aralkynyl include phenethyl, benzyl, styryl, phenylacetylenyl, cyclohexylmethyl, cyclopentylmethyl, cyclobutylmethyl, cyclopropylmethyl, and cyclopentenylmethyl.

[0811] When present, and if indicated, the hydrocarbon group may be optionally substituted with one or more substituents.

[0812] As a group or part of a group, the term "C 1-4"alkoxy" or "C" 1-6 "alkoxy" refers to -O-C 1-4 alkyl or -O-C 1-6 alkyl, where C 1-4 alkyl or C 1-6 alkyl is defined as described herein. Examples of such groups include methoxy, ethoxy, propoxy, butoxy, etc.

[0813] As a group or part of a group, the term "hydroxy C" 1-4 alkyl" or "hydroxy C" 1-6 alkyl" refers to C 1-4 alkyl or C 1-6 alkyl as defined herein, where one or more than one hydrogen atom is replaced by a hydroxy group. Thus, the term "hydroxy C" 1-4 alkyl" or "hydroxy C" 1-6 alkyl" includes monohydroxy C 1-4 alkyl, monohydroxy C 1-6 alkyl, and also includes polyhydroxy C 1-4 alkyl and polyhydroxy C 1-6 alkyl. One, two, three, or more hydrogen atoms may be replaced by hydroxy groups. Thus, hydroxy C 1-4 alkyl or hydroxy C 1-6 alkyl may have one, two, three, or more hydroxy groups. Examples of such groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, etc.

[0814] As a group or part of a group, the term "halo C" 1-4 alkyl" or "halo C" 1-6 alkyl" refers to C 1-4 alkyl or C 1-6 alkyl as defined herein, where one or more than one hydrogen atom is replaced by a halogen. Thus, "halo C" 1-4 alkyl" or "halo C" 1-6 alkyl" includes monohalo C 1-4 alkyl, monohalo C 1-6 alkyl, and also includes polyhalo C 1-4 alkyl and polyhalo C 1-6 alkyl. One, two, three, or more hydrogen atoms may be replaced by halogen atoms. Thus, halo C 1-4 alkyl or halo C 1-6 alkyl may have one, two, three, or more halogens. Examples of such groups include fluoroethyl, fluoromethyl, trifluoromethyl, or trifluoroethyl, etc.

[0815] As a group or part of a group, the term "halo C" 1-4 alkoxy" refers to -O-C 1-4An alkyl group in which one or more hydrogen atoms are replaced by a halogen. Thus, the term "halo C" 1-4 alkoxy includes monohalo C 1-4 alkoxy and also includes polyhalo C 1-4 alkoxy. One, two, three or more hydrogen atoms may be replaced by a halogen, and thus, halo C 1-4 alkoxy may have one, two, three or more halogens. Examples of such groups include fluoroethoxy, difluoromethoxy or trifluoromethoxy, etc.

[0816] As used herein, the term phenyl C 1-6 alkyl refers to a C 1-6 alkyl as defined herein that is substituted by one phenyl group.

[0817] As used herein, the term cyano C 1-6 alkyl refers to a C 1-6 alkyl as defined herein that is substituted by one cyano group.

[0818] Unless the context otherwise indicates, the "carbocyclic" and "heterocyclic" groups referred to herein shall include aromatic and non-aromatic ring systems. Thus, for example, the term "carbocyclic and heterocyclic groups" includes within its scope aromatic, non-aromatic unsaturated, partially saturated and fully saturated carbocyclic and heterocyclic systems.

[0819] In general, unless the context otherwise indicates, such groups may be monocyclic or bicyclic (including fused and bridged bicyclic groups), may include, for example, 3 to 12 ring members, more typically 5 to 10 ring members. 4 to 7 ring members means that the ring includes 4, 5, 6 or 7 atoms, and 4 to 6 ring members means that the ring includes 4, 5 or 6 atoms. Examples of monocyclic groups are groups including 3, 4, 5, 6, 7 and 8 ring members, more typically 3 to 7 ring members, especially groups including 5, 6 or 7 ring members, more especially groups including 5 or 6 ring members. Examples of bicyclic groups are those including 8, 9, 10, 11 and 12 ring members, more typically those including 9 or 10 ring members. Heterocyclic groups can be heteroaryl groups having 5 to 12 ring members, more typically 5 to 10 ring members. When referring to a heterocyclic or carbocyclic group in the present invention, unless the context otherwise indicates, the heterocyclic or carbocyclic ring may be optionally substituted, i.e., it may be an unsubstituted group or a group substituted by one or more (e.g., 1, 2, 3 or 4, especially 1 or 2) substituents as defined herein.

[0820] For example, the heterocyclic group may be a five- or six-membered monocyclic ring, or a bicyclic structure formed by fused five- and six-membered rings, or two fused six-membered rings, or two fused five-membered rings, or fused six- and seven-membered rings, or fused five- and seven-membered rings. Each ring may contain no more than 5 heteroatoms, especially selected from nitrogen, sulfur, and oxygen. Generally, the heterocycle will contain no more than 4 heteroatoms, more especially no more than 3 heteroatoms, and more commonly no more than 2 heteroatoms, for example, one heteroatom. In one embodiment, the heterocycle will contain one or two heteroatoms selected from N, O, S, and the oxidized forms of N or S. In one embodiment, the heterocycle contains at least one ring nitrogen atom. The nitrogen atom in the ring of the heterocycle may be basic, as in the case of imidazole or pyridine, or substantially non-basic, as in the case of indole or pyrrole. Generally speaking, the number of basic nitrogen atoms present in the heterocyclic group, including any amino substituents in the ring, will be less than 5.

[0821] The heterocyclic group may be linked through a carbon atom or a heteroatom (e.g., nitrogen). Similarly, the heterocyclic group may be substituted on a carbon atom or a heteroatom (e.g., nitrogen).

[0822] As used herein, the term "heteroaryl" refers to a heterocyclic group having aromaticity. The term "heteroaryl" includes polycyclic (e.g., bicyclic) ring systems in which one or more rings are non-aromatic, provided that at least one ring is aromatic. In such polycyclic systems, the group may be linked through an aromatic ring or through a non-aromatic ring.

[0823] Examples of heteroaryl groups include monocyclic and bicyclic groups containing five to twelve ring members, and more commonly five to ten ring members.

[0824] Examples of five-membered heteroaryl groups include, but are not limited to, pyrrole, furan, thiophene (thienyl), imidazole, furazan, oxazole, oxadiazole, oxatriazole, isoxazole, thiazole, thiadiazole, isothiazole, pyrazole, triazole, and tetrazole groups.

[0825] Examples of six-membered heteroaryl groups include, but are not limited to, pyridine, pyrazine, pyridazine, pyrimidine, and triazine.

[0826] Examples of bicyclic heteroaryl groups may be, for example, selected from the following groups:

[0827] a) A benzene ring fused to a 5-, 6-, or 7-membered ring containing 1, 2, or 3 ring heteroatoms;

[0828] b) A pyridine ring fused to a 5-, 6-, or 7-membered ring containing 0, 1, 2, or 3 ring heteroatoms;

[0829] c) A pyrimidine ring fused to a 5-, 6-, or 7-membered ring containing 0, 1, or 2 ring heteroatoms;

[0830] d) A pyrrole ring fused to a 5-, 6- or 7-membered ring containing 0, 1, 2 or 3 ring heteroatoms;

[0831] e) A pyrazole ring fused to a 5- or 6-membered ring containing 0, 1 or 2 ring heteroatoms;

[0832] f) An imidazole ring fused to a 5- or 6-membered ring containing 0, 1 or 2 ring heteroatoms;

[0833] g) An oxazole ring fused to a 5- or 6-membered ring containing 0, 1 or 2 ring heteroatoms;

[0834] h) An isoxazole ring fused to a 5- or 6-membered ring containing 0, 1 or 2 ring heteroatoms;

[0835] i) A thiazole ring fused to a 5- or 6-membered ring containing 0, 1 or 2 ring heteroatoms;

[0836] j) An isothiazole ring fused to a 5- or 6-membered ring containing 0, 1 or 2 ring heteroatoms;

[0837] k) A thiophene ring fused to a 5- or 6-membered ring containing 0, 1, 2 or 3 ring heteroatoms;

[0838] l) A furan ring fused to a 5- or 6-membered ring containing 0, 1, 2 or 3 ring heteroatoms;

[0839] m) A cyclohexyl ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms;

[0840] and

[0841] n) A cyclopentyl ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms.

[0842] Specific examples of bicyclic heteroaryls containing a five-membered ring fused to another five-membered ring include, but are not limited to, imidazothiazole (e.g., imidazo[2,1-b]thiazole) and imidazoimidazole (e.g., imidazo[1,2-a]imidazole).

[0843] Specific examples of bicyclic heteroaryls containing a six-membered ring fused to a five-membered ring include, but are not limited to, benzofuran, benzothiophene, benzimidazole, benzoxazole, isobenzoxazole, benzisoxazole, benzothiazole, benzisothiazole, isobenzofuran, indole, isoindole, indolizine, indoline, isoindoline, purine (e.g., adenine, guanine), indazole, pyrazolopyrimidine (e.g., pyrazolo[1,5-a]pyrimidine), triazolopyrimidine (e.g., [1,2,4]triazolo[1,5-a]pyrimidine), triazolopyrazine, tetrahydrotriazolopyrazine, benzodioxole, imidazopyridine and pyrazolopyridine (e.g., pyrazolo[1,5-a]pyridine) groups.

[0844] Specific examples of bicyclic heteroaryls containing two fused six-membered rings include, but are not limited to, quinoline, isoquinoline, chroman, dihydrobenzothiopyran, isochroman, chromene, isochromene, benzodioxane, quinazine, benzoxazine, pyridopyridine, quinoxaline, quinazoline, cinnoline, phthalazine, naphthyridine, and pteridine groups.

[0845] Specific examples of bicyclic heteroaryls containing a five-membered ring fused to a seven-membered ring include pyrrolobenzodiazepine, dihydro-pyrrolobenzodiazepine, and tetrahydro-pyrrolobenzodiazepine.

[0846] Specific examples of bicyclic heteroaryls containing a six-membered ring fused to a seven-membered ring include dihydrobenzazepine, dihydro- and tetrahydro-benzodiazepine, and dihydrobenzoxazepine.

[0847] Examples of polycyclic heteroaryls containing an aromatic ring and a non-aromatic ring include tetrahydroisoquinoline, tetrahydroquinoline, dihydrobenzothiophene, dihydrobenzofuran, 2,3-dihydro-benzo[1,4]dioxin, benz[1,3]dioxolene, 4,5,6,7-tetrahydrobenzofuran, tetrahydrotriazolopyrazine (e.g., 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine), chroman, dihydrobenzothiopyran, isochroman, chromene, isochromene, benzodioxane, benzoxazine, benzodiazepine, indoline, isoindoline, 5,6-dihydro-1,7-naphthyridine (e.g., 5,6-dihydro-1,7-naphthyridin-7(8H)-yl), 3,4-dihydropyrrolo[1,2-a]pyrazine (e.g., 3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl), 4,5-dihydro-1H-benzo[d]azepine (e.g., 4,5-dihydro-1H-benzo[d]azepin-3(2H)-yl), 4,5-dihydro-1H-benzo[c]azepine (e.g., 4,5-dihydro-1H-benzo[c]azepin-2(3H)-yl), 2,3,4,5-tetrahydro-1H-benzo[b]azepine (e.g., 2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl), 1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl (e.g., 1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl), 2,3-dihydrobenzo[f][1,4]oxazepine (e.g., 2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl), and 7,8-dihydropyrido[4,3-d]pyrimidine (e.g., 7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl) groups.

[0848] The nitrogen-containing heteroaryl ring must contain at least one ring nitrogen atom. The nitrogen-containing heteroaryl ring can be N-linked or C-linked. In addition, each ring may contain no more than about 4 other heteroatoms, usually selected from nitrogen, sulfur, and oxygen. Generally, the heteroaryl ring will contain no more than 3 heteroatoms, e.g., 1, 2, or 3 heteroatoms, more usually no more than 2 nitrogen atoms, e.g., one nitrogen atom. The nitrogen atoms in the heteroaryl ring can be basic, as in the case of imidazole or pyridine, or substantially non-basic, as in the case of indole or pyrrole. Generally speaking, the number of basic nitrogen atoms present in the heteroaryl group, including any amino substituents in the ring, will be less than 5.

[0849] Examples of nitrogen-containing heteroaryl groups include, but are not limited to, monocyclic groups such as pyridyl, pyrrolyl, imidazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl), tetrazolyl, and bicyclic groups such as quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl and benzisothiazolyl, indolyl, 3H-indolyl, isoindolyl, indolizinyl, isoindolinyl, purinyl (e.g., adenine [6-aminopurine], guanine [2-amino-6-hydroxypurine]), indazolyl, quinazolinyl, benzoxazinyl, benzodiazepinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl.

[0850] Examples of nitrogen-containing polycyclic heteroaryl groups containing aromatic and non-aromatic rings include tetrahydroisoquinolinyl, tetrahydroquinolinyl, isoindolinyl, and indolinyl.

[0851] The oxygen-containing heteroaryl ring must contain at least one oxygen ring atom. The oxygen-containing heteroaryl ring is usually C-linked. In addition, each ring may contain no more than about 4 other heteroatoms, usually selected from nitrogen, sulfur, and oxygen. Generally, the heteroaryl ring will contain no more than 3 heteroatoms, e.g., 1, 2, or 3 heteroatoms, more usually containing no more than 2 additional nitrogen atoms and 1 oxygen atom.

[0852] Examples of oxygen-containing heteroaryl groups include, but are not limited to, monocyclic groups such as furan, oxazole, isoxazole, 1,2,3-oxadiazole, or pyran (e.g., 2H-pyran or 4H-pyran).

[0853] In the definition of a cyclic group or ring, when it is said that a cyclic group contains a certain number of heteroatom ring members, e.g., in the phrase "a 5- or 6-membered ring containing 0, 1, or 2 nitrogen ring members", it should be understood that other than the specified number of heteroatom ring members, the other ring members are carbon atoms.

[0854] Unless the context indicates otherwise, the term "non-aromatic group" includes unsaturated ring systems without aromaticity, partially saturated and fully saturated heterocyclic systems. The terms "unsaturated" and "partially saturated" refer to a ring structure of a ring having atoms sharing more than one valence bond, i.e., the ring contains at least one multiple bond, e.g., a C═C bond, a C≡C or an N═C bond. The term "saturated" or "fully saturated" refers to a ring in which there are no multiple bonds between ring atoms. Saturated heterocyclic groups include piperidine, morpholine, and thiomorpholine. Partially saturated heterocyclic groups include pyrazolines, e.g., 2-pyrazoline and 3-pyrazoline.

[0855] Examples of non-aromatic heterocyclic groups are groups having from 3 to 12 ring members, more usually having from 5 to 10 ring members. Such groups can be monocyclic or bicyclic groups, e.g., usually having from 1 to 5 heteroatom ring members (more usually having 1, 2, 3, or 4 heteroatom ring members), the heteroatom ring members usually being selected from nitrogen, oxygen, and sulfur. For example, the heterocyclic group can contain a cyclic ether moiety (e.g., as in the case of tetrahydrofuran and dioxane), a cyclic thioether moiety (e.g., as in the case of tetrahydrothiophene and dithiane), a cyclic amine moiety (as in the case of pyrrolidine), a cyclic amide moiety (as in the case of pyrrolidone, piperidone, or caprolactam), a cyclic thioamide, a cyclic thioester, a cyclic urea (as in the case of imidazolin-2-one), a cyclic ester moiety (as in the case of butyrolactone), a cyclic sulfone (e.g., as in the case of sulfolane and cyclobutene sulfone), a cyclic sulfoxide, a cyclic sulfonamide (such as 1,1-dioxoisothiazolidine, 1,1-dioxo[1,2]thiazinane, or 1,1-dioxo[1,2]thiazepane) and combinations thereof (e.g., morpholine, thiomorpholine, and thiomorpholine-S,S-dioxide).

