Condensed pyridine derivatives substituted with an amide functionality as ACSS2 inhibitors

Abstract

The present invention relates to substituted amide derivatives. These compounds can be used for the prevention and / or treatment of several medical conditions, including hyperproliferative disorders and diseases.

Description

TECHNICAL FIELD

[0001] The present invention relates to substituted amide derivatives. These compounds can be used to inhibit acetyl-CoA synthetase 2 (ACSS2) and for the prevention and / or treatment of several medical conditions, including hyperproliferative disorders and diseases affected by ACSS2 activity. BACKGROUND ART

[0002] It has been well established that the rapid and uncontrolled growth of tumors and the proliferation of cancer cells require increased energy (ATP) and biomass (lipid) production compared to normal healthy cells.

[0003] In recent years, the role of acetate metabolism in cancer cell proliferation has become increasingly of interest in cancer research and the development of cancer therapies. It has been shown that some tumors mainly utilize acetate to generate energy, while others mainly utilize it to synthesize lipids (i.e., biomass) or regulate histone acetylation and thus gene transcription (Z.T. Schug, et al., Nature Reviews Cancer 16, 707-717 (2016)). In all these processes, acetate is converted to acetyl-CoA by acetyl-CoA synthetase ACSS via mitochondrially localized ACSS1 or nucleocytoplasmically localized ACSS2. Thus, acetyl-CoA is an important metabolite in cancer cells, being involved not only in energy production in mitochondria, but also in lipid and fatty acid synthesis in the cancer cell cytosol and histone acetylation in the cell nucleus.

[0004] Studies have shown that ACSS2, in particular, is highly expressed in many cancer tissues. These findings and the fact that ACSS2 is upregulated by hypoxia and low nutrient availability make ACSS2 an attractive target for cancer therapy (Z.T. Schug, et al., Cancer Cell (2015) 27, 57-71; Z.T. Schug, et al., Nature Reviews Cancer 16, 707-717 (2016)).

[0005] Prior art

[0006] WO 2015 / 175845 A1 discloses certain benzimidazole derivatives as inhibitors of ACSS2.

[0007] WO 2020 / 252407 A1 discloses certain benzimidazole derivatives as inhibitors of ACSS2. SUMMARY OF THE INVENTION

[0008] The object of the present invention is to provide compounds which can be used for the prevention and / or treatment of medical conditions, disorders and / or diseases (in particular hyperproliferative disorders / diseases), said compounds being inhibitors of ACSS2.

[0009] This object is unexpectedly solved by the compounds of the present invention. The present invention provides amide derivatives of formula I-a, I-b or I-c

[0010]

[0011] wherein independently of one another

[0012] R 1 represents Ar A or Hetar A ;

[0013] R 2 represents Ar B or Hetar B ;

[0014] R 3 represents C 1-6 -aliphatic or -O-C 1-6 -aliphatic;

[0015] R 4 represents H, D, C 1-6 -aliphatic or -O-C 1-6 -aliphatic;

[0016] R 5 represents H, D, C 1-6 -aliphatic, -O-C 1-6 -aliphatic or halogen;

[0017] R 6 represents Hetar C or -CH2-Hetar C ;

[0018] Ar A is a monoaryl or diaryl having 5, 6, 7, 8, 9, 10, 11 ring carbon atoms, wherein the aryl may be unsubstituted or substituted by substituents R A1 、R A2 、R A3 、R A4 and / or R A5 which may be the same or different;

[0019] Ar B is a monoaryl or diaryl having 5, 6, 7, 8, 9, 10, 11 ring carbon atoms, wherein the aryl may be unsubstituted or substituted by substituents R B1 、RB2 、R B3 、R B4 and / or R B5 substituted;

[0020] Hetar A is a monocyclic or bicyclic heteroaryl having 5, 6, 7, 8, 9, 10, 11 ring atoms, wherein 1, 2, 3, 4, 5 of the said ring atoms are heteroatoms selected from N, O and / or S and the remaining are carbon atoms, and wherein the heteroaryl may be unsubstituted or substituted by substituents R A1 、R A2 、R A3 、R A4 and / or R A5 substituted;

[0021] Hetar B is a monocyclic or bicyclic heteroaryl having 5, 6, 7, 8, 9, 10, 11 ring atoms, wherein 1, 2, 3, 4, 5 of the said ring atoms are heteroatoms selected from N, O and / or S and the remaining are carbon atoms, and wherein the heteroaryl may be unsubstituted or substituted by substituents R B1 、R B2 、R B3 、R B4 and / or R B5 substituted;

[0022] Hetar C is a monocyclic or bicyclic heteroaryl having 5, 6, 7, 8, 9, 10, 11 ring atoms, wherein 1, 2, 3, 4, 5 of the said ring atoms are heteroatoms selected from N, O and / or S and the remaining are carbon atoms, and wherein the heteroaryl may be unsubstituted or substituted by substituents R C1 、R C2 、R C3 、R C4 and / or R C5 substituted;

[0023] R A1 、R A2 、R A3 、R A4 、R A5 、R B1 、R B2 、R B3 、R B4 、R B5 、R C1 、R C2 、R C3 、R C4 、R C5 are each independently H, D, halogen, C1-6 -aliphatic, -O-C 1-6 -aliphatic;

[0024] Halogen means F, Cl, Br or I;

[0025] or any derivative thereof, any N-oxide, prodrug, solvate, tautomer or stereoisomer and / or any pharmaceutically acceptable salt of each of the foregoing, including mixtures of all ratios thereof.

[0026] Generally, all residues, radicals, substituents, groups, moieties, etc. that occur more than once may be the same or different, i.e., independent of one another. Unless expressly indicated otherwise, the residues and parameters above and below have the meanings indicated for formula I-a, I-b or I-c. Accordingly, the present invention particularly relates to compounds of formula I-a, I-b or I-c, wherein at least one of said residues, radicals, substituents has one of the preferred meanings indicated below.

[0027] Unless otherwise indicated, any one of those particular or even preferred embodiments of the present invention as specified below or in the claims refers not only to the specified compounds of formula I-a, I-b or I-c, but also to their derivatives, N-oxides, prodrugs, solvates, tautomers or stereoisomers and pharmaceutically acceptable salts of each of the foregoing, also including mixtures of all ratios thereof.

[0028] In a particular embodiment PE1, the compounds of the present invention are amides of formula I-a, I-b or I-c, or any derivative thereof, N-oxide, prodrug, solvate, tautomer or stereoisomer and / or any pharmaceutically acceptable salt of each of the foregoing, including mixtures of all ratios thereof, wherein R 1 and R 2 have the same meaning. This means that, for example, if R 1 represents Ar A , then R 2 represents Ar B , which in turn represents the same Ar 1 as for R A , i.e., it is the same substituent; likewise, if R 1 represents Hetar A , then R 2 refers to Hetar B , which in turn refers to the same Hetar 1 as for R A (i.e., it is the same substituent).

[0029] Other specific embodiments of the present invention (designated as PE2) are amides of formula I-a, I-b or I-c, or any derivatives, N-oxides, prodrugs, solvates, tautomers or stereoisomers thereof and / or any pharmaceutically acceptable salts of each of the foregoing, including mixtures of all ratios thereof, wherein R 1 and R 2 have different meanings. In this embodiment, the substituents R 1 and R 2 are selected to be different. For example, if R 1 represents 2-methylphenyl (i.e., Ar A is a monocyclic 6-membered aromatic ring, and one of the substituents R A1 , R A2 , R A3 , R A4 and / or R A5 is a methyl group at the 2-position relative to the attachment point of Ar A to the carbon atom substituted with a hydroxyl group, and the others are hydrogen), then R 2 can be Hetar B as defined herein or Ar B other than 2-methylphenyl.

[0030] It must be recognized that any amide derivative of PE2 has a chiral center at the carbon atom carrying the different substituents R 1 and R 2 since that carbon atom will then be substituted with four different substituents.

[0031] In yet another specific embodiment of the present invention (designated as PE3), the amide derivative of the present invention is an amide of formula I-a, I-b or I-c, or any derivative, N-oxide, prodrug, solvate, tautomer or stereoisomer thereof and / or any pharmaceutically acceptable salt of each of the foregoing, including mixtures of all ratios thereof, wherein the substituents R 1 and R 2 are each independently monocyclic, i.e.,

[0032] Ar A is phenyl, which may be unsubstituted or mono-, di-, tri-, tetra- or penta-substituted by R A1 , R A2 , R A3 , R A4 , R A5 ;

[0033] Ar B is phenyl, which may be unsubstituted or mono-, di-, tri-, tetra- or penta-substituted by R B1 , R B2 , R B3 , RB4 , R B5 mono-, di-, tri-, tetra- or penta-substituted;

[0034] Hetar A is a monocyclic heteroaryl having 5 or 6 ring atoms or a bicyclic heteroaryl having 10 ring atoms, wherein 1 or 2 of said ring atoms are heteroatoms selected from N, O and / or S and the remainder are carbon atoms, wherein the heteroaryl may be unsubstituted or substituted by R A1 , R A2 , R A3 , R A4 , R A5 mono-, di-, tri-, tetra- or penta-substituted;

[0035] Hetar B is a monocyclic heteroaryl having 5 or 6 ring atoms, wherein 1 or 2 of said ring atoms are heteroatoms selected from N, O and / or S and the remainder are carbon atoms, wherein the heteroaryl may be unsubstituted or substituted by R B1 , R B2 , R B3 , R B4 , R B5 mono-, di-, tri-, tetra- or penta-substituted;

[0036] wherein R A1 , R A2 , R A3 , R A4 , R A5 may be the same or different; and R B1 , R B2 , R B3 , R B4 , R B5 may be the same or different.

[0037] If R 1 and R 2 are the same, i.e., have the same meaning, then this PE3 is also within the scope of PE1. Similarly, if R 1 and R 2 do not have the same meaning, this PE3 is within the scope of PE2.

[0038] In a preferred specific embodiment PE3a of PE3,

[0039] Ar A is phenyl, which may be unsubstituted or mono- or di-substituted by R A1 and / or R A2 , wherein R A1 and / or R A2 are as defined herein; or is trideuteriophenyl, tetradeuteriophenyl or pentadeuteriophenyl;

[0040] Ar B is phenyl, which may be unsubstituted or mono- or di-substituted by R B1 and / or R B2 , where R B1 and / or R B2 is as defined herein; or is tri-deutero phenyl, tetra-deutero phenyl or penta-deutero phenyl;

[0041] Hetar A is a monocyclic heteroaryl having 5 or 6 ring atoms or a bicyclic heteroaryl having 10 ring atoms, wherein 1 or 2 of said ring atoms are heteroatoms selected from N, O and / or S and the remaining are carbon atoms, and wherein the heteroaryl may be unsubstituted or substituted by substituents R A1 and / or R A2 ;

[0042] Hetar B is a monocyclic heteroaryl having 5 or 6 ring atoms, wherein 1 or 2 of said ring atoms are heteroatoms selected from N, O and / or S and the remaining are carbon atoms, and wherein the heteroaryl may be unsubstituted or substituted by substituents R B1 and / or R B2 .

[0043] In yet another preferred specific embodiment PE3b of PE3a,

[0044] R A1 , R A2 , R B1 , R B2 are each independently H, D, F, Cl, unsubstituted or substituted C 1-4 -aliphatic, unsubstituted or substituted -O-C 1-4 -aliphatic.

[0045] If the substituent Ar A of phenyl in PE3a or PE3b is mono-substituted by the substituent R A1 or R A2 , then the substituent R A1 or R A2 is preferably located at the 2- or 4-position of the benzene ring. If the benzene ring Ar A is di-substituted by R A1 and R A2 , then the two substituents, which may be the same or different, are preferably at the 2- and 4-positions of the benzene ring.

[0046] Likewise, if the substituent Ar B of phenyl in PE3a or PE3b is substituted by the substituent R B1 or RB2 is monosubstituted, the substituent R B1 or R B2 is preferably located at the 2- or 4-position of the benzene ring. If the benzene ring Ar B is substituted by R B1 and R B2 is disubstituted, the two substituents, which may be the same or different, are preferably at the 2- and 4-positions of the benzene ring.

[0047] In yet another specific embodiment PE4, the amide derivative of the present invention is an amide of formula I-a, I-b or I-c, or any derivative, N-oxide, prodrug, solvate, tautomer or stereoisomer and / or any pharmaceutically acceptable salt of each of the foregoing, including mixtures of all ratios thereof, wherein independently of one another

[0048] R 3 represents C 1-4 -alkyl, preferably C 1-2 -alkyl, which is unsubstituted or monosubstituted by -OH, -OCH3 or -N(CH3)2;

[0049] R 4 represents H;

[0050] R 5 represents H, C 1-4 -alkyl, -O-C 1-4 -alkyl, F or Cl; preferably H, C 1-2 -alkyl, -O-C 1-2 -alkyl, F or Cl;

[0051] and, wherein the remaining radicals, residues, groups or substituents are as defined above generally for formula I-a, I-b and I-c or for any of the other specific embodiments above (i.e., PE1, PE2, PE3, PE3a, PE3b).

[0052] In yet another specific embodiment PE5, the amide derivative of the present invention is an amide of formula I-a, I-b or I-c, or any derivative, N-oxide, prodrug, solvate, tautomer or stereoisomer and / or any pharmaceutically acceptable salt of each of the foregoing, including mixtures of all ratios thereof, wherein

[0053] R 6 represents -CH2-Hetar C or Hetar C ;

[0054] Hetar Cis a monocyclic heteroaryl having 5 or 6 ring atoms, wherein 1, 2 or 3 of said ring atoms are heteroatoms selected from N, O and / or S and the remainder are carbon atoms, wherein the heteroaryl may be unsubstituted or substituted by substituents R C1 and / or R C2 substituted;

[0055] R C1 、R C2 represents H or substituted or unsubstituted C 1-4 -alkyl, wherein R C1 and R C2 at least one of which is not H.

[0056] In a preferred specific embodiment PE5a of PE5,

[0057] R 6 represents Hetar C ;

[0058] Hetar C is a monocyclic heteroaryl having 5 ring atoms, wherein 2 or 3 of said ring atoms are heteroatoms selected from N and / or O and the remainder are carbon atoms, wherein the heteroaryl may be unsubstituted or substituted by one substituent R C1 substituted;

[0059] R C1 represents ethyl, 2-aminoethyl, 2-hydroxyethyl, 2-methoxyethyl.

[0060] In a specific specific embodiment PE5b of PE5a, the substituent R C1 is at the 3-position of the monocyclic heteroaryl Hetar C relative to the attachment point of the adjacent amido nitrogen atom to the heteroaryl moiety Hetar C .

[0061] In another specific specific embodiment PE5c of PE5 or PE5a or PE5b, R 1 and R 2 are the same. In another specific specific embodiment PE5d of PE5 or PE5a or PE5b, R 1 and R 2 are different.

[0062] In yet another specific embodiment PE6, the amide derivatives of the present invention are amides of formula I-a, I-b or I-c, or any derivatives, N-oxides, prodrugs, solvates, tautomers or stereoisomers thereof and / or any pharmaceutically acceptable salts of each of the foregoing, including mixtures of all ratios thereof, wherein independently of each other

[0063] R 1 represents Ar A or Hetar A ;

[0064] R 2 represents Ar B or Hetar B ;

[0065] R 3 represents methyl, ethyl, 2-dimethylaminoethyl, 2-hydroxyethyl, 2-methoxyethyl;

[0066] R 4 represents H;

[0067] R 5 represents H, methyl, ethyl, methoxy, F or Cl;

[0068] R 6 represents Hetar C ;

[0069] Ar A is phenyl; mono-, di-, tri-, tetra- or pentadeuteriophenyl; preferably pentadeuteriophenyl; fluorophenyl, preferably 2-fluorophenyl; methylphenyl (tolyl), preferably 2-methylphenyl; methoxyphenyl, preferably 2-methoxyphenyl; difluoromethoxy, preferably 4-difluoromethoxy; 4-difluoromethoxy-2-fluorophenyl;

[0070] Ar B is phenyl; mono-, di-, tri-, tetra- or pentadeuteriophenyl; preferably pentadeuteriophenyl; fluorophenyl, preferably 2-fluorophenyl; methylphenyl (tolyl), preferably 2-methylphenyl; methoxyphenyl, preferably 2-methoxyphenyl; difluoromethoxy, preferably 4-difluoromethoxy; 4-difluoromethoxy-2-fluorophenyl;

[0071] Hetar A is methylpyrazolyl, preferably 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl; thiophen-2-yl, thiophen-3-yl; methylthiophenyl, preferably 5-methylthiophen-2-yl; thiazolyl, preferably 1,3-thiazol-2-yl; pyridyl, preferably pyridin-2-yl; pyrimidinyl, preferably pyrimidin-4-yl; pyridazinyl, preferably pyridazin-3-yl; quinolinyl, preferably quinolin-2-yl;

[0072] Hetar B is thiophen-2-yl, thiophen-3-yl; methylthiophenyl, preferably 5-methylthiophen-2-yl; pyridyl, preferably pyridin-2-yl;

[0073] Hetar Cis an ethylpyrazolyl group, preferably 1-ethylpyrazol-3-yl, 1-ethylpyrazol-4-yl; hydroxyethylpyrazolyl group, preferably 1-(2-hydroxyethyl)pyrazol-4-yl; methoxyethylpyrazolyl group, preferably 1-(2-methoxyethyl)pyrazol-4-yl; ethylimidazolyl group, preferably 1-ethyl-1H-imidazol-4-yl; ethyloxazolyl group, preferably 4-ethyl-1,3-oxazol-2-yl, 5-ethyl-1,3-oxazol-2-yl; ethyltriazolyl group, preferably 1-ethyl-1H-1,2,4-triazol-3-yl, 2-ethyl-2H-1,2,3-triazol-4-yl; aminoethyltriazolyl group, preferably 1-(2-aminoethyl)-1H-1,2,4-triazol-3-yl; hydroxyethyltriazolyl group, preferably 1-(2-hydroxyethyl)-1H-1,2,4-triazol-3-yl; methoxyethyltriazolyl group, preferably 1-(2-methoxyethyl)-1H-1,2,4-triazol-3-yl; ethyloxadiazolyl group, preferably 5-ethyl-1,3,4-oxadiazol-2-yl, 5-ethyl-1,2,4-oxadiazol-3-yl.

[0074] If R 1 and R 2 are the same, i.e., have the same meaning, then this is another specific embodiment PE6a of PE6. Similarly, if R 1 and R 2 do not have the same meaning, this is yet another specific embodiment PE6b of PE6.

[0075] In yet another specific embodiment PE7, the amide derivative of the present invention is selected from compounds of formula I-a (i.e., 1H-imidazo[4,5-b]pyridine derivatives), or any derivative, N-oxide, prodrug, solvate, tautomer or stereoisomer thereof and / or any pharmaceutically acceptable salt of each of the foregoing, including mixtures of all ratios thereof, wherein R 1 、R 2 、R 3 、R 4 、R 5 and R 6 are as defined herein or for any specific embodiment PE1, PE2, PE3, PE3a, PE3b, PE4, PE5, PE5a, PE5b, PE5c, PE5d, PE6, PE6a, PE6b. In a specific specific embodiment PE7a of PE7,

[0076] R 1represents phenyl; mono-, di-, tri-, tetra- or pentadeuteriophenyl, preferably pentadeuteriophenyl; fluorophenyl, preferably 2-fluorophenyl; methylphenyl (tolyl), preferably 2-methylphenyl; methoxyphenyl, preferably 2-methoxyphenyl; difluoromethoxy, preferably 4-difluoromethoxy; 4-difluoromethoxy-2-fluorophenyl; methylpyrazolyl, preferably 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl; thiophen-2-yl, thiophen-3-yl; methylthiophenyl, preferably 5-methylthiophen-2-yl; thiazolyl, preferably 1,3-thiazol-2-yl; pyridyl, preferably pyridin-2-yl; pyrimidinyl, preferably pyrimidin-4-yl; pyridazinyl, preferably pyridazin-3-yl; quinolinyl, preferably quinolin-2-yl;

[0077] R 2 represents phenyl; mono-, di-, tri-, tetra- or pentadeuteriophenyl, preferably pentadeuteriophenyl; fluorophenyl, preferably 2-fluorophenyl; methylphenyl (tolyl), preferably 2-methylphenyl; difluoromethoxy, preferably 4-difluoromethoxy; thiophen-2-yl, thiophen-3-yl; methylthiophenyl, preferably 5-methylthiophen-2-yl; pyridyl, preferably pyridin-2-yl;

[0078] R 3 represents methyl, ethyl, 2-dimethylaminoethyl, 2-hydroxyethyl, 2-methoxyethyl; preferably methyl or ethyl;

[0079] R 4 is H;

[0080] R 5 represents H, methyl, methoxy, F, Cl;

[0081] R 6 represents ethylpyrazolyl, preferably 1-ethylpyrazol-3-yl, 1-ethylpyrazol-4-yl; hydroxyethylpyrazolyl, preferably 1-(2-hydroxyethyl)pyrazol-4-yl; methoxyethylpyrazolyl, preferably 1-(2-methoxyethyl)pyrazol-4-yl; ethylimidazolyl, preferably 1-ethyl-1H-imidazol-4-yl; ethyloxazolyl, preferably 4-ethyl-1,3-oxazol-2-yl, 5-ethyl-1,3-oxazol-2-yl; ethyltriazolyl, preferably 1-ethyl-1H-1,2,4-triazol-3-yl, 2-ethyl-2H-1,2,3-triazol-4-yl; aminoethyltriazolyl, preferably 1-(2-aminoethyl)-1H-1,2,4-triazol-3-yl; hydroxyethyltriazolyl, preferably 1-(2-hydroxyethyl)-1H-1,2,4-triazol-3-yl; methoxyethyltriazolyl, preferably 1-(2-methoxyethyl)-1H-1,2,4-triazol-3-yl; ethyloxadiazolyl, preferably 5-ethyl-1,3,4-oxadiazol-2-yl, 5-ethyl-1,2,4-oxadiazol-3-yl.

