Fused pyridine derivatives substituted with an amide function as ACSS2 inhibitors

Abstract

The present invention relates to substituted amide derivatives that are useful in the prevention and / or treatment of several medical conditions, including hyperproliferative disorders and diseases.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to substituted amide derivatives that are useful for inhibiting 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 technology]

[0002] Background of the Invention It is well established that rapid and uncontrolled tumor growth and proliferation of cancer cells requires 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 attracted interest in cancer research and the development of cancer therapies. It has been demonstrated that some tumors utilize acetate primarily for energy production, while others utilize it primarily for lipid (i.e., biomass) synthesis or for regulating histone acetylation and, ultimately, gene transcription (Z.T. Schug, et al., Nature Reviews Cancer 16, 707-717 (2016)). In all of these processes, acetate is converted to acetyl-CoA using the acetyl-CoA synthetase ACSS, either by the mitochondrial ACSS1 or the nucleocytosolic ACSS2. Therefore, acetyl-CoA is an important metabolite in cancer cells not only for energy production in mitochondria, but also for lipid and fatty acid synthesis in the cytoplasm of cancer cells and histone acetylation in the nucleus of cancer cells.

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

[0005] prior art WO 2015 / 175845 A1 discloses certain benzimidazole derivatives as inhibitors of ACSS2. WO 2020 / 252407 A1 discloses certain benzimidazole derivatives as inhibitors of ACSS2. Summary of the Invention

[0006] Description of the invention It is an object of the present invention to provide compounds useful in the prevention and / or treatment of medical conditions, disorders and / or diseases, especially hyperproliferative disorders / diseases, which compounds are inhibitors of ACSS2.

[0007] The object is surprisingly solved by the compounds of the present invention, which are represented by formula Ia, Ib or Ic [ka] wherein, independently of one another, R 1 Ar A or Hetar A Showing; R 2 Ar B or Hetar B Showing; R3 is C 1~6 -Aliphatic or -OC 1~6 -indicating aliphatic; R 4 H, D, C 1~6 -Aliphatic, or -OC 1~6 -indicating aliphatic; R 5 H, D, C 1~6 -aliphatic, -OC 1~6 -Aliphatic, or halogen; R 6 Hetar C or -CH2-Hetar C Showing; Ar A is a mono- or biaryl having 5, 6, 7, 8, 9, 10, or 11 ring carbon atoms, where the aryl may be unsubstituted or may contain a substituent R A1 , R A2 , R A3 , R A4 , and / or R A5 and optionally substituted with, said substituents may be the same or different; Ar B is a mono- or biaryl having 5, 6, 7, 8, 9, 10, or 11 ring carbon atoms, where the aryl may be unsubstituted or may contain a substituent R B1 , R B2 , R B3 , R B4 , and / or R B5 and optionally substituted with, said substituents may be the same or different; 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 ring atoms are heteroatom(s) selected from N, O, and / or S, and the remainder are carbon atoms, wherein the heteroaryl may be unsubstituted or may contain a substituent R A1 , R A2 , R A3 , R A4 , and / or R A5and optionally substituted with, said substituents may be the same or different; 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 ring atoms are heteroatom(s) selected from N, O, and / or S, and the remainder are carbon atoms, wherein the heteroaryl may be unsubstituted or may contain a substituent R B1 , R B2 , R B3 , R B4 , and / or R B5 and optionally substituted with, said substituents may be the same or different; 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 ring atoms are heteroatom(s) selected from N, O, and / or S, and the remainder are carbon atoms, wherein the heteroaryl may be unsubstituted or may contain a substituent R C1 , R C2 , R C3 , R C4 , and / or R C5 and optionally substituted with, said substituents may be the same or different; 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, independently of each other, H, D, halogen, C 1~6 -aliphatic, -OC 1~6 -Aliphatic; Halogen denotes F, Cl, Br, or I; or any derivative, any N-oxide, prodrug, solvate, tautomer, or stereoisomer thereof, and / or any pharmaceutically acceptable salt of each of the above, including mixtures thereof in any ratio.

[0008] Generally, all residues, radicals, substituents, groups, moieties, etc., which occur more than once, may be identical or different, i.e., are independent of each other. Above and below, residues and parameters have the meanings indicated for formula Ia, Ib, or Ic, unless expressly indicated otherwise. Consequently, the present invention relates, inter alia, to compounds of formula Ia, Ib, or Ic, in which at least one of the residues, radicals, substituents has one of the preferred meanings indicated below. DETAILED DESCRIPTION OF THE INVENTION

[0009] Any of these specific or even preferred embodiments of the invention as specified below and in the claims refers not only to compounds of the specified formula Ia, Ib, or Ic, but also to derivatives, N-oxides, prodrugs, solvates, tautomers, or stereoisomers thereof, as well as pharmaceutically acceptable salts of each of the foregoing, including mixtures thereof in all proportions unless otherwise specified.

[0010] In a specific embodiment PE1, the compound of the present invention is an amide of formula Ia, Ib, or Ic, or any derivative, N-oxide, prodrug, solvate, tautomer, or stereoisomer thereof, and / or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios, wherein R 1 and R 2 have the same meaning. This is illustrated by the example 1 Ar A If we show that, then R 2 Ar B which also indicates R1 Same as Ar A , i.e., this is the same substituent; 1 Hetar A If we show that, then R 2 Hetar B means, which is also R 1 Same as Hetar A (i.e., this is the same substituent).

[0011] A further specific embodiment of the present invention, designated PE2, is an amide of formula Ia, Ib, or Ic, or any derivative, N-oxide, prodrug, solvate, tautomer, or stereoisomer thereof, and / or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all proportions, wherein R 1 and R 2 have different meanings. In this embodiment, the substituent R 1 and R 2 are chosen so that they are not identical. 1 is 2-methylphenyl (i.e., Ar A is a monocyclic 6-membered aromatic ring, and the substituent R A1 , R A2 , R A3 , R A4 , and / or R A5 One of them is Ar A and methyl at the 2-position relative to the point of attachment of the hydroxy-substituted carbon atom to which it is attached, while the other is hydrogen), then R 2 is Hetar as defined herein B or Ar other than 2-methylphenyl B may be.

[0012] Each amide derivative represented by PE2 has a different substituent R 1 and R 2 It must be recognized that since the carbon atom bearing the formula is substituted with four different substituents, there is a chiral center at this carbon atom.

[0013] In yet another particular embodiment of the invention, designated PE3, the amide derivative of the invention is an amide of formula Ia, Ib, or Ic, or any derivative, N-oxide, prodrug, solvate, tautomer, or stereoisomer thereof, and / or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all proportions, in which the substituent R 1 and R 2 are, independently of each other, monocyclic rings, i.e., Ar A is unsubstituted or R A1 , R A2 , R A3 , R A4 , R A5 phenyl optionally mono-, di-, tri-, tetra-, or penta-substituted by; Ar B is unsubstituted or R B1 , R B2 , R B3 , R B4 , R B5 phenyl optionally mono-, di-, tri-, tetra-, or penta-substituted by; Hetar A is a monocyclic heteroaryl having 5 or 6 ring atoms, or a bicyclic heteroaryl having 10 ring atoms, where one or two of the ring atoms are heteroatom(s) selected from N, O, and / or S, and the remainder are carbon atoms, where the heteroaryl may be unsubstituted or may be selected from R A1 , R A2 , R A3 , R A4 , R A5 may be mono-, di-, tri-, tetra-, or penta-substituted with; Hetar Bis a monocyclic heteroaryl having 5 or 6 ring atoms, or a bicyclic heteroaryl having 10 ring atoms, where one or two of the ring atoms are heteroatom(s) selected from N, O, and / or S, and the remainder are carbon atoms, where the heteroaryl may be unsubstituted or may be selected from R B1 , R B2 , R B3 , R B4 , R B5 may be mono-, di-, tri-, tetra-, or penta-substituted with; where 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.