[0856] Specific examples of monocyclic non-aromatic heterocyclic groups include azetidine, pyrrolidine (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, and 3-pyrrolidinyl), piperidine (e.g., 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), piperidone, azepane, piperazine, diazepane, morpholine, homomorpholine, pyran (2H-pyran or 4H-pyran), imidazoline, imidazolidone, oxazoline, thiazoline, 6H-1,2,5-thiadiazine, pyrazoline (such as 2-pyrazoline and 3-pyrazoline), pyrazolidine, dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, tetrahydrofuran, tetrahydrothiophene, dioxane, oxacyclohexane (such as 4-oxacyclohexyl). In addition, it also includes pyrrolidinonyl, piperazinonyl, and N-alkylpiperazines, such as N-methylpiperazinyl. In general, typical non-aromatic heterocyclic groups include saturated groups, such as piperidinyl, pyrrolidinyl, azetidinyl, morpholinyl, piperazinyl, and N-alkylpiperazines, such as N-methylpiperazinyl.

[0857] The terms "oxan" and "oxanyl" refer to the following groups:

[0858]

[0859] Also known as "tetrahydropyran" or "tetrahydropyranyl".

[0860] Heterocyclic groups can be polycyclic fused-ring systems, spiro-ring systems or bridged-ring systems, such as oxa- and aza-analogues of bicycloalkanes and tricycloalkanes (e.g., oxa-adamantane and aza-adamantane). For an explanation of the difference between fused-ring and bridged-ring systems, see Advanced Organic Chemistry, by Jerry March, 4 th Edition, Wiley Interscience, pages 131 - 133, 1992.

[0861] Specific examples of bicyclic non-aromatic ring systems include aza-bicyclo[2.2.1]heptane (e.g., aza-bicyclo[2.2.1]heptan-2-yl), aza-bicyclo[2.2.2]octane (e.g., 1-aza-bicyclo[2.2.2]octan-3-yl or 2-aza-bicyclo[2.2.2]octan-2-yl), aza-bicyclo[3.2.1]octane (e.g., 8-aza-bicyclo[3.2.1]octan-8-yl), hexahydro-1H-isoindolyl (e.g., hexahydro-1H-isoindol-2(3H)-yl), hexahydrocyclopenta[b]pyrrol-1(2H)-yl (e.g., hexahydrocyclopenta[b]pyrrol-1(2H)-yl), octahydroisoquinolyl (e.g., cis-octahydro-isoquinolin-2(1H)-yl), 4-azaspiro[2.5]octan-4-yl (e.g., 4-azaspiro[2.5]octan-4-yl) and 2-oxaspiro[3.3]heptan-6-yl ring systems.

[0862] In nitrogen-containing non-aromatic heterocycles, the ring must contain at least one ring nitrogen atom. The nitrogen-containing heterocycle can be N-linked or C-linked. The heterocyclic group can contain, for example, a cyclic amine moiety (e.g., as in pyrrolidinyl), cyclic amides (such as pyrrolidinone, piperidone or caprolactam), cyclic sulfonamides (such as 1,1-dioxoisothiazolidinyl, 1,1-dioxo[1,2]thiazinyl or 1,1-dioxo[1,2]thiazepinyl) and combinations thereof.

[0863] Specific examples of the nitrogen-containing non-aromatic heterocyclic group include aziridinyl, morpholinyl, thiomorpholinyl, piperidinyl (e.g., piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, and piperidin-4-yl), pyrrolidinyl (e.g., pyrrolidin-1-yl, pyrrolidin-2-yl, and pyrrolidin-3-yl), pyrrolidinone group, dihydrothiazolyl, imidazolyl, imidazolinone group, oxazolinyl, thiazolinyl, 6H-1,2,5-thiadiazinyl, pyrazolin-2-yl, pyrazolin-3-yl, pyrazolidinyl, piperazinyl, and N-alkylpiperazine, such as N-methylpiperazinyl.

[0864] In the oxygen-containing non-aromatic heterocycle, the ring must contain at least one oxygen atom. The oxygen-containing heterocycle is usually C-linked. The heterocyclic group may contain, for example, a cyclic ether moiety (e.g., as in the case of oxane), a cyclic urea (e.g., as in the case of imidazolin-2-one), a cyclic ester moiety (e.g., as in the case of butyrolactone), and combinations thereof.

[0865] Specific examples of the oxygen-containing non-aromatic heterocyclic group include dioxolanyl, oxanyl, dihydrofuranyl, dioxanyl, or morpholinyl.

[0866] The carbocyclic group may be an alicyclic group (e.g., cycloalkyl or cycloalkenyl as defined herein) or an aryl group, having 5 to 12 ring members, more usually having 5 to 10 ring members. The term "aryl" as used herein refers to a carbocyclic aromatic group having at least one aromatic ring, including phenyl, naphthyl, indanyl, indenyl, and tetrahydronaphthyl. The term "aryl" includes polycyclic (e.g., bicyclic) ring systems in which one or more rings are non-aromatic, provided that at least one ring is aromatic. In such polycyclic systems, the group may be linked through an aromatic ring or through a non-aromatic ring.

[0867] The compound of formula (1) may contain a saturated cyclic group linked to other parts of the molecule through one or more bonds. When the cyclic group is linked to other parts of the molecule through two or more bonds, these bonds (or two of these bonds) may be linked to the same atom (usually a carbon atom) or different atoms on the ring. When linked to the same atom on the ring, a cyclic group in which an atom (usually a quaternary carbon atom) is linked to two groups is obtained. In other words, when the compound of formula (1) includes a cyclic group, the group may be linked to other parts of the molecule through a single bond, or the cyclic group and other parts of the molecule share an atom, for example, a spiro compound.

[0868] A heterocyclic or carbocyclic group may be an unsubstituted group or a group substituted with one or more substituents at the places mentioned. For example, a heterocyclic or carbocyclic group may be an unsubstituted group or a group substituted with 1, 2, 3, or 4 substituents. When the heterocyclic or carbocyclic group is a monocyclic or bicyclic group, generally, they are unsubstituted groups or groups having 1, 2, or 3 substituents as defined herein. When the cyclic group is a saturated group, there may be 2 substituents attached to the same carbon atom (when the substituents are the same, it is called geminal disubstitution or "gem" disubstitution).

[0869] Combinations of substituents are allowed as long as such combinations result in stable or chemically viable compounds (i.e., when maintained at 40 °C or lower for at least one week, such compounds do not substantially change).

[0870] The individual functional groups and substituents constituting the compounds of the present invention are generally selected such that the molecular weight of the compounds of the present invention does not exceed 1000. More typically, the molecular weight of the compound will be less than 750, for example, less than 700, or less than 650, or less than 600, or less than 550. More preferably, the molecular weight is less than 525, for example, the molecular weight is 500 or lower.

[0871] Salts, Solvates, Tautomers, Isomers, N-Oxides, Esters, Precursors Drugs and Isotopes

[0872] The compounds of formula (0) and the compounds of its subgroups also include their ionic forms, salts, solvates, isomers (including geometric isomers and stereochemical isomers), tautomers, N-oxides, esters, prodrugs, isotopes, and protected forms, for example, as discussed below; in particular, their salts, tautomers, or isomers, or N-oxides, or solvates; more particularly, their salts, tautomers, or N-oxides, or solvates; even more particularly, their salts, tautomers, or solvates.

[0873] Salts

[0874] Many compounds of formula (0) may exist in the form of salts, for example, acid addition salts, or in some cases, in the form of organic and inorganic base salts, such as carboxylates, sulfonates, and phosphates. All such salts are within the scope of the present invention, and when referring to the compounds of formula (0), the salt forms of the compounds are included.

[0875] The salts of the present invention can be synthesized from the parent compounds containing basic or acidic moieties by conventional chemical methods, such as those described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002. Generally, these salts can be prepared by reacting the free acids or bases of these compounds with suitable bases or acids in water or organic solvents or in mixtures of both; generally, non-aqueous media such as ethers, ethyl acetate, ethanol, isopropanol or acetonitrile are employed.

[0876] Acid addition salts (mono- or di-salts) can be formed with a wide variety of acids (inorganic and organic acids). Examples of acid addition salts include mono- or di-salts formed with the following acids: acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid (e.g., L-ascorbic acid), L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, butyric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, glucuronic acid (e.g., D-glucuronic acid), glutamic acid (e.g., L-glutamic acid), α-oxoglutaric acid, glycolic acid, hippuric acid, hydrohalic acids (e.g., hydrobromic acid, hydrochloric acid, hydroiodic acid), isethionic acid, lactic acid (e.g., (+)-L-lactic acid, (±)-DL-lactic acid), lactobionic acid, maleic acid, malic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, pyruvic acid, L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid and valeric acid, as well as acylated amino acids and cation exchange resins.

[0877] A specific group of salts consists of salts formed with the following acids: acetic acid, hydrochloric acid, hydroiodic acid, phosphoric acid, nitric acid, sulfuric acid, citric acid, lactic acid, succinic acid, maleic acid, malic acid, isethionic acid, fumaric acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid (mesylic acid), ethanesulfonic acid, naphthalenesulfonic acid, valeric acid, acetic acid, propionic acid, butyric acid, malonic acid, glucuronic acid and lactobionic acid. A specific salt is the hydrochloride.

[0878] If the compound is anionic or has a functional group that can be anionic (e.g., -COOH can be -COO - ), the salt can be formed by an organic or inorganic base to generate a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Li + , Na + , and K + , alkaline earth metal cations such as Ca 2+ , and Mg 2+ , and other cations such as Al 3+ or Zn + . Examples of suitable organic cations include, but are not limited to, ammonium ions (i.e., NH4+) and substituted ammonium ions (e.g., NH 3 R + , NH 2 R 2 2+ , NHR 3 + , NR 4 + ). Examples of certain suitable substituted ammonium ions are derived from: methylamine, ethylamine, diethylamine, propylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids such as lysine and arginine. An example of a common quaternary ammonium ion is N(CH 3 ) 4 + .

[0879] When the compounds of formula (0) contain amine functional groups, these compounds may form quaternary ammonium salts, for example, by reacting with an alkylating agent using methods familiar to those skilled in the art to form quaternary ammonium salts. Such quaternary ammonium compounds are within the scope of formula (0).

[0880] Depending on the pKa of the acid forming the salt, the compounds of the present invention may exist in the form of a mono-salt or a di-salt.

[0881] The salt forms of the compounds of the present invention are generally pharmaceutically acceptable salts, and examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, "Pharmaceutically Acceptable Salts," J. Pharm. Sci., Vol. 66, pp. 1-19. However, non-pharmaceutically acceptable salts can also be prepared as intermediate forms and then converted into pharmaceutically acceptable salts. Such non-pharmaceutically acceptable salt forms can be used, for example, for the purification or separation of the compounds of the present invention and are also part of the present invention.

[0882] In one embodiment of the present invention, there is provided a pharmaceutical composition comprising a solution (such as an aqueous solution), said solution comprising the compound of formula (0) and its subgroups and examples herein in salt form, at a concentration greater than 10 mg / ml, usually greater than 15 mg / ml, particularly greater than 20 mg / ml.

[0883] N-Oxides

[0884] The compound of formula (0) containing an amine functional group may also form an N-oxide. The compound of formula (0) containing an amine functional group mentioned herein also includes the N-oxide.

[0885] If the compound contains several amine functional groups, one or more than one nitrogen atom may be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen atoms of nitrogen-containing heterocycles.

[0886] The N-oxide can be prepared by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (such as a peroxycarboxylic acid), see, for example, Advanced Organic Chemistry, by Jerry March, 4 th Edition, WileyInterscience, pages. More specifically, the N-oxide can be prepared by the method of L.W. Deady (Syn.Comm. 1977, 7, 509 - 514), in which the amine compound is reacted with meta-chloroperoxybenzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane.

[0887] In one embodiment of the present invention, the compound is an N-oxide, for example, from a nitrogen atom on a heteroaryl, for example, pyridine N-oxide.

[0888] Geometric Isomers and Tautomers

[0889] The compound of formula (0) may exist in a variety of different geometric isomers and tautomeric forms, and all such forms are included when referring to the compound of formula (0). For the sake of clarity, when the compound may exist in one of several geometric isomers or tautomeric forms, and only one form is specifically described or illustrated, nevertheless, formula (0), (1) and their sub-formulas also include all other forms.

[0890] For example, certain heteroaromatic rings can exist in two tautomeric forms, A and B as shown below. For the sake of brevity, a formula may only illustrate one form, but the formula should be considered to include both tautomeric forms.

[0891]

[0892] Other examples of tautomeric forms include, for example, the keto-, enol-, and enolate-forms, such as, for example, the following tautomeric pairs: keto / enol (shown below), imine / enamine, amide / iminoalcohol, amidine / enediamines, nitroso / oxime, thioketone / enethiol, and nitro / is nitro.

[0893]

[0894] Stereoisomers

[0895] Unless specifically stated or indicated, the chemical name of a compound represents all possible stereochemical isomeric forms.

[0896] If a structure is not limited to a specific isomeric form, but includes any isomeric form of a compound and mixtures of various isomeric forms, the configuration of the stereogenic center is not specified and is represented by a straight line.

[0897] The convention of using "hash lines" or "wedge lines" to indicate stereochemistry is used to specify a specific stereochemical form, for example, as shown in the following two synthetic intermediates.

[0898] (S)-Methyl 2-(6-bromo-1-oxoisoindolin-2-yl)-3-hydroxypropionate

[0899] (R)-tert-Butyl 2-(6-bromo-1-oxoisoindolin-2-yl)propionate

[0900] When the compounds of formula (0), (1) and their sub-formula compounds contain one or more chiral centers and can exist in the form of two or more optical isomers, unless the context otherwise indicates, the reference to the compounds of formula (0), (1) and their sub-formula compounds includes all their optical isomeric forms (e.g., enantiomers, epimers and diastereomers), which can be individual optical isomers, or mixtures of two or more optical isomers (e.g., racemic and scalemic mixtures).

[0901] Optical isomers can be characterized and identified by their optical rotation (i.e., as + and - isomers, or d and l isomers) or they can be characterized according to their absolute stereochemistry using the "R and S" nomenclature developed by Cahn, Ingold and Prelog, see Advanced Organic Chemistry by Jerry March, 4 thEdition, John Wiley & Sons, New York, 1992, pp. 109 - 114, and see Cahn, Ingold & Prelog, Angew. Chem. Int. Ed. Engl., 1966, 5, 385 - 415. Optical isomers can be separated by a variety of methods including chiral chromatography (chiral support chromatography), which are familiar to those skilled in the art.

[0902] As an alternative to chiral chromatography, optical isomers can form diastereomeric salts with chiral acids such as (+)-tartaric acid, (-)-pyroglutamic acid, (-)-di - p - toluoyl - L - tartaric acid, (+)-mandelic acid, (-)-malic acid, and (-)-camphorsulfonic acid, the diastereomers are separated by preferential crystallization, and then the salt is dissociated to obtain the individual enantiomers of the free base. Similarly, the optical isomers of acidic compounds can be separated by forming diastereomeric salts with chiral amines such as strychnine, cinchonidine, quinine, etc.

[0903] In addition, the separation of enantiomers can be achieved by covalently linking an enantiomerically pure chiral auxiliary to the compound, and then carrying out diastereomer separation using conventional methods such as chromatography. Then, the aforementioned covalent linkage is cleaved to obtain the appropriate enantiomerically pure product. For example, the optical isomers of chiral compounds containing free hydroxyl groups can be separated by forming Mosher's acid esters, then separating the resulting diastereomers by chromatography, and then cleaving the ester to regenerate the free hydroxyl group.

[0904] If the compounds of formula (0), (1) and their sub - formulas exist in two or more optically isomeric forms, one isomer in a pair of enantiomers may be better than the other, for example, better in terms of biological activity. Thus, in some cases, it may be required to use only one of the enantiomers in a pair, or only one of the multiple diastereomers as a therapeutic agent. Accordingly, the present invention provides a composition comprising a compound of formula (0), (1) and their sub - formulas having one or more chiral centers, wherein at least 55% (e.g., at least 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%) of the compounds of formula (0), (1) and their sub - formulas are present in the form of a single optical isomer (e.g., enantiomer or diastereomer). In a general embodiment, 99% or more (e.g., substantially all) of the compounds of formula (0), (1) and their sub - formulas are present in the form of a single optical isomer (e.g., enantiomer or diastereomer).

[0905] Compounds containing a double bond can have E (entgegen, opposite) or Z (zusammen, together) stereochemistry at the double bond. Substituents on a divalent ring or (partially) saturated radical may have a cis- or trans-configuration. Here, the terms cis and trans conform to Chemical Abstracts nomenclature (J. Org. Chem. 1970, 35(9), 2849 - 2867) and refer to the positions of substituents on the ring moiety.

[0906] Particularly interesting are those compounds that are stereochemically pure of formula (0), (1) and their sub-formulas. When a compound of formula (0), (1) and their sub-formulas is specified, for example, as R, this means that the compound is substantially free of the S isomer. When a compound of formula (0), (1) and their sub-formulas is specified, for example, as E, this means that the compound is substantially free of the Z isomer. The terms cis, trans, R, S, E and Z are familiar to those skilled in the art.