[0082] In another specific particular embodiment PE7b of PE7 or PE7a, R 1 and R 2 are the same. In another specific particular embodiment PE7c of PE7 or PE7a, R 1 and R 2 are different.

[0083] In yet another specific embodiment PE8, the amide derivative of the present invention is selected from compounds of formula I-b (i.e., pyrazolo[1,5-a]pyridine derivatives), or any of their derivatives, N-oxides, prodrugs, solvates, tautomers or stereoisomers and / or any pharmaceutically acceptable salts of each of the foregoing, including mixtures of all ratios thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined herein or for any specific embodiment PE1, PE2, PE3, PE3a, PE3b, PE4, PE5, PE5a, PE5b, PE5c, PE5d, PE6, PE6a, PE6b. In a specific particular embodiment PE8a of PE8,

[0084] R 1 represents phenyl, 2-fluorophenyl;

[0085] R 2 represents phenyl, 2-fluorophenyl;

[0086] R 3 represents ethyl;

[0087] R 4 is H;

[0088] R 5 represents H, methyl, methoxy, Cl;

[0089] R 6 represents ethylpyrazolyl, ethyltriazolyl; preferably 1-ethylpyrazol-4-yl, 1-ethyl-1H-1,2,4-triazol-3-yl.

[0090] In another specific particular embodiment PE8b of PE8 or PE8a, R 1 and R 2 are the same. In another specific particular embodiment PE8c of PE8 or PE8a, R 1 and R 2 are different.

[0091] In yet another specific embodiment PE9, the amide derivatives of the present invention are selected from the compounds of formula I-c (i.e., imidazo[1,2-a]pyridine derivatives), or any derivatives, N-oxides, prodrugs, solvates, tautomers or stereoisomers thereof and / or any pharmaceutically acceptable salts of each of the foregoing, including mixtures of all ratios thereof, wherein R 1 、R 2 、R 3 、R 4 、R 5 and R 6 are as defined herein or for any specific embodiment PE1, PE2, PE3, PE3a, PE3b, PE4, PE5, PE5a, PE5b, PE5c, PE5d, PE6, PE6a, PE6b. In a specific particular embodiment PE9a of PE9,

[0092] R 1 represents phenyl, 2-fluorophenyl, 1-methylpyrazol-3-yl, 5-methylthiophen-2-yl, 1,3-thiazol-2-yl, pyridin-2-yl;

[0093] R 2 represents phenyl;

[0094] R 3 represents ethyl;

[0095] R 4 represents H;

[0096] R 5 represents H, ethyl, methoxy, F, Cl;

[0097] R 6 represents ethylpyrazolyl, ethyltriazolyl; preferably 1-ethylpyrazol-4-yl, 1-ethyl-1H-1,2,4-triazol-3-yl.

[0098] In another specific particular embodiment PE9b of PE9 or PE9a, R 1 and R 2 are the same. In another specific particular embodiment PE9c of PE9 or PE9a, R 1 and R 2 are different.

[0099] In yet another specific embodiment PE10, the amide derivatives of formula I-a, I-b or I-c are selected from the compounds shown in Table 1 (which is divided into Table 1a, 1b, 1c and 1d) and any derivatives, any N-oxides, prodrugs, solvates, tautomers or stereoisomers thereof and / or any pharmaceutically acceptable salts of each of the foregoing, including mixtures of all ratios thereof.

[0100] Unless otherwise specified or specifically defined elsewhere in the specification and / or claims, the following definitions will apply to specific substituents, radicals, residues, groups or moieties used herein.

[0101] As used herein, the term "aliphatic" or "aliphatic group" refers to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or contains one or more unsaturated units, or a monocyclic hydrocarbon or bicyclic hydrocarbon or tricyclic hydrocarbon that is completely saturated or contains one or more unsaturated units, such as one or more C═C double bonds and / or C≡C triple bonds, but is not aromatic (also referred to herein as "carbocyclic", "alicyclic" or "cycloalkyl"), which typically and unless otherwise defined in this specification or the appended claims has a single point of attachment to the remainder of the molecule. Unless otherwise specified, an aliphatic group contains 1-8 or 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In still other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in yet other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "alicyclic" ("cycloalkyl") refers to a monocyclic C3-C7 hydrocarbon that is completely saturated or contains one or more unsaturated units, but is not aromatic, which has a single point of attachment to the remainder of the molecule. In another embodiment, the term "carbocyclic" refers to a monocyclic or bicyclic alicyclic ring system that is fused to an aromatic, heteroaromatic or heterocyclic or ring system via two adjacent ring atoms of the aromatic, heteroaromatic or heterocyclic or ring system; in other words, such a carbocyclic ring shares two ring atoms with the ring or ring system to which it is fused, thus having two points of attachment to the remainder of the molecule. Suitable aliphatic groups include, but are not limited to, straight-chain or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl and their hybrids, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0102] The term "alkyl" generally refers to a saturated aliphatic and acyclic moiety, the term "alkenyl" generally refers to an unsaturated aliphatic and acyclic moiety having one or more C═C double bonds, and the term "alkynyl" generally refers to an aliphatic and acyclic moiety having one or more C≡C triple bonds. Exemplary aliphatic groups are straight-chain or branched, substituted or unsubstituted C 1-8 -alkyl, C 1-6 -alkyl, C 1-4 -alkyl, C 2-8 -alkenyl, C 2-6 -alkenyl, C 2-8 -alkynyl, C 2-6-alkynyl and its hybrids, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0103] In particular, the term "C 1-3 -alkyl" refers to an alkyl group having 1, 2 or 3 carbon atoms, i.e., a saturated acyclic aliphatic group. Exemplary C 1-3 -alkyls are methyl, ethyl, propyl and isopropyl. The term "C 1-4 -alkyl" refers to an alkyl group having 1, 2, 3 or 4 carbon atoms. Exemplary C 1-4 -alkyls are methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl. The term "C 1-6 -alkyl" refers to an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms. Exemplary C 1-6 -alkyls are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl and 2-hexyl. The term "C 1-8 -alkyl" refers to an alkyl group having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms. Exemplary C 1-8 -alkyls are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, 2-hexyl, n-heptyl, 2-heptyl, n-octyl, 2-octyl and 2,2,4-trimethylpentyl. Each of these alkyl groups can be straight-chain or (except for C1-alkyl and C2-alkyl) branched-chain, and can be unsubstituted or substituted with 1, 2 or 3 substituents, which can be the same or different, and if not otherwise specified elsewhere in this specification, are selected from halogen, hydroxy, alkoxy, unsubstituted amino or amino mono- or di-substituted with alkyl or aralkyl.

[0104] In some cases, C 1-3 -alkyl, C 1-4 -alkyl, C 1-6 -alkyl, C 1-8 -alkyl may also include those residues in which 1 or 2 of the non-terminal and non-adjacent -CH2- (methylene) groups are replaced by -O-, -S- and / or 1 or 2 of the non-terminal and non-adjacent -CH2- or -CH- groups are replaced by -NH- or -N-. These replacements result in, for example, (modified) alkyls such as -CH2-CH2-O-CH3, -CH2-CH2-CH2-S-CH3, CH2-CH2-NH-CH2-CH3, CH2-CH2-O-CH2-CH2-O-CH3, CH2-CH2-N(CH3)-CH2-CH3, etc. For specific alkyl substituents or radicals elsewhere in the specification and / or claims, further and / or different replacements of -CH- and -CH2- groups can be defined.

[0105] The term "C 3-7 -cycloalkyl" means an alicyclic hydrocarbon as defined above having 3, 4, 5, 6 or 7 ring carbon atoms. C 3-7 -cycloalkyl may be unsubstituted or substituted with 1, 2 or 3 substituents (unless otherwise specified elsewhere in this specification), the substituents may be the same or different, and unless otherwise specified elsewhere in this specification, are selected from C 1-6 -alkyl, O-C 1-6 -alkyl (alkoxy), halogen, hydroxy, unsubstituted or mono- or di-substituted amino. Exemplary C 3-7 -cycloalkyls are cyclopropyl, 2-methyl-cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl.

[0106] The term "aliphatic oxy" means a saturated or unsaturated aliphatic group or substituent as defined above attached to another structural moiety via an oxygen atom (-O-). The term "alkoxy" is a specific subgroup of saturated aliphatic oxy, i.e., an alkyl substituent and residue attached to another structural moiety via an oxygen atom (-O-). Sometimes, it is also referred to as "O-alkyl", and more specifically as "O-C 1-4 -alkyl", "O-C 1-6 -alkyl", "O-C 1-8 -alkyl". Similar to the analogous alkyls, it can be straight-chain or (except for -O-C1-alkyl and -O-C2-alkyl) branched-chain, and can be unsubstituted or substituted with 1, 2 or 3 substituents, the substituents may be the same or different, and if not otherwise specified elsewhere in this specification, are selected from halogen, unsubstituted or mono- or di-substituted amino. Exemplary alkoxys are methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy.

[0107] The term "alkylene" means a divalent aliphatic group, and in particular a divalent alkyl. An "alkylene chain" is polymethylene, i.e., -(CH2) x -, where x is a positive integer, preferably 1, 2, 3, 4, 5 or 6. In the context of the present invention, "C 1-3 -alkylene" means an alkylene moiety having 1, 2 and 3 -CH2- groups respectively; however, the term "alkylene" includes not only straight-chain alkylene, i.e., "alkylene chain", but also branched-chain alkylene. The term "C 1-6"-alkylene" refers to an alkylene moiety which is straight-chain, i.e., an alkylene chain, or branched and has 1, 2, 3, 4, 5 or 6 carbon atoms. A substituted alkylene chain is a polymethylene in which one or more methylene hydrogen atoms are replaced (or substituted) by substituents. Suitable substituents include those described herein for substituted alkyl groups. In some cases, 1 or 2 methylenes of the alkylene chain may be replaced by, for example, O, S and / or NH or N-C 1-4 -alkyl substitution. Exemplary alkylenes are -CH2-, -CH2-CH2-, -CH2-CH2-CH2-CH2-, -O-CH2-O-, -O-CH2-CH2-O-, -O-CH2-CH2-CH2-O-, -CH2-NH-CH2-CH2-, -CH2-N(CH3)-CH2-CH2-.

[0108] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene containing at least one double bond, in which one or more hydrogen atoms are replaced by substituents. Suitable substituents include those described herein for substituted aliphatic groups.

[0109] The term "alkynylene" refers to a divalent alkynyl group. A substituted alkynylene chain is a polymethylene containing at least one triple bond, in which one or more hydrogen atoms are replaced by substituents. Suitable substituents include those described herein for substituted aliphatic groups.

[0110] The term "halogen" refers to F, Cl, Br or I.

[0111] The term "heteroatom" refers to one or more of oxygen (O), sulfur (S) or nitrogen (N), including any oxidized form of nitrogen or sulfur, such as N-oxides, sulfoxides and sulfones; any basic nitrogen or quaternized form of a replaceable nitrogen in a heterocyclic or heteroaromatic ring, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or N-SUB, where SUB is a suitable substituent (as in N-substituted pyrrolidinyl).

[0112] The term "aryl", used alone or as part of a larger moiety such as "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to monocyclic, bicyclic, and tricyclic ring systems having a total of 5 - 14 ring members, which are carbon atoms, wherein at least one of the rings in the system is aromatic, i.e., it has (4n + 2)π (π) electrons (where n is an integer selected from 0, 1, 2, 3), the electrons are delocalized over the system, and each ring in the system contains 3 - 7 ring members. Preferably, all of the rings or the entire ring system in the aryl system is aromatic. The term "aryl" is used interchangeably with the term "aromatic ring". In certain embodiments of the present invention, "aryl" refers to an "aromatic ring system". More specifically, those aromatic ring systems can be monocyclic, bicyclic, or tricyclic having 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 ring carbon atoms. Even more specifically, those aromatic ring systems can be monocyclic or bicyclic having 6, 7, 8, 9, 10 ring carbon atoms. The term "monoaryl" refers to a monocyclic aryl. The term "biaryl" refers to a bicyclic aryl. Exemplary aryls are phenyl, biphenyl, naphthyl, anthracenyl, etc., which may be unsubstituted or substituted with one or more identical or different substituents. Also included within the scope of the term "aryl" or "aromatic ring system" as used herein are groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimido, naphthalimido, phenanthridinyl, or tetrahydronaphthyl, etc. In the latter case, the "aryl" or substituent is attached to its side group via the aromatic portion of the ring system.

[0113] The term "benzo" refers to a six-membered aromatic ring (having carbon ring atoms) fused to another ring via two adjacent carbon atoms, which is an alicyclic, aromatic, heteroaromatic, or heterocyclic (heteroalicyclic) ring; resulting in a ring system having at least two rings, wherein the benzo ring shares two common carbon atoms with the other ring to which it is fused. For example, if the benzo ring is fused to a benzene ring, a naphthalene ring system is formed, while fusing the benzo ring to pyridine provides quinoline or isoquinoline.

[0114] The terms "heteroaryl" and "heteroar-" when used alone or as part of a larger moiety such as "heteroarylalkyl" or "heteroaryloxy" refer to groups having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 ring atoms (said atoms being carbon and heteroatoms), preferably 5, 6, 9 or 10 ring atoms; sharing 6, 10 or 14 π (pi) electrons in a cyclic array; and having 1, 2, 3, 4 or 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen or sulfur and includes any oxidized form of nitrogen or sulfur, as well as any quaternized form of basic nitrogen. Heteroaryl includes, but is not limited to, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, furazanyl, pyridyl (pyridinyl), pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl and pyrrolopyridyl, particularly pyrrolo[2,3-b]pyridinyl. The terms "heteroaryl" and "heteroar-" as used herein also include groups in which a heteroaryl ring is fused to one or more aryl, cycloaliphatic or heterocyclic rings, where the attached radical or point is preferably on the heteroaromatic or, if present, on the aryl ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl (benzothiophenyl), benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, 9H-carbazolyl, dibenzofuranyl and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. For example, an indolyl ring can be attached via a ring atom of a six-membered aryl ring or via a ring atom of a five-membered heteroaryl ring. Heteroaryl is optionally monocyclic, bicyclic or tricyclic. The term "heteroaryl" is used interchangeably with the terms "heteroaryl ring", "heteroaryl" or "heteroaromatic", any of said terms including rings that are unsubstituted or substituted with one or more identical or different substituents. The term "heteroarylalkyl" refers to an alkyl group substituted with a heteroaryl group, where the alkyl and heteroaryl moieties are independently optionally substituted.

[0115] The heteroaryl ring can be attached to its side group at any of its hetero or carbocyclic atoms, such attachment giving rise to a stable structure or molecule: any ring atom can be unsubstituted or substituted.

[0116] Typical examples of the structures of "heteroaryl" substituents used in the present invention are shown below:

[0117]

[0118]

[0119]

[0120]

[0121] Those heteroaryl substituents may be attached to any side group via any ring atom thereof suitable for such attachment.

[0122] When referring to the use of ring atoms of a heterocycle, the term "nitrogen" includes substituted nitrogen. By way of example, in a saturated or partially unsaturated ring having 1-3 heteroatoms selected from oxygen, sulfur or nitrogen, nitrogen is N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or N-SUB, where SUB is a suitable substituent (as in N-substituted pyrrolidinyl).

[0123] As used herein, the term "unsaturated" means that a moiety or group or substituent has one or more unsaturation units.

[0124] As used herein, the terms "bicyclic", "bicyclic ring" or "bicyclic system" refer to any bicyclic system, i.e., carbocyclic or heterocyclic, saturated or having one or more unsaturation units (i.e., partially unsaturated) or aromatic, having one or more common atoms between the two rings of the ring system. Thus, the term includes any permissible ring fusion, such as ortho-fusion or spiro. As used herein, the term "heterobicyclic" is a subset of "bicyclic" which requires that one or more heteroatoms be present in one or both rings of the bicyclic. Such heteroatoms may be present at the ring junction and optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc. In some embodiments, the bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Similarly, the terms "tricyclic", "tricyclic ring" or "tricyclic system" refer to any tricyclic system, i.e., carbocyclic or heterocyclic, saturated or having one or more unsaturation units (i.e., partially unsaturated) or aromatic, wherein a bicyclic system (as defined above) is fused to another third ring. Thus, the term includes any permissible ring fusion. As used herein, the term "heterotricyclic" is a subset of "tricyclic" which requires that one or more heteroatoms be present in one or two rings of the tricyclic. Such heteroatoms may be present at the ring junction and optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc. In some embodiments, the tricyclic group has 10-14 ring members and 0-5 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0125] As described herein, certain compounds of the invention contain "substituted" or "optionally substituted" moieties. In general, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogens of the designated moiety are replaced by a suitable substituent. "Substituted" applies to one or more hydrogens that are explicitly or implicitly present in the structure. Unless otherwise specified, a "substituted" or "optionally substituted" group has a suitable substituent at each replaceable position of the group, and when more than one position in any given structure is substituted by more than one substituent selected from the designated group, the substituents are the same or different at each position. If a group, substituent, moiety, or radical is "monosubstituted", it bears one (1) substituent. If it is "disubstituted", it bears two (2) substituents, which are the same or different; if it is "trisubstituted", it bears three (3) substituents, where all three are the same, or two are the same and the third is different, or all three are different from each other. Combinations of substituents contemplated by the invention are preferably those that result in the formation of stable or chemically viable compounds. As used herein, the term "stable" refers to a compound that does not substantially change when subjected to conditions that permit its production, detection, and in some embodiments, its recovery, purification, and use for one or more of the purposes disclosed herein.

[0126] If not otherwise indicated elsewhere in the specification or the appended claims, it is to be understood that each optional substituent on a replaceable carbon is independently selected from the following monovalent substituents: halogen; -(CH2) 0-4 R o ; -(CH2) 0- 4OR o ; -O(CH2) 0-4 R o , -O-(CH2) 0-4 C(O)OR o ; -(CH2) 0-4 CH(OR o )2; -(CH2) 0-4 SR o ; -(CH2) 0-4 Ph, which may be substituted by one or more R o ; -(CH2) 0-4 O(CH2) 0-1 Ph, which may be substituted by one or more R o ; -CH=CHPh, which may be substituted by one or more R o ; -(CH2) 0-4 O(CH2) 0-1 -pyridyl, which may be substituted by one or more R o ; -NO2; -CN; -N3; -(CH2)0-4 N(R o )2; -(CH2) 0-4 N(R o )C(O)R o ; -N(R o )C(S)R o ; -(CH2) 0-4 N(R o )C(O)NR o 2; -N(R o )C(S)NR o 2; -(CH2) 0-4 N(R o )C(O)OR o ; -N(R o )N(R o )C(O)R o ; -N(R o )N(R o )C(O)NR o 2; -N(R o )N(R o )C(O)OR o ; -(CH2) 0-4 C(O)R o ; -C(S)R o ; -(CH2) 0-4 C(O)OR o ; -(CH2) 0-4 C(O)SR o ; -(CH2) 0-4 C(O)OSiR o 3; -(CH2) 0-4 OC(O)R o ; -OC(O)(CH2) 0-4 SR-; SC(S)SR o ; -(CH2) 0-4 SC(O)R o ; -(CH2) 0-4 C(O)NR o 2; -C(S)NR o 2; -C(S)SR o ; -SC(S)SR o , -(CH2) 0-4 OC(O)NR o 2; -C(O)N(OR o )R o ; -C(O)C(O)R o ; -C(O)CH2C(O)R o ; -C(NOR o )Ro ; -(CH2) 0-4 SSR o ; -(CH2) 0-4 S(O)2R o ; -(CH2) 0-4 S(O)2OR o ; -(CH2) 0-4 OS(O)2R o ; -S(O)2NR o 2; -S(O)(NR o )R o ; -S(O)2N=C(NR o 2)2; -(CH2) 0-4 S(O)R o ; -N(R o )S(O)2NR o 2; -N(R o )S(O)2R o ; -N(OR o )R o ; -C(NH)NR o 2; -P(O)2R o ; -P(O)R o 2; -OP(O)R o 2; -OP(O)(OR o )2; SiR o 3; -(C 1-4 linear or branched alkylene)O-N(R o )2; or -(C 1-4 linear or branched alkylene)C(O)O-N(R o )2. It should be understood that "Ph" refers to phenyl; and "-(CH2) 0-4 " means the absence of an alkylene group (if the subscript is "0" (zero)) or an alkylene group having 1, 2, 3 or 4 CH2 units.