[0014] R 1 and R 2 are identical, i.e., have the same meaning, then PE3 is also within the scope of PE1. 1 and R 2 If PE3 and PE2 do not have the same meaning, then PE3 is within the scope of PE2.

[0015] In a preferred specific embodiment PE3a of PE3, Ar A may be unsubstituted or R A1 and / or R A2 phenyl optionally mono- or di-substituted by R A1 and / or R A2 is as defined in any one of the preceding claims; or is trideuterophenyl, tetradeuterophenyl, or pentadeuterophenyl; Ar B may be unsubstituted or R B1 and / or RB2 phenyl optionally mono- or di-substituted by R B1 and / or R B2 is as defined in any one of the preceding claims; or is trideuterophenyl, tetradeuterophenyl, or pentadeuterophenyl; Hetar A is a monocyclic heteroaryl having 5 or 6 ring atoms, or a bicyclic heteroaryl having 10 ring atoms, where one or two of the ring atoms are heteroatom(s) selected from N, O, and / or S, and the remainder are carbon atoms, and the heteroaryl may be unsubstituted or contain a substituent R A1 and / or R A2 and optionally substituted with, said substituents may be the same or different; Hetar B is a monocyclic heteroaryl having 5 or 6 ring atoms, where one or two of the ring atoms are heteroatom(s) selected from N, O, and / or S, and the remainder are carbon atoms, where the heteroaryl may be unsubstituted or contain a substituent R B1 and / or R B2 and wherein said substituents may be the same or different.

[0016] In yet another preferred specific embodiment PE3b of PE3a, R A1 , R A2 , R B1 , R B2 are, independently of each other, H, D, F, Cl, unsubstituted or substituted C 1~4 -Aliphatic, unsubstituted or substituted -OC 1~4 -It is aliphatic.

[0017] In PE3a or PE3b, the substituent Ar is phenyl. A is a substituent R A1 or R A2If it is monosubstituted with, then this substituent R A1 or R A2 is preferably located at the 2- or 4-position of the phenyl ring. A But R A1 and R A2 If it is disubstituted by then the two substituents may be the same or different, but are preferably at the 2- and 4-positions of the phenyl ring.

[0018] Similarly, in PE3a or PE3b, the substituent Ar is phenyl. B is a substituent R B1 or R B2 If it is monosubstituted with, then this substituent R B1 or R B2 is preferably located at the 2- or 4-position of the phenyl ring. B But R B1 and R B2 If it is disubstituted by then the two substituents may be the same or different, but are preferably at the 2- and 4-positions of the phenyl ring.

[0019] In yet another specific embodiment PE4, the amide derivative of the present invention is an amide of formula Ia, Ib, or Ic, or any derivative, N-oxide, prodrug, solvate, tautomer, or stereoisomer thereof, and / or any pharmaceutically acceptable salt of each of the above, including mixtures thereof in any ratio, wherein, independently of one another, R 3 is C 1~4 - alkyl, preferably unsubstituted or monosubstituted with -OH, -OCH3, or -N(CH3)2 1~2 - denotes alkyl; R 4 indicates H; R 5 is H, C 1~4 -Alkyl, -OC 1~4 - alkyl, F, or Cl; preferably H, C1~2 -Alkyl, -OC 1~2 - denotes alkyl, F, or Cl; wherein the remaining radicals, residues, groups, or substituents are as generally defined above for Formulas Ia, Ib, and Ic, or as defined for any other specific embodiment mentioned above, i.e., PE1, PE2, PE3, PE3a, PE3b.

[0020] In another specific embodiment PE5, the amide derivative of the present invention is an amide of formula Ia, Ib, or Ic, or any derivative, N-oxide, prodrug, solvate, tautomer, or stereoisomer thereof, and / or any pharmaceutically acceptable salt of each of the above, including mixtures thereof in any ratio, wherein: R 6 is -CH2-Hetar C or Hetar C Showing; Hetar C is a monocyclic heteroaryl having 5 or 6 ring atoms, where 1, 2, or 3 of the ring atoms are heteroatom(s) selected from N, O, and / or S, and the remainder are carbon atoms, where the heteroaryl may be unsubstituted or may contain a substituent R C1 and / or R C2 and optionally substituted with, said substituents may be the same or different; R C1 , R C2 is H or substituted or unsubstituted C 1~4 -alkyl, where R C1 and R C2 At least one of them is not H.

[0021] In a preferred specific embodiment PE5a of PE5, R 6 Hetar C Showing; Hetar Cis a monocyclic heteroaryl having five ring atoms, where two or three of the ring atoms are heteroatom(s) selected from N and / or O, and the remainder are carbon atoms, where the heteroaryl may be unsubstituted or may contain one substituent R C1 may be substituted with; R C1 indicates ethyl, 2-aminoethyl, 2-hydroxyethyl, and 2-methoxyethyl.

[0022] In certain specific embodiments PE5b of PE5a, the substituent R C1 is a monocyclic heteroaryl moiety, Hetar C the heteroaryl group relative to the point of attachment to the nitrogen atom of the adjacent amide group. C It is ranked third.

[0023] In another particular embodiment PE5c of PE5 or PE5a or PE5b, R 1 and R 2 In another particular embodiment PE5d of PE5 or PE5a or PE5b, R 1 and R 2 is different.

[0024] In yet another specific embodiment PE6, the amide derivative of the present invention is an amide of formula Ia, Ib, or Ic, or any derivative, N-oxide, prodrug, solvate, tautomer, or stereoisomer thereof, and / or any pharmaceutically acceptable salt of each of the above, including mixtures thereof in any ratio, wherein, independently of one another, R 1 Ar A or Hetar A Showing; R 2 Ar B or Hetar B Showing; R 3indicates methyl, ethyl, 2-dimethylaminoethyl, 2-hydroxyethyl, and 2-methoxyethyl; R 4 indicates H; R 5 denotes H, methyl, ethyl, methoxy, F, or Cl; R 6 Hetar C Showing; Ar A denotes phenyl; mono-, di-, tri-, tetra-, or pentadeuterophenyl; preferably pentadeuterophenyl; fluorophenyl, preferably 2-fluorophenyl; methylphenyl (tolyl), preferably 2-methylphenyl; methoxyphenyl, preferably 2-methoxyphenyl; difluoromethoxy, preferably 4-difluoromethoxy; 4-difluoromethoxy-2-fluorophenyl; Ar B denotes phenyl; mono-, di-, tri-, tetra-, or pentadeuterophenyl; preferably pentadeuterophenyl; fluorophenyl, preferably 2-fluorophenyl; methylphenyl (tolyl), preferably 2-methylphenyl; methoxyphenyl, preferably 2-methoxyphenyl; difluoromethoxy, preferably 4-difluoromethoxy; 4-difluoromethoxy-2-fluorophenyl; Hetar A denotes methylpyrazolyl, preferably 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl; thien-2-yl, thien-3-yl; methylthienyl, preferably 5-methylthien-2-yl; thiazolyl, preferably 1,3-thiazol-2-yl; pyridinyl, preferably pyridin-2-yl; pyrimidinyl, preferably pyrimidin-4-yl; pyridazinyl, preferably pyridazin-3-yl; quinolinyl, preferably quinolin-2-yl; Hetar B denotes thien-2-yl, thien-3-yl; methylthienyl, preferably 5-methylthien-2-yl; pyridinyl, preferably pyridin-2-yl; HetarC is 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-triazolyl 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.

[0025] R 1 and R 2 are identical, i.e. have the same meaning, then this is another specific embodiment PE6a of PE6. 1 and R 2 do not have the same meaning, this is another specific embodiment PE6b of PE6.