[0907] Isotope Variations

[0908] The present invention includes all pharmaceutically acceptable isotopically labeled compounds of the compounds of the present invention, i.e., compounds of formula (0), (1) and their sub-formulas, wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.

[0909] Examples of isotopes suitable for inclusion in the compounds of the present invention include isotopes of hydrogen such as 2 H(D) and 3 H(T), isotopes of carbon such as 11 C, 13 C and 14 C, isotopes of chlorine such as 36 Cl, isotopes of fluorine such as 18 F, isotopes of iodine such as 123 l, 125 l and 131 l, isotopes of nitrogen such as 13 N and 15 N, isotopes of oxygen such as 15 O, 17 O and 18 O, isotopes of phosphorus such as 32 P, isotopes of sulfur such as 35 S.

[0910] Certain isotopically labeled compounds of formula (0), (1) and their sub-formulas, for example, those containing radioactive isotopes, are used in studies of drug and / or substrate tissue distribution. Compounds of formula (0), (1) and their sub-formulas also have valuable diagnostic properties and can be used to detect or identify the formation of complexes between labeled compounds and other molecules, peptides, proteins, enzymes or receptors. Such detection or identification methods can employ compounds labeled with labeling reagents such as radioactive isotopes, enzymes, fluorescent substances, luminescent substances (e.g., luminol, luminol derivatives, fluorescein, aequorin and luciferase), etc. The radioactive isotope tritium, i.e., 3 H(T) and carbon-14, i.e., 14 C, are particularly useful for such purposes due to their ease of introduction and detection.

[0911] Replacement with heavier isotopes such as deuterium, i.e., 2 H(D), may have certain therapeutic advantages due to more stable metabolism, such as an extended in vivo half-life or reduced dose requirements, and may therefore be preferred in certain cases. In particular, when hydrogen is provided in an application, it should be considered to include 1 H and 2 H, whether hydrogen is explicitly defined or only implicitly present to satisfy the valence of the relevant atom (especially a carbon atom).

[0912] Replacement with positron-emitting isotopes such as 11 C, 18 F, 15 O and 13 N can be used in positron emission tomography (PET) studies for detecting target occupancy.

[0913] Isotopically labeled compounds of formula (0), (1) and their sub-formulas can generally be prepared by conventional methods familiar to those skilled in the art, or by methods similar to those described in the attached examples and preparations, using appropriate isotopically labeled reagents in place of the non-labeled reagents previously employed.

[0914] Esters

[0915] Formula (0), (1) and their sub-formulas also include esters of compounds of formula (0), (1) and their sub-formulas with carboxylic acid groups or hydroxyl groups, such as carboxylic acid esters, acyloxy esters and phosphate esters. Examples of esters are compounds containing a -C(=O)OR group, where R is an ester substituent, e.g., C 1-7 alkyl, C 3-12 heterocyclic group or C 5-12 aryl, especially C 1-6 alkyl. Specific examples of ester groups include, but are not limited to, -C(=O)OCH3 、 -C(=O)OCH 2 CH 3 、 -C(=O)OC(CH 3 ) 3 and -C(=O)OPh. Examples of acyloxy (reverse ester) are represented by -OC(=O)R, where R is an acyloxy substituent, for example, C 1-6 alkyl, C 3-12 heterocyclic group or C 5-12 aryl, especially C 1-6 alkyl. Specific examples of acyloxy include but are not limited to -OC(=O)CH 3 (acetoxy), -OC(=O)CH 2 CH 3 , -OC(=O)C(CH 3 ) 3 , -OC(=O)Ph and -OC(=O)CH 2 Ph. Examples of phosphates are those esters derived from phosphoric acid.

[0916] In one embodiment of the present invention, the compounds of formula (0), (1) and their sub-formulas include, within their scope, esters of the compounds of formula (0), (1) and their sub-formulas containing a carboxylic acid group or a hydroxyl group. In another embodiment of the present invention, the compounds of formula (0), (1) and their sub-formulas do not include, within their scope, esters of the compounds of formula (0), (1) and their sub-formulas containing a carboxylic acid group or a hydroxyl group.

[0917] Solvates and Crystal Forms

[0918] The compounds of formula (0), (1) and their sub-formulas also include any polymorphic forms and solvates of the said compounds, such as hydrates, alcoholates, etc.

[0919] The compounds of the present invention can form solvates, for example, with water (i.e., form hydrates) or common organic solvents. In the present invention, the term "solvate" refers to the physical association of the compounds of the present invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding (including hydrogen bonding). In some cases, the solvate can be separated, for example, when one or more solvent molecules are introduced into the lattice of a crystalline solid. The term "solvate" includes solution-phase and separable solvates. Non-limiting examples of suitable solvates include compounds of the present invention in combination with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid or ethanolamine, etc. The compounds of the present invention can exert their biological effects in solution.

[0920] Solvates are familiar in pharmaceutical chemistry. They are very important for the method of preparing a substance (e.g., related to purity), the storage of the substance (e.g., its stability), and the simplicity of handling the substance, and usually form part of the separation or purification stage of chemical synthesis. A person skilled in the art can use standard techniques that have been used for a long time to determine whether a hydrate or other solvate has been formed under the separation conditions or purification conditions for preparing a given compound. Examples of such techniques include thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray crystallography (e.g., single crystal X-ray crystallography or X-ray powder diffraction), and solid state NMR (SS-NMR, also known as magic angle spinning NMR or MAS-NMR). Like NMR, IR, HPLC, and MS, these techniques are part of the standard analytical toolkit of a skilled chemist.

[0921] Alternatively, a person skilled in the art can utilize crystallization conditions to incorporate a solvent in an amount required for a specific solvate to form the solvate. Then, the standard methods described above can be used to determine whether a solvate has been formed.

[0922] In addition, the compounds of the present invention can have one or more polymorphic or amorphous crystalline forms, and these forms are included within the scope of the present invention.

[0923] Complexes

[0924] Formulas (0), (1) and their sub-formulas also include within their scope complexes of these compounds (e.g., complexes or inclusion compounds with compounds such as cyclodextrin, or complexes with metals). Complexes, inclusion compounds, and metal complexes can be formed by methods familiar to those skilled in the art.

[0925] Prodrugs

[0926] Formulas (0), (1) and their sub-formulas also include any prodrugs of the compounds of formulas (0), (1) and their sub-formulas. "Prodrug" refers to, for example, any compound that is converted in vivo into a bioactive compound of formulas (0), (1) and their sub-formulas.

[0927] For example, some prodrugs are esters of the active compound (e.g., physiologically acceptable metabolically labile esters). During metabolism, the ester group (-C(=O)OR) is cleaved to give the active drug. Such esters can be formed by, for example, esterification of any carboxylic acid group (-C(=O)OH) in the parent compound, and if appropriate, any other reactive groups present in the parent compound are first protected and then deprotected if necessary.

[0928] Examples of such metabolically unstable esters include those of the formula -C(=O)OR, where R is:

[0929] C 1-7 alkyl (e.g., -Me, -Et, -nPr, -iPr, -nBu, -sBu, -iBu, -tBu);

[0930] C 1-7 aminoalkyl (e.g., aminoethyl; 2-(N,N -diethylamino)ethyl; 2-(4 -morpholino)ethyl); and

[0931] acyloxy -C 1-7 alkyl (e.g., acyloxymethyl, acyloxyethyl, pivaloyloxymethyl, acetoxymethyl, 1 -acetoxyethyl, 1-(1 -methoxy -1 -methyl)ethyl -carbonyloxyethyl, 1-(benzoyloxy)ethyl, isopropoxy -carbonyloxymethyl), 1 -isopropoxy -carbonyloxyethyl, cyclohexyl -carbonyloxymethyl, 1 -cyclohexyl -carbonyloxyethyl, cyclohexyloxy -carbonyloxymethyl, 1 -cyclohexyloxy -carbonyloxyethyl, (4 -oxacyclohexyloxy)carbonyloxymethyl, 1-(4 -oxacyclohexyloxy)carbonyloxyethyl, (4 -oxacyclohexyl)carbonyloxymethyl and 1-(4 -oxacyclohexyl)carbonyloxyethyl.

[0932] In addition, some prodrugs are activated by enzymes to give the active compound, or give a compound which, upon further chemical reaction, gives the active compound (e.g., as in antigen -directed enzyme prodrug therapy (ADEPT), gene -directed enzyme prodrug therapy (GDEPT) and ligand -directed enzyme prodrug therapy (LIDEPT), etc.). For example, a prodrug can be a sugar derivative or other glycoside conjugate, or can be an amino acid ester derivative. In one embodiment, the formula (0), (1) and their sub -formulas do not include prodrugs of the compounds of formula (0), (1) and their sub -formulas within their scope.

[0933] Preparation Methods of Compounds of Formula (0), (1) and Their Sub-formula Compounds

[0934] Unless the context otherwise indicates, as in other parts of this application, the formula (1) mentioned in this part also includes the formula (0) and all other subgroups (e.g., formula (2), (3), (3A), (3B), (4), (4A), (4B), (5), (5A), (5B), (6), (6A), (6B), (7), (7A), (7B), (8), (8A), (8B), (9), (9A), (9B), (10) and (11)), subsets and examples defined herein.

[0935] The compounds of formula (0), (1) and their sub-formulas can be prepared by synthetic methods familiar to those skilled in the art.

[0936] According to another aspect of the present invention (Example 2.1), there is provided a method for preparing the compounds of formula (0), (1) and their sub-formulas as defined herein, the method comprising:

[0937] (a)(i) reacting a compound of formula (II):

[0938]

[0939] with a compound of formula HNR 8 R 9 ; or

[0940] (ii) reacting a compound of formula (III):

[0941]

[0942] in the presence of a palladium catalyst with a compound of formula (IV):

[0943] wherein Hal is a suitable leaving group, such as a halide; or

[0944] (iii) reacting a compound of formula (V):

[0945]

[0946] (wherein Hal is a suitable leaving group, such as a halide) with a compound of formula R 1 NH 2 ; or

[0947] (iv) reacting a compound of formula (VI):

[0948]

[0949] with a compound of formula R 7 L 1 -J, wherein J is a suitable leaving group; and / or

[0950] (b) deprotecting the protected derivatives of the compounds of formula (0), (1) and their sub-formulas; and / or

[0951] (c) interconverting the compounds of formula (0), (1) and their sub-formulas or their protected derivatives into another compound of formula (0), (1) and their sub-formulas or their protected derivatives; and

[0952] (d) optionally forming a pharmaceutically acceptable salt of the compounds of formula (0), (1) and their sub-formulas;

[0953] wherein R 1 、R 2 、R 4 、R 4a 、R 7 、L 1 、X, Y and Z are as defined in any one of Examples 0.1 to 1.179.

[0954] Method (a)(i) generally comprises stirring Compound (II) with Compound HNR 8 R 9 in the presence of a suitable amide coupling agent (such as HATU, TBTU or HBTU or 1-propane phosphoric anhydride) and a suitable base (such as triethylamine or DIPEA) in a suitable solvent such as dioxane, DMF or DCM or a mixture thereof. This method can be carried out at room temperature or at a high temperature such as 60 °C. An example of this reaction is illustrated in Example 1.

[0955] Method (a)(ii) generally comprises stirring Compound (III) with Compound (IV) in a suitable aqueous solvent mixture such as dioxane / water in an inert atmosphere in the presence of a suitable catalyst such as tetrakis(triphenylphosphine)palladium and a suitable base such as potassium carbonate. This method can be carried out at room temperature or at a high temperature such as 80 °C or 100 °C. An example of this reaction is illustrated in Example 124.

[0956] Method (a)(iii) generally comprises stirring Compound (V) with Compound R 1 NH 2 in a suitable solvent such as dioxane, EtOH or a mixture thereof. This method can be carried out at room temperature or at a high temperature such as 60 °C or 90 °C. An example of this reaction is illustrated in Example 102.

[0957] Method (a)(iii) alternatively comprises stirring Compound (V) with Compound R 1 NH 2 in a suitable solvent such as acetonitrile in an inert atmosphere in the presence of a suitable catalyst (such as bis(dibenzylideneacetone)palladium), a suitable ligand (such as XPhos) and a suitable base (such as potassium carbonate). This method can be carried out at room temperature or at a high temperature such as 90 °C or 150 °C. An example of this reaction is illustrated in Example 189.

[0958] Method (b) generally includes any suitable deprotection reaction, and the reaction conditions depend on the nature of the protecting group. When the protecting group is tBoc or 2,4-dimethoxybenzyl, such deprotection reaction will generally include using a suitable acid in a suitable solvent. For example, suitable acids may include trifluoroacetic acid or hydrochloric acid, and suitable solvents may include dichloromethane, ethyl acetate, dioxane, methanol or water, or mixtures thereof. Examples of such reactions are illustrated in Example 113.

[0959] It should be understood that when the protecting group is tBoc, deprotection with the suitable acid described above may give pharmaceutically acceptable salts of the compounds of formula (0), (1) and their sub-formulas that can be directly separated. Alternatively, the compounds of formula (0), (1) and their sub-formulas can be separated into the free base by methods familiar to those skilled in the art, and then optionally converted into pharmaceutically acceptable salts according to method (d).

[0960] Method (c) generally includes tautomerization methods familiar to those skilled in the art. For example, in the compounds of formula (0), (1) and their sub-formulas, the first substituent can be converted into the second alternative substituent by methods familiar to those skilled in the art. Those skilled in the art are familiar with a wide range of well-known functional group interconversion methods for converting precursor compounds into the compounds of formula (0), (1) and their sub-formulas, as described, for example, in Advanced Organic Chemistry by Jerry March & Michael B Smith, 7 th edition, John Wiley & Sons, 2013.

[0961] Method (d) can be carried out by dissolving the compounds of formula (0), (1) and their sub-formulas in the free base form in a suitable solvent, treating them with a stoichiometric or excess amount of a pharmaceutically acceptable organic or inorganic acid, and then separating the resulting salt by methods familiar to those skilled in the art such as solvent evaporation or crystallization.

[0962] If appropriate, one or more reactions familiar to those skilled in the art can be carried out in a suitable order after or before the reactions described in methods (a), (b) and (c) above, so as to effect the necessary substitutions to obtain other compounds of formula (0), (1) and their sub-formulas. Non-limiting examples of such reactions for which reaction conditions are given in the literature include:

[0963] Protection of reactive functional groups,

[0964] Deprotection of reactive functional groups,

[0965] Halogenation,

[0966] Debromination,

[0967] Dealkylation

[0968] Alkylation of amines, anilines, alcohols and phenols

[0969] Mitsunobu reaction of hydroxyl groups

[0970] Cycloaddition reaction of suitable groups

[0971] Reduction of nitro groups, esters, nitriles, aldehydes

[0972] Transition metal-catalyzed coupling reaction

[0973] Acylation

[0974] Sulfonylation / introduction of sulfonyl groups

[0975] Saponification / hydrolysis of ester groups

[0976] Amidation or transesterification of ester groups

[0977] Esterification or amidation of carboxyl groups

[0978] Halogen exchange

[0979] Nucleophilic substitution with amines, thiols or alcohols

[0980] Reductive amination

[0981] Oxime formation of carbonyl and hydroxylamine groups

[0982] S-oxidation

[0983] N-oxidation, and

[0984] Salification

[0985] Intermediates of Method (a)

[0986] Compound of formula (II), wherein n, R 1 、R 2 and Z are as defined above, R 3 is -CH 2 CONR 8 R 9 ,R 4 and R 4a are H, Y is CH, X is N, and can be prepared according to the following Scheme 1:

[0987] Step (i) of Scheme 1 generally involves stirring the compound of formula (VII) with R 1 NH 2Compound. This method can be carried out at room temperature or high temperature, such as 60 °C or 90 °C. An example of this reaction is illustrated in Preparation 4.

[0988] Scheme 1

[0989]

[0990] Step (ii) of Scheme 1 generally involves stirring Compound (VIII) with a suitable acid such as trifluoroacetic acid or hydrochloric acid in a suitable solvent such as dichloromethane, ethyl acetate, dioxane, methanol or water, or a mixture thereof. An example of this reaction is illustrated in Preparation 5 herein.

[0991] Compound of formula (VII), wherein n, R 2 , R 3 and Z are as defined in formula (0), (1) and their sub-formulae, R 4 and R 4a are H, X is N, Y is CH, can be prepared according to the following Scheme 2:

[0992] Scheme 2

[0993]

[0994] In Scheme 2, Hal is a suitable halogen leaving group, such as Cl, Br or I.