[0127] Each R o independently is hydrogen, halogen, C 1-6 aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -CH2-(5-6 membered heteroaryl ring) or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or despite the above definition, two independently occurring R o together with one or more of their intervening atoms form a 3-12 membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted by R selected from =O and =S osubstituted by a divalent substituent on a saturated carbon atom; or each R o is optionally substituted by a monovalent substituent independently selected from the following: halogen, -(CH2) 0-2 R · -, -(haloR · ), -(CH2) 0-2 OH, -(CH2) 0-2 OR · -, -(CH2) 0-2 CH(OR · )2, -O(haloR · ), -CN, -N3, -(CH2) 0-2 C(O)R · -, -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR · -, -(CH2) 0-2 SR · -, -(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR · -, -(CH2) 0-2 NR · 2, -NO2, -SiR · 3, -OSiR · 3, -C(O)SR · -, -(C 1-4 linear or branched alkylene)C(O)OR · or -SSR · . It should be understood that "Ph" refers to phenyl; "halo" refers to halogen; and "-(CH2) 0-2 " means the absence of an alkylene group (if the subscript is "0" (zero)) or an alkylene group having 1 or 2 CH2 units.

[0128] Each R · is independently selected from C 1-4 aliphatic, -CH2Ph, -O(CH2) 0-1 Ph or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, and wherein each R · is unsubstituted or, when preceded by halo, is substituted only by one or more halogens; or wherein the optional substituent on the saturated carbon is a divalent substituent independently selected from the following: =O, =S, =NNR * 2, =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R* , =NR * , =NOR * , -O(C(R * 2)) 2-3 O- or -S(C(R * 2)) 2-3 S-, or a divalent substituent bonded to an adjacent replaceable carbon of an "optionally substituted" group is -O(CR * 2) 2-3 O-, where each independently occurring R * is selected from hydrogen, C 1-6 aliphatic or an unsubstituted 5- or 6-membered saturated, partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0129] When R * is C 1-6 aliphatic, R * is optionally substituted by halogen, -R · , -(haloR · ), -OH, -OR · , -O(haloR · ), -CN, -C(O)OH, -C(O)OR · , -NH2, -NHR · , -NR · 2, or -NO2, where each R · is independently selected from C 1-4 aliphatic, -CH2Ph, -O(CH2) 0-1 Ph or a 5- or 6-membered saturated, partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, and where each R · is unsubstituted or, when preceded by halo, is substituted only by one or more halogens.

[0130] Optional substituents on replaceable nitrogen are independently where each is independently hydrogen, C 1-6 aliphatic, unsubstituted -OPh, or an unsubstituted 5- or 6-membered saturated, partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or two independently occurring together with one or more of their intervening atoms form an unsubstituted monocyclic or bicyclic 3- to 12-membered saturated, partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; where when is C 1-6 aliphatic, Optionally substituted by halogen, -R · , -(haloR · ), -OH, -OR · , -O(haloR · ), -CN, -C(O)OH, -C(O)OR · , -NH2, -NHR · , -NR · 2 or -NO2, where each R · is independently selected from C 1-4 aliphatic, -CH2Ph, -O(CH2) 0- 1Ph, or a 5- to 6-membered saturated, partially unsaturated or aryl ring having 0 - 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, and where each R · is unsubstituted or, when preceded by halo, is substituted only by one or more halogens. It is understood that "Ph" refers to phenyl; and "halo" refers to halogen.

[0131] In the context of the present invention, the term "derivative" refers to any non-toxic salt, ester, salt of an ester or other derivative of a compound of the present invention which, upon administration to a recipient, is capable of directly or indirectly providing the compound of the present invention or a metabolite or residue thereof having inhibitory activity.

[0132] The compounds of the present invention may be in the form of prodrug compounds. "Prodrug" and "prodrug compound" refer to derivatives which are converted into the bioactive compounds according to the present invention under physiological conditions in vivo, for example by oxidation, reduction, hydrolysis, etc., each of which may be enzyme-catalyzed or occur without the participation of an enzyme. Examples of prodrugs are compounds in which the amino group in the compound of the present invention is acylated, alkylated or phosphorylated, such as eicosanoylamino, alanylamino, pivaloyloxymethylamino, or in which the hydroxyl group is acylated, alkylated, phosphorylated or converted to a borate, such as acetoxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaroyloxy, alanyloxy, or in which the carboxyl group is esterified or amidated, or in which the thiol group forms a disulfide bridge with a carrier molecule (such as a peptide), the carrier molecule selectively delivering the drug to the target and / or the cytosol of the cell. These compounds can be produced from the compounds of the present invention according to known methods. Other examples of prodrugs are compounds in which the carboxylic acid ester in the compound of the present invention is, for example, converted to an alkyl-, aryl-, choline-, amino-, acyloxymethyl ester, linolenoyl ester.

[0133] The term "solvate" refers to an addition form of a compound of the present invention with a solvent, preferably a pharmaceutically acceptable solvent containing a stoichiometric or non-stoichiometric amount of the solvent. Some compounds have a tendency to trap solvent molecules in a fixed molar ratio in the crystalline solid state, thus forming solvates. If the solvent is water, the solvate formed is a hydrate, such as a monohydrate or a dihydrate. If the solvent is an alcohol, the solvate formed is an alcoholate, such as a methanolate or an ethanolate. If the solvent is an ether, the solvate formed is an etherate, such as an ethyl etherate.

[0134] The term "N-oxide" refers to a compound of the present invention containing an amine oxide moiety, i.e., the oxide of a tertiary amine group.

[0135] The compounds of formula I-a, I-b or I-c may have one or more chiral centers. Thus, they can exist in various enantiomeric and diastereomeric forms, as the case may be, and can be in racemic or optically active forms. Accordingly, the present invention also relates to optically active forms, enantiomers, racemates, diastereomers, mixtures of all ratios thereof, and collectively refers to these compounds as "stereoisomers" for the purposes of the present invention. Since the pharmacological activities of the racemates or stereoisomers of the compounds according to the present invention may be different, it may be desirable to use a specific stereoisomer, such as a specific enantiomer or diastereomer. In these cases, the compounds according to the present invention obtained as racemates or even as intermediates thereof can be separated into stereoisomeric (enantiomeric, diastereomeric) compounds by chemical or physical measures known to those skilled in the art. Another method that can be used to obtain one or more specific stereoisomers of the compounds of the present invention in enriched or pure form utilizes stereoselective synthesis procedures, such as applying starting materials in stereoisomerically enriched or pure form (e.g., using pure or enriched (R)- or (S)-enantiomers of a specific starting material with a chiral center) or utilizing chiral reagents or catalysts, especially enzymes. In the context of the present invention, the term "pure enantiomer" generally means that the relative purity of one enantiomer with respect to the other enantiomer (its enantiomer) is equal to or greater than 95%, preferably ≥98%, more preferably ≥98.5%, still more preferably ≥99%.

[0136] Thus, for example, the compounds of the present invention having one or more chiral centers and existing as racemates or as mixtures of enantiomers or diastereomers can be fractionated or resolved into their optically pure or enriched isomers, i.e., enantiomers or diastereomers, by methods known per se. The separation of the compounds of the present invention can be carried out by chromatography, such as column separation on a chiral or achiral phase, or by recrystallization from an optionally optically active solvent or by using an optically active acid or base or by derivatization with an optically active reagent (such as an optically active alcohol) and subsequent elimination of the radical.

[0137] In the context of the present invention, the term "tautomer" refers to a compound of the present invention that can exist in tautomeric forms and exhibit tautomerism; for example, a carbonyl compound can exist in its keto and / or its enol forms and exhibit keto-enol tautomerism. These tautomers can exist in their individual forms, such as the keto or enol form, or as a mixture thereof, and are claimed both individually and together as a mixture in any ratio. This also applies to cis / trans isomers, E / Z isomers, conformational isomers, etc.

[0138] In one embodiment, the compounds of the present invention are in the form of the free base or acid, which may be, as the case may be, i.e., their non-salt (or salt-free) form. In another embodiment, the compounds of the present invention are in the form of a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt.

[0139] The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable bases or acids, including inorganic and organic bases or acids. Where the compounds of the present invention contain one or more acidic or basic groups, the present invention also encompasses their corresponding pharmaceutically acceptable salts. Thus, compounds of the present invention containing acidic groups (such as carboxyl groups) may exist in the form of salts and may be used, for example, as alkali metal salts, alkaline earth metal salts, aluminum salts or ammonium salts in accordance with the present invention. More specific examples of such salts include lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, barium salts or salts with ammonia or organic amines (such as ethylamine, ethanolamine, diethanolamine, triethanolamine, piperidine, N-methylglutamine or amino acids). These salts are readily obtainable, for example, by reacting a compound having an acidic group with a suitable base, such as lithium hydroxide, sodium hydroxide, sodium propoxide, potassium hydroxide, potassium ethoxide, magnesium hydroxide, calcium hydroxide or barium hydroxide. Other base salts of the compounds of the present invention include, but are not limited to, copper(I), copper(II), iron(II), iron(III), manganese(II) and zinc salts. Compounds of the present invention containing one or more basic groups (such as groups that can be protonated) may exist in salt form and may be used in accordance with the present invention in the form of their addition salts with inorganic or organic acids. Examples of suitable acids include hydrogen chloride, hydrogen bromide, hydrogen iodide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, sulfoacetic acid, trifluoroacetic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, carbonic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, pamoic acid, mandelic acid, aminosulfonic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, taurocholic acid, glutaric acid, stearic acid, glutamic acid or aspartic acid, and other acids known to those skilled in the art. The salts formed are especially hydrochlorides, chlorides, hydrobromides, bromides, iodides, sulfates, phosphates, methanesulfonates (mesylates), toluenesulfonates, carbonates, bicarbonates, formates, acetates, sulfoacetates, trifluoromethanesulfonates, oxalates, malonates, maleates, succinates, tartrates, malates, pamoates, mandelates, fumarates, lactates, citrates, glutarates, stearates, aspartates and glutamates. In addition, the stoichiometry of the salts formed from the compounds of the present invention may be an integral or non-integral multiple of one.

[0140] Compounds of the present invention containing basic nitrogen-containing groups may be quaternized using reagents such as (C1-C4) alkyl halides, such as methyl, ethyl, isopropyl and tert-butyl chlorides, bromides and iodides; di(C1-C4) alkyl sulfates, such as dimethyl, diethyl and dipentyl sulfates; (C 10 -C 18Alkyl halides, such as decyl, dodecyl, tetradecyl and octadecyl chlorides, bromides and iodides; and aryl(C1-C4)alkyl halides, such as benzyl chloride and phenethyl bromide. Such salts can be used to prepare both water-soluble and oil-soluble compounds according to the present invention.

[0141] If the compounds of the present invention contain both acidic and basic groups in the molecule, in addition to the salt forms described above, the present invention also includes inner salts or betaines (zwitterions). The corresponding salts can be obtained by conventional methods known to those skilled in the art, such as by contacting these with organic or inorganic acids or bases in a solvent or dispersant, or by anion exchange or cation exchange with other salts. The present invention also includes all salts of the compounds of the present invention which are not directly applicable to drugs due to their low physiological compatibility, but which can be used, for example, as intermediates in chemical reactions or for the preparation of pharmaceutically acceptable salts.

[0142] Therefore, the following items are also in accordance with the present invention:

[0143] (a) All stereoisomers or tautomers of the compounds, including mixtures of all ratios thereof;

[0144] (b) Prodrugs of the compounds, or stereoisomers or tautomers of these prodrugs;

[0145] (c) Pharmaceutically acceptable salts of the compounds and the items mentioned in (a) and (b);

[0146] (d) Pharmaceutically acceptable solvates of the compounds and the items mentioned in (a), (b) and (c);

[0147] (e) N-oxides of the compounds and the items mentioned in (a), (b), (c) and (d).

[0148] It should be understood that all compounds mentioned above and below refer to those including these items, in particular pharmaceutically acceptable solvates of the compounds, or pharmaceutically acceptable solvates of their pharmaceutically acceptable salts.

[0149] In addition, it is intended that the compounds of the present invention include their isotopically labeled forms. Isotopically labeled forms of the compounds of formula I-a, I-b or I-c are identical to the compound except that one or more atoms of the compound are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes which are readily commercially available and which can be incorporated into the compounds of the present invention by known methods include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C,15 N, 18 O, 17 O, 31 P, 32 P, 33 S, 34 S, 35 S, 36 S, 18 F and 36 Cl. Compounds of formula I-a, I-b or I-c containing one or more of the above isotopes and / or other isotopes of other atoms, or pharmaceutically acceptable salts thereof, are intended to be part of the present invention. The isotopically labeled compounds of formula I-a, I-b or I-c can be used in many useful ways. For example, isotopically labeled compounds of the present invention in which a radioactive isotope (e.g., 3 H or 14 C) has been incorporated are suitable for drug and / or substrate tissue distribution assays. These radioactive isotopes (i.e., tritium ( 3 H) and carbon-14 ( 14 C)) are particularly preferred due to their simple preparation and excellent detectability. Incorporation of a heavier isotope (e.g., deuterium ( 2 H)) into a compound of formula I-a, I-b or I-c has a therapeutic advantage due to the higher metabolic stability of the isotopically labeled compound. The higher metabolic stability directly translates into an increased in vivo half-life or a lower dose, which in most cases represents a preferred embodiment of the present invention. The isotopically labeled compounds of formula I-a, I-b or I-c can generally be prepared by carrying out the synthetic schemes and procedures disclosed in the relevant descriptions in the Examples section and the Preparation section herein, and replacing the non-isotopically labeled reactants with readily available isotopically labeled reactants.

[0150] Deuterium ( 2 H) can also be incorporated into compounds of formula I-a, I-b or I-c for the purpose of manipulating the oxidative metabolism of the compound by the primary kinetic isotope effect. The primary kinetic isotope effect is a change in the rate of a chemical reaction caused by the exchange of isotopic nuclei, which in turn is caused by a change in the ground state energy required to form a covalent bond after the isotopic exchange. Exchange of a heavier isotope generally results in a decrease in the ground state energy of the chemical bond and thus a decrease in the rate of the rate-limiting bond breakage. If the bond breakage occurs in or near the saddle point region along the coordinate of a multi-product reaction, the product distribution ratio can be significantly altered. By way of explanation: if deuterium is bonded to a carbon atom at a non-exchangeable position, the typical rate difference is k M / k D= 2 - 7. If such rate differences are successfully applied to oxidation-sensitive compounds of formulae Ia and Ib, the in vivo properties of the compounds can be significantly altered, resulting in improved pharmacokinetic properties.

[0151] When discovering and developing therapeutic agents, those skilled in the art attempt to optimize pharmacokinetic parameters while maintaining desired in vitro properties. It is reasonably assumed that many compounds with poor pharmacokinetic properties are sensitive to oxidative metabolism. Currently available in vitro liver microsome assays provide valuable information about this type of oxidative metabolic process, which in turn allows for the rational design of deuterated compounds of formula I-a, I-b, or I-c with improved stability through resistance to such oxidative metabolism. Thus, a significant improvement in the pharmacokinetic properties of the compounds of formula I-a, I-b, or I-c is obtained, and it can be quantitatively represented in terms of an increase in the in vivo half-life (t1 / 2), maximum therapeutic concentration (C max ), area under the dose-response curve (AUC), and F; as well as a decrease in clearance rate, dose, and material cost.

[0152] The following is intended to illustrate the above: Compounds of formula I-a, I-b, or I-c having multiple potential sites for oxidative metabolic attack, such as benzylic hydrogen atoms and hydrogen atoms bonded to nitrogen atoms, are prepared as a series of analogues in which various combinations of hydrogen atoms are replaced by deuterium atoms such that some, most, or all of these hydrogen atoms are replaced by deuterium atoms. Half-life determination enables the advantageous and accurate determination of the degree of improvement in resistance to oxidative metabolism. In this way, it has been determined that the half-life of the parent compound can be extended by up to 100% due to this type of deuterium-hydrogen exchange.

[0153] Deuterium-hydrogen exchange in the compounds of the present invention can also be used to achieve a favorable modification of the metabolite profile of the starting compound to reduce or eliminate unwanted toxic metabolites. For example, if a toxic metabolite is produced by oxidative carbon-hydrogen (C-H) bond cleavage, it can be reasonably assumed that the deuterated analogue will greatly reduce or eliminate the production of the unwanted metabolite, even if the specific oxidation is not the rate-determining step. Further information on the prior art regarding deuterium-hydrogen exchange can be found, for example, in Hanzlik et al., J. Org. Chem. 55, 3992 - 3997, 1990, Reider et al., J. Org. Chem. 52, 3326 - 3334, 1987, Foster, Adv. Drug Res. 14, 1 - 40, 1985, Gillette et al., Biochemistry 33(10) 2927 - 2937, 1994, and Jarman et al., Carcinogenesis 16(4), 683 - 688, 1995.

[0154] Furthermore, the present invention relates to a pharmaceutical composition comprising, as an active ingredient, at least one compound of formula I-a, I-b or I-c or a derivative, prodrug, solvate, tautomer or stereoisomer thereof, and a pharmaceutically acceptable salt of each of the foregoing, including mixtures in all ratios thereof, and a pharmaceutically acceptable carrier.

[0155] For the purposes of the present invention, the term "pharmaceutical composition" (or "pharmaceutical formulation") means a composition or product comprising one or more active ingredients and one or more inert ingredients that constitute a carrier, as well as any product directly or indirectly resulting from the combination, complexation or aggregation of any two or more ingredients, or from the dissociation of one or more ingredients, or from other types of reaction or interaction of one or more ingredients. Thus, the pharmaceutical compositions of the present invention include any composition prepared by mixing at least one compound of the present invention and a pharmaceutically acceptable carrier. It may further contain physiologically acceptable excipients, adjuvants, adjuvants, diluents and / or additional pharmaceutically active substances other than the compounds of the present invention.

[0156] Pharmaceutical compositions include compositions and pharmaceutical formulations suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation) or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the condition being treated and the nature of the active ingredient. They may conveniently be presented in unit dosage form and prepared by any method well known in the pharmaceutical art.

[0157] The pharmaceutical composition of the present invention may additionally comprise one or more other compounds as active ingredients (drugs), such as one or more additional compounds of the present invention. In certain embodiments, the pharmaceutical composition further comprises a second active ingredient or its derivative, prodrug, solvate, tautomer or stereoisomer and pharmaceutically acceptable salts of each of the foregoing, including mixtures of all ratios thereof, wherein the second active ingredient is not a compound of formula I-a, I-b or I-c; preferably, the second active ingredient is a compound that can be used for treating, preventing, inhibiting and / or ameliorating a medical condition or pathology, for which the compounds of the present invention can also be used, and the condition or pathology is listed elsewhere above or below. Such a combination of two or more active ingredients or drugs may be safer or more effective than the individual drugs or active ingredients alone, or the combination is safer or more effective than would be expected based on the additive properties of the individual drugs. Such one or more other drugs may be administered by the routes and in the amounts that are typically used concurrently or sequentially with the compounds of the present invention. When the compounds of the present invention are used concurrently with one or more other drugs or active ingredients, a combination product containing such one or more other drugs and the compounds of the present invention is preferred, also referred to as a "fixed-dose combination". However, combination therapy also includes therapies in which the compounds of the present invention and one or more other drugs are administered on different overlapping schedules. It is expected that when used in combination with other active ingredients, the compounds of the present invention or the other active ingredients or both may be effectively used at lower doses than when used alone. Accordingly, in addition to the compounds of the present invention, the pharmaceutical compositions of the present invention include those that further contain one or more other active ingredients.

[0158] The compounds of the present invention or their derivatives, N-oxides, prodrugs, solvates, tautomers or stereoisomers and / or pharmaceutically acceptable salts of each of the foregoing (including mixtures of all ratios thereof) can be used as drugs. They have been found to exhibit pharmacological activity by inhibiting acetyl-CoA synthetase 2 (ACSS2). In addition, when tested for genotoxicity in the MNT (micronucleus) in vitro assay, they may exhibit improved properties compared to prior art ACSS2 inhibitors, namely a negative MNT assay readout.