[0026] In another specific embodiment PE7, the amide derivative of the present invention is selected from a compound of formula Ia (i.e., a 1H-imidazo[4,5-b]pyridine derivative), or any derivative, N-oxide, prodrug, solvate, tautomer, or stereoisomer thereof, and / or any pharmaceutically acceptable salt of each of the above, including mixtures thereof in all ratios, wherein R 1 , R 2 , R3 , R 4 , R 5 and R 6 is as defined in claim 1 or for any of the specific embodiments PE1, PE2, PE3, PE3a, PE3b, PE4, PE5, PE5a, PE5b, PE5c, PE5d, PE6, PE6a, PE6b. In a particular specific embodiment PE7a of PE7, R 1 denotes phenyl; mono-, di-, tri-, tetra-, or pentadeuterophenyl, preferably pentadeuterophenyl; 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; thien-2-yl, thien-3-yl; methylthienyl, preferably 5-methylthien-2-yl; thiazolyl, preferably 1,3-thiazol-2-yl; pyridinyl, preferably pyridin-2-yl; pyrimidinyl, preferably pyrimidin-4-yl; pyridazinyl, preferably pyridazin-3-yl; quinolinyl, preferably quinolin-2-yl; R 2 denotes phenyl; mono-, di-, tri-, tetra-, or pentadeuterophenyl, preferably pentadeuterophenyl; fluorophenyl, preferably 2-fluorophenyl; methylphenyl (tolyl), preferably 2-methylphenyl; difluoromethoxy, preferably 4-difluoromethoxy; thien-2-yl, thien-3-yl; methylthienyl, preferably 5-methylthien-2-yl; pyridinyl, preferably pyridin-2-yl; R 3 denotes methyl, ethyl, 2-dimethylaminoethyl, 2-hydroxyethyl, 2-methoxyethyl; preferably denotes methyl or ethyl; R 4 is H; R5 indicates H, methyl, methoxy, F, Cl; R 6 is 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-triazolyl 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.

[0027] In another particular embodiment PE7b of PE7 or PE7a, R 1 and R 2 In another particular embodiment PE7c of PE7 or PE7a, R 1 and R 2 is different.

[0028] In another specific embodiment PE8, the amide derivative of the present invention is selected from a compound of formula Ib (i.e., a pyrazolo[1,5-a]pyridine derivative), or any derivative, N-oxide, prodrug, solvate, tautomer, or stereoisomer thereof, and / or any pharmaceutically acceptable salt of each of the above, including mixtures thereof in all ratios, wherein R1 , R 2 , R 3 , R 4 , R 5 and R 6 is as defined in claim 1 or for any of the specific embodiments PE1, PE2, PE3, PE3a, PE3b, PE4, PE5, PE5a, PE5b, PE5c, PE5d, PE6, PE6a, PE6b. In a particular specific embodiment PE8a of PE8, R 1 indicates phenyl, 2-fluorophenyl; R 2 indicates phenyl, 2-fluorophenyl; R 3 indicates ethyl; R 4 is H; R 5 indicates H, methyl, methoxy, Cl; R 6 represents ethylpyrazolyl, ethyltriazolyl; preferably 1-ethylpyrazol-4-yl, 1-ethyl-1H-1,2,4-triazol-3-yl.

[0029] In another particular embodiment PE8b of PE8 or PE8a, R 1 and R 2 In another particular embodiment PE8c of PE8 or PE8a, R 1 and R 2 is different.

[0030] In another specific embodiment PE9, the amide derivative of the present invention is selected from a compound of formula Ic (i.e., an imidazo[1,2-a]pyridine derivative), or any derivative, N-oxide, prodrug, solvate, tautomer, or stereoisomer thereof, and / or any pharmaceutically acceptable salt of each of the above, including mixtures thereof in any ratio, wherein R 1 , R 2 , R 3 , R 4 , R 5 and R6 is as defined in claim 1 or for any of the specific embodiments PE1, PE2, PE3, PE3a, PE3b, PE4, PE5, PE5a, PE5b, PE5c, PE5d, PE6, PE6a, PE6b. In a particular specific embodiment PE9a of PE9, R 1 indicates phenyl, 2-fluorophenyl, 1-methylpyrazol-3-yl, 5-methylthien-2-yl, 1,3-thiazol-2-yl, pyridin-2-yl; R 2 indicates phenyl; R 3 indicates ethyl; R 4 indicates H; R 5 indicates H, ethyl, methoxy, F, Cl; R 6 represents ethylpyrazolyl, ethyltriazolyl; preferably 1-ethylpyrazol-4-yl, 1-ethyl-1H-1,2,4-triazol-3-yl.

[0031] In another particular embodiment PE9b of PE9 or PE9a, R 1 and R 2 In another particular embodiment PE9c of PE9 or PE9a, R 1 and R 2 is different.

[0032] In yet another specific embodiment PE10, the amide derivative represented by formula Ia, Ib, or Ic is selected from the group consisting of the compounds set forth in Table 1, divided into Tables 1a, 1b, 1c, and 1d, and any derivative, any N-oxide, prodrug, solvate, tautomer, or stereoisomer thereof, and / or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios.

[0033] As used herein, the following definitions shall apply unless otherwise specifically indicated or defined anywhere in the description and / or claims for a particular substituent, radical, residue, group, or moiety.

[0034] The terms "aliphatic" or "aliphatic group," as used herein, refer to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain, or a monocyclic, bicyclic, or tricyclic hydrocarbon, which is fully saturated or contains one or more units of unsaturation (such as one or more C=C double bond(s) and / or C≡C triple bond(s)), but is not aromatic (also referred to herein as "carbocycle," "cycloaliphatic," or "cycloalkyl"), which—generally, and unless otherwise defined in the specification or appended claims—have a single point of attachment to the rest 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, aliphatic groups contain 1-3 aliphatic carbon atoms, and in other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, "cycloaliphatic" ("cycloalkyl") refers to a monocyclic C3-C7 hydrocarbon that is fully saturated or contains one or more units of unsaturation, but which is not aromatic, and has a single point of attachment to the rest of the molecule. In another embodiment, the term "carbocycle" refers to a monocyclic or bicyclic cycloaliphatic ring system that is fused to an aromatic, heteroaromatic, or heterocyclic ring or ring system through two adjacent ring atoms of the aromatic, heteroaromatic, or heterocyclic ring or ring system; in other words, such a carbocycle shares two ring atoms with the ring or ring system to which it is fused, thereby having two points of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0035] The term "alkyl" often refers to saturated aliphatic and acyclic moieties, while the term "alkenyl" often refers to unsaturated aliphatic and acyclic moieties with one or more C=C double bonds, and the term "alkynyl" often refers to aliphatic and acyclic moieties with one or more C≡C triple bonds. Exemplary aliphatic groups include linear or branched, substituted or unsubstituted C 1~8 -Alkyl group, C 1~6 -Alkyl group, C 1~4 -Alkyl group, C 2~8 -alkenyl group, C 2~6 -alkenyl group, C 2~8 -alkynyl group, C 2~6 -alkynyl groups, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0036] In particular, the term "C 1~3 "-alkyl" refers to an alkyl group, i.e., a saturated acyclic aliphatic group having 1, 2, or 3 carbon atoms. Exemplary C 1~3 The alkyl groups are methyl, ethyl, propyl, and isopropyl. 1~4 "-alkyl" refers to an alkyl group having 1, 2, 3, or 4 carbon atoms. Exemplary C 1~4 The alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl. 1~6 "-alkyl" refers to an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms. Exemplary C 1~6 -Alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, and 2-hexyl. 1~8 "-alkyl" refers to an alkyl group having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. Exemplary C 1~8- alkyl groups 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 may be linear or - with the exception of C1-alkyl and C2-alkyl - branched, and may be unsubstituted or substituted with one, two, or three substituents which may be the same or different and, unless specified differently elsewhere in this specification, are selected from the group comprising halogen, hydroxy, alkoxy, unsubstituted amino, or amino mono- or disubstituted by alkyl or aralkyl.