[0995] Step (i) of Scheme 2 generally involves stirring Compound (IX) with bis(pinacolato)diboron in a suitable solvent (such as dioxane) and an inert atmosphere in the presence of a suitable catalyst such as PdCl 2 (dppf) complex and a suitable base such as potassium acetate. This method can be carried out at room temperature or high temperature, such as 80 °C to 100 °C. An example of this reaction is illustrated in Preparation 2 herein.

[0996] Step (ii) of Scheme 2 generally involves stirring Compound (X) with Compound (XI) in a suitable aqueous solvent mixture such as dioxane / water in an inert atmosphere in the presence of a suitable catalyst such as tetrakis(triphenylphosphine)palladium and a suitable base such as potassium carbonate. This method can be carried out at room temperature or high temperature, such as 80 °C to 100 °C. An example of this reaction is illustrated in Preparation 3 herein.

[0997] Compound of formula (IX), wherein n = 1 or 2, Y and Z are CH, can be prepared according to the following Scheme 3:

[0998] Scheme 3

[0999]

[1000] Step (i) of Scheme 3 generally involves stirring a commercially available compound of formula (XII) with a suitable alkylating agent such as tert-butyl 2-bromoacetate in a suitable solvent such as DMF in the presence of a suitable base such as sodium hydride. This method can be carried out at room temperature or at a low temperature such as 4 °C. An example of this reaction is illustrated in Preparation 1 herein.

[1001] The compound of formula (IX), wherein n = 1, Y = CH, and Z is as defined in the general formula (0), (1) and its sub-formulas above, can be prepared according to the following Scheme 4:

[1002] Scheme 4

[1003]

[1004] Step (i) of Scheme 4 generally involves stirring a compound of formula (XIII) with a suitable brominating agent such as N-bromosuccinimide in a suitable solvent such as dichloroethane in the presence of a suitable radical initiator such as benzoyl peroxide or azobisisobutyronitrile. This method can be carried out at room temperature or at a high temperature such as 80 °C. An example of this reaction is illustrated in Preparation 6 herein.

[1005] Step (ii) of Scheme 4 generally involves stirring a compound of formula (XIV) with tert-butyl glycinate in a suitable solvent such as toluene or acetonitrile in the presence of a suitable base such as trimethylamine or diisopropylethylamine. This method can be carried out at room temperature or at a high temperature such as 120 °C. An example of this reaction is illustrated in Preparation 7 herein.

[1006] Bromination and ring closure to form the lactam (shown in formula (IX) above) can also be used to prepare higher intermediate compounds. For example, intermediates in which the "Hal" group in formula (IX) is replaced by a 2-halopyrimidinyl group. Examples of the series of reactions for preparing these intermediates are provided in Preparations 225 to 227, 401 and 402 below.

[1007] Alternatively, the compound of formula (II), wherein n, R 1 , R 2 , X and Z are as defined above, and Y is CH, can be prepared according to the following Scheme 5:

[1008] Scheme 5

[1009]

[1010] Step (i) of Scheme 5 generally involves stirring the compound of formula (X) with the compound of formula (XVI) in a suitable aqueous solvent mixture such as dioxane / water, in an inert atmosphere, in the presence of a suitable catalyst such as tetrakis(triphenylphosphine)palladium or XPhos Pd G3 and a suitable base such as potassium carbonate. This method can be carried out at room temperature or elevated temperature, for example, from 80 °C to 100 °C. An exemplary method for steps (i) and (ii) is illustrated in Preparation 19 herein.

[1011] Step (ii) of Scheme 5 generally involves stirring the compound of formula (XVIII) with a suitable acid such as trifluoroacetic acid or hydrochloric acid in a suitable solvent such as dichloromethane, ethyl acetate, dioxane, methanol or water, or a mixture thereof. An example of such a reaction is illustrated in Preparation 20 herein.

[1012] The compound of formula (IV) wherein X is N can be prepared according to Scheme 6 below:

[1013] Scheme 6

[1014]

[1015] Step (i) of Scheme 6 generally involves stirring the compound of formula (XIX) with the compound of formula R 1 NH 2 in a suitable solvent such as dioxane, THF, EtOH or a mixture thereof. This method can be carried out at room temperature or elevated temperature, for example, from 60 °C to 90 °C. An example of such a reaction is illustrated in Preparation 17 herein.

[1016] In a variant of the reaction shown in Scheme 6 above, a compound of formula (XIX) in which "Hal" is replaced by OH (i.e., the compound is 4-pyrimidinone) and the chlorine atom is replaced by methylsulfanyl can be reacted with the amine R 1 NH 2 at elevated temperature (e.g., about 130 °C). Then, the hydroxyl group on the pyrimidine ring can be replaced by chlorine by reaction with a chlorinating reagent such as POCl 3 This sequence of reactions is illustrated in Preparations 112 and 113 below.

[1017] As another variant of the reaction shown in Scheme 6 above, a palladium-catalyzed amination reaction can be used (e.g., under Buchwald-Hartwig reaction conditions) to convert the chloro-intermediate (XIX) to the amine (IV).

[1018] The compound of formula (IV) wherein X is CH can be prepared according to Scheme 7 below:

[1019] Scheme 7

[1020]

[1021] Step (i) of Scheme 7 generally involves stirring compound (XX) with a suitable ketone R 1 =O in a suitable solvent such as dichloroethane in the presence of a suitable reducing agent such as sodium triacetoxyborohydride. This method can be carried out at ambient temperature or low or high temperature, for example, in the range of 0 °C to 60 °C. An example of this reaction is illustrated in Preparation 135 herein.

[1022] Compound of formula (II), wherein R 1 , R 2 and X are as defined above, Y and Z are CH, n = 1, R 4 is alkyl and R 4a is H, can be prepared according to the following Scheme 8:

[1023] Scheme 8

[1024]

[1025] Step (i) of Scheme 8 generally involves stirring compound (XXI) with a compound of formula R 1 NH 2 in a suitable solvent such as dioxane, EtOH or a mixture thereof. This method can be carried out at ambient temperature or elevated temperature, for example, 60 °C or 90 °C. An example of this reaction is illustrated in Preparation 33 herein.

[1026] Step (ii) of Scheme 1 generally involves stirring compound (XXII) with a suitable acid such as trifluoroacetic acid or hydrochloric acid in a suitable solvent such as dichloromethane, ethyl acetate, dioxane, methanol or water, or a mixture thereof. An example of this reaction is illustrated in Preparation 5 herein.

[1027] Compound of formula (XXI), wherein R 2 and X are as defined in formula (0), (1) and their sub-formulae, Y and Z are CH, n = 1, R 4 is alkyl and R 4a is H, can be prepared according to the following Scheme 9:

[1028] Scheme 9

[1029]

[1030] In Scheme 9, Hal is a suitable halogen leaving group such as Cl, Br or I.

[1031] Step (i) of Scheme 9 generally involves stirring Compound (XXIII) with bis(pinacolato)diboron in a suitable solvent such as dioxane in an inert atmosphere in the presence of a suitable catalyst such as a PdCl 2 (dppf) complex and a suitable base such as potassium acetate. This method can be carried out at room temperature or at an elevated temperature such as 80 °C or 100 °C.

[1032] Step (ii) of Scheme 9 generally involves stirring Compound (XXIV) with Compound (XI) in a suitable aqueous solvent mixture such as dioxane / water in an inert atmosphere in the presence of a suitable catalyst such as tetrakis(triphenylphosphine)palladium and a suitable base such as potassium carbonate. This method can be carried out at room temperature or at an elevated temperature such as 80 °C or 100 °C. An exemplary method for steps (i) and (ii) is illustrated in Preparation 32 herein.

[1033] Compound (XXIII) wherein n = 1, Y and Z are CH, R 4 is alkyl, R 4a is H, can be prepared according to Scheme 10 below:

[1034] Scheme 10

[1035]

[1036] In Scheme 10, Hal is a suitable halogen leaving group such as Cl, Br or I.

[1037] Step (i) of Scheme 10 generally involves stirring Compound (XXV) with di-tert-butyl dicarbonate in a suitable solvent such as dichloromethane in the presence of a suitable base such as trimethylamine and a nucleophilic catalyst such as DMAP. This method can be carried out at room temperature or at an elevated temperature such as 60 °C. An exemplary method for step (i) is illustrated in Preparation 21 herein.

[1038] Step (ii) of Scheme 10 generally involves stirring Compound (XXVI) with a suitable base such as lithium hexamethyldisilazide in a suitable solvent such as THF for a suitable period of time, e.g., 1 hour, and then treating with a suitable alkylating agent such as an alkyl halide, methanesulfonic acid or trifluoromethanesulfonic acid. This method can be carried out at room temperature or at a low temperature such as -78 °C to 0 °C. An exemplary method for step (ii) is illustrated in Preparation 29 herein.

[1039] Step (iii) of Scheme 10 generally involves stirring Compound (XXVII) with a suitable acid such as trifluoroacetic acid or hydrochloric acid in a suitable solvent such as dichloromethane or dioxane. This method is generally carried out at room temperature, but can also be carried out at low or elevated temperatures. Exemplary methods for step (ii) are illustrated in Preparation 30 herein.

[1040] Step (iv) of Scheme 10 generally involves stirring compound (XXVIII) with a suitable alkylating agent, such as tert-butyl 2-bromoacetate, in a suitable solvent, such as dimethylformamide or NMP, in the presence of a suitable base, such as sodium hydride. This method is typically carried out at room temperature, but can also be carried out under low or high temperature conditions. An example method for step (ii) is illustrated in Preparation 1 herein.

[1041] Compound of formula (XXIII) wherein n = 1, Y and Z are CH, R 4 is alkyl and R 4a is H, can also be prepared by varying the reaction sequence of Scheme 4 above, but wherein the bromomethyl in compound (XIV) of Scheme 4 is replaced with the group Alk-CH(Br)-. Examples of such variations are illustrated in Preparations 347 and 348 below.

[1042] Compounds of formula (III) can be prepared according to Scheme 11 below:

[1043] Scheme 11

[1044]

[1045] Step (i) of Scheme 11 generally involves stirring compound (XXIII) with bis(pinacolato)diboron in a suitable solvent, such as dioxane, in an inert atmosphere, in the presence of a suitable catalyst, such as a PdCl 2 (dppf) complex or XPhos Pd G3 and a suitable base, such as potassium acetate. This method can be carried out at room temperature or high temperature, such as 80 °C or 100 °C. An example method for step (ii) is illustrated in Preparation 86 herein.

[1046] Compounds of formula (XXIX) can be prepared according to Scheme 12 or Scheme 13 below, wherein R 7 L is as defined in formulae (0), (1) and their sub-formulae:

[1047] Scheme 12

[1048]

[1049] Scheme 13

[1050]

[1051] Step (i) of Scheme 12 generally involves stirring the compound of formula (XIV) with a suitable amine in a suitable solvent such as THF, methanol or toluene in the presence of a suitable base such as triethylamine. This method can be carried out at room temperature or elevated temperature such as 70 °C or 100 °C. An example of this reaction is illustrated in Preparation 78.

[1052] Step (i) of Scheme 13 generally involves stirring a commercially available compound of formula (XII) with a suitable alkylating agent in a suitable solvent such as DMF in the presence of a suitable base such as sodium hydride. This method can be carried out at room temperature or low temperature such as 4 °C. An example of this reaction is illustrated in Preparation 43.

[1053] The compound of formula (V) can be prepared according to Scheme 14 below:

[1054] Scheme 14

[1055]

[1056] In Scheme 14, Hal is a suitable halogen leaving group such as Cl, Br or I.

[1057] Step (i) of Scheme 14 generally involves stirring the compound of formula (III) with the compound of formula (XI) in a suitable aqueous solvent mixture such as dioxane / water in the presence of a suitable catalyst such as tetrakis(triphenylphosphine)palladium and a suitable base such as potassium carbonate under an inert atmosphere. This method can be carried out at room temperature or elevated temperature, such as 80 °C or 100 °C. An example of the method for step (ii) is illustrated in Preparation 90.

[1058] Intermediates of Method (b)

[1059] Compounds of formula (0), (1) and their sub-formulas, where n = 1, Y and Z are CH, R 4 is a hydroxyalkyl group, R 4a is H, can be prepared according to Scheme 15 below:

[1060] Scheme 15

[1061]

[1062] In Scheme 15, Hal is a suitable halogen leaving group such as Cl, Br or I.

[1063] Step (i) of Scheme 15 generally involves stirring compound (XXVI) with a suitable base such as lithium hexamethyldisilazide in a suitable solvent such as THF for a suitable time, e.g., 1 hour, and then treating with a suitable alkylating agent such as 2-(trimethylsilyl)ethoxymethyl chloride. This method can be carried out at room temperature or low temperature, e.g., -78 °C to 0 °C or under different temperature conditions in combination with different times. An example method of step (i) is illustrated in Preparation 22.

[1064] Step (ii) of Scheme 15 generally involves stirring compound (XXX) with a suitable acid, e.g., trifluoroacetic acid or hydrochloric acid, in a suitable solvent such as dichloromethane or dioxane. This method is generally carried out at room temperature, but can also be carried out under low temperature or high temperature conditions. An example method of step (ii) is illustrated in Preparation 23.

[1065] Step (iii) of Scheme 15 generally involves stirring compound (XXXI) with a suitable alkylating agent, such as methyl 2-bromoacetate, in a suitable solvent such as THF, dimethylformamide or NMP in the presence of a suitable base such as sodium hydride. This method is generally carried out at 0 °C, but can also be carried out under low temperature or high temperature conditions. An example method of step (iii) is illustrated in Preparation 24.

[1066] Step (iv) of Scheme 15 generally involves stirring compound (XXXII) with bis(pinacolato)diboron in a suitable solvent, such as dioxane, in an inert atmosphere in the presence of a suitable catalyst such as PdCl 2 (dppf) complex or XPhos PdG3 and a suitable base such as potassium acetate. This method can be carried out at room temperature or high temperature, e.g., 80 °C or 100 °C. An example method of step (ii) is illustrated in Preparation 25.

[1067] Step (v) of Scheme 15 generally involves stirring compound (XXXIII) with compound (XI) in a suitable aqueous solvent mixture such as dioxane / water in an inert atmosphere in the presence of a suitable catalyst such as tetrakis(triphenylphosphine)palladium and a suitable base such as potassium carbonate. This method can be carried out at room temperature or high temperature, e.g., 80 °C or 100 °C. An example method of step (ii) is illustrated in Preparation 26.

[1068] Step (vi) of Scheme 15 generally involves stirring compound (XXXIV) with compound R 1 NH 2 in a suitable solvent such as dioxane, EtOH or a mixture thereof. This method can be carried out at room temperature or high temperature, e.g., 60 °C or 90 °C. An example of this reaction is illustrated in Preparation 27.

[1069] Step (vii) of Scheme 15 generally involves stirring compound (XXXV) with a suitable base, such as lithium hydroxide, in a suitable aqueous solvent mixture such as THF - water. This method can be carried out at room temperature or elevated temperature, for example, 60 °C or 90 °C. An example of this reaction is illustrated in Preparation 28.

[1070] Step (viii) of Scheme 15 generally involves stirring compound (XXXVI) with a compound of formula HNR 8 R 9 in the presence of a suitable amide coupling agent (such as HATU or HBTU or 1 - propanephosphonic anhydride) and a suitable base (such as triethylamine or DIPEA) in a suitable solvent such as dioxane, DMF or DCM or a mixture thereof. This method can be carried out at room temperature or elevated temperature, for example, 60 °C. An example of this reaction is illustrated in Example 1.

[1071] Step (ix) of Scheme 15 generally involves stirring compound (XXX) with a suitable acid, such as trifluoroacetic acid, in a suitable solvent such as dichloromethane. This method is generally carried out at room temperature, but can also be carried out at low or elevated temperature. An example method of step (ix) is illustrated in Preparation 98.

[1072] Scheme 15 specifically illustrates a method for preparing compounds in which R 4 is hydroxymethyl, but other hydroxyalkyl compounds can be prepared in step (i) using a suitable alkylating agent.

[1073] R 4 is hydroxyethyl can also be prepared by the methods described in Examples 601 to 604 below.

[1074] Compounds of formula (XI), (XII), (XIII), (XIV), (XIX) and (XX) can be commercially available, are familiar in the literature, or can be prepared by methods similar to those described in the literature or by methods similar to those described in the experimental methods of the examples below. Other compounds can be prepared by functional group interconversion by methods familiar in the art.