[0159] Thus, the compounds of the present invention, as ACSS2 inhibitors, can be particularly used for treating, preventing, inhibiting, and / or ameliorating hyperproliferative disorders and cancers, particularly tumors, including solid tumors of the bladder, breast, colorectal, colon, kidney, liver, lung, head and neck, esophagus, bladder, gallbladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma; leukemia, acute lymphoblastic leukemia, acute lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma, mantle cell lymphoma, myeloma, and Burkitt lymphoma; chronic lymphocytic leukemia ("CLL"), acute and chronic myelogenous leukemia, myelodysplastic syndromes, and promyelocytic leukemia; fibrosarcoma, rhabdomyosarcoma; mantle cell lymphoma, myeloma; astrocytoma, neuroblastoma, glioma, glioblastoma, malignant glioma, astrocytoma, hepatocellular carcinoma, gastrointestinal stromal tumor ("GIST"), and schwannoma; melanoma, multiple myeloma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular thyroid carcinoma, endometrial cancer, gastrointestinal cancer, and Kaposi sarcoma; acanthoma, acinar cell carcinoma, acoustic neuroma, acral lentiginous melanoma, apical helicoma, acute eosinophilic leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute myeloblastic leukemia with maturation, acute myeloid dendritic cell leukemia, acute myeloid leukemia, acute promyelocytic leukemia, ameloblastoma, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor, adrenocortical carcinoma, adult T-cell leukemia, aggressive NK-cell leukemia, AIDS-related carcinoma, AIDS-related lymphoma, alveolar soft part sarcoma, ameloblastic fibroma, anal cancer, anaplastic large cell lymphoma, anaplastic thyroid carcinoma, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, appendiceal cancer, astrocytoma, atypical teratoid rhabdoid tumor, basal cell carcinoma, basaloid carcinoma, B-cell leukemia, B-cell lymphoma, collecting duct carcinoma of the kidney, biliary tract cancer, bladder cancer, blastoma, bone cancer, bone tumor, brainstem glioma, brain tumor, breast cancer, ovarian fibroma, bronchial tumor, bronchioloalveolar carcinoma, brown tumor, Burkitt lymphoma, carcinoid tumor, carcinoma, carcinosarcoma, Castleman disease, central nervous system embryonal tumor, cerebellar astrocytoma, cerebral astrocytoma, cervical cancer, cholangiocarcinoma, chondroma, chondrosarcoma, chordoma, choriocarcinoma, choroid plexus papilloma, chronic lymphocytic leukemia, chronic monocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disorders, chronic neutrophilic leukemia, clear cell renal cell carcinoma, clear cell tumor, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, dermatofibrosarcoma protuberans, dermoid cyst, desmoplastic small round cell tumor, diffuse large B-cell lymphoma, dysembryoplastic neuroepithelial tumor, embryonal carcinoma,Endodermal sinus tumor, endometrial cancer, endometrial carcinoma, endometrioid tumor, enteropathy-associated T-cell lymphoma, ependymoblastoma, ependymoma, epithelioid sarcoma, erythroleukemia, esophageal cancer, sensory neuroblastoma, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, extramammary Paget's disease, fallopian tube cancer, fibroma, fibrosarcoma, follicular thyroid cancer, gallbladder cancer, ganglioglioma, ganglioneuroma, gastric cancer, gastric lymphoma, gastrointestinal cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, germ cell tumor, gestational choriocarcinoma, gestational trophoblastic tumor, giant cell tumor of bone, glioblastoma multiforme, glioma, gliomatosis cerebri, glomus tumor, glucagonoma, gonadoblastoma, granulosa cell tumor, hairy cell leukemia, head and neck cancer, heart cancer, hemangioblastoma, hemangiopericytoma, hemangiosarcoma, hematological malignancy, hepatocellular carcinoma, hepatosplenic T-cell lymphoma, Hodgkin lymphoma, hypopharyngeal cancer, hypothalamic glioma, inflammatory breast cancer, intraocular melanoma, islet cell carcinoma, juvenile myelomonocytic leukemia, Kaposi sarcoma, kidney cancer, Klatskin tumor, Krukenberg tumor, laryngeal cancer, malignant lentigo melanoma, leukemia, lip and oral cavity cancer, liposarcoma, lung cancer, luteoma, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoid leukemia, lymphoma, macroglobulinemia, malignant fibrous histiocytoma, malignant glioma, malignant mesothelioma, malignant peripheral nerve sheath tumor, malignant rhabdoid tumor, malignant triton tumor, malt lymphoma, mantle cell lymphoma, mast cell leukemia, mediastinal germ cell tumor, mediastinal tumor, medullary thyroid cancer, medulloblastoma, medulloepithelioma, melanoma, meningioma, Merkel cell carcinoma, mesothelioma, metastatic squamous neck cancer with occult primary carcinoma, metastatic urothelial carcinoma, mixed Müllerian tumor, monocytic leukemia, oral cancer, mucinous tumor, multiple endocrine neoplasia syndrome, multiple myeloma, mycosis fungoides, myelodysplastic disease, myeloid leukemia, myeloid sarcoma, myeloproliferative disease, myxoma, nasal cavity cancer, nasopharyngeal cancer, neoplasm, schwannoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, non-Hodgkin lymphoma, non-melanoma skin cancer, non-small cell lung cancer, ocular oncology, oligodendroastrocytoma, oligodendroglioma, oncocytoma, optic nerve sheath meningioma, oral cavity cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, Pancoast tumor, pancreatic cancer, papillary thyroid cancer, papillomatosis, paraganglioma, paranasal sinus cancer, parathyroid cancer, penile cancer, perivascular epithelioid cell tumor, pharyngeal cancer, pheochromocytoma, intermediate differentiated pineal parenchymal tumor, pineoblastoma, pituitary cell tumor, pituitary adenoma, pituitary tumor, plasma cell neoplasm, pleuropulmonary blastoma, polyembryoma, precursor T-lymphoblastic lymphoma, primitive neuroectodermal tumor, prostate cancer, pseudomyxoma peritonei, rectal cancer, renal cell carcinoma,Retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter transformation, sacrococcygeal teratoma, salivary gland carcinoma, sarcoma, schwannomatosis, sebaceous gland carcinoma, secondary neoplasm, seminoma, serous tumor, Sertoli-Leydig cell tumor, gonadal stromal tumor, Sezary syndrome, signet ring cell carcinoma, skin cancer, blue round cell tumor, small cell carcinoma, small cell lung cancer, small cell lymphoma, small intestine cancer, soft tissue sarcoma, somatostatinoma, soot wart tumor, spinal tumor, splenic marginal zone lymphoma, squamous cell carcinoma, stomach cancer, superficial spreading melanoma, supratentorial primitive neuroectodermal tumor, surface epithelial-stromal tumor, synovial sarcoma, T-cell acute lymphoblastic leukemia, T-cell large granular lymphocyte leukemia, T-cell leukemia, T-cell lymphoma, T-cell prolymphocytic leukemia, teratoma, advanced lymphoma, testicular cancer, theca cell tumor, laryngeal cancer, thymic carcinoma, thymoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, transitional cell carcinoma, urachal carcinoma, urethral cancer, uro-genital neoplasm, uterine sarcoma, uveal melanoma, vaginal cancer, Vohwinkel syndrome, verrucous carcinoma, visual pathway glioma, vulvar cancer, Waldenström macroglobulinemia, Warthin tumor, Wilms tumor, or any combination thereof. However, since the activity of ACSS2 also plays a role in acetyl-CoA synthesis in normal (i.e., non-cancer) cells, the compounds of the present invention can also be used to treat, prevent, inhibit, and / or improve inflammatory disorders or diseases, particularly Crohn's disease, ulcerative colitis, idiopathic pulmonary fibrosis, muscular dystrophy, rheumatoid arthritis, and systemic sclerosis (scleroderma); neurological tissue generation disorders or diseases, particularly Huntington's disease; lipid metabolism disorders, such as NASH (non-alcoholic steatohepatitis), NAFLD (non-alcoholic fatty liver disease), fatty liver disease; viral infections, such as being infected with cytomegalovirus; post-traumatic stress disorder (PTSD); bipolar disorder, depression, Tourette syndrome, schizophrenia, obsessive-compulsive disorder, anxiety disorder, panic disorder, phobia, addiction to, for example, alcohol, tobacco, opioids, sedatives, hypnotics, anti-anxiety drugs, cocaine, marijuana, amphetamines, hallucinogens, inhalants, phencyclidine, impulse control disorders, behavioral addictions.

[0160] In certain embodiments, the compounds of the invention are used for the prevention and / or treatment (especially treatment) of any of the disorders or diseases listed above, preferably cancer, especially tumors, including solid tumors of the specific types of cancer disclosed in the foregoing paragraphs; inflammatory disorders or diseases, especially Crohn's disease, ulcerative colitis, idiopathic pulmonary fibrosis, muscular dystrophy, rheumatoid arthritis, and systemic sclerosis (scleroderma); neurogenic disorders or diseases, especially Huntington's disease; lipid metabolism disorders such as NASH (non-alcoholic steatohepatitis), NAFLD (non-alcoholic fatty liver disease), fatty liver disease; viral infections such as infection with cytomegalovirus; post-traumatic stress disorder (PTSD); bipolar disorder, depression, Tourette syndrome, schizophrenia, obsessive-compulsive disorder, anxiety disorder, panic disorder, phobia, addiction to, for example, alcohol, tobacco, opioids, sedatives, hypnotics, anti-anxiety drugs, cocaine, marijuana, amphetamines, hallucinogens, inhalants, phencyclidine, impulse control disorders, behavioral addictions.

[0161] Another specific embodiment of the invention is a method for the prevention and / or treatment (preferably treatment) of a disorder or disease selected from the group consisting of: hyperproliferative disorders and cancer, especially tumors, including solid tumors of the specific types of cancer disclosed in the foregoing paragraphs; inflammatory disorders or diseases, especially Crohn's disease, ulcerative colitis, idiopathic pulmonary fibrosis, muscular dystrophy, rheumatoid arthritis, and systemic sclerosis (scleroderma); neurogenic disorders or diseases, especially Huntington's disease; lipid metabolism disorders such as NASH (non-alcoholic steatohepatitis), NAFLD (non-alcoholic fatty liver disease), fatty liver disease; viral infections such as infection with cytomegalovirus; post-traumatic stress disorder (PTSD); bipolar disorder, depression, Tourette syndrome, schizophrenia, obsessive-compulsive disorder, anxiety disorder, panic disorder, phobia, addiction to, for example, alcohol, tobacco, opioids, sedatives, hypnotics, anti-anxiety drugs, cocaine, marijuana, amphetamines, hallucinogens, inhalants, phencyclidine, impulse control disorders, behavioral addictions.

[0162] Another specific embodiment of the present invention is the use of a compound of the present invention or its derivative, N-oxide, prodrug, solvate, tautomer or stereoisomer and / or a pharmaceutically acceptable salt of each of the foregoing (including mixtures of all ratios thereof) for the manufacture of a medicament, said medicament being particularly for the prevention and / or treatment (preferably treatment) of a disorder or disease selected from the following: hyperproliferative disorders and cancers, particularly tumors, including solid tumors of the specific types of cancers disclosed in the foregoing paragraphs; inflammatory disorders or diseases, particularly Crohn's disease, ulcerative colitis, idiopathic pulmonary fibrosis, muscular dystrophy, rheumatoid arthritis and systemic sclerosis (scleroderma); neurogenesis disorders or diseases, particularly Huntington's disease; lipid metabolism disorders, such as NASH (non-alcoholic steatohepatitis), NAFLD (non-alcoholic fatty liver disease), fatty liver disease; viral infections, such as being infected with cytomegalovirus; post-traumatic stress disorder (PTSD); bipolar disorder, depression, Tourette syndrome, schizophrenia, obsessive-compulsive disorder, anxiety disorder, panic disorder, phobia, addiction to, for example, alcohol, tobacco, opioids, sedatives, hypnotics, anti-anxiety drugs, cocaine, cannabis, amphetamines, hallucinogens, inhalants, phencyclidine, impulse control disorders, behavioral addictions.

[0163] Preferably, the present invention relates to a compound of the present invention for the prevention and / or treatment of a disease, or a method for preventing and / or treating a disease by administering an effective amount of a compound of the present invention; or, in another alternative, the use of a compound of the present invention for the manufacture of a medicament for the prevention and / or treatment of a disease, wherein the disease is cancer, particularly a tumor, including solid tumors of the specific types of cancers disclosed in the foregoing paragraphs; and more preferably, wherein the administration of the compound is carried out simultaneously, successively or alternately with the administration of at least one other active agent.

[0164] The compounds of formulae I-a, I-b and I-c disclosed may be administered in combination with other known therapeutic agents (including anti-cancer agents). The term "anti-cancer agent" as used herein relates to any agent administered to a cancer patient for the purpose of treating cancer. The anti-cancer treatment defined above may be applied as a single therapy, or in addition to the compounds of formulae I-a, I-b and I-c disclosed herein, may involve conventional surgery or radiotherapy or drug therapy. Such drug therapy (e.g., chemotherapy or targeted therapy) may include one or more (but preferably one) of the following anti-tumor agents:

[0165] Alkylating agent

[0166] For example, altretamine, bendamustine, busulfan, carmustine, chlorambucil, chlormethine, cyclophosphamide, dacarbazine, ifosfamide, improsulfan tosilate, lomustine, melphalan, dibromomannitol, dibromodulcitol, nimustine, ranimustine, temozolomide, thiotepa, trofosfamide, chlormethine, carboquone, apaziquone, fotemustine, glufosfamide, palifosfamide, pipobroman, triaziquone, uramustine, TH-302 4 、VAL-083 4 ;

[0167] Platinum compound

[0168] For example, carboplatin, cisplatin, etoplatin, nedaplatin hydrate, oxaliplatin, lobaplatin, nedaplatin, picoplatin, satraplatin;

[0169] Lobaplatin, nedaplatin, picoplatin, satraplatin;

[0170] DNA modifying agent

[0171] For example, amrubicin, bizelesin, decitabine, mitoxantrone, procarbazine, trabectedin, clofarabine;

[0172] Amsacrine, brostallicin, picoplatin, laromustine 1,3 ;

[0173] Topoisomerase inhibitor

[0174] For example, etoposide, irinotecan, razoxane, sobuzoxane, teniposide, topotecan;

[0175] Amonafide, belotecan, elixiramine, voreloxin;

[0176] Microtubule modifier

[0177] For example, cabazitaxel, docetaxel, eribulin, ixabepilone, paclitaxel, vinblastine, vincristine, vinorelbine, vindesine, vinflunine, fosbretabulin, tesetaxel;

[0178] Antimetabolite

[0179] For example, asparaginase 3, azacitidine, leucovorin calcium, capecitabine, cladribine, cytarabine, enocitabine, floxuridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine, methotrexate, nelarabine, pemetrexed, pralatrexate, azathioprine, thioguanine, carmofur, doxifluridine, asilapecin, raltitrexed, sapacitabine, tegafur 2,3 , trimetrexate;

[0180] Anticancer antibiotic

[0181] For example, bleomycin, actinomycin D, doxorubicin, epirubicin, idarubicin, levamisole, miltefosine, mitomycin C, romidepsin, streptozocin, valrubicin, zinostatin, zorubicin, daunorubicin, plicamycin; aclarubicin, peplomycin, pirarubicin;

[0182] Hormone / antagonist

[0183] For example, abarelix, abiraterone, bicalutamide, buserelin, calusterone, chlorotrianisene, degarelix, dexamethasone, estradiol, flocortolone, fluoxymesterone, flutamide, fulvestrant, goserelin, histrelin, leuprorelin, megestrol acetate, mitotane, nafarelin, nandrolone, nilutamide, octreotide, prednisolone, raloxifene, tamoxifen, thyrotropin alpha, toremifene, trilostane, triptorelin, diethylstilbestrol, acolbifene, danazol, deslorelin, cyproterone acetate, orteronel, enzalutamide 1,3 ;

[0184] Aromatase inhibitor

[0185] For example, aminoglutethimide, anastrozole, exemestane, fadrozole, letrozole, testolactone, formestane;

[0186] Small molecule kinase inhibitor

[0187] For example, crizotinib, dasatinib, erlotinib, imatinib, lapatinib, nilotinib, pazopanib, regorafenib, ruxolitinib, sorafenib, sunitinib, vandetanib, vemurafenib, bosutinib, gefitinib, axitinib, afatinib, alectinib, dabrafenib, dacomitinib, dinaciclib, dovitinib, ensartinib, nintedanib, lenvatinib, linifanib, linsitinib, masitinib, midostaurin, motesanib, neratinib, orantinib, perifosine, ponatinib, radotinib, rigosertib, tepotinib, tipifarnib, tivantinib, tivozanib, trametinib, pimasertib, brivanib alaninate, cediranib, apatinib 4 , cabozantinib S-malate 1,3 , ibrutinib 1,3 , icotinib 4 , bulgaritinib 2 , ciprotonib 4 , cobimetinib 1,3 , alitinib 1,3 , fedratinib 1 , XL-647 4 ;

[0188] Photosensitizer

[0189] For example, methoxsalen 3 ; porfimer sodium, talaporfin, temoporfin;

[0190] Antibody

[0191] For example, alemtuzumab, besilesomab, brentuximab vedotin, cetuximab, denosumab, ipilimumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, bevacizumab, pertuzumab 2,3 ; casotuzumab, elotuzumab, epratuzumab, farletuzumab, moxetumomab pasudotox, necitumumab, nimotuzumab, obinutuzumab, ocaratuzumab, oregovomab, ramucirumab, rilotumumab, siltuximab, tocilizumab, zalutumumab, zanolimumab, matuzumab, dalotuzumab 1,2,3 , onartuzumab 1,3 , racotumomab 1 , tabalumab 1,3 , EMD-525797 4, Atezolizumab, Durvalumab, Pembrolizumab, Nivolumab 1,3 ;

[0192] Cytokine

[0193] For example, Aldesleukin, Interferon α 2 , Interferon α2a3, Interferon α2b 2,3 ;

[0194] Simotil, Tasonermin, Tilsotil, Oprelvekin 1,3 , Recombinant Interferon β-1a 4 ;

[0195] Drug conjugate

[0196] For example, Denileukin, Ibritumomab, Iobenguane I 123, Prednimustine, Trastuzumab, Estramustine, Gemtuzumab, Ozogamicin, Aflibercept, Cintredekin Besudotox, Exenatide, Inotuzumab Ozogamicin, Naptumomab Estafenatox, Oportuzumab Monatox, Technetium (99mTc) Asimab 1,3 , Vintafolide 1,3 ;

[0197] Vaccine

[0198] For example, Sipuleucel 3 ; Vitespen 3 , Emepepimut-S 3 , OncoVAX 4 , Rindopepimut 3 , TroVax 4 , MGN-1601 4 , MGN-1703 4 ;

[0199] Miscellaneous

[0200] Tretinoin, Bexarotene, Bortezomib, Everolimus, Ibandronic Acid, Imiquimod, Lenalidomide, Lentinan, Metirosine, Mitoguazone, Pamidronic Acid, Pegaspargase, Pentostatin, Sipuleucel 3, sizofiran, tamibarotene, temsirolimus, thalidomide, tretinoin, vismodegib, zoledronic acid, vorinostat, celecoxib, cilengitide, enzastaurin, etanidazole, ganetespib, iliparcil, iniparib, ixazomib, lonidamine, nimorazole, panobinostat, isotretinoin, plitidepsin, pomalidomide, picoplatin, deforolimus, tasisulam, telotristat, thymalfasin, tirapazamine, tosedostat, trabedersen, bestatin, vosaroxin, gendicine 4 , hemolytic streptococcus preparation 4 , reolysin 4 , retaspimycin hydrochloride 1,3 , trebananib 2,3 , verrucarin 4 , carfilzomib 1,3 , endostatin 4 , immucothel 4 , belinostat 3 , MGN-1703 4 ;

[0201] PARP inhibitor

[0202] Olaparib, Veliparib.

[0203] MCT1 inhibitor

[0204] AZD3965 4 , BAY-8002 4 .

[0205] 1 Prop.INN (Proposed International Nonproprietary Name)

[0206] 2 Rec.INN (Recommended International Nonproprietary Name)

[0207] 3 USAN (United States Adopted Name)

[0208] 4 No INN.

[0209] Other embodiments of the present invention are methods for manufacturing the pharmaceutical compositions of the present invention, characterized in that one or more compounds according to the present invention and one or more compounds other than the compounds according to the present invention selected from solid, liquid or semi-liquid excipients, adjuvants, adjuvants, diluents, carriers and pharmaceutically active agents are converted in a suitable dosage form.

[0210] In another aspect of the present invention, there is provided a set or kit which comprises a therapeutically effective amount of at least one compound of the present invention and / or at least one pharmaceutical composition described herein and a therapeutically effective amount of at least one other pharmacologically active substance other than the compounds of the present invention. Preferably, the set or kit comprises separate packages of the following

[0211] a) an effective amount of a compound of formula I-a, I-b or I-c, or a derivative, prodrug, solvate, tautomer or stereoisomer thereof and a physiologically acceptable salt of each of the foregoing, including mixtures in all ratios thereof, and

[0212] b) an effective amount of other active ingredients that are not compounds of formula I-a, I-b or I-c.

[0213] The pharmaceutical compositions (formulations) of the present invention can be administered in any manner that achieves their intended purpose. For example, administration can be via oral, parenteral, topical, enteral, intravenous, intramuscular, inhalation, nasal, intra-articular, intraspinal, intratracheal, intraocular, subcutaneous, intraperitoneal, transdermal or buccal routes. Alternatively, or concurrently, administration can be via the oral route. The dosage administered will depend on the age, health and weight of the recipient, the type of concurrent treatment (if any), the frequency of treatment and the nature of the desired effect. Parenteral administration is preferred. Oral administration is particularly preferred.