[0037] In some cases, C 1~3 -Alkyl group, C 1~4 -Alkyl group, C 1~6 -Alkyl group, C 1~8 The -alkyl group may also include those residues in which one or two non-terminal, non-adjacent -CH- (methylene) groups are replaced by -O-, -S-, and / or one or two non-terminal, non-adjacent -CH- or -CH- groups are replaced by -NH- or -N-. These replacements illustratively produce (modified) alkyl groups such as -CH-CH-O-CH, -CH-CH-CH-S-CH, CH-CH-NH-CH-CH, CH-CH-O-CH-CH-O-CH, CH-CH-N(CH)-CH-CH, etc. Further and / or different replacements of -CH- and -CH- groups may be defined elsewhere in the description and / or claims for a particular alkyl substituent or radical.

[0038] The term “C 3~7 "-cycloalkyl" refers to a cycloaliphatic hydrocarbon, as defined above, having 3, 4, 5, 6, or 7 ring carbon atoms. 3~7- a cycloalkyl group may be unsubstituted or - unless specified otherwise elsewhere in this specification - substituted with 1, 2 or 3 substituents which may be the same or different, and said group - unless specified otherwise elsewhere in this specification - C 1~6 -Alkyl, OC 1~6 - selected from the group comprising alkyl (alkoxy), halogen, hydroxy, unsubstituted or mono- or di-substituted amino. 3~7 -Cycloalkyl groups are cyclopropyl, 2-methyl-cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl.

[0039] The term "aliphatoxy" refers to a saturated or unsaturated aliphatic group or substituent, as defined above, connected to another structural moiety through an oxygen atom (-O-). The term "alkoxy" refers to a specific subgroup of saturated aliphatoxy, namely, alkyl substituents and residues connected to another structural moiety through an oxygen atom (-O-). Sometimes, this is also referred to as "O-alkyl," more specifically, "OC 1~4 -alkyl," "OC 1~6 -alkyl," "OC 1~8 Like similar alkyl groups, it can be straight-chain or -O-C. 1~ Alkyl and -OC 2~With the exception of alkyl - which may be branched and may be unsubstituted or substituted with 1, 2 or 3 substituents which may be the same or different, and unless specified otherwise elsewhere in this specification, is selected from the group including halogen, unsubstituted or mono- or di-substituted amino. Exemplary alkoxy groups are methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy.

[0040] The term "alkylene" refers to a divalent aliphatic group, especially a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH) 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 The terms "C-alkylene" and "C-alkylene" refer to alkylene moieties having one, two, and three -CH2- groups, respectively; however, the term "alkylene" includes not only linear alkylene groups, i.e., "alkylene chains," but also branched alkylene groups. 1~6 "-Alkylene" refers to an alkylene moiety, either linear, i.e., an alkylene chain, or branched, and having 1, 2, 3, 4, 5, or 6 carbon atoms. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms have been replaced by (or with) a substituent. Suitable substituents include those described herein for substituted alkyl groups. In some cases, one or two methylene groups of the alkylene chain may be replaced by, for example, O, S, and / or NH, or NC. 1~4 Exemplary alkylene groups are -CH-, -CH-CH-, -CH-CH-CH-CH-, -O-CH-O-, -O-CH-CH-O-, -O-CH-CH-CH-O-, -CH-NH-CH-CH-, -CH-N(CH)-CH-CH-.

[0041] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described herein for substituted aliphatic groups.

[0042] The term "alkynylene" refers to a divalent alkynyl group. A substituted alkynylene chain is a polymethylene group containing at least one triple bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described herein for substituted aliphatic groups.

[0043] The term "halogen" means F, Cl, Br, or I.

[0044] The term "heteroatom" means one or more of oxygen (O), sulfur (S), or nitrogen (N), and includes any oxidized form of nitrogen or sulfur, such as N-oxide, sulfoxide, and sulfone; the quaternized form of any basic or substitutable nitrogen of a heterocyclic or heteroaromatic ring, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or N-SUB (as in N-substituted pyrrolidinyl), where SUB is a suitable substituent.

[0045] The term "aryl," used alone or as part of a larger moiety, as in "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to monocyclic, bicyclic, and tricyclic ring systems having a total of 5 to 14 ring members (the ring members are carbon atoms), wherein at least one ring in the system is aromatic, i.e., it has (4n+2) π (pi) electrons (where n is an integer selected from 0, 1, 2, and 3), the electrons are delocalized throughout the system, and wherein each ring in the system contains 3 to 7 ring members. Preferably, all rings in an aryl system or the entire ring system are aromatic. The term "aryl" is used interchangeably with the term "aryl ring." In some embodiments of the present invention, "aryl" refers to an "aromatic ring system." More specifically, the aromatic ring systems may be mono-, bi-, or tricyclic, having 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring carbon atoms. Even more specifically, the aromatic ring systems may be mono- or bicyclic, having 6, 7, 8, 9, or 10 ring carbon atoms. The term "monoaryl" refers to a monocyclic aryl. The term "biaryl" refers to a bicyclic aryl. Exemplary aryl groups are phenyl, biphenyl, naphthyl, anthracyl, and the like, which may be unsubstituted or substituted with one or more identical or different substituents. Also included within the scope of the terms "aryl" or "aromatic ring system," as they are used herein, are groups of aromatic rings fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl. In the latter case, the "aryl" group or substituent is attached to its pendant group via the aromatic portion of the ring system.

[0046] The term "benzo" refers to a six-membered aromatic ring (having carbon ring atoms) fused through two adjacent carbon atoms to another ring, which is a cycloaliphatic, aromatic, heteroaromatic, or heterocyclic (heteroaliphatic) ring; resulting in a ring system having at least two rings, in which the benzo ring shares two common carbon atoms with the other ring to which it is fused. For example, when a benzo ring is fused with a phenyl ring, a naphthalene ring system is formed, while when a benzo ring is fused with a pyridine, either a quinoline or an isoquinoline is provided.

[0047] The terms "heteroaryl" and "heteroar-," used alone or as part of a larger moiety, e.g., "heteroaralkyl" or "heteroaralkoxy," refer to groups having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms (the atoms being carbon atoms and heteroatoms), preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 π (pi) electrons shared in the cyclic array; and having 1, 2, 3, 4, or 5 heteroatoms in addition to the carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur and any quaternized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, furazanyl, pyridyl(pyridinyl), pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, and pyrrolopyridinyl, especially pyrrolo[2,3-b]pyridinyl. The terms "heteroaryl" and "heteroara-," as used herein, also include groups in which a heteroaromatic ring is fused with one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is preferably on the heteroaromatic or, if present, aryl ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl (benzothiophenyl), benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, 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 may be attached through one of the ring atoms of a 6-membered aryl ring or one of the ring atoms of a 5-membered heteroaryl ring. Heteroaryl groups are optionally mono-, bi-, or tricyclic. The term "heteroaryl" is used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," all of which include unsubstituted rings or rings substituted with one or more of the same or different substituents. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, where the alkyl and heteroaryl portions are independently optionally substituted.

[0048] A heteroaryl ring can be attached to its pendant group at any heterocyclic or carbon ring atom, which attachment results in a stable structure or molecule; any of the ring atoms can be unsubstituted or substituted.

[0049] Exemplary structures of "heteroaryl" substituents, as used herein, are depicted below: [ka]

[0050] [ka]

[0051] [ka]

[0052] [ka]

[0053] The heteroaryl substituents may be attached to any pendant group via any of its ring atoms suitable for such attachment.