[1075] It should be understood that certain compounds, for example, compounds of formula (0), (1) and their sub - formulas, can exist in different diastereoisomeric and / or enantiomeric forms, and their preparation methods can use enantiomerically pure synthetic precursors.

[1076] Alternatively, a racemic precursor can be used, and the mixture of diastereomers obtained by these methods can be separated by methods familiar to those skilled in the art. For example, by using achiral or chiral preparative chromatography or by resolving diastereomeric derivatives: for example, forming a salt with an enantiomerically pure acid such as L-tartaric acid and crystallizing the salt; or enantiomeric separation, by covalently attaching an enantiomerically pure chiral auxiliary to the compound to form a diastereomeric derivative, and then separating by conventional methods such as chiral chromatography. Then, the aforementioned covalent bond is cleaved to obtain the appropriate enantiomerically pure product.

[1077] In another embodiment, the present invention provides a novel intermediate. In one embodiment, the present invention provides a novel intermediate selected from the compounds of formula (II), (III), (IV), (V) and (VI).

[1078] Protecting Groups

[1079] In many of the reactions described above, it may be necessary to protect one or more groups to prevent reaction at unwanted positions in the molecule. Examples of protecting groups, and methods for the protection and deprotection of functional groups, can be found in Protective Groups in Organic Synthesis (T. Green and P. Wuts; 3rd Edition; John Wiley and Sons, 1999). In particular, the compound can be synthesized in a protected form and then the protecting group removed to obtain the compound of formula (1).

[1080] The hydroxyl group can be protected, for example, as an ether (-OR) or an ester (-OC(=O)R), for example, as: tert-butyl ether; oxacyclohexane (THP) ether; benzyl, diphenylmethyl (diphenylmethyl) or triphenylmethyl (triphenylmethyl) ether; trimethylsilyl or tert-butyldimethylsilyl ether; or an acetyl ester (-OC(=O)CH 3 )

[1081] The aldehyde or ketone group can be protected, for example, as an acetal (R-CH(OR) 2 ) or a ketal (R 2 C(OR) 2 ), where the carbonyl (>C=O) is treated with, for example, a primary alcohol. In the presence of an acid, hydrolysis with a large excess of water easily regenerates the aldehyde or ketone group.

[1082] The amino group can be protected, for example, as an amide (-NRCO-R) or a carbamate (-NRCO-OR), for example, as: a methyl amide (-NHCO-CH 3);Benzyl carbamate (-NHCO-OCH 2 C 6 H 5 、 -NH-Cbz or NH-Z); As tert-butyl carbamate (-NHCO-OC(CH 3 ) 3 , -NH-Boc); 2-Biphenyl-2-propyl carbamate (-NHCO-OC(CH 3 ) 2 C 6 H 4 C 6 H 5 、 -NH-Bpoc), as 9-fluorenylmethyl carbamate (-NH-Fmoc), as 6-nitroveratryl carbamate (-NH-Nvoc), as 2-trimethylsilylethyl carbamate (-NH-Teoc), as 2,2,2-trichloroethyl carbamate (-NH-Troc), as allyl carbamate (-NH-Alloc), or as 2-(phenylsulfonyl)ethyl carbamate (-NH-Psec).

[1083] For example, in Scheme 1 above, R 1 NH-CHR 2 -C(=O)NH 2 portion contains two amino groups, the first amino group R 1 NH- can be protected by the protecting groups defined above, a specific example of such a protecting group is tert-butoxycarbonyl (Boc), and the second amino group introduces an amide NH 2 for protection. If no subsequent modification of the amino group is required, the protecting group can remain throughout the reaction sequence to obtain the N-protected forms of the compounds of formula (0), (1) and their sub-formulas, and then, deprotection can be carried out using standard methods (e.g., acid treatment if it is a Boc group) to obtain the compounds of formula (0), (1) and their sub-formulas.

[1084] Other protecting groups for amines (such as cyclic amines and heterocyclic N-H groups) include tosyl and mesyl, benzyl (such as p-methoxybenzyl (PMB)) and tetrahydropyranyl (THP).

[1085] The carboxylic acid group can be protected as an ester, for example, as: C 1-7 alkyl ester (e.g., methyl ester, tert-butyl ester); C 1-7 haloalkyl ester (e.g., C 1-7 trihaloalkyl ester); tri-C 1-7 alkylsilyl-C 1-7 alkyl ester; or C5-20 Aryl-C 1-7 alkyl esters (e.g., benzyl esters, nitrobenzyl esters, p-methoxybenzyl esters). The thiol group can be protected as, for example, a thioether (-SR), e.g., as: benzyl thioether, acetamidomethyl ether (-S-CH 2 NHC(=O)CH 3 ).

[1086] Separation, Purification and Analysis of Compounds of the Invention

[1087] The compounds of the present invention can be separated and purified according to standard methods familiar to those skilled in the art. Examples of such methods include chromatography, such as column chromatography (e.g., flash chromatography) and HPLC.

[1088] Preparative LC-MS

[1089] A particularly useful method for purifying compounds is preparative liquid chromatography using mass spectrometry to detect the purified compound eluting from the chromatography column.

[1090] Preparative LC-MS is a standard and effective method for purifying organic small molecules such as the compounds described herein. The liquid chromatography (LC) and mass spectrometry (MS) methods can be varied to better separate the crude material and improve the detection of the sample by MS. Optimization of the preparative gradient LC method includes changing the column, volatile eluents and modifiers, and the gradient. Methods for optimizing preparative LC-MS are familiar to those skilled in the art, and these methods can be used to purify compounds. These methods are described in Rosentreter U, Huber U.; Optimal fraction collecting in preparative LC-MS; J Comb Chem.; 2004; 6(2), 159-64 and Leister W, Strauss K, Wisnoski D, Zhao Z, Lindsley C., Development of a custom high-throughput preparative liquid chromatography / mass spectrometer platform for the preparative purification and analytical analysis of compound libraries; J Comb Chem.; 2003; 5(3); 322-9. Examples of such systems for purifying compounds by preparative LC-MS are illustrated in the Examples section of this application.

[1091] Achiral Preparative Chromatography

[1092] The HPLC purification of the compound can be carried out by the methods described in Snyder L.R., Dolan J.W., High-Performance Gradient Elution, The Practical Application of the Linear-Solvent-Strength Model, Wiley, Hoboken, 2007 and their similar methods.

[1093] Chiral Preparative Chromatography

[1094] The preparative separation using Chiral Stationary Phases (CSP) is a natural method for resolving enantiomeric mixtures. Similarly, it can be used to separate diastereoisomers and achiral molecules. The methods for optimizing CSP preparative chiral separation are familiar to those skilled in the art, and these methods can be used to purify the compound. These methods are described in Beesley T.E., Scott R.P.W.; Chiral Chromatography; Wiley, Chichester, 1998.

[1095] Recrystallization

[1096] The recrystallization method of the compounds of formula (0), (1) and their sub-formula compounds and their salts can be carried out by methods familiar to those skilled in the art - see, for example, (P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Chapter 8, Publisher Wiley-VCH). Products obtained from organic reactions are rarely pure when directly separated from the reaction mixture. If the compound (or its salt) is a solid, it can be recrystallized in a suitable solvent for purification and / or crystallization. A good recrystallization solvent should be able to dissolve an appropriate amount of the substance to be purified at high temperature, but only a small amount of the substance at low temperature. It should be able to easily dissolve impurities at low temperature or not dissolve impurities at all. Finally, the solvent should be easily removed from the purified product. This usually means that the boiling point of the solvent is relatively low. Those skilled in the art are familiar with the recrystallization solvents for specific substances, or if no information in this regard is available, several solvents can be tested. To obtain a good yield of purified material, the minimum amount of hot solvent is used to dissolve all the impure material. In fact, the solvent amount exceeds the necessary amount by 3-5% to make the solution unsaturated. If the impure compound contains impurities insoluble in the solvent, they can be removed by filtration, and then the solution is allowed to crystallize. In addition, if the impure compound contains trace amounts of colored materials not inherent to the compound, it may be necessary to add a small amount of decolorizing agent (such as activated carbon) to the hot solution to remove the material, filter, and then crystallize. Usually, crystallization occurs spontaneously when the solution cools. If crystallization does not occur, the solution can be cooled below room temperature or a single crystal (seed crystal) of the pure material can be added to induce crystallization. Recrystallization and / or the use of anti-solvents or co-solvents can also be carried out to optimize the yield. In this case, the compound is dissolved in a suitable solvent at high temperature, filtered, and then an additional solvent in which the required compound has low solubility is added to assist crystallization. Then, the crystals are usually separated by vacuum filtration, washed, and then dried, for example, in an oven or by desiccation.

[1097] Other Purification Methods

[1098] Other examples of purification methods include sublimation, which includes a vacuum heating step (e.g., using a cold finger), and melt crystallization (Crystallization Technology Handbook 2nd Edition, edited by A. Mersmann, 2001).

[1099] Analysis

[1100] The compounds of the present invention can be analyzed, and their structures are determined by standard methods, for example, spectroscopic methods such as liquid chromatography - mass spectrometry (LC - MS) and nuclear magnetic resonance spectroscopy (NMR). The LC - MS systems that can be used are given in the Examples section of this application.

[1101] Biological Properties

[1102] The compounds of the present invention are contemplated for use in medicine and therapy.

[1103] The compounds of the present invention, their subgroups and examples are inhibitors of ERK1 / 2 and will be used to prevent or treat the disease states or conditions described herein in which ERK1 / 2 plays a role, for example, the diseases and conditions discussed below and the diseases and conditions described in the "Background Art" above. In addition, the compounds of the present invention and their subgroups will be used to prevent or treat ERK1 / 2 - mediated diseases or conditions, for example, diseases or conditions that require ERK1 / 2 activity or up - regulate ERK1 / 2 activity due to activating mutations in upstream components of the MAPK pathway (such as RAS, K - RAS, NRAS and RAF), such as cancer.

[1104] Preventing or preventing or treating a disease state or condition (such as cancer) includes reducing or decreasing the incidence of the disease or condition within its scope. Thus, for example, it is contemplated that the compounds of the present invention will be used to reduce or lower the incidence of cancer.

[1105] Therefore, in other embodiments of the present invention (Embodiments 3.1 to 3.7) it is provided that:

[1106] 3.1 A compound defined in any one of Embodiments 0.1 to 1.179 for use in a medicament.

[1107] 3.2 A compound defined in any one of Embodiments 0.1 to 1.179 for preventing or treating an ERK1 / 2 - mediated disease or condition.

[1108] 3.3 Use of a compound defined in any one of Embodiments 0.1 to 1.179 for the preparation of a medicament for preventing or treating an ERK1 / 2 - mediated disease or condition.

[1109] 3.4 A method of preventing or treating an ERK1 / 2 - mediated disease or condition in a subject (e.g., a mammalian subject in need of prevention or treatment, such as a human), the method comprising administering to the subject a therapeutically effective dose of a compound defined in any one of Embodiments 0.1 to 1.179.

[1110] The compound defined in any one of Examples 0.1 to 1.179 is used to reduce or lower the incidence of ERK1 / 2-mediated diseases or conditions.

[1111] Use of the compound defined in any one of Examples 0.1 to 1.179 for the preparation of a medicament for reducing or lowering the incidence of ERK1 / 2-mediated diseases or conditions.

[1112] 3.7 A method for reducing or lowering the incidence of ERK1 / 2-mediated diseases or conditions in a subject (e.g., a mammalian subject in need, such as a human), the method comprising administering to the subject a therapeutically effective dose of the compound defined in any one of Examples 0.1 to 1.179.

[1113] More specifically, the compounds of formula (0), (1) and their sub-formulas and subgroups are inhibitors of ERK1 / 2. For example, the compounds of the present invention have inhibitory potency against ERK1 or ERK2, especially ERK1 / 2.

[1114] Specific compounds of the present invention are those with an IC 50 value less than 0.1 uM.

[1115] The ERK inhibitor compounds of formula (0), (1) and their sub-formulas are capable of binding to ERK1 / 2 and are effective against ERK1 / 2. In one embodiment, the inhibitor compounds of formula (0), (1) and their sub-formulas have selectivity for ERK1 / 2 over other kinase family members and preferentially bind to and / or inhibit ERK1 and / or ERK2 relative to other kinase family members.

[1116] The function of ERK1 / 2 in controlling cell signaling is also associated with many diseases, including diseases related to cell accumulation (such as cancer, autoimmune disorders, inflammation and restenosis), diseases caused by excessive apoptosis leading to cell loss (such as stroke, heart failure, neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis), AIDS, ischemia (stroke, myocardial infarction)) and osteoporosis or for treating autoimmune diseases such as multiple sclerosis (MS).

[1117] The ERK1 / 2-mediated diseases or conditions mentioned in any one of Examples 3.2 to 3.7 can be any one or more of the diseases and disorders mentioned above.

[1118] Accordingly, it is also contemplated that the compounds defined in any of embodiments 0.1 to 1.179 of the present invention can be used to treat other diseases, such as inflammation, hepatitis, ulcerative colitis, gastritis, autoimmune diseases, restenosis, stroke, heart failure, neurodegenerative conditions (such as Alzheimer's disease, Parkinson's disease, Huntington's disease, myotonic dystrophy, and amyotrophic lateral sclerosis), AIDS, ischemia (such as traumatic brain injury, spinal cord injury, cerebral ischemia, cerebral ischemia / reperfusion (I / R) injury, acute and chronic CNS injury ischemia, stroke, or myocardial infarction), musculoskeletal system degenerative diseases (such as osteoporosis), autoimmune diseases, such as multiple sclerosis (MS) and type I diabetes, and eye diseases, such as retinal degeneration caused by uncontrolled programmed cell death.

[1119] Due to the affinity of the compounds of the present invention for ERK1 / 2, they will be used to provide methods for controlling cell signaling. Accordingly, these compounds are expected to prove useful in the treatment or prevention of proliferative diseases such as cancer.

[1120] Accordingly, in other embodiments (embodiments 3.8 to 3.13), the present invention provides:

[1121] 3.8 A compound defined in any of embodiments 0.1 to 1.179, for preventing or treating a proliferative disease such as cancer.

[1122] 3.9 Use of a compound defined in any of embodiments 0.1 to 1.179 for the preparation of a medicament for preventing or treating a proliferative disease (such as cancer).

[1123] 3.10 A method for preventing or treating a proliferative disease (such as cancer) in a subject (e.g., a mammalian subject in need, such as a human), the method comprising administering to the subject a therapeutically effective dose of a compound defined in any of embodiments 0.1 to 1.179.

[1124] 3.11 A compound defined in any of embodiments 0.1 to 1.179, for reducing or lowering the incidence of a proliferative disease (such as cancer).

[1125] 3.12 Use of a compound defined in any of embodiments 0.1 to 1.179 for the preparation of a medicament for reducing or lowering the incidence of a proliferative disease (such as cancer).

[1126] 3.13 A method for reducing or lowering the incidence of a proliferative disease (such as cancer) in a subject (e.g., a mammalian subject in need, such as a human), the method comprising administering to the subject a therapeutically effective dose of a compound defined in any of embodiments 0.1 to 1.179.