[0214] Suitable dosage forms include, but are not limited to, capsules, tablets, pills, dragees, semi-solids, powders, granules, suppositories, ointments, creams, lotions, inhalants, injections, pastes, gels, tapes, eye drops, solutions, syrups, aerosols, suspensions, emulsions, which can be prepared by methods known in the art, for example as described below:

[0215] Tablets: One or more active ingredients and adjuvants are mixed, and the mixture is compressed into tablets (direct compression), optionally granulating part of the mixture before compression.

[0216] Capsules: One or more active ingredients and adjuvants are mixed to obtain a free-flowing powder, optionally the powder is granulated, the powder / granules are filled into open capsules, and the capsules are capped.

[0217] Semi-solids (ointments, gels, creams): One or more active ingredients are dissolved / dispersed in an aqueous or fatty carrier; subsequently the aqueous phase / fatty phase is mixed with the complementary fatty phase / aqueous phase and homogenized (only for creams).

[0218] Suppositories (rectal and vaginal): One or more active ingredients are dissolved / dispersed in a carrier material liquefied by heating (rectal: the carrier material is usually wax; vaginal: the carrier is usually a heated solution of a gelling agent), the mixture is cast into suppository form, annealed and the suppository is removed from the form.

[0219] Aerosol: One or more active agents are dispersed / dissolved in a propellant, and the mixture is bottled into an atomizer.

[0220] Generally, non-chemical routes for the production of pharmaceutical compositions and / or pharmaceutical preparations include processing steps on suitable mechanical devices known in the art, which transfer one or more compounds of the present invention into a dosage form suitable for administration to a patient in need of such treatment. Generally, transferring one or more compounds of the present invention into such a dosage form includes adding one or more compounds selected from carriers, excipients, auxiliaries, and pharmaceutically active ingredients other than the compounds of the present invention. Suitable processing steps include, but are not limited to, combining, grinding, mixing, granulating, dissolving, dispersing, homogenizing, casting, and / or pressing the corresponding active and inactive ingredients. Mechanical devices for performing the said processing steps are known in the art, for example, obtained from Ullmann's Encyclopedia of Industrial Chemistry, 5th Edition. In this regard, the active ingredient is preferably at least one compound of the present invention and optionally one or more additional compounds other than the compounds of the present invention, which exhibit valuable pharmaceutical properties, preferably those pharmaceutically active agents other than the compounds of the present invention disclosed herein.

[0221] Particularly suitable for oral use are tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops, suitable for rectal use are suppositories, suitable for parenteral use are solutions, preferably oil-based or aqueous solutions, furthermore suspensions, emulsions or implants, and suitable for topical use are ointments, creams or powders. The compounds of the present invention can also be lyophilized, and the resulting lyophilizates are used, for example, for the preparation of injection preparations. The preparations can be sterile and / or contain auxiliaries such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for adjusting osmotic pressure, buffer substances, dyes, flavoring agents and / or a variety of other active ingredients, such as one or more vitamins.

[0222] Suitable excipients are organic or inorganic substances, which are suitable for enteral (e.g., oral), parenteral or topical administration and do not react with the compounds of the present invention, such as water, vegetable oils, benzyl alcohol, alkylene glycols, polyethylene glycols, glyceryl triacetate, gelatin, carbohydrates such as lactose, sucrose, mannitol, sorbitol or starch (corn starch, wheat starch, rice starch, potato starch), cellulose preparations and / or calcium phosphate (e.g., tricalcium phosphate or calcium hydrogen phosphate), magnesium stearate, talc, gelatin, tragacanth, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone and / or petrolatum.

[0223] If desired, disintegrants can be added, such as the above-mentioned starches and carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar or alginic acid or its salts, such as sodium alginate. Auxiliaries include, but are not limited to, flow regulators and lubricants, such as silica, talc, stearic acid or its salts, such as magnesium stearate or calcium stearate, and / or polyethylene glycol. The sugar-coated cores are provided with a suitable coating which, if desired, can resist gastric juice. For this purpose, concentrated sugar solutions can be used which can optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. In order to produce a gastric juice-resistant coating or to provide a dosage form with the advantage of prolonged action, tablets, sugar-coated pills or pills can contain an inner dosage and an outer dosage component, the latter in the form of an envelope enclosing the former. These two components can be separated by an enteric layer which is used to resist disintegration in the stomach and to allow the inner component to pass intact into the duodenum or to be released in a delayed manner. A variety of materials can be used for such an enteric layer or coating, such materials including a variety of polymeric acids and mixtures of polymeric acids with materials such as shellac, acetyl alcohol, using solutions of suitable cellulose preparations, such as acetylcellulose phthalate, cellulose acetate or hydroxypropylmethylcellulose phthalate. For example, in order to identify or to characterize a combination of active compound dosages, dyes or pigments can be added to the tablet or sugar-coated pill coating.

[0224] Suitable carrier substances are organic or inorganic substances which are suitable for enteral (e.g. oral) or parenteral administration or topical application and which do not react with the new compounds, such as water, vegetable oils, benzyl alcohol, polyethylene glycol, gelatin, carbohydrates (such as lactose or starch), magnesium stearate, talc and petrolatum. In particular, tablets, coated tablets, capsules, syrups, suspensions, drops or suppositories are used for enteral administration, solutions (preferably oily or aqueous solutions), furthermore suspensions, emulsions or implants for parenteral administration, and ointments, creams or powders for topical application. The compounds of the invention can also be lyophilized and the obtained lyophilizates can be used, for example, for the production of injection preparations.

[0225] Other pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer (such as glycerol or sorbitol). Push-fit capsules can contain the active compound in particulate form which can be mixed with fillers (such as lactose), binders (such as starch) and / or lubricants (such as talc or magnesium stearate) and optionally stabilizers. In soft capsules, the active compound is preferably dissolved or suspended in a suitable liquid (such as fatty oil or liquid paraffin). In addition, stabilizers can be added.

[0226] The liquid forms in which the new compositions of the invention can be incorporated for oral administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and flavored emulsions with edible oils (such as cottonseed oil, sesame oil, coconut oil or peanut oil), as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums, such as tragacanth, acacia, alginates, dextrans, sodium carboxymethyl cellulose, methyl cellulose, polyvinylpyrrolidone or gelatin.

[0227] Preparations suitable for parenteral administration include aqueous solutions of the active compound in water-soluble form, such as water-soluble salts and alkaline solutions. In addition, suspensions of the active compound can be administered, as suitable oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides or polyethylene glycol-400 (the compound is soluble in PEG-400).

[0228] Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, including, for example, sodium carboxymethyl cellulose, sorbitol and / or dextran, and optionally the suspension may also contain stabilizers.

[0229] For administration as an inhaled spray, sprays in which the active ingredient is dissolved or suspended in a propellant gas or a mixture of propellant gases (such as CO2 or chlorofluorocarbons) can be used. The active ingredient is advantageously used in micronized form, in which case one or more additional physiologically acceptable solvents, such as ethanol, may be present. Inhalation solutions can be administered with the aid of conventional inhalers.

[0230] Possible pharmaceutical preparations for rectal use include, for example, suppositories which consist of a combination of one or more active compounds with a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides or paraffins. In addition, gelatin rectal capsules can also be used, which consist of a combination of the active compound with a base. Possible base materials include, for example, liquid triglycerides, polyethylene glycols or paraffins.

[0231] For use in medicaments, the compounds of the invention may be in the form of pharmaceutically acceptable salts. However, other salts may be used in the preparation of the compounds of the invention or their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of the invention are those described above and include acid addition salts, which may be formed, for example, by mixing a solution of a compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, methanesulfonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. In addition, when the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; and salts formed with suitable organic bases such as quaternary ammonium salts.

[0232] The pharmaceutical formulations may be used as medicaments in human and veterinary medicine. As used herein, the term "effective amount" refers to the amount of a drug or agent that will elicit a biological or medical response of a tissue, system, animal or human, which biological or medical response is, for example, sought by a researcher or clinician. In addition, the term "therapeutically effective amount" refers to any amount that results in an improvement in the treatment, healing, prevention or amelioration of a disease, disorder or side effect, or a decrease in the rate of progression of a disease or disorder, compared to the corresponding subject who has not received such an amount. The term also includes within its scope amounts that effectively enhance normal physiological functions. The therapeutically effective amount of one or more compounds of the invention is known to those of ordinary skill in the art or can be readily determined by standard methods known in the art.

[0233] The compounds of the invention and optionally additional active substances are generally administered in a manner similar to commercial formulations. Generally, a suitable therapeutically effective dose is between 0.0005 mg and 1000 mg per dose unit, preferably between 0.005 mg and 500 mg, and especially between 0.5 mg and 100 mg. The daily dose is preferably between about 0.001 mg / kg and 10 mg / kg body weight.

[0234] Those skilled in the art will readily appreciate that the dosage levels may vary with the specific compound, the severity of the symptoms and the susceptibility of the subject to side effects. Some specific compounds are more effective than others. The preferred dosage of a given compound can be readily determined by those skilled in the art in a variety of ways. The preferred way is to measure the physiological potency of the given compound.

[0235] However, for an individual patient, particularly for a specific dosage in an individual human patient, it depends on a variety of factors, such as the efficacy of the specific compound used, age, body weight, general health status, gender, diet type, time and route of administration, excretion rate, type of administration and dosage form of the drug, drug combination, and the severity of the specific disease condition involved in the therapy. The specific therapeutically effective dosage for an individual patient can be readily determined by routine experimentation, such as being recommended by a doctor or physician or participating in a therapeutic treatment.

[0236] The compounds of the present invention can be prepared using appropriate materials according to the procedures of the following schemes and examples and are further illustrated by the following specific examples. They can also be prepared by methods known per se, as described in the literature (e.g., in standard works, such as Houben - Weyl, Methoden der Organischen Chemie [Methods of Organic Chemistry], Georg Thieme Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc., New York), precisely under the reaction conditions known and suitable for the said reactions. Variants known per se but not mentioned in more detail herein can also be used.

[0237] Similarly, the starting materials for preparing the compounds of the present invention can be prepared by the methods described in the examples or by methods known per se, as described in the literature of synthetic organic chemistry and known to those skilled in the art, or can be commercially available. If desired, the starting materials for the claimed and / or used methods can also be formed in situ without separating them from the reaction mixture but immediately further converting them into the compounds or intermediate compounds of the present invention. On the other hand, the reactions can generally be carried out step by step.

[0238] Preferably, the reaction of the compound is carried out in the presence of a suitable solvent, which is preferably inert under the respective reaction conditions. Examples of suitable solvents include, but are not limited to, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers such as ethylene glycol monomethyl ether or ethylene glycol monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones such as acetone or butanone; amides such as acetamide, dimethylacetamide, dimethylformamide (DMF) or N-methylpyrrolidone (NMP); nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide (DMSO); nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate, or mixtures of the solvents or mixtures with water.

[0239] The reaction temperature is between about -100 °C and 300 °C, depending on the reaction step and the conditions used.

[0240] The reaction time generally ranges from fractions of a minute to several days, depending on the reactivity of the respective compound and the respective reaction conditions. Suitable reaction times can be readily determined by methods known in the art such as reaction monitoring. Based on the reaction temperature given above, suitable reaction times generally range between 10 minutes and 48 hours.

[0241] In addition, by using the procedures described herein, in combination with ordinary skill in the art, additional compounds of the present invention claimed herein can be readily prepared. However, the compounds illustrated in the examples should not be construed as forming the only species considered to be the present invention. The examples further illustrate in detail the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and methods of the following preparation procedures can be used to prepare these compounds.

[0242] The present invention also relates to a method for manufacturing the compounds of formula I-a, I-b or I-c in their most general form and any specific embodiments PE1, PE2, PE3, PE3a, PE3b, PE4, PE5, PE5a, PE5b, PE5c, PE5d, PE6, PE6a, PE6b, PE7, PE7a, PE7b, PE7c, PE8, PE8a, PE8b, PE8c, PE9, PE9a, PE9a, PE9b, PE9c, PE10 described herein, or their derivatives, N-oxides, prodrugs, solvates, tautomers or stereoisomers, and pharmaceutically acceptable salts of each of the foregoing, the method being characterized in that

[0243] (a) In the case of an amide-1H-imidazo[4,5-b]pyridine derivative of formula I-a

[0244] A carboxylic acid of general formula II-a

[0245]

[0246] wherein R 1 、R 2 、R 3 、R 4 and R 5 are as defined above for formula I-a and in the appended claims,

[0247] is subjected to an amidation reaction with a compound of formula III:

[0248] R 6 -NH2

[0249] (III)

[0250] wherein R 6 is as defined above and in the appended claims, optionally in the presence of a suitable catalyst (e.g., triethylamine and HATU ([dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammonium hexafluorophosphate)) to produce an amide derivative of formula I-a:

[0251]

[0252] wherein R 1 、R 2 、R 3 、R 4 、R 5 and R 6 are as defined above for formula I-a and in the appended claims;

[0253] Or

[0254] (b) In the case of an amide-1-pyrazolo[1,5-a]pyridine derivative of formula I-b

[0255] A carboxylic acid of general formula II-b

[0256]

[0257] wherein R 1 、R 2 、R 3 、R 4 and R 5 are as defined above for formula I-b and in the appended claims,

[0258] is subjected to an amidation reaction with a compound of formula III:

[0259] R 6 -NH2

[0260] (III)

[0261] wherein R 6 as described above and in the appended claims, optionally in the presence of a suitable catalyst (such as triethylamine and HATU ([dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammonium hexafluorophosphate)) to produce an amide derivative of formula I-b:

[0262]

[0263] wherein R 1 、R 2 、R 3 、R 4 、R 5 and R 6 as described above for formula I-b and in the appended claims;

[0264] or

[0265] (c) in the case of an amide-imidazo[1,2-a]pyridine derivative of formula I-c

[0266] a carboxylic acid of general formula II-c

[0267]

[0268] wherein R 1 、R 2 、R 3 、R 4 and R 5 as described above for formula I-c and in the appended claims,

[0269] undergoes an amidation reaction with a compound of formula III:

[0270] R 6 -NH2

[0271] (III)

[0272] wherein R 6 as described above and in the appended claims, optionally in the presence of a suitable catalyst (such as triethylamine and HATU ([dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammonium hexafluorophosphate)) to produce an amide derivative of formula I-c

[0273]

[0274] wherein R 1 、R 2 、R 3 、R 4 、R 5 and R 6 are as described above for formula I-c and in the appended claims.

[0275] As will be appreciated by those skilled in the art of organic synthesis, the compounds of the present invention (in particular, compounds of formulae I-a, I-b or I-c) can be readily obtained by a variety of synthetic routes, some of which are illustrated in the appended experimental section. To obtain the compounds of the present invention, in any particular case (wherever required or used), the skilled person will readily recognize which reagents and reaction conditions will be used and how to apply and adjust them. In addition, some of the compounds of the present invention can be readily synthesized by reacting other compounds of the present invention under suitable conditions, for example, by applying standard synthetic methods such as reduction, oxidation, addition or substitution reactions to convert one specific functional group present in a compound of the present invention or a suitable precursor molecule thereof into another; those methods are well known to those skilled in the art. Similarly, whenever required or useful, the skilled person will apply synthetic protecting (or protective) groups; suitable protecting groups and methods for introducing and removing them are well known to those skilled in the art of chemical synthesis and are described in more detail, for example, in P.G.M. Wuts, T.W. Greene, “Greene’s Protective Groups in Organic Synthesis”, 4th Edition (2006) (John Wiley & Sons).

[0276] The following general synthetic routes that can be used to prepare the compounds of the present invention are described in more detail in Schemes A to E:

[0277]

[0278] Protocol A

[0279] The above Scheme A describes a general synthetic route for the preparation of the amide compounds of formula I-a. The 2-amino-3-nitro-pyridine derivative A-a (which can be readily obtained by using known synthetic methods or from commercial sources) is converted into the 5-bromo-substituted derivative B-a by a suitable bromination reaction (step a), for example by using N-bromo-succinimide (NBS), preferably in a slightly excess amount of about 1.05 - 1.15 equivalents relative to A-a, in a suitable solvent (such as dimethylformamide (DMF)). Then, in the presence of a suitable metal catalyst (such as a nickel sponge catalyst), the nitro substituent of the bromo-substituted pyridine derivative B-a can be converted into an amino group by a reduction reaction with gaseous hydrogen (step b), thereby obtaining the 2,3-diamino-5-bromo-substituted pyridine derivative C-a. This derivative can be isolated, or preferably without isolation, it is reacted with a reaction partner suitable for the desired cyclization under sufficient reaction conditions to produce the 3H-imidazo[4.5-b]pyridine derivative of formula D-a (step c); such reaction partners and conditions can be, for example, the addition of triethyl orthoformate and formic acid, and subsequent heating. After usual work-up, compound D-a is obtained, which can then be converted into the 1H-imidazo[4.5-b]pyridine derivative of formula E-a and its regioisomer E-a-iso (step d). An example of such a conversion to E-a (and E-a-iso) is alkylation with a suitable alkyl halide R 3 -Hal (such as alkyl iodide) in the presence of a strong base (such as sodium hydride), followed by neutralization with, for example, ammonium chloride solution. Generally, the desired regioisomer E-a is obtained as the major product, and the other isomer E-a-iso as the minor product, and these products are then separated by conventional techniques (such as silica gel chromatography). Then, the 1H-imidazo[4.5-b]pyridine derivative E-a is converted into the nitrile derivative of formula F-a by bromide / cyanide exchange (step e); such an exchange can be achieved, for example, by adding K4[Fe(CN)6] and potassium acetate in a suitable solvent (such as dioxane), then adding a suitable catalyst (such as a suitable palladium catalyst, such as tBuBrettPhos Pd G3), and subsequently heating the resulting reaction mixture. Then, by reacting the nitrile with a compound of formula R 1 -C(=O)-R 2 (where R 1 and R 2As defined for the amides of formula I-a and which may be the same or different), the nitrile F-a can be converted to the tertiary alcohol G-a (step f) by reacting a ketone in the presence of a strong base (such as lithium dimethylsilylamide) in a suitable solvent (such as THF). Then, under typical conditions for the saponification of a nitrile, for example by reacting the nitrile G-a with a strong base (such as sodium hydroxide) in a suitable solvent (such as ethanol), the nitrile G-a can be converted to the corresponding carboxylic acid II-a (step g). In the final step (step h), the desired amide derivative I-a can be obtained by reacting a compound of formula II-a with an amine of formula III (R 6 -NH2) under typical conditions for the amidation reaction (step h), for example in the presence of a tertiary amine (such as triethylamine or DIPEA (N-ethyl-N-isopropylpropan-2-amine)) and a suitable catalyst (such as 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) and N,N-dimethylpyridin-4-amine (DMAP)).

[0280] Alternatively, the bromide E-a can be converted to the corresponding carboxylic acid ester H-a (where R is an alkyl)

[0281]

[0282] Under carbonylation reaction conditions, for example in the presence of a suitable catalyst such as 1,1'-bis(diphenylphosphino)ferrocene) dichloropalladium(II) (dichloromethane complex), 1,1-bis(diphenylphosphino)ferrocene and triethylamine, in a suitable dry solvent or solvent mixture (such as dry methanol / tetrahydrofuran), gaseous carbon monoxide is reacted. Then, in the subsequent reaction steps f (introduction of the tertiary alcohol and immediate hydrolysis of the carboxylic acid ester to provide the carboxylic acid J-a) and h (amidation), the carboxylic acid ester H-a can be used instead of the nitrile F-a to prepare the amide derivative I-a, thus saving one reaction step compared to the route using the nitrile F-a.

[0283]

[0284] Protocol B

[0285] where R 1 and R 2The same amide compounds of formula I-b are readily obtainable via the synthetic route described in Scheme B above: By using a suitable reagent, such as 2,4,6-trimethylbenzenesulfonic acid amide in dichloromethane, the 2-propyl-4-cyanosubstituted pyridine derivative A-b (which is commercially available or obtainable via synthetic procedures known to those skilled in the art) is converted into the corresponding 1-aminopyridinium compound B-b (step a). Then, under typical conditions, B-b is subjected to a cyclization reaction with a suitable reaction partner such as ethyl oxalyl chloride (H5C2-O-C(=O)-C(=O)-Cl) to produce the pyrazolo[1,5-a]pyridine derivative C-b (step b). Then, by reaction with a suitable C-nucleophile, for example, in a classical Grignard reaction with, for example, R 1 -Mg-Cl (or R 2 -Mg-Cl), C-b can be converted into the tertiary alcohol D-b (step c). Similar to step g in Scheme A, the nitrile II-b is converted into the carboxylic acid II-b (step d), and then into the amide derivative I-b under conditions similar to those described for step h in Scheme A (step e).