[0054] When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 1 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen is N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or N-SUB (as in N-substituted pyrrolidinyl), where SUB is a suitable substituent.

[0055] The term "unsaturated," as used herein, means that a moiety or group or substituent has one or more units of unsaturation.

[0056] As used herein, the terms "bicyclic," "bicyclic ring," or "bicyclic ring system" refer to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or having one or more units of unsaturation (i.e., partially unsaturated or aromatic), with one or more atoms common to the two rings of the ring system. Thus, the term encompasses any permissible ring fusion, such as ortho-fused or spirocyclic. As used herein, the term "heterobicyclic" is a subset of "bicyclic," requiring one or more heteroatoms to be present in one or both rings of the bicycle. Such heteroatoms may be present at ring junctions, may be 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, and the like. In some embodiments, bicyclic groups have 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Similarly, the terms "tricyclic," "tricyclic ring," or "tricyclic ring system" refer to any tricyclic ring system, i.e., carbocyclic or heterocyclic, saturated or having one or more units of unsaturation (i.e., partially unsaturated or aromatic), in which a bicyclic ring system (as defined above) is fused to another, third ring. Thus, the term encompasses any permissible ring fusion. As used herein, the term "heterotricyclic" is a subset of "tricyclic," requiring that one or more heteroatoms be present in one or both rings of the tricycle. Such heteroatoms may be present at ring junctions, may be 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, tricyclic groups have 10 to 14 ring members and 0 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0057] 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," means that one or more hydrogens of the specified moiety have been replaced with a suitable substituent. "Substituted" applies to one or more hydrogens from a structure, either explicitly or implicitly. Unless otherwise indicated, a "substituted" or "optionally substituted" group has a suitable substituent at each substitutable position of the group; when more than one position in any given structure is substituted with more than one substituent selected from a specified group, the substituents are either the same or different at each position. When a group, substituent, moiety, or radical is "monosubstituted," it has one (1) substituent. If it is "disubstituted," it has two (2) substituents, which are either the same or different; if it is "trisubstituted," it has 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 one another. Combinations of substituents envisioned by the present invention are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable," as used herein, refers to compounds that are substantially unchanged when subjected to conditions that permit their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0058] Unless otherwise specified elsewhere in this specification or the appended claims, each optional substituent on a substitutable carbon is independently selected from the group consisting of halogen; -(CH) 0~4 R o ;-(CH2) 0~4 OR 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 ;R ≥ 1 o optionally substituted with -(CH2) 0~4 Ph; 1 or higher R o optionally substituted with -(CH2) 0~4 O(CH2) 0~1 Ph; 1 or higher R o -CH=CHPh, optionally substituted with one or more R o optionally substituted with -(CH2) 0~4 O(CH2) 0~1 -pyridyl; -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 )R o ;-(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)NR 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)ON(R o )2; or -(C 1~4 Linear or branched alkylene)C(O)ON(R oIt is understood that "Ph" means phenyl; and "-(CH) 0~4 " is understood to mean that when the subscript is "0" (zero), there is no alkylene group, or an alkylene group with 1, 2, 3, or 4 CH2 units.

[0059] Each R o are independently hydrogen, halogen, C 1~6 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, -CH2- (a 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, notwithstanding the above definition, independently, two occurrences of R o R taken together with their intervening atom(s) 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, selected from =O and =S. o or each R o are independently halogen, -(CH2) 0~2 R ● ,-(Halo R ● ), -(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 ● "Ph" means phenyl; "halo" means halogen; and "-(CH) 0~2 " is understood to mean that when the subscript is "0" (zero), there is no alkylene group, or an alkylene group with one or two CH2 units.

[0060] Each R ● independently, 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), wherein each R ● is unsubstituted or, if preceded by halo, substituted only with one or more halogens; or, where any substituents on the saturated carbon are independently selected from: =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 attached to an adjacent substitutable carbon of an "optionally substituted" group is -O(CR * 2) 2~3 O-, where each R independently * is hydrogen, C 1~6aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl rings (having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur).

[0061] R * C 1~6 If aliphatic, R * is halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)O ● , -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● independently, 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, if preceded by halo, substituted only with one or more halogens.

[0062] The optional substituents on a substitutable nitrogen are independently -R † , -NR † 2. -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CHC(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR † 2. -C(NH)NR † 2, or -N(R † )S(O)2R † where each R † are independently hydrogen, C 1~6an aliphatic, unsubstituted -OPh, or an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring (having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur), or two independently occurring R † together with their intervening atom(s) form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring (having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur); where R † C 1~6 When it is aliphatic, R † is halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● independently, 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, if preceded by halo, substituted only with one or more halogens. "Ph" means phenyl; and "halo" is understood to mean halogen.

[0063] In the context of this invention, the term "derivative" means any non-toxic salt, ester, salt of an ester, or other derivative of a compound of this invention that is capable, upon administration to a recipient, of providing, either directly or indirectly, the compound of this invention or an inhibitory active metabolite or residue thereof.

[0064] The compounds of the present invention may be in the form of prodrug compounds. "Prodrug" and "prodrug compound" refer to derivatives that are converted into biologically active compounds according to the present invention under physiological conditions in the living body, for example, by oxidation, reduction, hydrolysis, or the like (each of which is carried out enzymatically or without the involvement of enzymes). Examples of prodrugs include compounds of the present invention in which the amino group is acylated, alkylated, or phosphorylated (e.g., eicosanoylamino, alanylamino, pivaloyloxymethylamino), or in which the hydroxyl group is acylated, alkylated, or phosphorylated, or in which the borate is converted (e.g., acetyloxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, alanyloxy), or in which the carboxyl group is esterified or amidated, or in which the sulfhydryl group forms a disulfide bridge with a carrier molecule (e.g., a peptide) that selectively delivers the drug to a target and / or to the cytoplasm of a cell. These compounds can be produced from the compounds of the present invention according to well-known methods. Other examples of prodrugs are compounds in which the carboxylate in the compound of the present invention is converted to, for example, an alkyl-, aryl-, choline-, amino-, acyloxymethyl ester, or linolenoyl ester.

[0065] The term "solvate" refers to the addition form of the compound of the present invention with a solvent, preferably a pharmaceutically acceptable solvent containing either a stoichiometric amount of solvent or a non-stoichiometric amount of solvent.Some compounds have the tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate.When the solvent is water, the solvate formed is a hydrate, for example, a mono- or dihydrate.When the solvent is alcohol, the solvate formed is an alcoholate, for example, a methanolate or an ethanolate.When the solvent is ether, the solvate formed is an etherate, for example, diethyl etherate.

[0066] The term "N-oxide" refers to those compounds of the present invention that contain an amine oxide moiety, i.e., an oxide of a tertiary amine group.

[0067] The compounds of formula Ia, Ib, or Ic may have one or more centers of chirality. This may result in various enantiomeric and diastereomeric forms, and may, as the case may be, and be, racemic or optically active. Therefore, the present invention also relates to optically active forms, enantiomers, racemates, diastereomers, and mixtures thereof in any ratio, collectively referred to as "stereoisomers" of these compounds for the purposes of the present invention. While the pharmaceutical activity of the racemates or stereoisomers of the compounds according to the present invention may differ, it may be desirable to use a specific stereoisomer, e.g., one specific enantiomer or diastereomer. In these cases, the compounds according to the present invention obtained as racemates—or even their intermediates—may be separated into stereoisomeric (enantiomeric, diastereomeric) compounds by chemical or physical means known to those skilled in the art. Another approach that may be applied to obtain one or more specific stereoisomers of the compounds of the invention in enriched or pure form uses stereoselective synthetic procedures, for example, applying starting materials in stereomerically enriched or pure form (illustratively, using pure or enriched (R)- or (S)-enantiomers of particular starting materials having chiral centers), or utilizing chiral reagents or catalysts, especially enzymes. In the context of the present invention, the term "pure enantiomer" often refers to a relative purity of one enantiomer with respect to the other enantiomer (its antipode) that is equal to or greater than 95%, preferably ≧98%, more preferably ≧98.5%, and even more preferably ≧99%.