[1127] Examples of cancers (and their benign counterparts) that can be treated (or inhibited) by the above Examples 3.8 to 3.13 include, but are not limited to, tumors of epithelial origin (various types of adenomas and carcinomas, including adenocarcinoma, squamous cell carcinoma, transitional cell carcinoma, and other carcinomas), such as bladder cancer and urethral cancer, breast cancer, gastrointestinal cancers (including esophageal cancer, gastric (stomach) cancer, small intestine cancer, colon cancer, rectal cancer, and anal cancer), liver cancer (hepatocellular carcinoma), gallbladder cancer and biliary tract system cancer, pancreatic exocrine cancer, kidney cancer, lung cancer (e.g., adenocarcinoma, small cell lung cancer, non-small cell lung cancer, bronchioloalveolar carcinoma, and mesothelioma), head and neck cancers (e.g., tongue cancer, oral cancer, laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, tonsillar cancer, salivary gland cancer, nasal cavity cancer, and paranasal sinus cancer), ovarian cancer, fallopian tube cancer, peritoneal cancer, vaginal cancer, vulvar cancer, penile cancer, cervical cancer, myometrial cancer, endometrial cancer, thyroid cancer (e.g., thyroid follicular carcinoma), adrenal cancer, prostate cancer, skin cancer, and appendageal cancers (e.g., melanoma, basal cell carcinoma, squamous cell carcinoma, keratoacanthoma, dysplastic nevus); hematological malignancies (i.e., leukemia, lymphoma) and pre-cancerous hematological diseases and borderline malignant diseases, including lymphatic system hematological malignancies and related diseases (e.g., acute lymphoblastic leukemia [ALL], chronic lymphocytic leukemia [CLL], B-cell lymphoma (such as diffuse large B-cell lymphoma [DLBCL]), follicular lymphoma, Burkitt lymphoma, mantle cell lymphoma, T-cell lymphoma and leukemia, natural killer [NK] cell lymphoma, Hodgkin lymphoma, hairy cell leukemia, monoclonal gammopathy of uncertain significance, plasmacytoma, multiple myeloma, and post-transplant lymphoproliferative disorder), and myeloid hematological malignancies and related diseases (e.g., acute myeloid leukemia [AML], chronic myelogenous leukemia [CML], chronic myelomonocytic leukemia [CMML], hypereosinophilic syndrome, myeloproliferative diseases (such as polycythemia vera, essential thrombocythemia, and primary myelofibrosis), myeloproliferative syndromes, myelodysplastic syndromes, and promyelocytic leukemia); stromal origin tumors, such as soft tissue sarcoma, bone or cartilage sarcoma (such as osteosarcoma, fibrosarcoma, chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma, liposarcoma, angiosarcoma, Kaposi sarcoma, Ewing sarcoma, synovial sarcoma, epithelioid sarcoma), gastrointestinal stromal tumor, benign and malignant histiocytoma, and dermatofibrosarcoma protuberans; neural crest cell-derived tumors, including melanocytic tumors (e.g., malignant melanoma or uveal melanoma), peripheral and cranial nerve tumors, peripheral neuroblastic tumors (e.g., neuroblastoma), CNS embryonal tumors, paraganglioma;Tumors of the central nervous system or peripheral nervous system (such as astrocytoma, glioma, and glioblastoma, meningioma, ependymoma, pinealoma, and schwannoma); endocrine tumors (such as pituitary tumor, adrenal tumor, islet cell tumor, parathyroid adenoma, carcinoid tumor, and medullary thyroid carcinoma); tumors of the eye and its appendages (such as retinoblastoma); germ cell and trophoblastic tumors (such as teratoma, seminoma, dysgerminoma, hydatidiform mole, and choriocarcinoma); and pediatric and embryonic tumors (such as neuroectodermal tumor, neuroblastoma, nephroblastoma, and primitive neuroectodermal tumor); or various syndromes, congenital diseases, or other diseases that make patients prone to malignancy (such as xeroderma pigmentosum). Other examples of cancers (and their benign counterparts) that can be treated (or inhibited) by [Examples 3.8 to 3.13 above] include, but are not limited to, testicular tumors and brain tumors (such as neuroma).;

[1128] Accordingly, the pharmaceutical compositions, uses, or methods of the present invention are for treating diseases or conditions that include abnormal cell growth (i.e., uncontrolled and / or rapid cell growth), and in one embodiment, the disease or condition that includes abnormal cell growth is cancer.

[1129] In one embodiment, the hematological malignancy is leukemia. In another embodiment, the hematological malignancy is lymphoma. In one embodiment, the compounds of the present invention are for preventing or treating leukemia, for example, acute or chronic leukemia, particularly acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), or chronic myeloid leukemia (CML). In one embodiment, the compounds of the present invention are for preventing or treating lymphoma, for example, acute or chronic lymphoma, particularly Burkitt lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, or diffuse large B-cell lymphoma. In one embodiment, the compounds of the present invention are for preventing or treating acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL). In one embodiment, the cancer is AML. In another embodiment, the cancer is CLL.

[1130] Many diseases are characterized by persistent and unregulated angiogenesis. Chronic proliferative diseases are usually accompanied by profound angiogenesis, which contributes to or maintains the inflammatory and / or proliferative state, or causes tissue destruction through angiogenic invasive proliferation. It has been found that tumor growth and metastasis are angiogenesis-dependent. Accordingly, the compounds of the present invention can be used for preventing and disrupting the initiation of tumor angiogenesis. In particular, the compounds of the present invention can be used for treating metastasis and metastatic cancer.

[1131] Metastatic or metastatic disease is the spread of a disease from one organ or site to another non-adjacent organ or site. Cancers that can be treated with the compounds of the present invention include primary tumors (i.e., cancer cells at the site of origin), locally invasive tumors (cancer cells that infiltrate and penetrate the surrounding normal tissue in the local area), and metastatic (or secondary) tumors, i.e., tumors formed by malignant tumor cells that circulate to other parts and tissues of the body through the bloodstream (hematogenous spread) or through the lymphatics or body cavities (implantation metastasis).

[1132] Specific cancers in Examples 3.8 to 3.13 above include hepatocellular carcinoma, melanoma, esophageal cancer, renal cancer, colon cancer, colorectal cancer, lung cancer (e.g., mesothelioma or lung adenocarcinoma), breast cancer, bladder cancer, gastrointestinal cancer, ovarian cancer, and prostate cancer.

[1133] Another subgroup of cancers in Examples 3.8 to 3.13 above includes renal cancer, melanoma, colon cancer, lung cancer, breast cancer, ovarian cancer, and prostate cancer.

[1134] Another subgroup of cancers includes pancreatic cancer.

[1135] Another subgroup of cancers in Examples 3.8 to 3.13 above includes leukemias, such as acute and chronic leukemias, acute myeloid leukemia (AML), and chronic lymphocytic leukemia (CLL).

[1136] Another subgroup of cancers in Examples 3.8 to 3.13 above includes mesothelioma, including malignant peritoneal mesothelioma or malignant pleural mesothelioma.

[1137] Certain cancers are resistant to the treatment of specific drugs. This is due to the tumor type (most common epithelial malignancies have intrinsic chemoresistance), or resistance spontaneously appears as the disease progresses or with treatment. In this regard, mesothelioma includes mesotheliomas that are resistant to topoisomerase poisons, alkylating agents, anti-tubulin agents, folic acid antagonists, platinum compounds, and radiotherapy, especially cisplatin-resistant mesotheliomas. Similarly, multiple myeloma includes multiple myelomas that are sensitive to bortezomib or refractory multiple myelomas, and chronic myeloid leukemia includes chronic myeloid leukemias that are sensitive to imatinib and refractory chronic myeloid leukemias. In this regard, prostate cancer includes prostate cancers that are resistant to anti-androgen therapy, especially prostate cancers that are resistant to abiraterone or enzalutamide or orchiectomy. Melanoma includes melanomas that are resistant to BRAF and / or MEK inhibitor therapy.

[1138] These cancers can be cancers that are sensitive to inhibiting ERK1 or ERK2 or especially to inhibiting ERK1 / 2.

[1139] It is further contemplated that the compounds of the present invention, particularly those with ERK1 / 2 inhibitory potency, will be particularly useful in the treatment or prevention of cancer types associated with or characterized by elevated Ras, BRAF and / or MEK signaling.

[1140] Elevated levels of Ras, BRAF or MEK signaling are present in many cancers and are associated with poor prognosis. In addition, cancers with activating Ras, BRAF or MEK mutations may also be sensitive to ERK1 / 2 inhibitors. Elevated levels of Ras, BRAF or MEK signaling and Ras, BRAF or MEK mutations can be identified using the methods listed herein. Whether a particular cancer is sensitive to ERK1 / 2 inhibition can be determined by the methods set forth in the section entitled "Diagnostic Methods".

[1141] Another subgroup of cancers in Examples 3.8 to 3.13 above includes NRas melanoma and NRas AML.

[1142] Another subgroup of cancers in Examples 3.8 to 3.13 above includes KRas lung cancer, KRas pancreatic cancer and KRas colorectal cancer (CRC).

[1143] Another subgroup of cancers includes BRAF colorectal cancer (CRC), BRAF lung cancer and BRAF melanoma.

[1144] In other embodiments (Examples 3.14 to 3.19), the present invention provides:

[1145] A compound as defined in any one of Examples 0.1 to 1.179 of 3.14 for the prevention or treatment of a disease or condition in which mutant Ras, mutant BRAF or mutant MEK is present.

[1146] Use of a compound as defined in any one of Examples 0.1 to 1.179 of 3.15 for the preparation of a medicament for the prevention or treatment of a disease or condition in which mutant Ras, mutant BRAF or mutant MEK is present.

[1147] A method of preventing or treating a disease or condition in a subject (e.g., a mammalian subject in need, such as a human) in which mutant Ras, mutant BRAF or mutant MEK is present, the method comprising administering to the subject a therapeutically effective dose of a compound as defined in any one of Examples 0.1 to 1.179.

[1148] A compound as defined in any one of Examples 0.1 to 1.179 of 3.17 for reducing or lowering the incidence of a disease or condition in which mutant Ras, mutant BRAF or mutant MEK is present.

[1149] 3.18 Use of a compound as defined in any one of Examples 0.1 to 1.179 for the preparation of a medicament for reducing or decreasing the incidence of a disease or condition in which mutant Ras, mutant BRAF or mutant MEK is present.

[1150] 3.19 A method of reducing or decreasing the incidence of a disease or condition in a subject (e.g., a mammalian subject in need thereof, such as a human) in which mutant Ras, mutant BRAF or mutant MEK is present, the method comprising administering to the subject a therapeutically effective dose of a compound as defined in any one of Examples 0.1 to 1.179.

[1151] 3.19A A compound as defined in any one of Examples 0.1 to 1.179 for the treatment of (or for reducing the incidence of) a cancer selected from NRas melanoma and NRas AML.

[1152] 3.19B A compound as defined in any one of Examples 0.1 to 1.179 for the treatment of (or for reducing the incidence of) a cancer selected from KRas lung cancer, KRas pancreatic cancer and Kras colorectal cancer (CRC).

[1153] 3.19C A compound as defined in any one of Examples 0.1 to 1.179 for the treatment of (or for reducing the incidence of) a cancer selected from BRAF colorectal cancer (CRC), BRAF lung cancer and BRAF melanoma.

[1154] 3.19D A compound as defined in any one of Examples 0.1 to 1.179 for the treatment of (or for reducing the incidence of) the cancer BRAF melanoma.

[1155] 3.19E Use of a compound as defined in any one of Examples 0.1 to 1.179 for the preparation of a medicament for preventing or treating a cancer as defined in any one of Examples 3.19A to 3.19D.

[1156] 3.19F A method of treating (or for reducing the incidence of) a cancer as defined in any one of Examples 3.19A to 3.19D in a subject (e.g., a mammalian subject, such as a human), the method comprising administering to the subject a therapeutically effective dose of a compound as defined in any one of Examples 0.1 to 1.179.

[1157] In other embodiments (Examples 3.20 to 3.25), the present invention provides:

[1158] 3.20 A compound as defined in any one of Examples 0.1 to 1.179 for the treatment of a disease or condition as described herein, particularly a cancer.

[1159] Use of a compound as defined in any one of Examples 0.1 to 1.179 for the preparation of a medicament for treating a disease or condition as described herein, in particular cancer.

[1160] 3.22 A method for preventing or treating a disease or condition as described herein, in particular cancer, in a subject (e.g., a mammalian subject in need thereof, such as a human), said method comprising administering to the subject a therapeutically effective dose of a compound as defined in any one of Examples 0.1 to 1.179.

[1161] 3.33 A compound as defined in any one of Examples 0.1 to 1.179 for reducing or lowering the incidence of a disease or condition as described herein, in particular cancer.

[1162] 3.34 Use of a compound as defined in any one of Examples 0.1 to 1.179 for the preparation of a medicament for reducing or lowering the incidence of a disease or condition as described herein, in particular cancer.

[1163] 3.35 A method for reducing or lowering the incidence of a disease or condition as described herein, in particular cancer, in a subject (e.g., a mammalian subject in need thereof, such as a human), said method comprising administering to the subject a therapeutically effective dose of a compound as defined in any one of Examples 0.1 to 1.179.

[1164] The compounds of formula (0), (1) and their sub-formulas as defined in any one of Examples 0.1 to 1.179 can also be used for treating tumor growth, onset, resistance to chemotherapy and radiotherapy, and as anti-metastatic agents by sensitizing cells to chemotherapy.

[1165] All types of therapeutic anti-cancer interventions necessarily increase the stress imposed on target tumor cells. To mitigate the harmful effects of this stress, ERK1 / 2 is directly involved in resisting the effects of cancer drugs and treatment regimens. Thus, ERK1 / 2 inhibitors represent a class of chemotherapies with the potential to: (i) sensitize malignant tumor cells to anti-cancer drugs and / or treatments; (ii) reduce or lower the incidence of resistance to anti-cancer drugs and / or treatments; (iii) reverse resistance to anti-cancer drugs and / or treatments; (iv) enhance the activity of anti-cancer drugs and / or treatments; (v) delay or prevent the development of resistance to anti-cancer drugs and / or treatments.

[1166] Due to the inhibitory effect of the compounds of the present invention on ERK1 / 2, they will be used to control cell signaling. Accordingly, it is also contemplated that the compounds of the present invention can be used to treat other diseases, such as inflammatory diseases, such as hepatitis, ulcerative colitis and gastritis; neurodegenerative conditions, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, myotonic dystrophy and amyotrophic lateral sclerosis); AIDS, ischemia (such as restenosis, traumatic brain injury, spinal cord injury, cerebral ischemia, cerebral ischemia / reperfusion (I / R) injury, acute and chronic CNS injury ischemia, stroke or myocardial infarction); musculoskeletal system degenerative diseases (such as osteoporosis); autoimmune diseases, such as multiple sclerosis (MS) and type I diabetes, and eye diseases, such as retinal degeneration.

[1167] The affinity of the compounds of the present invention as ERK1 / 2 inhibitors can be determined using the bioanalytical and biophysical assays presented in the examples herein, and the inhibitory level of a given compound is defined by the IC50 value. Particular compounds of the present invention are those with an IC 50 value less than 1 μM, more preferably less than 0.1 μM.

[1168] In other embodiments of the present invention (Example 3.36), the diseases or conditions defined in any one of Examples 3.2 to 3.35 are ERK1 / 2-mediated diseases or conditions, and the compounds of any one of Examples 0.1 to 1.179 are inhibitors of ERK1 / 2, and their IC 50 value for inhibiting ERK1 or ERK2 measured in at least one assay method (e.g., enzyme activity assay) is less than 10 μM. ERK1 / 2-mediated diseases or conditions can be, for example, cancers characterized by Ras, BRAF or MEK mutations.

[1169] Diagnostic Methods

[1170] Before administering the compounds of formula (0), (1) and their sub-formulas, it is necessary to screen the subject (e.g., patient) to determine whether the disease or condition the patient has or may have is sensitive to treatment with a compound that inhibits ERK1 / 2. The term "patient" includes human patients and veterinary patients.

[1171] For example, the collected patient biological specimens are analyzed to determine whether the characteristics of the disease or condition the patient has or may have, such as cancer, are characterized by gene abnormalities or abnormal protein expression, resulting in upregulation of ERK1 / 2 signaling levels, or sensitivity to the normal ERK1 / 2 functional pathway, or upregulation of the biochemical pathway downstream of ERK1 / 2 activation.

[1172] Examples of such abnormalities that result in or are sensitive to ERK1 / 2 pathway activation include activating Ras isoform mutations (e.g., KRAS) or BRAF mutations, as described in the Background section.

[1173] Ras mutations have been detected in cell lines and primary tumors including, but not limited to, melanoma, colorectal cancer, non-small cell lung cancer, and pancreatic cancer, prostate cancer, thyroid cancer, urothelial cancer, and upper respiratory tract cancer (Cancer Res. 2012; 72: 2457-2467).

[1174] The term upregulation includes high expression or overexpression, including gene amplification (i.e., multiple gene copies), cytogenetic abnormalities, and increased expression caused by transcriptional effects, or increased signal transduction caused by ERK1 / 2 activation. Accordingly, patients may need to undergo diagnostic tests to detect characteristic markers of ERK1 / 2 upregulation. The term diagnosis includes screening. As for markers, we included gene markers, including, for example, assays of DNA composition to identify the presence of Ras (e.g., KRAS) or BRAF mutations. The term markers also includes markers of the characteristics of ERK1 / 2 upregulation, including the protein level, protein status, and mRNA level of the aforementioned proteins. Gene amplification includes greater than 7 copies, as well as an increase from 2 to 7 copies.