[0286]

[0287] Protocol C

[0288] wherein R 1 and R 2 are not the same but different amide compounds of formula I-b are readily obtainable via the synthetic route described in Scheme C above: By using a suitable reagent (such as 2,4,6-trimethylbenzenesulfonic acid amide in dichloromethane) to convert the 2-propyl-4-bromosubstituted pyridine derivative E-b (which is commercially available or obtainable via synthetic procedures known to those skilled in the art) into the corresponding 1-aminopyridinium compound F-b (step a). Then, under typical conditions, F-b is subjected to a cyclization reaction with a suitable reaction partner such as a substituted α-halo-substituted ethyl oxalate (C2H5-O-C(=O)-C(=O)-Hal, for example, C2H5-O-C(=O)-C(=O)-Hal if Hal = Cl) to produce the pyrazolo[1,5-a]pyridine derivative G-b (step b). Then, under usual saponification conditions, for example, by adding a base (such as LiOH, NaOH or KOH), G-b is converted into its carboxylic acid H-b. Subsequently, under appropriate conditions, for example, in the presence of EDC N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, HOBt (1-hydroxybenzotriazole) and an amine base (such as triethylamine), the carboxylic acid H-b is converted into the formamide J-b by reaction with methoxy(methyl)amine hydrochloride. Then the formamide J-b can react with 1 equivalent of a suitable Grignard reagent R1 -Mg-Hal reaction to provide ketone K-b (step e). Subsequently, bromo-cyanide exchange (step f) by reacting K-b with, for example, Zn(CN)2 and a palladium catalyst (such as Pd2(dba)3) and XantPhos in DMF yields nitrile L-b, which in turn reacts with a suitable organometallic compound (such as R 2 -Li, which can be prepared in situ by reacting a suitable halide R 2 -Hal with a suitable lithium-organic base (such as n-butyllithium)) to provide tertiary alcohol M-b (step g). Similar to step g in Scheme A, nitrile M-b is converted to carboxylic acid II-b (step h), which in turn is converted to amide derivative I-b (step i) under conditions similar to those described in step h of Scheme A.

[0289]

[0290] In an alternative method, amide derivative I-b can be obtained by converting ketone K-b to tertiary alcohol N-b by utilizing a suitable organometallic compound (such as R 2 -Li), similar to step g above; subsequent carbonylation reaction (e.g., reaction with gaseous carbon monoxide in a suitable dry solvent or solvent mixture such as dry methanol / tetrahydrofuran in the presence of a suitable catalyst such as 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium(II) (dichloromethane complex), 1,1-bis-(diphenylphosphino)ferrocene and triethylamine) yields ester derivative O-b, which can in turn be converted to amide derivative I-b by saponification and subsequent amidation reaction.

[0291]

[0292] Protocol D

[0293] wherein R 1 and R 2 The same amide compound of formula I-c can be readily obtained via the synthetic route described in Scheme D above: Under typical conditions, with a suitable reaction pair such as a substituted α-halo-ethyl oxalate (C2H5-O-C(=O)-C(=O)-CHHal-R 3 , such as C2H5-O-C(=O)-C(=O)-CHBr-C2H5, if Hal = Br and R 3=ethyl (B-c)), subjecting the 2-amino-5-bromo-substituted pyridine derivative A-c (which is commercially available or obtainable via synthetic procedures known to the person skilled in the art) to a cyclization reaction to produce the imidazo[1,2-a]pyridine derivative C-c (step a). Subsequently, C-c is converted to the tertiary alcohol D-c by reaction with a suitable C-nucleophile, for example, in a classical Grignard reaction, with, for example, R 1 -Mg-Cl (or R 2 -Mg-Cl) (step b). Subsequently, the bromo-cyanide exchange (step c) by reacting D-c with, for example, Zn(CN)2 and a palladium catalyst (such as Pd(PPh3)4) in DMF gives the nitrile E-c, which is then converted to the carboxylic acid II-c under conditions similar to those in step g of Scheme A (step d). Then it is converted to the amide derivative I-c under those conditions similar to those described for step h in Scheme A (step e).

[0294]

[0295] Alternatively, the amide derivative I-c can be obtained by converting the bromo-substituted derivative D-c to the corresponding ester K-c via a carbonylation reaction and subsequent saponification and amidation reactions.

[0296]

[0297] Protocol E

[0298] wherein R 1 and R 2 are not the same but different amide compounds of formula I-c can be readily obtained via the synthetic routes described in Scheme E above: As shown and described in Scheme D, the 2-amino-5-bromo-substituted pyridine derivative A-C is converted to the imidazo[1,2-a]pyridine derivative C-c (step a). Then, under usual saponification conditions, for example, by adding a base (such as LiOH, NaOH or KOH), the ester C-c is converted to its carboxylic acid E-c (step b). Subsequently, under appropriate conditions, for example, in the presence of EDC N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, HOBt (1-hydroxybenzotriazole) and an amine base (such as triethylamine), the carboxylic acid E-c is converted to the formamide F-c by reaction with methoxy(methyl)amine hydrochloride (step c). Then the formamide F-c can be reacted with 1 equivalent of a suitable Grignard reagent R 1-Mg-Hal reaction to provide ketone G-c (step d). Subsequently, bromo-cyanide exchange (step e) is carried out by reacting K-b with, for example, Zn(CN)2 in DMF in the presence of a palladium catalyst (such as Pd2(dba)3) and XantPhos to produce nitrile H-c, which in turn reacts with a suitable organometallic compound (such as R 2 -Li, which can be prepared in situ by reacting a suitable halide R 2 -Hal with a suitable lithium-organic base (such as n-butyllithium)) to provide tertiary alcohol J-c (step f). Similar to step g in Scheme A, compound J-c is converted to carboxylic acid II-c (step g), which in turn is converted to amide derivative I-c (step h) under conditions similar to those described for step h in Scheme A.

[0299] Alternatively, by using, for example, an organolithium compound R 2 -Li, bromide G-c can be converted to the corresponding tertiary alcohol; subsequent carbonylation and amidation reactions to provide the corresponding alkyl ester will then produce amide derivative I-c.

[0300] The present invention also relates to carboxylic acids of formula II-a, II-b or II-c, which are useful intermediates for preparing the amides of the present invention of formula I-a, I-b or I-c, respectively:

[0301]

[0302] wherein R 1 、R 2 、R 3 、R 4 、R 5 and R 6 are as defined above for formulae I-a, I-b and I-c.

[0303] As used herein, "treating" or "treatment" refers to completely or partially alleviating symptoms associated with a disorder or disease, or slowing or stopping the further progression or worsening of these symptoms, or preventing or precluding a disease or disorder, in a subject at risk of developing a disease or disorder.

[0304] The term "effective amount" in relation to the amides of formula I-a, I-b or I-c refers to the amount of (a compound, drug, pharmaceutical composition, etc.) that is capable of completely or partially alleviating symptoms associated with a disorder or disease, or slowing or stopping the further progression or worsening of these symptoms, or preventing or providing prophylaxis against a disease or disorder, in a subject suffering from a disease disclosed herein (such as an inflammatory condition, an immunological condition, cancer or a metabolic condition) or at risk of developing a disease disclosed herein.

[0305] It should be noted that, unless otherwise specified or a different meaning is provided by the context, the terms are generally used in their numerical quantity (i.e., their singular and plural forms) and can be read interchangeably. For example, the term "compound" in the singular form can also include or refer to multiple compounds, while the term "compounds" in the plural form can also include or refer to a single compound.

[0306] Experimental section

[0307] Abbreviations

[0308] The compounds of the present invention can be prepared using appropriate materials according to the procedures of the following schemes and examples, and are further illustrated by the following specific examples. The compounds are shown in Table 1, which is divided into Table 1a, 1b, 1c, and 1d. The analytical data of the compounds prepared according to the following examples are also shown in Table 1 (Table 1a, 1b, 1c, and 1d).

[0309] The present invention will be illustrated by reference to the specific embodiments described in the following examples, but is not limited thereto. Unless otherwise indicated in the scheme, the variables have the same meanings as described above and in the claims.

[0310] Unless otherwise specified, all starting materials are obtained from commercial suppliers and can be used without further purification. Unless otherwise specified, all temperatures are expressed in °C, and all reactions are carried out at RT (room temperature). The compounds are purified by silica gel chromatography or preparative HPLC.

[0311] 1 1H NMR:

[0312] 1 The 1H-NMR data are provided in Table 1 below. Unless otherwise reported, they are generally obtained under standard conditions on a Bruker Avance DRX 500, Bruker Avance 400, or Bruker DPX 300 NMR spectrometer using TMS (tetramethylsilane) as the internal standard and DMSO-d6 as the standard solvent. 1 1H NMR spectra. NS (number of scans): 32, SF (spectrometer frequency) as shown. TE (temperature): 297K. Chemical shifts (δ) are reported in ppm relative to the residual solvent signal (for 1 1H NMR in DMSO-d6, δ = 2.5 ppm, for 1 1H NMR in CDCl3, δ = 7.27 ppm, and for methanol-d4, δ = 3.31 ppm). 1The \(^1\)H NMR data are reported as follows: chemical shift (multiplicity, coupling constant and number of hydrogens). The multiplicity abbreviations are as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublets), tt (triplet of triplets), td (doublet of triplets), br (broad) and the coupling constant (J) is reported in Hz.

[0313] HPLC-MS:

[0314] The HPLC-MS data provided in Table 1 are given in mass, in m / z. The results can be obtained by one of the following methods. HPLC-MS analysis is generally carried out on a Shimadzu LCMS-2020, Shimadzu SP-M20A 2010EV or Shimadzu UFLC-MS 2010EV system using one of the following columns: Shim-pack VP-ODS, Shim-pack XR-ODS, Kinetex XB-C18 100A, Xbridge BEH C18, Gemini-NX 3u C18 110A or ACE UltraCore 2.5 SuperC18. The standard conditions applied:

[0315] Standard solvent gradient, using

[0316] A: water + 0.1% v / v formic acid, B: acetonitrile + 0.1% v / v formic acid; or

[0317] A: water + 0.05% v / v trifluoroacetic acid, B: acetonitrile + 0.05% v / v trifluoroacetic acid

[0318] Detection wavelength: 220 nm, MS type: API-ES

[0319] General synthesis 1

[0320]

[0321] Example 1 (nitrile precursor)

[0322] 2-[Bis(2-fluorophenyl)(hydroxy)methyl]-3-ethyl-6-methoxypyrazolo[1,5-a]pyridine-5-carbonitrile

[0323]

[0324] a) At -30 °C, nBuLi (42.5 mL, 2.5 M) was added dropwise to a solution of 2,2,6,6-tetramethylpiperidine (15 g, 106.19 mmol) in THF (250 mL). The resulting mixture was stirred at -30 °C for 30 minutes and then cooled to -78 °C. A solution of 2-propylpyridine-4-carbonitrile (7.8 g, 53.36 mmol) in THF (20 mL) was slowly added to the mixture. The reaction mixture was stirred at -78 °C for 30 minutes and then hexachloroethane (25 g, 105.6 mmol) was slowly added. The reaction mixture was slowly warmed to room temperature and stirred at room temperature for 30 minutes. Then, the reaction mixture was carefully quenched with saturated NH4Cl solution (100 mL) and diluted with water (300 mL). The resulting mixture was extracted with EtOAc (300 mL × 3), and the organic phases were combined, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography, eluting with EtOAc / petroleum ether (1% to 10% gradient), to afford 5-chloro-2-propylpyridine-4-carbonitrile as a brown oil (1 g, 10.4%). LC / MS [M+H] + 181.1。

[0325] b) To a solution of 5-chloro-2-propylpyridine-4-carbonitrile (500 mg, 2.77 mmol) in DMSO (8 mL) was slowly added a solution of NaOMe (30 wt% in MeOH, 1.35 g, 9.1 mmol). The resulting mixture was stirred at room temperature for 2 hours. Then the reaction mixture was quenched with water (30 mL) and extracted with EtOAc (40 mL × 3). The organic phases were combined, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography, eluting with EtOAc / petroleum ether (5% to 50% gradient), to afford 5-methoxy-2-propylpyridine-4-carbonitrile as a yellow oil (700 mg, 90%). LC / MS [M+H] + 177.1。

[0326] c) To a solution of 5-methoxy-2-propylpyridine-4-carbonitrile (650 mg, 3.69 mmol) in DCM (10 mL) was slowly added 2,4,6-trimethylbenzenesulfonamide (3.68 g, 17.08 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to afford 1-amino-4-cyano-5-methoxy-2-propylpyridin-1-ium 2,4,6-trimethylbenzenesulfonate as a white solid (700 mg), which was used in the next step without further purification. LC / MS [M] + 192.1。

[0327] d) A mixture of 1-amino-4-cyano-5-methoxy-2-propylpyridin-1-ium 2,4,6-trimethylbenzenesulfonate (2.8 g, 6.16 mmol) and ethyl oxalyl chloride (4.0 g, 27.8 mmol) in pyridine (10 mL) was stirred at 100 °C for 2 h. The reaction mixture was then diluted with water (30 mL) and extracted with EtOAc (40 mL × 4). The combined organic phases were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography, eluting with EtOAc / petroleum ether (10% to 50% gradient) to afford ethyl 5-cyano-3-ethyl-6-methoxypyrazolo[1,5-a]pyridine-2-carboxylate as a yellow oil (500 mg). LC / MS [M+H] + 274.0。

[0328] e) Using Method E described below for Example 5, 2-[bis(2-fluorophenyl)(hydroxy)methyl]-3-ethyl-6-methoxypyrazolo[1,5-a]pyridine-5-carbonitrile was prepared from ethyl 5-cyano-3-ethyl-6-methoxypyrazolo[1,5-a]pyridine-2-carboxylate. LC / MS [M-OH] + 366.0。

[0329] Example 2

[0330] 2-[bis(2-fluorophenyl)(hydroxy)methyl]-3-ethyl-N-(1-ethyl-1H-1,2,4-triazol-3-yl)-6-methoxypyrazolo[1,5-a]pyridine-5-carboxamide

[0331]

[0332] a) Method A: NaOH (104 mg, 2.46 mmol) was slowly added to a solution of 2-[bis(2-fluorophenyl)(hydroxy)methyl]-3-ethyl-6-methoxypyrazolo[1,5-a]pyridine-5-carbonitrile (90 mg, 0.16 mmol) (Example 1) in EtOH (4 mL) and H2O (1 mL). The resulting mixture was stirred at 80 °C for 3 h. The reaction mixture was then cooled to room temperature and the pH was adjusted to 6 with 6M HCl solution. The resulting mixture was extracted with DCM and the combined organic phases were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure to afford 2-[bis(2-fluorophenyl)(hydroxy)methyl]-3-ethyl-6-methoxypyrazolo[1,5-a]pyridine-5-carboxylic acid as a yellow solid (60 mg, 82%), which was used in the next step without further purification. LCMS [M+H] + 439.0。

[0333] b) Method B: To a solution of 2-[bis(2-fluorophenyl)(hydroxy)methyl]-3-ethyl-6-methoxypyrazolo[1,5-a]pyridine-5-carboxylic acid (21 mg, 0.05 mmol) in DCM (3 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (21.9 mg, 0.05 mmol), N-ethyl-N-isopropylpropan-2-amine (DIPEA) (74.3 mg, 0.56 mmol), N,N-dimethylpyridin-4-amine (DMAP) (1.1 mg, 0.01 mmol) and 1-ethyl-1H-1,2,4-triazol-3-amine hydrochloride (53.7 mg, 0.36 mmol). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD column, 19×150 mm, 5 μm; mobile phase, MeCN / water (with 10 mM NH4HCO3 and 0.1% NH3.H2O), 40% to 43% gradient over 8 min; detector, UV 254 / 220 nm. 2-[bis(2-fluorophenyl)(hydroxy)methyl]-3-ethyl-N-(1-ethyl-1H-1,2,4-triazol-3-yl)-6-methoxypyrazolo[1,5-a]pyridine-5-carboxamide was obtained as a white solid (2.9 mg, 11%). LCMS [M+H] + 533.3。

[0334] General Synthesis 2

[0335]

[0336] Example 3 - Bromo-Substituted Precursor [6-bromo-3-ethyl-7-methoxyimidazo[1,2-a]pyridin-2-yl]diphenylmethanol

[0337]

[0338] a) Method C: A mixture of 5-bromo-4-methoxypyridin-2-amine (4 g, 19.70 mmol) and ethyl 3-bromo-2-oxopentanoate (8 g, 35.86 mmol) in EtOH (40 mL) was stirred at 80 °C for 16 h. The reaction mixture was then cooled to room temperature and the pH was adjusted to 8 with NaHCO3. The mixture was diluted with water (100 mL) and extracted with DCM (100 mL×3). The combined organic phases were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography, eluting with EtOAc / petroleum ether (5% to 30% gradient) to afford ethyl 6-bromo-3-ethyl-7-methoxyimidazo[1,2-a]pyridine-2-carboxylate as a pale yellow solid (2.8 g, 38%). LC / MS: [M+H] + 327.1 / 329.1.

[0339] b) Method D: At 0 °C, PhMgBr (1 M in THF, 11.9 mL, 11.9 mmol) was added dropwise to a solution of ethyl 6-bromo-3-ethyl-7-methoxyimidazo[1,2-a]pyridine-2-carboxylate (1.3 g, 3.97 mmol) in THF (130 mL). The resulting mixture was kept stirring at 0 °C for 1 h. The reaction mixture was then carefully quenched with saturated NH4Cl solution (20 mL) and diluted with water (100 mL). The aqueous phase was extracted with DCM (150 mL×2) and the combined organic phases were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography, eluting with MeOH / DCM (1% to 5% gradient) to afford [6-bromo-3-ethyl-7-methoxyimidazo[1,2-a]pyridin-2-yl]diphenylmethanol as a yellow solid (1.4 g, 80%). LC / MS [M+H] + 437.1 / 439.1.

[0340] Example 4

[0341] 3-Ethyl-2-(hydroxy-diphenyl-methyl)-7-methoxy-imidazo[1,2-a]pyridine-6-carboxylic acid (1-ethyl-1H-[1,2,4]triazol-3-yl)-amide

[0342]

[0343] a) A mixture of [6-bromo-3-ethyl-7-methoxyimidazo[1,2-a]pyridin-2-yl]diphenylmethanol (300 mg, 0.68 mmol) (Example 3), Pd(dppf)Cl2 (50 mg, 0.067 mmol), and triethylamine (208 mg, 2.06 mmol) in MeOH (13 mL) was stirred at 100 °C for 6 h under a CO (10 atm) atmosphere. The reaction mixture was then diluted with water (40 mL) and extracted with DCM (40 mL × 3). The combined organic phases were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography, eluting with MeOH / DCM (1% to 5% gradient) to afford methyl 3-ethyl-2-(hydroxydiphenylmethyl)-7-methoxyimidazo[1,2-a]pyridine-6-carboxylate as a light brown solid (230 mg, 80%). LCMS [M+H] + 417.3。

[0344] b) LiOH (36 mg, 1.51 mmol) was slowly added to a solution of methyl 3-ethyl-2-(hydroxydiphenylmethyl)-7-methoxyimidazo[1,2-a]pyridine-6-carboxylate (650 mg, 1.56 mmol) in THF (10 mL) and H2O (5 mL). The resulting mixture was stirred at room temperature for 16 h. The pH of the reaction mixture was then adjusted to ~6 with 2 M HCl solution. The resulting mixture was extracted with DCM (30 mL × 5), and the combined organic phases were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure to afford 3-ethyl-2-(hydroxydiphenylmethyl)-7-methoxyimidazo[1,2-a]pyridine-6-carboxylic acid as a yellow solid (600 mg, 95%), which was used in the next step without further purification. LCMS [M+H] + 403.2。

[0345] c) Using Method B, prepare 3-ethyl-N-(1-ethyl-1H-1,2,4-triazol-3-yl)-2-(hydroxydiphenylmethyl)-7-methoxyimidazo[1,2-a]pyridine-6-carboxamide from 3-ethyl-2-(hydroxydiphenylmethyl)-7-methoxyimidazo[1,2-a]pyridine-6-carboxylic acid. Purify the product by preparative HPLC under the following conditions: column, XBridge ShieldRP18 OBD column, 30×150 mm, 5 μm; mobile phase, MeCN / water (with 10 mM NH4HCO3 and 0.1% NH3.H2O), 35% to 50% gradient, within 8 minutes; detector, UV 254 / 220 nm. Obtain 3-ethyl-N-(1-ethyl-1H-1,2,4-triazol-3-yl)-2-(hydroxydiphenylmethyl)-7-methoxyimidazo[1,2-a]pyridine-6-carboxamide as a white solid (50 mg, 22%). LCMS [M+H] + 497.2。

[0346] Example 5 - Nitrile Precursor

[0347] 2-[Bis(2-fluorophenyl)(hydroxy)methyl]-3-ethyl-7-methoxyimidazo[1,2-a]pyridine-6-carbonitrile

[0348]

[0349] a) Method F: Under a nitrogen atmosphere, stir a mixture of ethyl 6-bromo-3-ethyl-7-methoxyimidazo[1,2-a]pyridine-2-carboxylate (1.5 g, 4.58 mmol) (see Example 3a)), Zn(CN)2 (0.3 g, 2.51 mmol), Pd2(dba)3 (1.2 g, 1.3 mmol), and XantPhos (0.7 g, 1.3 mmol) in DMF (30 mL) at 90 °C for 3 hours. Then dilute the reaction mixture with water and extract with CH2Cl2. Combine the organic phases, wash with brine, and dry over Na2SO4. Remove the solvent under reduced pressure, and purify the residue by flash chromatography, eluting with MeOH / DCM (1% to 7% gradient) to yield ethyl 6-cyano-3-ethyl-7-methoxyimidazo[1,2-a]pyridine-2-carboxylate as a yellow solid (1.2 g, 92%). LC / MS [M+H] + 274.1。