[0068] Thus, for example, compounds of the present invention which have one or more centers of chirality and which exist 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 chromatographic methods, for example, column separation on chiral or non-chiral phases, or by recrystallization from any optically active solvent, or by the use of optically active acids or bases, or by derivatization with an optically active reagent (such as, for example, an optically active alcohol), followed by elimination of the radical.

[0069] In the context of the present invention, the term "tautomer" refers to compounds of the present invention that may exist in tautomeric forms and may exhibit tautomerism; for example, carbonyl compounds may exist in their keto and / or enol forms and may exhibit keto-enol tautomerism. These tautomers may exist in their individual forms, for example, in the keto or enol form, or as mixtures thereof, and are claimed individually and together as mixtures in all ratios. The same applies to cis / trans isomers, E / Z isomers, conformers, etc.

[0070] In one embodiment, the compounds of the present invention are in their free base or acid form, as the case may be, i.e., in 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.

[0071] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable base or acid, including inorganic and organic bases or acids. In cases where the compounds of the present invention contain one or more acidic or basic groups, the present invention also includes their corresponding pharmaceutically acceptable salts. Thus, compounds of the present invention containing an acidic group, such as a carboxyl group, can exist in the form of a salt and can be used in accordance with the present invention, for example, as an alkali metal salt, alkaline earth metal salt, aluminum salt, or ammonium salt. More specific examples of such salts include salts with lithium, sodium, potassium, calcium, magnesium, barium, or ammonia, or salts with organic amines such as ethylamine, ethanolamine, diethanolamine, triethanolamine, piperidine, N-methylglutamine, or amino acids. These salts are readily available, 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 basic salts of the compounds of the present invention include, but are not limited to, salts of copper(I), copper(II), iron(II), iron(III), manganese(II), and zinc. Compounds of the present invention containing one or more basic groups, such as protonatable groups, can exist in the form of salts and can 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, malonic acid, maleic acid, malic acid, embonic acid, mandelic acid, sulfamic 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 include, among others, hydrochloride, chloride, hydrobromide, bromide, iodide, sulfate, phosphate, methanesulfonate (mesylate), tosylate, carbonate, bicarbonate, formate, acetate, sulfoacetate, triflate, oxalate, malonate, maleate, succinate, tartrate, malate, embonate, mandelate, fumarate, lactate, citrate, glutaric acid, stearate, aspartate, and glutamate. Moreover, the stoichiometry of the salts formed from the compounds of the present invention may be an integer multiple of 1 or a non-integer multiple.

[0072] Compounds of the invention containing basic nitrogen-containing groups include (C1-C4) alkyl halides, such as methyl, ethyl, isopropyl, and tert-butyl chlorides, bromides, and iodides; di(C1-C4) alkyl sulfates, such as dimethyl sulfate, diethyl sulfate, and diamyl sulfate; (C 10 ~C 18 ) alkyl halides, such as decyl, dodecyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; and aryl (C1-C4) alkyl halides, such as benzyl chloride and phenethyl bromide. Both water- and oil-soluble compounds according to the invention can be prepared using such salts.

[0073] When the compounds of the present invention contain both acidic and basic groups in the molecule, the present invention also encompasses internal salts or betaines (zwitterions) in addition to the aforementioned salt forms. The respective salts can be obtained by conventional methods known to those skilled in the art, for example, by contacting them with organic or inorganic acids or bases in a solvent or dispersant, or by anion or cation exchange with other salts. The present invention also encompasses all salts of the compounds of the present invention that are not directly suitable for use in medicines due to their low physiological compatibility, but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.

[0074] Thus, the following items are also in accordance with the invention: (a) all stereoisomers or tautomers of the compound, including mixtures thereof in all proportions; (b) prodrugs of the compounds, or stereoisomers or tautomers of these prodrugs; (c) pharmaceutically acceptable salts of compounds and pharmaceutically acceptable salts of items referred to under (a) and (b); (d) pharmaceutically acceptable solvates of the compounds and pharmaceutically acceptable solvates of the items referred to under (a), (b), and (c); (e) N-oxides of compounds and N-oxides of items referred to under (a), (b), (c), and (d).

[0075] It should be understood that all references hereinbefore to compounds are intended to encompass those items, particularly pharmaceutically acceptable solvates of the compounds, or pharmaceutically acceptable salts thereof.

[0076] Furthermore, the compounds of the present invention are intended to encompass isotopically labeled forms thereof. Isotopically labeled forms of compounds of Formula Ia, Ib, or Ic are identical to the compounds except for the fact that one or more atoms of the compound have been replaced by an atom or atoms having an atomic mass or mass number different from the atomic mass or mass number of most naturally occurring atoms. Examples of isotopes that are readily commercially available and can be incorporated into compounds of the present invention by well-known methods include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example: 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 CI, respectively. Compounds of Formula Ia, Ib, or Ic, or pharmaceutically acceptable salts thereof, that contain one or more of the above isotopes and / or other isotopes of other atoms are intended to be part of the present invention. Isotopically labeled compounds of the present invention can be used in a number of beneficial ways. For example, 3 H or 14 Isotopically labeled compounds of formula I, incorporating radioactive isotopes such as C, are suitable for drug and / or substrate tissue distribution assays. 3 H) and carbon-14 ( 14 C) is particularly preferred due to its simple preparation and excellent detectability. Heavier isotopes (e.g., deuterium ( 2 Incorporation of H)) into compounds of Formula Ia, Ib, or Ic has therapeutic advantages due to the higher metabolic stability of the isotopically labeled compounds. Higher metabolic stability translates directly into increased in vivo half-life or lower dosages, which will represent a preferred embodiment of the present invention under most circumstances. Isotopically labeled compounds of Formula I can generally be prepared by carrying out the procedures disclosed in the synthetic schemes and related descriptions herein, in the Examples section, and in the Preparations section, replacing non-isotopically labeled reactants with readily available isotopically labeled reactants.

[0077] deuterium( 2H) can also be incorporated into compounds of Formula Ia, Ib, or Ic for the purpose of manipulating the oxidative metabolism of the compound through the primary kinetic isotope effect. The primary kinetic isotope effect is the change in the rate of a chemical reaction due to the exchange of an isotope nucleus, which is secondary to the change in the ground state energy required for covalent bond formation after this isotope exchange. The exchange of a heavier isotope usually results in a lowering of the ground state energy for the chemical bond, which in turn causes a reduction in the rate of rate-limiting bond breaking. If the bond breaking occurs in or near a saddle point region along the coordinate of a multi-product reaction, the product distribution ratio can be substantially altered. By way of illustration: when deuterium is attached to a carbon atom at a non-exchangeable position, k M / k D A rate difference of 2 to 7 is typical. If this rate difference is successfully applied to oxidation-prone compounds of formula Ia and Ib, the in vivo profile of the compounds can be dramatically altered, resulting in improved pharmacokinetic properties.

[0078] When discovering and developing therapeutic agents, those skilled in the art attempt to optimize pharmacokinetic parameters while retaining desirable in vitro properties. It is reasonable to assume that many compounds with poor pharmacokinetic profiles are prone to oxidative metabolism. Currently available in vitro liver microsome assays provide valuable information about the course of this type of oxidative metabolism, which in turn allows for the rational design of deuterated compounds of Formula Ia, Ib, or Ic with improved stability through resistance to such oxidative metabolism. Significant improvements in the pharmacokinetic profile of compounds of Formula Ia, Ib, or Ic can thereby be obtained, improving in vivo half-life (t), concentration at maximum therapeutic effect (C), and other properties. max ), area under the dose-response curve (AUC), and F; and quantitatively in terms of reduced clearance, dose, and material cost.