[1175] Diagnostic assays for detecting KRAS and BRAF mutations are described in Castro et al. Br. J. Cancer. 2012 Jul 10; 107(2): 345-51. doi: 10.1038 / bjc.2012.259. Epub 2012 Jun 19, "A comparison of three methods for detecting KRAS mutations in formalin-fixed colorectal cancer specimens."; and Gonzalez et al., Br J Dermatol. 2013, Apr; 168(4): 700-7. doi: 10.1111 / bjd.12248, "BRAF mutation testing algorithm for vemurafenib treatment in melanoma: recommendations from an expert panel" and the literature cited therein.

[1176] Multiple diagnostic tests for BRAF mutations have been approved by the FDA, and the details of these tests can be found on the FDA website. Examples of these diagnostic tests are the cobas 4800 BRAF V600 mutation test, the companion test for Roche vemurafenib products, and the THxID BRAF test - the companion test for Tafinlar (dabrafenib) and Mekinist (trametinib) products.

[1177] Diagnostic tests and screening are typically performed on biological specimens (i.e., body tissues or fluids), which are selected from tumor biopsy specimens, blood samples (with exfoliated tumor cell isolation and enrichment), cerebrospinal fluid, plasma, serum, saliva, fecal biopsies, sputum, chromosome analysis, pleural fluid, peritoneal fluid, oral mucosal smears, skin biopsies, or urine.

[1178] Methods for the identification and analysis of cytogenetic abnormalities, gene amplifications, protein mutations, and upregulations are familiar to those skilled in the art. Clinical trials for most gene variations include but are not limited to standard methods such as allele-specific polymerase chain reaction (PCR), reverse transcription polymerase chain reaction (RT-PCR), traditional Sanger DNA sequencing, or next-generation sequencing methods, Sanger dideoxy sequencing, pyrosequencing, multiplex ligation-dependent probe amplification (MLPA), or ARMS-PCR. Clinical trials for gene copy numbers and structural gene variations include but are not limited to standard methods such as RNA sequencing (RNAseq), Nanostring hybridization proximity RNA nCounter assay, or in situ hybridization such as fluorescence in situ hybridization (FISH). Updated next-generation sequencing (NGS) technologies such as massively parallel sequencing technologies allow for whole exome sequencing or whole genome sequencing.

[1179] In RT-PCR screening, the mRNA level of a tumor is evaluated by creating cDNA copies of the mRNA and then amplifying the cDNA using PCR. The methods for PCR amplification, the selection of primers, and the amplification conditions are familiar to those skilled in the art. Nucleic acid manipulations and PCR are carried out using standard methods, as described, for example, in Ausubel, F.M. et al., eds. (2004) Current Protocols in Molecular Biology, John Wiley & Sons Inc. or Innis, M.A. et al., eds. (1990) PCR Protocols: a guide to methods and applications, Academic Press, San Diego. Methods for reactions and manipulations involving nucleic acids are also described in Sambrook et al., (2001), 3 rdIt is described in Ed, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press. Alternatively, commercially available RT-PCR kits (e.g., Roche Molecular Biochemicals) can be used, or the methods described in U.S. Patents 4,666,828, 4,683,202, 4,801,531, 5,192,659, 5,272,057, 5,882,864, and 6,218,529 can be employed, which are incorporated herein by reference. Examples of in situ hybridization methods for evaluating mRNA expression include fluorescence in situ hybridization (FISH) (see Angerer (1987) Meth. Enzymol., 152:649).

[1180] Generally, in situ hybridization includes the following main steps: (1) fixing the tissue to be analyzed; (2) pre-hybridizing the sample to improve the accessibility of the target nucleic acid and reduce non-specific binding; (3) hybridizing the nucleic acid mixture with the nucleic acid in the biological structure or tissue; (4) washing after hybridization to remove unbound nucleic acid fragments in the hybridization; and (5) detecting the hybridized nucleic acid fragments. Probes in this application are usually labeled with, for example, radioactive isotopes or fluorescent reporters. The specific probe is long enough, for example, with a length of about 50, 100, or 200 nucleotides to about 1000 or more nucleotides, so as to specifically hybridize with the target nucleic acid under stringent conditions. Standard methods for performing FISH are described in Ausubel, F.M. et al., eds. (2004) Current Protocols in Molecular Biology, John Wiley & Sons Inc and Fluorescence In Situ Hybridization: Technical Overview by John M.S.Bartlett in Molecular Diagnosis of Cancer, Methods and Protocols, 2nd ed.; ISBN: 1-59259-760-2; March 2004, pps.077-088; Series: Methods in Molecular Medicine.

[1181] The method of gene expression profiling was described in DePrimo et al. (2003), BMC Cancer, 3:3. Briefly, the protocol is as follows: Using (dT)24 oligomers, first-strand cDNA synthesis is primed from total RNA, e.g., from polyadenylated mRNA, and then second-strand cDNA synthesis is carried out using random hexamer primers to synthesize double-stranded cDNA. The double-stranded cDNA serves as a template for in vitro cRNA transcription using biotinylated ribonucleotides. The cRNA is chemically fragmented according to the protocol described by Affymetrix (Santa Clara, CA, USA) and then hybridized overnight to a human genome microarray or to gene-specific oligonucleotide probes on a human genome microarray. Alternatively, single nucleotide polymorphism (SNP) arrays - a type of DNA microarray - can be used to detect polymorphisms within a population.

[1182] Alternatively, the protein products of mRNA expression can be detected by immunohistochemistry or immunofluorescence of tumor specimens, microporous plate solid-phase immunoassay, Western blotting, capillary electrophoresis, two-dimensional SDS-polyacrylamide gel electrophoresis, ELISA, flow cytometry, and other specific protein detection methods familiar to those skilled in the art. The detection methods will include the use of site-specific antibodies. Those skilled in the art will recognize that all methods familiar for detecting ERK1 / 2 upregulation, detecting ERK1 / 2 variants or mutants, or detecting 11q22 amplification can be applied to the present invention.

[1183] Abnormal levels of proteins (such as ERK1 / 2) can be determined using standard protein detection methods, e.g., those described herein. By using, for example, the detection methods provided by Chemicon International, the levels of proteins can also be detected, such as high levels or overexpression of proteins in tissue specimens, e.g., tumor tissues. The target protein will be immunoprecipitated from the specimen lysate and then its level will be determined. The detection methods also include the use of labels.

[1184] ERK overexpression can be determined by tumor biopsy. Methods for evaluating gene copy changes include methods commonly used in cytogenetics laboratories, such as MLPA (multiplex ligation-dependent probe amplification) - a multiplex PCR method for detecting abnormal copy numbers, or other PCR methods that can detect gene amplification, gain, and deletion.

[1185] If appropriate, ex-functional assays can also be used, e.g., to determine circulating leukemia cells in cancer patients to evaluate the response to inhibitors.

[1186] Thus, all these methods can also be used to identify tumors that are particularly suitable for treatment with the compounds of the present invention.

[1187] Thus, in other embodiments (Embodiments 4.1 to 4.9), the present invention provides:

[1188] 4.1 A compound defined in any one of Embodiments 0.1 to 1.179, for treating or preventing a disease state or condition (or for reducing or lowering the incidence of these disease states or conditions) in a patient who has been screened and determined to have a disease or condition that is sensitive to treatment with a compound that inhibits ERK1 / 2 (i.e., an ERK1 / 2 inhibitor) or is at risk of developing these diseases or conditions.

[1189] 4.2 Use of a compound defined in any one of Embodiments 0.1 to 1.179 for preparing a medicament for treating or preventing a disease state or condition in a patient (or for reducing or lowering the incidence of these disease states or conditions), wherein the patient has been screened and determined to have a disease or condition that is sensitive to treatment with a compound that inhibits ERK1 / 2 (i.e., an ERK1 / 2 inhibitor) or is at risk of developing these diseases or conditions.

[1190] 4.3 A method for treating or preventing a disease state or condition in a patient (or for reducing or lowering the incidence of these disease states or conditions), wherein the patient has been screened and determined to have a disease or condition that is sensitive to treatment with a compound that inhibits ERK1 / 2 (i.e., an ERK1 / 2 inhibitor) or is at risk of developing these diseases or conditions, the method comprising administering to the subject a therapeutically effective amount of a compound defined in any one of Embodiments 0.1 to 1.179.

[1191] Another aspect of the present invention includes a compound of the present invention for preventing or treating cancer in a patient selected from the subgroup having overexpression or activating mutations of the ERK1 / 2 signaling pathway (such as Ras, BRAF or MEK). Thus, in other embodiments, the present invention provides:

[1192] 4.4 A compound defined in any one of Embodiments 0.1 to 1.179, for treating or preventing cancer in a patient (or reducing or lowering the incidence of cancer), the patient being selected from the subgroup having overexpression or activating mutations of the ERK1 / 2 signaling pathway (such as Raas (such as KRAS), BRAF or MEK).

[1193] 4.5 Use of a compound defined in any one of Embodiments 0.1 to 1.179 for preparing a medicament for treating or preventing cancer in a patient (or reducing or lowering the incidence of cancer), the patient being selected from the subgroup having overexpression or activating mutations of the ERK1 / 2 signaling pathway (such as Ras (such as KRAS), BRAF or MEK).

[1194] 4.6 A method for treating or preventing cancer in a patient (or reducing or lowering the incidence of cancer), said patient being selected from a subset having overexpression or activating mutations of Ras (such as KRAS), BRAF or MEK in the ERK1 / 2 signaling pathway.

[1195] 4.7 A method for diagnosing and treating an ERK1 / 2-mediated disease state or condition, said method comprising (i) screening a patient to determine whether the disease or condition the patient has or may have is sensitive to treatment with a compound having an affinity for ERK1 / 2; and (ii) if it is shown that the patient's disease or condition is sensitive, then administering to the patient a compound defined in any one of Examples 0.1 to 1.179.

[1196] 4.8 A compound defined in any one of Examples 0.1 to 1.179, for use in the method of Example 4.7.

[1197] 4.9 Use of a compound defined in any one of Examples 0.1 to 1.179 for the preparation of a medicament for use in the method of Example 4.7.

[1198] Pharmaceutical Preparations

[1199] Although the active compounds can be administered alone, they are generally presented in the form of a pharmaceutical composition (e.g., a formulation).

[1200] Thus, in other embodiments (Embodiment 5.1), the present invention provides a pharmaceutical composition comprising a compound defined in any one of Examples 0.1 to 1.179 and at least one pharmaceutically acceptable excipient and optionally other therapeutic or prophylactic agents described herein.

[1201] The present invention further provides a method for preparing the pharmaceutical composition of Embodiment 5.1, comprising combining (e.g., mixing) at least one of said compounds, at least one of said pharmaceutically acceptable excipients and optionally other therapeutic or prophylactic agents described herein.

[1202] The pharmaceutically acceptable excipient can be selected from, for example, carriers (e.g., solid, liquid or semi-solid carriers), adjuvants, diluents, fillers or stuffing agents, granulating agents, coating agents, release control agents, binders, disintegrants, lubricants, preservatives, antioxidants, buffers, suspending agents, thickening agents, flavoring agents, sweetening agents, taste masking agents, stabilizers or any other excipient conventionally used in pharmaceutical compositions. Examples of excipients for various pharmaceutical compositions are described in more detail below.

[1203] As used herein, the term "pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms that, within the scope of reasonable medical judgment, are suitable for contact with the tissues of a subject (e.g., a human subject), are without excessive toxicity, irritation, allergic response or other problems or complications and have a reasonable benefit / risk ratio. Each excipient must also be "acceptable" with respect to its compatibility with the other ingredients of the formulation.

[1204] Pharmaceutical compositions comprising compounds of formula (0), (1) and their sub-formulas can be formulated by methods well known in the art, see, e.g., Remington′s Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA.

[1205] The pharmaceutical composition can be in any form suitable for oral, parenteral, topical, intranasal, intrabronchial, sublingual, intraocular, intra-aural, rectal, intravaginal or transdermal administration. If the composition is administered parenterally, it can be formulated for intravenous, intramuscular, intraperitoneal, subcutaneous administration or directly into a target organ or tissue by injection, infusion or other delivery means. Delivery can be by bolus injection, short-term infusion or long-term infusion and can be effected by passive delivery or using a suitable infusion pump or injection syringe.

[1206] Pharmaceutical preparations suitable for gastrointestinal administration include aqueous and non-aqueous sterile injectable solutions which may contain antioxidants, buffers, bacteriostats, solubilizing agents, surfactants, mixtures of organic solvents, cyclodextrin complexing agents, emulsifying agents (for forming and stabilizing emulsion formulations), liposome components for forming liposomes, gelling polymers for forming polymeric gels, lyoprotectants and combinations of various agents, particularly for stabilizing the active ingredient in soluble form and rendering the formulation isotonic with the blood of the intended recipient. Pharmaceutical preparations for parenteral administration can also be in the form of aqueous and non-aqueous sterile suspensions which may include suspending and thickening agents (R.G. Strickly, Solubilizing Excipients in oral and injectable formulations, Pharmaceutical Research, Vol 21(2)2004, p 201-230).

[1207] These formulations can be provided in unit-dose or multi-dose containers, e.g., sealed ampoules, vials, and pre-filled syringes, and can be stored under lyophilized (freeze-dried) conditions. Immediately prior to use, only a sterile liquid carrier, e.g., water, need be added for injection. In one embodiment, the formulation is provided as an active pharmaceutical ingredient (i.e., in lyophilized or other subdivided dry form) contained in a vial and can be reconstituted with a suitable diluent.

[1208] The pharmaceutical formulations can be prepared by lyophilizing the compounds of formula (0), (1), and their sub-formulas or subgroups. Lyophilization refers to the method of freeze-drying a composition. Thus, freeze-drying and lyophilization are synonyms herein.

[1209] Immediate injection solutions and suspensions can be prepared using sterile powders, granules, and tablets.

[1210] The parenteral injection pharmaceutical compositions of the present invention can further include pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, as well as sterile powders, which are reconstituted into sterile injection solutions or dispersions immediately prior to use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, alcohols, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), carboxymethylcellulose, and suitable mixtures thereof, vegetable oils (such as olive oil, sunflower oil, safflower oil, or corn oil), and injectable organic esters, such as ethyl oleate. For example, coating (or thickening) materials, such as lecithin, can be used to maintain the required particle size during dispersion, and surfactants can be used to maintain suitable fluidity.

[1211] The compositions of the present invention can further include adjuvants, such as preservatives, wetting agents, emulsifying agents, and dispersing agents. By adding various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, etc., the effect of preventing microorganisms can be ensured. Reagents for adjusting osmotic pressure, such as sugars, sodium chloride, etc., can also be included. By adding agents for delaying absorption, such as aluminum monostearate and gelatin, the absorption of injectable pharmaceutical forms can be prolonged.

[1212] In one embodiment (Example 5.2) of the present invention, the pharmaceutical composition is in a form suitable for intravenous injection administration, e.g., injection or infusion. When administered by intravenous injection, the solution can be administered directly, or can be injected into an infusion bag (containing pharmaceutically acceptable excipients, such as 0.9% saline or 5% dextrose) prior to administration.

[1213] In another embodiment (Example 5.3), the pharmaceutical composition is in a form suitable for subcutaneous (s.c.) administration.

[1214] Pharmaceutical dosage forms suitable for oral administration include tablets (coated or uncoated), capsules (hard or soft shell), cachets, pills, lozenges, syrups, solutions, powders, granules, elixirs, and suspensions, sublingual tablets, discs, or patches, such as oral patches.

[1215] Thus, a tablet composition can include a unit dose of an active compound with an inert diluent or carrier such as sugar or sugar alcohol, e.g., lactose, sucrose, sorbose, or mannitol; and / or a non-sugar diluent (such as sodium carbonate, calcium phosphate, calcium carbonate), or a cellulose or its derivative (such as microcrystalline cellulose (MCC), methylcellulose, ethylcellulose, hydroxypropylmethylcellulose), and starch (such as corn starch). Tablets can also include standard ingredients such as binders and granulating agents, such as polyvinylpyrrolidone, disintegrants (such as swellable cross-linked polymers, such as cross-linked carboxymethylcellulose), lubricants (such as stearates), preservatives (such as parabens), antioxidants (such as BHT), buffering agents (such as phosphate or citrate buffers), and effervescent agents, such as citrate / bicarbonate mixtures. These excipients are well-known and do not require detailed discussion here.

[1216] Tablets can be designed to release the drug upon contact with gastric juice (i.e., immediate-release tablets) or to release the drug in a controlled manner over a longer period of time (controlled-release tablets) or to release the drug in a specific region of the gastrointestinal tract.