[0350] b) Method E: At -15 °C, iPrMgCl·LiCl (10.4 mL, 1.3 M in THF) was added dropwise to a solution of 1-bromo-2-fluorobenzene (2.37 g, 13.54 mmol) in THF (30 mL). The resulting mixture was stirred at -15 °C for 2 h, and then a solution of ethyl 6-cyano-3-ethyl-7-methoxyimidazo[1,2-a]pyridine-2-carboxylate (1.2 g, 4.40 mmol) in THF (10 mL) was added slowly. The reaction mixture was kept stirring at -15 °C for an additional 2 h. Then the reaction mixture was carefully quenched with saturated NH4Cl solution (20 mL) and diluted with water (30 mL). The resulting mixture was extracted with DCM (80 mL × 3), and the combined organic phases were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography, eluting with MeOH / DCM (1% to 5% gradient), to afford 2-[bis(2-fluorophenyl)(hydroxy)methyl]-3-ethyl-7-methoxyimidazo[1,2-a]pyridine-6-carbonitrile as a yellow solid (900 mg, 44%). LC / MS [M+H] + 420.1。

[0351] Example 6

[0352] 2-[bis(2-fluorophenyl)(hydroxy)methyl]-3-ethyl-N-(1-ethyl-1H-1,2,4-triazol-3-yl)-7-methoxyimidazo[1,2-a]pyridine-6-carboxamide

[0353]

[0354] 2-[bis(2-fluorophenyl)(hydroxy)methyl]-3-ethyl-N-(1-ethyl-1H-1,2,4-triazol-3-yl)-7-methoxyimidazo[1,2-a]pyridine-6-carboxamide was prepared from 2-[bis(2-fluorophenyl)(hydroxy)methyl]-3-ethyl-7-methoxyimidazo[1,2-a]pyridine-6-carbonitrile using Methods A and B. The final product was purified by preparative HPLC under the following conditions: column, XBridge Shield RP18 OBD Prep Column, 30×150 mm, 5 μm; mobile phase, MeCN / water (with 10 mM NH4HCO3 and 0.1% NH3.H2O), 35% to 40% gradient, in 8 min; detector, UV 254 / 220 nm. 2-[bis(2-fluorophenyl)(hydroxy)methyl]-3-ethyl-N-(1-ethyl-1H-1,2,4-triazol-3-yl)-7-methoxyimidazo[1,2-a]pyridine-6-carboxamide was obtained as a white solid (30 mg, 14%). LCMS [M+H]+ 533.1。

[0355] Example 7 - in which R 1 is different from R 2 Synthesis of the nitrile precursor

[0356] 7-chloro-3-ethyl-2-[hydroxy(phenyl)(pyridin-2-yl)methyl]imidazo[1,2-a]pyridine-6-carbonitrile

[0357]

[0358] Method C is used to prepare ethyl 6-bromo-7-chloro-3-ethylimidazo[1,2-a]pyridine-2-carboxylate from 5-bromo-4-chloropyridin-2-amine.

[0359] a) Lithium hydroxide (632 mg, 26.4 mmol) was added portionwise to a solution of ethyl 6-bromo-7-chloro-3-ethylimidazo[1,2-a]pyridine-2-carboxylate (2.5 g, 7.54 mmol) in THF (50 mL) and H2O (10 mL). The resulting mixture was stirred at room temperature for 16 h. Subsequently, the pH of the reaction mixture was carefully adjusted to 5 - 6 with 6 M aqueous HCl. The organic solvent was removed under reduced pressure, and the resulting solid was collected by filtration. The solid was washed with water and dried under high vacuum to give 6-bromo-7-chloro-3-ethylimidazo[1,2-a]pyridine-2-carboxylic acid as a yellow solid (2.1 g, 91%). LC / MS [M+H] + 302.8 / 304.8。

[0360] b) N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (2.65 g, 13.8 mmol), 1-hydroxybenzotriazole (1.87 g, 13.8 mmol), NEt3 (2.8 g, 27.7 mmol) and methoxy(methyl)amine hydrochloride (2.02 g, 20.76 mmol) were added to a solution of 6-bromo-7-chloro-3-ethylimidazo[1,2-a]pyridine-2-carboxylic acid (2.1 g, 6.91 mmol) in CH2Cl2 (200 mL). The reaction mixture was stirred at room temperature for 16 h. Then it was diluted with water and extracted with CH2Cl2. The combined organic phases were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography, eluting with EtOAc / petroleum ether (5% to 50% gradient) to give 6-bromo-7-chloro-3-ethyl-N-methoxy-N-methylimidazo[1,2-a]pyridine-2-carboxamide as a yellow solid (1.5 g, 63%). LC / MS [M+H] + 345.8 / 347.9。

[0361] c) Method G: At -78 °C, PhMgBr (5.8 mL, 1 M in THF) was added dropwise to a solution of 6-bromo-7-chloro-3-ethyl-N-methoxy-N-methylimidazo[1,2-a]pyridine-2-carboxamide (1.5 g, 4.33 mmol) in THF (200 mL). The mixture was kept stirring at -78 °C for 2 h, then carefully quenched with saturated NH4Cl solution and diluted with water. The aqueous layer was extracted with CH2Cl2, and the combined organic phases were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography, eluting with EtOAc / petroleum ether (10% to 50% gradient) to give 2-benzoyl-6-bromo-7-chloro-3-ethylimidazo[1,2-a]pyridine as a yellow solid (1.2 g, 72%). LC / MS [M+H] + 362.9 / 364.9。

[0362] d) Preparation of 2-benzoyl-7-chloro-3-ethylimidazo[1,2-a]pyridine-6-carbonitrile from 2-benzoyl-6-bromo-7-chloro-3-ethylimidazo[1,2-a]pyridine using Method F. LC / MS [M+H] + 310.0。

[0363] e) Method H: At -78 °C, nBuLi (1.72 mL, 2.5 M in THF) was added dropwise to a solution of 2-bromopyridine (893 mg, 5.65 mmol) in THF (100 mL). The resulting mixture was kept stirring at -78 °C for 1 h, then 2-benzoyl-7-chloro-3-ethylimidazo[1,2-a]pyridine-6-carbonitrile (700 mg, 2.26 mmol) in THF (20 mL) was added slowly. The mixture was kept stirring at -78 °C for an additional 1 h, then carefully quenched with saturated NH4Cl solution and diluted with water. The aqueous layer was extracted with CH2Cl2, and the combined organic phases were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography, eluting with MeOH / DCM (1% to 8% gradient) to give 7-chloro-3-ethyl-2-[hydroxy(phenyl)(pyridin-2-yl)methyl]imidazo[1,2-a]pyridine-6-carbonitrile as a yellow solid (500 mg, 53%). LC / MS [M+H] + 389.1。

[0364] Starting from the nitriles prepared according to or similar to the procedure given in Example 7 and using the methods described in Examples 2, 4, and 6, amide derivatives of the invention having different substituents R 1 and R 2 can be prepared.

[0365] Example 8

[0366] 1-Ethyl-2-(hydroxy-diphenyl-methyl)-5-methoxy-1H-imidazo[4,5-b]pyridine-6-carboxylic acid-(1-ethyl-1H-[1,2,4]triazol-3-yl)-amide

[0367]

[0368] a) Synthesis of 5-bromo-6-methoxy-3-nitro-pyridin-2-ylamine

[0369] In a 1 L two-necked flask, 6-methoxy-3-nitro-pyridin-2-ylamine (50 g, 286.75 mmol) was dissolved in dry N,N-dimethylformamide (500 ml). At 14 - 18 °C, N-bromosuccinimide (56.40 g, 313.69 mmol) was added portionwise over a period of 20 minutes. The reaction mixture was stirred at room temperature for 1 hour, and complete conversion to the desired product was then observed.

[0370] The reaction mixture was poured into 1.5 L of water and stirred at room temperature for an additional 30 minutes. The solid was filtered off and washed with water. The remaining residue was dried under vacuum at 50 °C overnight to yield pure 5-bromo-6-methoxy-3-nitro-pyridin-2-ylamine (69.76 g, 280.14 mmol). [M+H] + = 247.0 - 249.9 (mono-bromo isotope distribution).

[0371] b) 5-Bromo-6-methoxy-pyridine-2,3-diamine and

[0372] c) Synthesis of 6-bromo-5-methoxy-3H-imidazo[4.5-b]pyridine

[0373] 5-Bromo-6-methoxy-3-nitro-pyridin-2-ylamine (10 g, 40.32 mmol) was dissolved in tetrahydrofuran (100 ml). Subsequently, the reaction mixture was treated with Raney nickel catalyst (3 g, pH neutral, THF) and hydrogen overnight (16 h) at standard pressure and room temperature. After filtration and rinsing of the filter cake with additional tetrahydrofuran, a solution of 5-bromo-6-methoxy-pyridine-2,3-diamine (8.79 g, 40.3 mmol) in approximately 300 mL of THF was obtained and used in the next step without further purification. In a 1 L three-necked flask equipped with a condenser, triethyl orthoformate (219.75 ml) and formic acid (98 - 100% concentration, 3.84 ml, 100.78 mmol) were added to the solution. Then, the reaction mixture was heated at 90 °C for 3 h under an argon atmosphere. For work-up, the reaction mixture was evaporated in vacuo. Subsequently, the residue was dissolved in methanol (approx. 150 ml), diluted with aqueous HCl solution (2.0 M concentration, approx. 500 ml) and softened water (approx. 300 ml), and then extracted with ethyl acetate (twice, 300 ml each time). The organic layer was discarded. The aqueous layer was cooled in an ice bath and neutralized with aqueous KOH solution (47% concentration, approx. 50 ml) with stirring over a 30 minute period to obtain a solution with a pH of 6. The precipitate formed was filtered off by suction, washed twice with softened water (50 ml each time), and dried in a vacuum drying oven (approx. 60 mbar, at 65 °C, 63 h) to yield 6-bromo-5-methoxy-3H-imidazo[4.5-b]pyridine as a solid (6.39 g, purity 97.9%, 27.44 mmol, yield 68.1%). A second harvest of the title product was obtained by extracting the remaining aqueous layer with ethyl acetate (twice, 200 ml each time). The combined organic layers were dried over sodium sulfate, filtered by suction, and evaporated in vacuo to yield 6-bromo-5-methoxy-3H-imidazo[4.5-b]pyridine (1.17 g, purity 83.9%, 4.30 mmol, yield 10.7%). [M+H] + = 228.0 / 230.0 (mono-bromo isotope distribution).

[0374] d) Synthesis of 6-bromo-1-ethyl-5-methoxy-1H-imidazo[4.5-b]pyridine

[0375] 6-Bromo-5-methoxy-3H-imidazo[4,5-b]pyridine (11.50 g, 47.86 mmol) was suspended in a mixture of dry tetrahydrofuran (20.13 ml) and dry 1,4-dioxane (60.38 ml). The flask was inerted with argon and the suspension was cooled in an ice bath while maintaining at 0 - 5 °C. Subsequently, a sodium hydride suspension (60% strength, in paraffin oil, 2.39 g, 59.82 mmol) was added in portions (twice, 1.20 g each time, caution: hydrogen gas formation). After completion of the addition, the flask was again inerted with argon and the suspension was stirred at 0 - 5 °C for 15 minutes. Then, iodoethane (4.54 ml, 55.04 mmol, stabilized with silver) was added dropwise over 5 minutes and stirring was continued for 30 minutes. The reaction mixture was warmed to room temperature while stirring was continued for 63 hours (approx. 50% conversion). A second harvest of the sodium hydride suspension (60% strength, in paraffin oil, 2.39 g, 59.82 mmol) was added in two parts (1.12 g each part) and stirring was continued for 15 minutes, followed by the addition of iodoethane (4.54 ml, 55.04 mmol). After stirring at room temperature for 19 hours (approx. 32% of the starting material remaining), the procedure was repeated a third time with a sodium hydride suspension (60% strength, in paraffin oil, 4.31 g, 107.68 mmol) and iodoethane (8.48 ml, 102.89 mmol), diluting the suspension with additional dry tetrahydrofuran (20.13 ml). After warming to room temperature, stirring was continued for an additional 17 hours until the reaction was complete. For work-up, the reaction mixture was quenched with saturated aqueous ammonium chloride (approx. 20 ml) with stirring, followed by dilution with softened water (approx. 300 ml) and ethyl acetate (approx. 500 ml). After stirring for an additional 30 minutes, the mixture was filtered and extracted twice with ethyl acetate (200 ml each time). The combined organic layers were dried over sodium sulfate, filtered with suction, and evaporated to dryness. The crude product obtained was purified by flash silica gel chromatography (330 g, solvent gradient dichloromethane / 0 - 0.6 vol% ethanol) to yield the title product 6-bromo-1-ethyl-5-methoxy-1H-imidazo[4,5-b]pyridine (7.95 g, purity 96.7%, 29.99 mmol, yield 62.7%, HPTLC silica gel 60F254, Rf 0.61, using solvent mixture dichloromethane - ethanol 10:1, v / v) and the by-product 6-bromo-3-ethyl-5-methoxy-3H-imidazo[4,5-b]pyridine (2.40 g, purity 94.7%, 8.88 mmol, yield 18.6%). [M+H] + = 256.0 / 258.0 (monobromo isotope distribution).

[0376] e) Synthesis of methyl 1-ethyl-5-methoxy-1H-imidazo[4,5-b]pyridine-6-carboxylate

[0377] In an autoclave, 6-bromo-1-ethyl-5-methoxy-1H-imidazo[4,5-b]pyridine (859 mg, 3 mmol), 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium(II) (dichloromethane complex, 75 mg, 0.092 mmol), 1,1-bis-(diphenylphosphino)ferrocene (51 mg, 0.092 mmol) and triethylamine (596 μl, 4.3 mmol) were dissolved in dry methanol (15 ml) and tetrahydrofuran (15 ml). Subsequently, the reaction mixture was treated with carbon monoxide (grade 3.7, 68 ml) at a CO pressure of 3 - 5 bar and 100 °C for 21.5 h. For work-up, the obtained solution was neutralized with saturated aqueous ammonium chloride solution (5 ml), diluted with softened water (45 ml), and extracted four times with ethyl acetate (40 ml each time). The combined organic layers were dried over sodium sulfate, filtered by suction, and evaporated to dryness. The crude product was purified by flash silica gel chromatography (24 g, solvent gradient dichloromethane / 0 - 5 vol% ethanol) to yield the solid methyl 1-ethyl-5-methoxy-1H-imidazo[4,5-b]pyridine-6-carboxylate (733.1 mg, purity 94.8%, 2.95 mmol, yield 96.2%). [M+H] + = 236.1, HPTLC: dichloromethane / ethanol 20:1 (v / v) R f 0.33.

[0378] f) Synthesis of 1-ethyl-2-(hydroxy-diphenyl-methyl)-5-methoxy-1H-imidazo[4,5-b]pyridine-6-carboxylic acid

[0379] Under an argon atmosphere, methyl 1-ethyl-5-methoxy-1H-imidazo[4,5-b]pyridine-6-carboxylate (366 mg, 1.48 mmol) and benzophenone (339 mg, 1.84 mmol) were dissolved in dry tetrahydrofuran (5.5 ml). The suspension was cooled to 0 - 5 °C in an ice bath. Then, a solution of lithium bis(trimethylsilyl)amide (1.0 M in THF, 1.77 ml, 1.77 mmol) was added dropwise over 2 minutes, and the solution was stirred for an additional 1 hour. Then, tetrahydrofuran (5.5 ml), softened water (3.55 ml), and lithium hydroxide (144 mg, 5.9 mmol) were added, and stirring was continued at room temperature for an additional 16 hours. For workup, the reaction mixture was diluted with softened water (30 ml), basified to pH 14 with NaOH (2.0 M, 15 ml), and extracted twice with dichloromethane (20 ml each time). The organic layer was discarded. The combined aqueous layers were acidified to pH 2 with HCl (25%, ca. 8 ml) and extracted three times with ethyl acetate (40 ml each time). The combined organic layers were dried over sodium sulfate, filtered by suction, and evaporated in vacuo to give 1-ethyl-2-(hydroxy-diphenyl-methyl)-5-methoxy-1H-imidazo[4,5-b]pyridine-6-carboxylic acid (459.6 mg, purity 82.9%, 0.94 mmol, yield 64.1%), which was used in the next step without further purification. [M+H] + = 404.1

[0380] g) Synthesis of 1-ethyl-2-(hydroxy-diphenyl-methyl)-5-methoxy-1H-imidazo[4,5-b]pyridine-6-carboxylic acid (1-ethyl-1H-[1,2,4]triazol-3-yl)-amide

[0381] Under an argon atmosphere, 1-ethyl-2-(hydroxy-diphenyl-methyl)-5-methoxy-1H-imidazo[4,5-b]pyridine-6-carboxylic acid (140 mg, purity 82.9%, 0.29 mmol) and 1-ethyl-1H-[1,2,4]triazol-3-ylamine (96.8 mg, 0.86 mmol) were dissolved in dry N,N-dimethylformamide (2.80 ml). Subsequently, triethylamine (163 μl, 1.15 mmol) and [dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammonium hexafluorophosphate (HATU, 219 mg, 0.58 mmol) were added. The reaction mixture was stirred at room temperature for 19 hours. The crude product was first purified by chromatography (RP, pHPLC, solvent gradient water + 0.1% by volume TFA / 15 - 33% by volume acetonitrile + 0.1% by volume TFA). The product fractions were combined and basified with saturated sodium bicarbonate solution (5 ml), followed by extraction with ethyl acetate twice (40 ml each time). The combined organic layers were dried over sodium sulfate, filtered by suction, and evaporated in vacuo. Then, the remaining residue was finally purified by flash silica gel chromatography (4 g, solvent gradient: dichloromethane / 0 - 4.5% by volume ethanol) to yield pure 1-ethyl-2-(hydroxy-diphenyl-methyl)-5-methoxy-1H-imidazo[4,5-b]pyridine-6-carboxylic acid (1-ethyl-1H-[1,2,4]triazol-3-yl)-amide (108.9 mg, purity 96.8%, 0.21 mmol, yield 73.6%). [M+H] + = 498.2, HPTLC: dichloromethane / ethanol 10:1, R f 0.46.

[0382] Reference compound

[0383] The reference compound 3-ethyl-2-[hydroxy(diphenyl)methyl]-N-[(2R)-2-hydroxypropyl]benzimidazole-5-carboxamide can be obtained as described in WO 2015 / 175845 (compound number 79).

[0384] Table 1

[0385] Table 1, which is divided into Table 1a, 1b, 1c, and 1d, shows exemplary compounds of the present invention. All compounds described in Table 1 (including its sub-tables 1a, 1b, 1c, and 1d) were synthesized according to or similar to the methods described above for general synthesis 1-3 and Examples 1-8.

[0386] Table 1a - Exemplary compounds of formula I-b

[0387]

[0388]

[0389]

[0390]

[0391]

[0392] Table 1b Exemplary Compounds of Formula I-c

[0393]

[0394]

[0395]

[0396]

[0397]

[0398] Table 1c Exemplary Compounds of Formula I-a

[0399]

[0400]

[0401] Table 1d

[0402]

[0403]

[0404]

[0405]

[0406]

[0407]

[0408]

[0409]

[0410]

[0411]

[0412]

[0413]

[0414]

[0415]

[0416]

[0417]

[0418]

[0419]

[0420]

[0421]

[0422]

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

[0429] Biological activity

[0430] Biochemical Activity ACSS2 Assay (IC 50 ACSS2 Biochemistry)

[0431] The biochemical activity assay of ACSS2 is based on the detection of released AMP using an AMP-Glo TM assay kit (Promega, Madison). The assay is carried out in three steps: an enzymatic reaction in which human rec ACSS2 activates acetate with ATP and coenzyme A as cosubstrates for vinyl-CoA to release AMP, and an AMP detection reaction of the AMP Glo assay in which, after destroying residual ATP with AMP, the AMP produced by Glo reagent 1 is converted to ATP, and the ATP is measured in a luciferase assay system (detection reagent). The ACSS2 activity is correlated with the detected luminescence signal.

[0432] The assay is performed in a Perkin Elmer 384-well white Proxiplate with a total volume of 8 μl.