[0079] The following is intended to illustrate what has been described above: A compound represented by formula Ia, Ib, or Ic, which has multiple potential attack sites for oxidative metabolism (e.g., benzylic hydrogen atoms and hydrogen atoms attached to nitrogen atoms), is prepared as a series of analogs in which various combinations of hydrogen atoms are replaced with deuterium atoms (so that some, most, or all of these hydrogen atoms can be replaced with deuterium atoms). Determination of half-life allows for a convenient and accurate determination of the extent to which resistance to oxidative metabolism has been improved. In this way, it is determined that the half-life of the parent compound can be extended by up to 100% as a result of this type of deuterium-hydrogen exchange.

[0080] Deuterium-hydrogen exchange in the compounds of the invention can also be used to achieve favorable modification of the metabolic spectrum of the starting compound to reduce or eliminate undesired toxic metabolites. For example, if a toxic metabolite arises through oxidative carbon-hydrogen (C-H) bond cleavage, it can be reasonably expected that a deuterated analog will significantly reduce or eliminate the production of the unwanted metabolite, even if the specific oxidation is not the rate-limiting step. Further state-of-the-art information on deuterium-hydrogen exchange may 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.

[0081] Furthermore, the present invention relates to pharmaceutical compositions comprising, as an active ingredient, at least one compound represented by formula Ia, Ib, or Ic, or a derivative thereof, a prodrug thereof, a solvate thereof, a tautomer thereof, or a stereoisomer thereof, and a pharmaceutically acceptable salt of each of the above (including mixtures thereof in any ratio), together with a pharmaceutically acceptable carrier.

[0082] For purposes of the present invention, the term "pharmaceutical composition" (or "pharmaceutical formulation") refers to a composition or product comprising one or more active ingredients and one or more inactive ingredients that constitute the carrier, as well as any product resulting directly or indirectly from the combination, complexation, or aggregation of any two or more of the ingredients, or from the dissociation of one or more of the ingredients, or from any other type of reaction or interaction of one or more of the ingredients. Consequently, pharmaceutical compositions of the present invention encompass any composition made by admixing at least one compound of the present invention with a pharmaceutically acceptable carrier, which may further include pharmaceutically acceptable excipients, auxiliaries, adjuvants, diluents, and / or additional pharmaceutically active substances other than the compounds of the present invention.

[0083] Pharmaceutical compositions include compositions and pharmaceutical formulations suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (eye drops), 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. These may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.

[0084] The pharmaceutical compositions of the present invention may additionally contain one or more other compounds as active ingredients (drugs), such as one or more additional compounds of the present invention. In specific embodiments, the pharmaceutical compositions further contain a second active ingredient, or derivatives thereof, prodrugs thereof, solvates, tautomers, or stereoisomers thereof, and pharmaceutically acceptable salts of each of the foregoing (including mixtures thereof in any proportion), where the second active ingredient is other than a compound of Formula Ia, Ib, or Ic; preferably, the second active ingredient is a compound for which the compounds of the present invention are also useful and which is useful for treating, preventing, inhibiting, and / or ameliorating a disease state or condition listed anywhere above or below. Such combinations of two or more active ingredients or drugs may be safer or more effective than either drug or active ingredient alone, or the combination is safer or more effective than would be expected based on the additivity of the individual drugs. Such other drug(s) may be administered contemporaneously or sequentially with the compounds of the present invention by a commonly used route and in an amount thereof. When a compound of the present invention is used contemporaneously with one or more other drugs or active ingredients, a combination product containing such other drug(s) and a compound of the present invention—also referred to as a "fixed-dose combination"—is preferred. However, combination therapy also includes therapy in which a compound of the present invention and one or more other drugs are administered on different, overlapping schedules. It is contemplated that when used in combination with other active ingredients, the compound of the present invention, the other active ingredients, or both, may be effectively used in lower doses than when each is used alone. Consequently, pharmaceutical compositions of the present invention also include those containing one or more other active ingredients in addition to a compound of the present invention.

[0085] The compounds of the present invention, or their derivatives, N-oxides, prodrugs, solvates, tautomers, or stereoisomers, and / or pharmaceutically acceptable salts thereof, as well as mixtures thereof in any ratio, can be used as pharmaceuticals. They have been found to exhibit pharmacological activity by inhibiting acetyl-CoA synthetase 2 (ACSS2). Furthermore, when tested for genotoxicity in an MNT (micronuclear) in vitro assay, they may exhibit improved properties, i.e., a negative output value in the MNT assay, compared to prior art ACSS2 inhibitors.