[1217] Capsule formulations can be hard gelatin or soft gelatin and can contain the active ingredient in solid, semi-solid, or liquid form. Gelatin capsules can be formed from animal gelatin or from equivalent products of synthetic or plant origin.

[1218] Solid dosage forms (e.g., tablets, capsules, etc.) can be coated or uncoated. The coating can serve as a protective film (e.g., polymer, wax, or paint) or as a means of controlling drug release or for aesthetic or identification purposes. The coating (e.g., Eudragit TM type polymers) can be designed to release the active ingredient at a desired location in the gastrointestinal tract. Thus, the coating can be selected to degrade at a certain pH condition in the gastrointestinal tract, thereby selectively releasing the compound in the stomach or in the ileum, duodenum, colon, or jejunum.

[1219] Instead of, or in addition to, enteric coating, the drug may be presented in a solid matrix containing a controlled release agent (e.g., a sustained release agent adapted to release the compound in a controlled manner in the gastrointestinal tract). Alternatively, the drug is presented in a polymeric coating, e.g., a polymethacrylate polymer coating, which may be adapted to selectively release the compound under different acidic or basic conditions in the gastrointestinal tract. Alternatively, the matrix material or the release-retarding coating may be in the form of an erodible polymer (e.g., a maleic anhydride polymer), which is substantially continuously eroded as the dosage form passes through the gastrointestinal tract. In another alternative, the coating may be designed to decompose under the action of intestinal microorganisms. As another alternative, the active compound may be formulated into a delivery system that provides osmotic control over the release of the compound. Osmotic release and other delayed release or sustained release formulations (e.g., formulations based on ion exchange resins) may be formulated by methods familiar to those skilled in the art.

[1220] The compounds of formula (0), (1) and their sub-formulas may be formulated with a carrier and administered in the form of nanoparticles. Nanoparticles increase the surface area, assist in the absorption of the compound, and provide the possibility of direct penetration into cells. Nanoparticle delivery systems are described in “Nanoparticle Technology for Drug Delivery”, edited by Ram B Gupta and UdayB.Kompella, Informa Healthcare, ISBN 9781574448573, published 13 th March 2006. Nanoparticles for drug delivery are also described in J.Control.Release, 2003, 91(1-2), 167-172 and Sinha et al., Mol.Cancer Ther.August 1, (2006) 5, 1909.

[1221] According to Example 5.4 of the present invention, the pharmaceutical composition particularly comprises from about 1% (w / w) to about 95% active ingredient and from 99% (w / w) to 5% (w / w) pharmaceutically acceptable excipient or combination of excipients. In particular, the composition comprises from about 20% (w / w) to about 90% (w / w) active ingredient and from 80% (w / w) to 10% pharmaceutically acceptable excipient or combination of excipients. The pharmaceutical composition of the present invention comprises from about 1% to about 95%, particularly from about 20% to about 90% active ingredient. The pharmaceutical composition of the present invention may be, for example, in unit dosage form, such as ampoules, vials, suppositories, dragees, tablets or capsules, or in the form of pre-filled syringes.

[1222] The pharmaceutically acceptable excipients can be selected according to the desired physical form of the preparation and can be selected from, for example, diluents (such as solid diluents, such as fillers or bulking agents; liquid diluents, such as solvents or co-solvents), disintegrants, buffers, lubricants, glidants, c...

Claims

1. Use of a compound of formula (2), or a pharmaceutically acceptable salt or tautomer thereof, in the preparation of a medicament for treating melanoma: (2) Wherein: n is 1 or 2; Z is selected from C-R z and N; R z selected from hydrogen; halogen; methoxy; and C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with hydroxy or methoxy; R 1 is selected from: - (Alk 1 ) t -Cyc 1 ; where t is 0 or 1; Alk 1 is a C 1-4 linear or branched alkylene group, optionally substituted by one or two hydroxyl groups; and - C 1-6 An acyclic hydrocarbon group which is unsubstituted or substituted by 1, 2 or 3 substituents R 5 wherein R 5 is selected from hydroxy, oxygen, fluorine and cyano; provided that 1 or 2 but not all carbon atoms of said hydrocarbon group may be replaced by O or N; Cyc 1 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, wherein one heteroatom ring member is N and the other heteroatom ring members, if present, are selected from O, N and S; and (c) 3- to 7-membered monocyclic carbocyclic groups; wherein each of the cyclic groups (a), (b) and (c) is an unsubstituted or substituted group with 1, 2 or 3 substituents R 6 , R 6 being selected from hydroxy, oxygen, fluorine, amino, NH(Hyd 1 ), N(Hyd 1 ), 2 O-Hyd 1 , -C(=O)-Hyd 1 , -C(=O)-O-Hyd 1 and Hyd 1 ; wherein Hyd 1 is a C 1-4 non-aromatic group, optionally substituted with one or more substituents selected from fluorine, hydroxy and methoxy; R 2 is selected from hydrogen, halogen; and C 1-3 hydrocarbyl, said C 1-3 hydrocarbyl being optionally substituted with one or more fluorine atoms; R 3 is hydrogen or L 1 -R 7 group; R 4 selected from hydrogen; methoxy; and C 1-3 alkyl, said C 1-3 alkyl optionally substituted with hydroxy, amino, mono- or di-C 1-2 alkylamino, cycloamino or methoxy; wherein the cycloamino is a saturated 4-7 membered heterocyclic group containing a ring member nitrogen and a second heteroatom ring member optionally selected from O, N and S, wherein said cycloamino is attached to the C 1-3 alkyl via its ring member nitrogen, and wherein said cycloamino is optionally substituted with 1 or 2 methyl groups; provided that no more than 1 R 4 is not hydrogen or methyl; L 1 Selected from single bond, Alk 2 、Alk 2 -O and Alk 2 -C(=O), wherein Alk 2 is C 1-4 a straight-chain or branched alkylene group, optionally substituted by one or more substituents selected from hydroxy, methoxy, amino, methylamino, dimethylamino and fluoro; R 7 Selected from: • hydrogen; •CO 2 H; •NR 8 R 9 ; ·A carbocyclic or heterocyclic group having from 3 to 12 ring members, wherein 0, 1, 2 or 3 of the ring members are heteroatom ring members selected from O, N, S and the oxidized forms of S, and the carbocyclic or heterocyclic group is optionally substituted by one or more substituents R 10 substituted; and • Acyclic C 1 - 8 alkyl group, optionally substituted by one or more substituents selected from hydroxy, oxygen, halogen, cyano, carboxyl, amino, mono- or di-C 1 - 4 alkylamino and carbocyclic and heterocyclic groups having 3 to 12 ring members, wherein 0, 1, 2 or 3 ring members are heteroatom ring members selected from O, N, S and the S-oxidized form, and the carbocyclic or heterocyclic group is optionally substituted by one or more substituents R 10 ; wherein one or two but not all carbon atoms of the acyclic C 1 - 8 alkyl group may optionally be substituted by O, S, SO, SO 2 or NR 11 ; R 8 selected from hydrogen and C 1-4 hydrocarbyl groups, said C 1-4 hydrocarbyl groups being optionally substituted by 1 - 2 substituents selected from hydroxy, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino, and 4 - 7 membered saturated heterocycles containing 1 - 2 heteroatom ring members selected from O and N, wherein the mono-C 1-4 alkylamino, di-C 1-4 alkylamino, and 4 - 7 membered saturated heterocycles are optionally substituted by 1 - 2 hydroxy or C 1-3 alkyl substituents; R 9 Selected from: • hydrogen; • A carbocyclic or heterocyclic group having 3 to 12 ring members, wherein 0, 1, 2 or 3 of the ring members are heteroatom ring members selected from O, N, S and the oxidized forms of S, and the carbocyclic or heterocyclic group is optionally substituted with one or more substituents R 10 substituted; and • Acyclic C 1 - 8 hydrocarbyl, optionally substituted by one or more substituents selected from hydroxy, oxygen, halogen, cyano, carboxyl, amino, mono- or di-C 1 - 4 alkylamino; and carbocyclic and heterocyclic groups having 3 to 12 ring members, wherein 0, 1, 2 or 3 ring members are heteroatom ring members selected from O, N, S and the oxidized forms of S, said carbocyclic or heterocyclic group optionally substituted by one or more substituents R 10 ; wherein one or two but not all carbon atoms of the acyclic C 1 - 8 hydrocarbyl may optionally be substituted by O, S, SO, SO 2 or NR 11 ; or NR 8 R 9 forms a heterocyclic group having 4 to 12 ring members; wherein, in addition to the nitrogen atom of NR 8 R 9 the heterocyclic group optionally further contains 1 or 2 heteroatom ring members selected from O, N, S and the oxidized forms of S; and wherein the heterocyclic group is optionally substituted by one or more substituents R 10 substituted; R 10 Selected from: • halogen; hydroxy; oxygen; cyano; •OR 12 , wherein R 12 is C 1-6 alkyl or C 3-6 cycloalkyl, each optionally substituted by halogen; • Acyclic C 1-8 -hydrocarbyl, optionally substituted with one or more substituents selected from hydroxy, oxygen, halogen, cyano, carboxy, amino, mono- or di-C 1 - 4 -alkylamino, and carbocyclic and heterocyclic groups having from 3 to 7 ring members, wherein 0, 1, 2, 3 or 4 of the ring members are heteroatom ring members selected from N, O and S, wherein the carbocyclic and heterocyclic groups are optionally substituted with one or more substituents R 13 , R 13 being selected from hydroxy, halogen, cyano, amino, -NH(Hyd 1 ), -N(Hyd 1 ), 2 and -(O) v -Hyd 1 , where v is 0 or 1; wherein 1 or 2 but not all of the carbon atoms of the acyclic C 1 - 8 -hydrocarbyl may optionally be substituted with O, S, SO, SO 2 or NR 11 ; and • carbocyclic and heterocyclic groups having from 3 to 7 ring members, wherein 0, 1, 2, 3 or 4 ring members are heteroatom ring members selected from N, O and S, and wherein said carbocyclic or heterocyclic group is optionally substituted with one or more substituents R 13 substituted; and R 11 selected from hydrogen and C 1-4 hydrocarbyl group.

2. Use of the compound according to claim 1, wherein the compound is a compound of formula (5): (5) or a pharmaceutically acceptable salt or tautomer thereof.

3. Use of the compound according to claim 1, wherein the compound 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 thereof.

4. Use of the compound according to claim 1, wherein the compound 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.

5. A pharmaceutical composition in unit dosage form, comprising 1% (w / w) to 95% of an active ingredient and 99% (w / w) to 5% (w / w) of a pharmaceutically acceptable excipient or combination of excipients, wherein the active ingredient comprises a compound selected from: (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; (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; (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; (R)-2-(6-(5-chloro-2-((2-methoxypyridin-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)-N-((S)-1-(6-(dimethylamino)pyridin-2-yl)-2-hydroxyethyl)propanamide; (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; and (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; and its pharmaceutically acceptable salts or tautomers.

6. The pharmaceutical composition according to claim 5, wherein the unit dosage form comprises 20% (w / w) to 90% of the active ingredient and 80% (w / w) to 10% (w / w) of a pharmaceutically acceptable excipient or combination of excipients.

7. The pharmaceutical composition according to claim 5 or 6, wherein the active ingredient 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 thereof.

8. The pharmaceutical composition according to claim 5, wherein the unit dosage form comprises 20% (w / w) to 90% of the active ingredient and 80% (w / w) to 10% (w / w) of a pharmaceutically acceptable excipient or combination of excipients.

9. The pharmaceutical composition according to claim 8, wherein the active ingredient 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.

10. A method for preparing the compound of formula (2) as defined in claim 1 or a pharmaceutically acceptable salt or tautomer thereof, the method comprises: (a)(i) a compound of formula (II): (II) React under amide-forming conditions with a compound of the formula HNR 8 R 9 ; or (ii) a compound of formula (III): (III) reacting, in the presence of a palladium catalyst, with a compound of formula (IV): (IV) wherein Hal is a suitable leaving group, or (iii) a compound of formula (V), wherein Hal is a suitable leaving group: (V) React with the formula R 1 NH 2 compound; or (iv) reacting a compound of formula (VI) in which R 4a is hydrogen, X is N and Y is CH: (VI) React with a compound of formula R 7 L 1 -J, where J is a suitable leaving group; and / or (b) deprotecting a protected derivative of the compound of formula (2); and / or (c) interconverting the compound of formula (2) or its protected derivative into other compounds of formula (2) or their protected derivatives; and (d) optionally forming a pharmaceutically acceptable salt of the compound of formula (2). wherein R 1 , R 2 , R 4 , R 7 , R 8 , R 9 , L 1 , n and Z are as defined in claim 1, and wherein R 4a is hydrogen, X is N, and Y is CH.

11. The method according to claim 10, wherein R1 is an AA group: AA.

12. The method according to claim 10, wherein R 2 is chlorine.

13. The method according to claim 10, wherein Z is C-R z , wherein R z is hydrogen.

14. The method according to claim 10, wherein R 4 is hydrogen.

15. The method according to claim 10, wherein R 3 is L 1 -R 7 wherein L 1 is Alk 2 or Alk 2 -C(=O).

16. The method according to claim 15, wherein Alk 2 is CH(CH 3 ).

17. The method according to claim 16, wherein R 7 is an acyclic C 1 - 8 hydrocarbyl group, optionally substituted with one or more substituents selected from hydroxy, oxygen, halogen, cyano, carboxyl, amino, mono- or di-C 1 - 4 alkylamino and carbocyclic and heterocyclic groups having 3 to 12 ring members, wherein 0, 1, 2 or 3 of the ring members of the carbocyclic and heterocyclic groups are heteroatom ring members selected from O, N, S and the oxidized forms of S, and the carbocyclic or heterocyclic group is optionally substituted with one or more substituents R 10 ; wherein one or two but not all of the carbon atoms of the acyclic C 1 - 8 hydrocarbyl group may optionally be substituted with O, S, SO, SO 2 or NR 11 .

18. The method according to claim 10, wherein method (a)(i) comprises reacting a compound of formula (II) with a compound of formula HNR 8 R 9 in the presence of an amide coupling agent selected from HATU, TBTU, HBTU and 1-propane phosphoric anhydride.

19. The method according to claim 10, wherein method (a)(ii) comprises reacting the compound of formula (III) with the compound of formula (IV) in a solvent in the presence of a palladium catalyst and a base.

20. The method according to claim 10, wherein: - in formula (IV), Hal is a halide; and - in formula (V), Hal is a halide.

21. The method according to claim 20, wherein: - in formula (IV), Hal is chlorine; and - in formula (V), Hal is chlorine.

22. The method according to claim 10, for preparing a compound selected from: (a) a compound of formula (6): (6) or a pharmaceutically acceptable salt or a tautomer thereof; (b) a compound of formula (7): (7) or a pharmaceutically acceptable salt or a tautomer thereof, wherein v is 0, 1, 2 or 3; and (c) a compound of formula (8): (8) or a pharmaceutically acceptable salt or a tautomer thereof.

23. The method according to claim 22, wherein the method comprises method (a)(ii), which comprises reacting a compound of formula (III) with a compound of formula (IV) in a solvent in the presence of a palladium catalyst and a base.

24. The method according to claim 10, for preparing a compound wherein n is 1, the compound having formula (3): (3) or a pharmaceutically acceptable salt or a tautomer thereof.

25. The method according to claim 10, for preparing a compound selected from: (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; (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; (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; (R)-2-(6-(5-chloro-2-((2-methoxypyridin-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)-N-((S)-1-(6-(dimethylamino)pyridin-2-yl)-2-hydroxyethyl)propanamide; (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; and (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; and pharmaceutically acceptable salts thereof.

26. The method according to claim 25, for preparing (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 thereof.

27. The method according to claim 25, for preparing (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 thereof.

28. The method according to claim 25, for preparing (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 thereof.

29. The method according to claim 25, for preparing (R)-2-(6-(5-chloro-2-((2-methoxypyridin-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 thereof.

30. The method according to claim 25, for preparing (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 thereof.

31. The method according to claim 25, for preparing (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 thereof.

32. The method according to claim 25, for preparing (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.

33. A compound selected from: (i) (R)-2-(6-bromo-1-oxoisoindolin-2-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)propanamide; or (ii) (R)-N-((S)-1-(3-Fluoro-5-methoxyphenyl)-2-hydroxyethyl)-2-(1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)propanamide; (iii) (2R)-tert-Butyl 2-(6-bromo-1-oxo-2,3-dihydro-1H-isoindol-2-yl)propionate; (iv) 2-[2-(tert-Butoxy)ethyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindol-1-one.

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