[0433] In the absence or presence of a test compound (10-fold dilution, starting concentration 30 μM), a mixture of 1 nM (fc)C-term myc-tagged ACSS2 (human, recombinant, Origene, Rockville, US), 100 μM (fc)ATP, 100 μM (fc)coenzyme A, and 500 μM (fc)sodium acetate in a total volume of 5 μl (50 mM Hepes, 1 mM magnesium chloride, 150 mM NaCl, 1 mM DTT, 0.01% (w / v)BSA, 0.3% DMSO, pH 7.5) was incubated at 37 °C for 180 minutes. The reaction was stopped and residual ATP was destroyed by adding 1 μl of AMP Glo reagent solution (Promega, Madison, US). After incubation for 1 hour at room temperature, 2 μl of AMP Glo detection reagent was added and the assay was incubated at room temperature for 0.75 hours. The luminescence signal was measured in luminescence mode at 700 nm using an Envision multimode reader (Perkin Elmer LAS Germany GmbH). The full value used was the inhibitor-free reaction. A pharmacological zero value was generated by adding an ACSS2 inhibitor (Ac-CoA synthetase inhibitor - CAS 508186-14-9 - Calbiochem) at a final concentration of 5 μM. The inhibition value (IC50) was determined using the program Assay from GeneData Determine the inhibition value (IC50).

[0434] The experimental data of the compounds shown in Table 1 in the IC50 ACSS2 biochemical assay are shown in Table 2 below and classified into the following groups:

[0435] Group A IC 50 In the range of 0.01 nM to <1 nM

[0436] Group B IC 50 In the range of 1 nM to <10 nM

[0437] Group C IC 50 In the range of 10 nM to <100 nM

[0438] Group D IC 50 In the range of 100 nM to <10000 nM

[0439] 14 Cell assay for incorporation of C acetate into fatty acids ( IC 50 ACSS2 cell lipid)

[0440] This protocol describes a cell assay that can quantify endogenous fatty acid synthesis activity in the human HCT-15 cancer cell line and then incorporate radioactively labeled 14C acetate, and perform scintillation proximity based on the readout of the extracted fatty acids.

[0441] HCT-15 cells were grown in RPMI 1640 (Gibco) supplemented with 2 mM glutamine, 1 mM sodium pyruvate, 10 mM HEPES, and 10% FCS (heat-inactivated), and passaged every 2 - 3 days to maintain a sub-confluent live culture. A working cell bank was prepared with each aliquot containing 1×10 7 viable cells. After thawing, these cells were immediately diluted 1:20 in pre-warmed (37 °C) medium. Cells were collected by centrifugation at 200×g for 5 minutes, and the supernatant was replaced with 30 mL of fresh medium per aliquot to obtain a cell suspension containing 350,000 cells / mL. From this cell suspension, 100 μL was dispensed into each well of a collagen-coated 96-well plate (black, clear bottom, PS, F-bottom, Greiner) and cultured for 24 hours (37 °C, 5% CO2). After incubation, the medium was removed, and the wells were washed once with 100 μL of PBS++ (supplemented with Mg 2+ / Ca 2+ , Gibco), and 50 μL of assay medium (RPMI 1640 + 10 mM HEPES) was added to each well.

[0442] Compound serial dilutions were prepared from a 10 mM DMSO stock solution using a fixed dilution factor (usually 1:3). After preparing the serial dilutions in DMSO, each dilution was further diluted in assay medium. This working dilution was prepared such that the concentration was 7 times the final concentration in the assay. The maximum DMSO concentration in the final assay was 0.1%.

[0443] 10 μL of the compound working dilution or DMSO blank was added to each well, and the cells were cultured for 2 hours (37 °C, 5% CO2). Then, containing 14 μCi / mL 1410 μL of AlamarBlue reagent (Invitrogen) of C-acetate (Perkin Elmer) was added to each well (total volume of 70 μL), and the cells were cultured for another 2 hours. Cell viability was verified by measuring AlamarBlue fluorescence (Tecan Safire, excitation: 544 nm / emission: 590 nm). After incubation, the medium was removed, and the wells were carefully washed once with 100 μL of cold PBS++. For cell lysis and fatty acid recovery, 50 μl of 0.1 M NaOH and 0.1% Triton-X100 were added to each well. The plate was sealed with PlateLoc (transparent peelable heat seal, Agilent) and incubated at 70 °C for 16 - 24 hours. After cooling to room temperature, the plate was centrifuged at 1000 rpm for 1 minute, and the plate seal was removed. For acidification, 150 μL of 0.1 M HCl was added to each well, mixed, and 150 μL of the mixture was transferred to a 96-well Flashplate (Perkin Elmer). The plate was sealed with TopSeal-A (Perkin Elmer). To bind the fatty acids to the well surface, the plate was incubated at 70 °C for 4 hours. After cooling to room temperature, the plate was centrifuged at 1000 rpm for 1 minute and stored at room temperature in the dark for 0.5 - 2 hours. In a MicroBeta scintillation counter (Perkin Elmer), the 14 radioactivity of C incorporated into fatty acids was counted as CPM.

[0444] The compounds shown in Table 1 in the IC 50 experimental data in the ACSS2 cell lipid assay are shown in Table 2 below and classified into the following groups:

[0445] Group A IC 50 in the range of 0.01 nM to <1 nM

[0446] Group B IC 50 in the range of 1 nM to <10 nM

[0447] Group C IC 50 in the range of 10 nM to <100 nM

[0448] Group D IC 50 in the range of 100 nM to <10000 nM

[0449] 14 Cell assay for incorporation of C acetate into histones (IC 50 ACSS2 cells histones)

[0450] This protocol describes a cell assay that can quantify endogenous histone acetylation activity in the human HCT-15 cancer cell line and then incorporate radioactively labeled 14C acetate and scintillation is based on the readout of acid-extracted histones.

[0451] HCT-15 cells were trypsinized, washed and suspended in DMEM medium supplemented with penicillin / streptomycin (100 U / mL), sodium pyruvate (1 mM) and 10% FBS.

[0452] In a 96-well V-bottom microplate, a series of compound dilutions were prepared from a 10 mM DMSO stock solution. 0.5 μl was transferred from these dilutions to a fresh plate including pure DMSO as a negative control. The dilutions were prepared such that the final concentration in the assay was 1 / 400 of the concentration in the serial dilutions. The final DMSO concentration in the assay was 0.25%.

[0453] The cell suspension was seeded into each well of a 96-well plate at a density of 2×10 5 cells / 170 μL, each well containing an aliquot of 0.5 μL of the compound series dilution, and kept in a cell culture incubator for 1 hour. 30 μL of a mixture containing 0.5 mCi / mL of 14 C-acetate and complete medium was added to each well. Then, the wells were incubated in the cell culture incubator for 3 hours.

[0454] The other steps of this procedure should be carried out on ice or instruments pre-cooled to 4°C. The cells were sedimented in a 96-well V-bottom microplate by centrifugation (Eppendorf 5804R) at 1200 rpm for 5 minutes. The supernatant was removed, and the cells were washed twice with 200 μL of PBS-NaB (5 mM sodium butyrate) buffer by repeated resuspension and centrifugation. Finally, the cells were resuspended in 50 μL of TE buffer (PBS-NaB + 0.5% Triton X-100) and placed on ice for 10 minutes. After centrifugation at 2300 rpm for 10 minutes at 4°C, the supernatant was removed, the remaining pellet was suspended in 50 μL of 0.2 M HCl, and incubated overnight at 4°C. After incubation, the well plate was shaken in an MTP plate shaker set at 1200 rpm for 2 minutes, and then centrifuged at 3700 rpm for 10 minutes. The lysate (∼43 μL) was carefully aspirated and transferred to a white MTP plate (Greiner bio-one 65509). 90 μL of UltimaGold XR scintillation cocktail was added, and the plate was sealed with a transparent cover strip before being vigorously mixed using a plate shaker set at 1200 rpm. In a MicroBeta Trilux scintillation counter, the 14 C incorporation radioactivity in the wells was measured as CPM counts.

[0455] The compounds shown in Table 1 were at IC 50The experimental data in the ACSS2 cell histone assay are shown in Table 2 below and classified into the following groups:

[0456] Group A IC 50 In the range of 0.01 nM to <1 nM

[0457] Group B IC 50 In the range of 1 nM to <10 nM

[0458] Group C IC 50 In the range of 10 nM to <100 nM

[0459] Group D IC 50 In the range of 100 nM to <10000 nM

[0460] Micronucleus assay (MNT)

[0461] Due to the stable and well-characterized karyotype, high sensitivity, and applicability to high-content imaging methods, in vitro MNT assays were performed in CHO-K1 cells. They have a basal spontaneous micronucleus frequency of 3 - 4%.

[0462] Twenty-four hours after plating, CHO-K1 cells were treated with the test compound for 24 hours (in duplicate; fixed concentration between 0.2 μM and 100 μM, in 2-fold dilution steps). After changing the medium, the cells were incubated with cytochalasin B for 24 hours to block cytokinesis, then the cells were fixed and the nuclei / micronuclei were observed with a DNA stain. Images were obtained using a Molecular Devices high-content imager IXU or IXM and analyzed with the dedicated MetaXpress software micronucleus module. The criteria for micronucleus (MN) scoring are as follows:

[0463] · The diameter of the MN should be less than 1 / 3 of the main nucleus

[0464] · The MN should be separated from the main nucleus or overlap with the main nucleus at the edge ( = no bleb)

[0465] · The MN should have staining similar to the main nucleus

[0466] At least 1000 binucleated cells were evaluated for each treatment in duplicate. Mitomycin C was used as a reference stimulator for micronucleus formation. Cytotoxicity was evaluated in parallel and defined by comparing the total nuclear count in the compound-treated samples with that in the vehicle (1% DMSO)-treated negative control samples (100% cytotoxicity means all cells are dead or lost).

[0467] If micronuclei are observed and less than 60% cytotoxicity is exhibited at the same concentration, the test compound is considered positive. (If a data value contains more micronuclei than the mean of the negative control plus 3×standard deviation, the data value is considered positive.)

[0468] If micronuclei are not observed at a concentration exhibiting less than 60% cytotoxicity and at least one test concentration produces more than 60% cytotoxicity, the compound is reported as negative.

[0469] If micronuclei are not produced at any test concentration and less than 60% cytotoxicity is exhibited, the compound is reported as PN (presumptive negative).

[0470] At a certain concentration (regardless of whether micronuclei are produced), if it exhibits more than 60% cytotoxicity at that concentration, the compound is reported as ND (not determinable).

[0471] Compounds are scored only within the soluble concentration range.

[0472] The experimental data of the compounds shown in Table 1 in the MNT assay are shown in Table 2 below and classified into the following groups:

[0473] Group A negative, presumptive negative (detected micronuclei exceed 60% cytotoxicity threshold)

[0474] Group B positive

[0475] Table 2

[0476]

[0477]

[0478]

[0479]

[0480] The following examples relate to drugs:

[0481] Example A: Injection vial

[0482] Using 2N hydrochloric acid, adjust the solution of 100 g of the active ingredient of formula I-a, I-b or I-c and 5 g of disodium hydrogen phosphate in 3 liters of double-distilled water to pH 6.5, filter sterilize, transfer to injection vials, lyophilize under sterile conditions and seal under sterile conditions. Each injection vial contains 5 mg of the active ingredient.

[0483] Example B: Suppository

[0484] 20 g of the active ingredient of formula I-a, I-b or I-c are melted with a mixture of 100 g of soya lecithin and 1400 g of cocoa butter, poured into moulds and allowed to cool. Each suppository contains 20 mg of the active ingredient.

[0485] Example C: Solution

[0486] A solution is prepared from 1 g of the active ingredient of formula I-a, I-b or I-c, 9.38 g of NaH2PO4·2H2O, 28.48 g of Na2HPO4·12H2O and 0.1 g of benzalkonium chloride in 940 mL of double-distilled water. The pH is adjusted to 6.8, the solution is made up to 1 litre and sterilized by irradiation. The solution can be used in the form of eye drops.

[0487] Example D: Ointment

[0488] 500 mg of the active ingredient of formula I-a, I-b or I-c are mixed with 99.5 g of petrolatum under aseptic conditions.

[0489] Example E: Tablets

[0490] A mixture of 1 kg of the active ingredient of formula I-a, I-b or I-c, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed in a conventional manner to obtain tablets such that each tablet contains 10 mg of the active ingredient.

[0491] Example F: Dragees

[0492] Tablets are compressed analogously to Example E and subsequently coated in a conventional manner with a coating material of sucrose, potato starch, talc, tragacanth and dye.

[0493] Example G: Capsules

[0494] 2 kg of the active ingredient of formula I-a, I-b or I-c are introduced into hard gelatin capsules in a conventional manner such that each capsule contains 20 mg of the active ingredient.

[0495] Example H: Ampoules

[0496] A solution of 1 kg of the active ingredient of formula I-a, I-b or I-c in 60 litres of double-distilled water is sterile filtered, transferred to ampoules, freeze-dried under aseptic conditions and sealed under aseptic conditions. Each ampoule contains 10 mg of the active ingredient.

Claims

1. Amide derivatives of formula I-a, I-b or I-c wherein each is independently of the others R 1 represents Ar A or Hetar A ; R 2 represents Ar B or Hetar B ; R 3 represents methyl, ethyl, 2-dimethylaminoethyl, 2-hydroxyethyl, 2-methoxyethyl; R 4 represents H; R 5 represents H, methyl, ethyl, methoxy, F or Cl; R 6 represents Hetar C or -CH2-Hetar C ; Ar A is phenyl; mono-, di-, tri-, tetra- or pentadeuteriophenyl, fluorophenyl, methylphenyl (tolyl), methoxyphenyl, difluoromethoxyphenyl, 4-difluoromethoxy-2-fluorophenyl; Ar B is phenyl; mono-, di-, tri-, tetra- or pentadeuteriophenyl, fluorophenyl, methylphenyl (tolyl), difluoromethoxyphenyl; Hetar A is methylpyrazolyl, thien-2-yl, thien-3-yl; methylthienyl, thiazolyl, pyridyl, pyrimidinyl, pyridazinyl, quinolinyl; Hetar B thien-2-yl, thien-3-yl; methylthienyl, pyridyl; Hetar C is ethylpyrazolyl, hydroxyethylpyrazolyl, methoxyethylpyrazolyl, ethylimidazolyl, ethyloxazolyl, ethyltriazolyl, aminoethyltriazolyl, hydroxyethyltriazolyl, methoxyethyltriazolyl, ethyloxadiazolyl; or a tautomer or stereoisomer thereof and / or any pharmaceutically acceptable salt of each of the foregoing, including mixtures in all ratios thereof.

2. The amide derivative according to claim 1, or a tautomer or stereoisomer thereof and / or any pharmaceutically acceptable salt of each of the foregoing, including mixtures in all ratios thereof, wherein R 1 and R 2 have the same meaning.

3. The amide derivative according to claim 1, or a tautomer or stereoisomer thereof and / or any pharmaceutically acceptable salt of each of the foregoing, including mixtures in all ratios thereof, wherein R 1 and R 2 have different meanings.

4. The amide derivative according to claim 1, or a tautomer or stereoisomer thereof and / or any pharmaceutically acceptable salt of each of the foregoing, including mixtures in all ratios thereof, wherein Ar A is pentadeuteriophenyl; 2-fluorophenyl; 2-methylphenyl; 2-methoxyphenyl; 4-difluoromethoxyphenyl; Ar B is pentadeuteriophenyl; 2-fluorophenyl; 2-methylphenyl; 4-difluoromethoxyphenyl; Hetar A 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl; 5-methylthiophen-2-yl; 1,3-thiazol-2-yl; pyridin-2-yl; pyrimidin-4-yl; pyridazin-3-yl; quinolin-2-yl; Hetar B is 5-methylthiophen-2-yl; pyridin-2-yl; Hetar C 1-ethylpyrazol-3-yl, 1-ethylpyrazol-4-yl; 1-(2-hydroxyethyl)pyrazol-4-yl; 1-(2-methoxyethyl)pyrazol-4-yl; 1-ethyl-1H-imidazol-4-yl; 4-ethyl-1,3-oxazol-2-yl, 5-ethyl-1,3-oxazol-2-yl; 1-ethyl-1H-1,2,4-triazol-3-yl, 2-ethyl-2H-1,2,3-triazol-4-yl; 1-(2-aminoethyl)-1H-1,2,4-triazol-3-yl; 1-(2-hydroxyethyl)-1H-1,2,4-triazol-3-yl; 1-(2-methoxyethyl)-1H-1,2,4-triazol-3-yl; 5-ethyl-1,3,4-oxadiazol-2-yl, 5-ethyl-1,2,4-oxadiazol-3-yl.

5. The amide derivative according to claim 1, or a tautomer or stereoisomer thereof and / or any pharmaceutically acceptable salt of each of the foregoing, including mixtures in all ratios thereof, wherein the amide derivative is selected from the compounds shown in Table 1, which is divided into Tables 1a, 1b, 1c and 1d.

6. Use of the compound according to any one of claims 1-5, or a tautomer or stereoisomer thereof and / or any pharmaceutically acceptable salt of each of the foregoing, including mixtures in all ratios thereof, in the manufacture of a medicament for the prevention and / or treatment of a medical condition or disease affected by ACSS2 activity selected from: cancer; inflammatory disorders or diseases; nerve tissue generation disorders or diseases; lipid metabolism disorders; viral infections, addiction.

7. Use of the compound according to any one of claims 1-5, or a tautomer or stereoisomer thereof and / or any pharmaceutically acceptable salt of each of the foregoing, including mixtures in all ratios thereof, in the manufacture of a medicament for the prevention and / or treatment of a medical condition or disease affected by ACSS2 activity selected from: tumors, Crohn's disease, ulcerative colitis, idiopathic pulmonary fibrosis, muscular dystrophy, rheumatoid arthritis, systemic sclerosis (scleroderma), Huntington's disease, fatty liver disease, cytomegalovirus infection; post-traumatic stress disorder PTSD; bipolar disorder, depression, Tourette syndrome, schizophrenia, obsessive-compulsive disorder, anxiety disorder, alcohol addiction, tobacco addiction, opioid addiction, sedative addiction, hypnotic addiction, anti-anxiety drug addiction, cocaine addiction, marijuana addiction, amphetamine addiction, hallucinogen addiction, inhalant addiction, impulse control disorder, behavioral addiction.

8. The use according to claim 7, wherein the medical condition or disease affected by ACSS2 activity is solid tumor, alcohol addiction, tobacco addiction, opioid addiction, sedative addiction, hypnotic addiction, anti-anxiety drug addiction, cocaine addiction, marijuana addiction, amphetamine addiction, hallucinogen addiction, inhalant addiction, impulse control disorder, behavioral addiction, or non-alcoholic steatohepatitis NASH.

9. Use according to claim 7, wherein the medical condition or disease affected by ACSS2 activity is non-alcoholic fatty liver disease (NAFLD), panic disorder, phobia, or addiction to phencyclidine.

10. A pharmaceutical composition comprising, as an active ingredient, at least one amide derivative according to any one of claims 1-5, or a tautomer or stereoisomer thereof and / or any pharmaceutically acceptable salt of each of the foregoing, including mixtures of all ratios thereof, and a pharmaceutically acceptable carrier.

11. The pharmaceutical composition according to claim 10, further comprising a second active ingredient or a tautomer or stereoisomer thereof and a pharmaceutically acceptable salt of each of the foregoing, including mixtures of all ratios thereof, wherein the second active ingredient is not an amide derivative of formula I-a, I-b or I-c as defined in any one of claims 1-5.

12. A set or kit comprising separate packages of: a) an effective amount of an amide derivative of formula I-a, I-b or I-c according to any one of claims 1-5, or a tautomer or stereoisomer thereof and / or any pharmaceutically acceptable salt of each of the foregoing, including mixtures of all ratios thereof; and b) an effective amount of another active ingredient, which is not an amide derivative of formula I-a, I-b or I-c as defined in any one of claims 1-5.

13. A method for manufacturing an amide derivative of formula I-a, I-b or I-c according to any one of claims 1-5, or a tautomer or stereoisomer thereof and / or any pharmaceutically acceptable salt of each of the foregoing, characterized in that (a) a carboxylic acid of general formula II-a wherein R 1 、R 2 、R 3 、R 4 and R 5 are as defined in any one of claims 1-5, is subjected to an amidation reaction with a compound of formula III: R 6 -NH2 (III) wherein R 6 as defined in any one of claims 1 - 5, optionally in the presence of a suitable catalyst, to produce an amide derivative of formula I-a: wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined in any one of claims 1 - 5; or (b) a carboxylic acid of general formula II-b wherein R 1 , R 2 , R 3 , R 4 and R 5 are as defined in any one of claims 1 - 5, is subjected to an amidation reaction with a compound of formula III: R 6 -NH2 (III) wherein R 6 as defined in any one of claims 1 - 5, optionally in the presence of a suitable catalyst, to produce an amide derivative of formula I-b: wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined in any one of claims 1 - 5; or c) a carboxylic acid of general formula II-c wherein R 1 、R 2 、R 3 、R 4 and R 5 are as defined in any one of claims 1-5, is subjected to an amidation reaction with a compound of formula III: R 6 -NH2 (III) wherein R 6 as defined in any one of claims 1 - 5, optionally in the presence of a suitable catalyst, to produce an amide derivative of formula I - c: wherein R 1 、R 2 、R 3 、R 4 、R 5 and R 6 are as defined in any one of claims 1 - 5.

14. A carboxylic acid of formula II-a, II-b or II-c wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined in any one of claims 1 - 5.

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