[0086] Thus, the compounds of the present invention, being ACSS2 inhibitors, are particularly useful in the treatment, prevention, inhibition, and / or amelioration of hyperproliferative disorders and cancers of the bladder, breast, colorectal, colon, kidney, liver, lung, head and neck, esophagus, bladder, gallbladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, especially tumors, including solid tumors, such as squamous cell carcinoma; leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, mantle cell lymphoma, myeloma, and Burkitt's lymphoma; chronic lymphocytic leukemia ("CLL"), acute and chronic myelogenous leukemia, myelodysplastic syndrome, and promyelocytic leukemia; fibrosarcoma, rhabdomyosarcoma; mantle cell lymphoma, myeloma; astrocytoma, neuroblastoma, glioma, glioblastoma, malignant glioma tumors), astrocytoma, hepatocellular carcinoma, gastrointestinal stromal tumor ("GIST"), and schwannoma; melanoma, multiple myeloma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular thyroid cancer, endometrial cancer, gastrointestinal cancer, and Kaposi's sarcoma; acanthoma, acinic cell carcinoma, acoustic neuroma, acral lentiginous melanoma, acrohidradenoma, acute eosinophilic leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute myeloblastic leukemia with differentiation, acute myeloid dendritic cell leukemia, acute myeloid (myeloid) leukemia, acute promyelocytic leukemia, adamantinoma, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenoid odontogenic tumor, adrenocortical carcinoma, adult T-cell carcinoma, alveolar leukemia, aggressive NK cell leukemia, AIDS-related cancer, AIDS-related lymphoma, alveolar soft part sarcoma, ameloblastic fibroma, anal cancer, anaplastic large cell lymphoma, anaplastic thyroid cancer, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, appendix cancer, astrocytoma, atypical teratoid / rhabdomyosarcoma-like tumor, basal cell carcinoma, basal-like carcinoma, B-cell leukemia, B-cell lymphoma, Bellini duct carcinoma, biliary tract cancer, bladder cancer, blastoma, bone cancer, bone tumor, brainstem glioma, brain tumor, breast cancer, Brenner tumor, bronchial tumor, bronchioloalveolar carcinoma, pheochromocytoma, Burkitt lymphoma, carcinoid tumor, cancer, carcinosarcoma, Castleman disease,Central nervous system embryonal tumors, cerebellar astrocytoma, cerebral astrocytoma, cervical cancer, bile duct carcinoma, chondroma, chondrosarcoma, chordoma, choriocarcinoma, choroid plexus papilloma, chronic lymphocytic leukemia, chronic monocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disorder, chronic neutrophilic leukemia, clear cell renal carcinoma, clear cell tumor, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, dermatofibrosarcoma protuberans, dermoid cyst, desmoplastic small round cell tumor tumors, diffuse large B-cell lymphoma, dysembryoplastic neuroepithelial tumor, embryonal carcinoma, endodermal sinus tumor, endometrial cancer, uterine cancer of the endometrium, endometrial tumor, enteropathy-associated T-cell lymphoma, ependymoblastoma, ependymoma, epithelioid sarcoma, erythroleukemia, esophageal cancer, nasal 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 lymphoma, follicular thyroid cancer, gallbladder cancer, ganglioglioma , ganglioneuroma, gastric cancer, gastric lymphoma, gastrointestinal cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, germ cell tumor, germ cell tumor, gestational choriocarcinoma, gestational trophoblastic tumor, giant cell tumor of bone, glioblastoma multiforme, glioma, gliomatosis cerebri, glomus tumor, glucagon-producing tumor, gonadoblastoma, granulosa cell tumor, hairy cell leukemia, head and neck cancer, cardiac cancer, hemangioblastoma, hemangiopericytoma, angiosarcoma, hematologic malignancies, hepatocellular carcinoma, hepatosplenic T-cell lymphoma, Hodgkin's disease Lymphoma, hypopharyngeal cancer, hypothalamic glioma, inflammatory breast cancer, intraocular melanoma, islet cell carcinoma, juvenile myelomonocytic leukemia, Kaposi's sarcoma, kidney cancer, Klatskin tumor, Krukenberg tumor, laryngeal cancer, lentigo maligna melanoma, leukemia, oral cancer of the lip and oral cavity, liposarcoma, lung cancer, luteoma, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoid leukemia, lymphoma, macroglobulinemia, malignant fibrous histiocytoma, malignant glioma glioma), malignant mesothelioma, malignant peripheral nerve sheath tumor, malignant rhabdomyoid tumor, malignant Triton tumor, Malt lymphoma, mantle cell lymphoma, mast cell leukemia, mediastinal germ cell tumor, mediastinal tumor, medullary thyroid carcinoma, medulloblastoma, medulloepithelioma, melanoma, meningioma, Merkel cell carcinoma, mesothelioma, metastatic squamous cell carcinoma of the neck of unknown primary, metastatic urothelial carcinoma, mixed Müllerian tumor, monocytic leukemia, oral cavity (mouth) cancer, mucinous tumor, multiple endocrine neoplasia syndrome, multiple myeloma,Mycosis fungoides, myelodysplastic disorders, myeloid leukemia, myelosarcoma, myeloproliferative disorders, myxoma, nasal cancer, nasopharyngeal cancer, neoplasms, schwannoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, non-Hodgkin's lymphoma, non-melanoma skin cancer, non-small cell lung cancer, ocular oncology, oligoastrocytoma, oligodendroglioma, eosinophilic granular cell tumor, optic nerve sheath meningioma, oral 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, moderately differentiated pineal parenchymal tumor, pineoblastoma, pituitary cell tumor, pituitary adenoma, pituitary tumor, plasmacytoma, pleuropulmonary blastoma, polygerminoma, 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 cancer, sarcoma, schwannomatosis, sebaceous gland carcinoma, secondary neoplasm, seminoma, serous tumor, Sertoli-Leydig cell tumor, sex cord-stromal tumor, Sézary syndrome, signet ring cell carcinoma, skin cancer, small round cytoplasm blue round cell tumor, small cell carcinoma, small cell lung cancer, small cell lymphoma, small intestine cancer, soft tissue sarcoma, somatostatin-producing tumor, sooty wart, spinal tumor, splenic marginal zone lymphoma, squamous cell carcinoma, stomach cancer, superficial spreading melanoma, supratentorial primitive neuroectodermal tumor, superficial epithelial-stromal tumor, synovial sarcoma, T-cell acute lymphoblastic leukemia, T-cell large granular lymphocytic leukemia, T-cell leukemia, T-cell lymphoma, T-cell prolymphocytic leukemia, teratoma, terminal lymphatic carcinoma Cancers of the human body include testicular cancer, theca cell carcinoma, throat cancer, thymic carcinoma, thymoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, transitional cell carcinoma, urachal cancer, urethral cancer, genitourinary neoplasms, uterine sarcoma, uveal melanoma, vaginal cancer, Werner-Morrison syndrome, verrucous carcinoma, visual pathway glioma, vulvar cancer, Waldenstrom's macroglobulinemia, Warthin's tumor, Wilms' tumor, or any combination thereof. However, ACSS2 activity is not observed in normal cells.Thus, the compounds of the present invention also play a role in acetyl-CoA synthesis in non-cancer cells. They are also useful for the treatment, prevention, suppression, and / or amelioration of inflammatory disorders or diseases, particularly Crohn's disease, ulcerative colitis, idiopathic pulmonary fibrosis, muscular dystrophy, rheumatoid arthritis, and systemic sclerosis (scleroderma); neurodegenerative disorders or diseases, particularly Huntington's disease; lipid metabolism disorders, such as NASH (non-alcoholic steatohepatitis), NAFLD (non-alcoholic fatty liver disease), and fatty liver disease; viral infections, such as those caused by cytomegalovirus; post-traumatic stress disorder (PTSD); bipolar disorder, depression, Tourette's syndrome, schizophrenia, obsessive-compulsive disorder, anxiety disorders, panic disorders, phobias, and addictions to substances such as alcohol, tobacco, opioids, sedatives, hypnotics, anti-anxiety drugs, cocaine, cannabis, amphetamines, hallucinogens, inhalants, phencyclidine, impulse control disorders, and behavioral addictions.

[0087] In particular embodiments, the compounds of the invention are useful in the prevention and / or treatment, in particular of any of the disorders or diseases listed above, preferably of cancer, especially of tumors including solid tumors, of the specific types of cancer disclosed in the preceding paragraph; inflammatory disorders or diseases, especially Crohn's disease, ulcerative colitis, idiopathic pulmonary fibrosis, muscular dystrophy, rheumatoid arthritis, and systemic sclerosis (scleroderma); neurodegenerative disorders or diseases, especially Huntington's disease; lipid metabolism disorders, such as NASH (non-alcoholic fatty liver disease). viral infections, e.g., due to cytomegalovirus; post-traumatic stress disorder (PTSD); bipolar disorder, depression, Tourette's syndrome, schizophrenia, obsessive-compulsive disorder, anxiety disorders, panic disorders, phobias, addiction to e.g., alcohol, tobacco, opioids, sedatives, hypnotics, anxiolytics, cocaine, cannabis, amphetamines, hallucinogens, inhalants, phencyclidine, impulse control disorders, behavioral addictions.

[0088] Other specific aspects of the present invention comprise hyperproliferative disorders and cancers, particularly the specific types of cancer disclosed in the preceding paragraph, comprising tumors including solid tumors; inflammatory disorders or diseases, particularly Crohn's disease, ulcerative colitis, idiopathic pulmonary fibrosis, muscular dystrophy, rheumatoid arthritis, and systemic sclerosis (scleroderma); neurodegenerative 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. a viral infection, such as that caused by cytomegalovirus; post-traumatic stress disorder (PTSD); bipolar disorder, depression, Tourette's syndrome, schizophrenia, obsessive-compulsive disorder, anxiety disorder, panic disorder, phobias, addiction to, for example, alcohol, tobacco, opioids, sedatives, hypnotics, anti-anxiety drugs, cocaine, cannabis, amphetamines, hallucinogens, inhalants, phencyclidine, impulse control disorders, and behavioral addictions.

[0089] Yet another specific embodiment of the present invention relates to the use of the compounds of the present invention - or the derivatives, N-oxides, prodrugs, solvates, tautomers, or stereoisomers thereof, and / or pharmaceutically acceptable salts of each of the above, and mixtures thereof in any proportion, in the pharmaceutical treatment of, among other things, hyperproliferative disorders and cancers, especially tumors including solid tumors, and the specific types of cancer disclosed in the preceding paragraph; inflammatory disorders or diseases, especially Crohn's disease, ulcerative colitis, idiopathic pulmonary fibrosis, muscular dystrophy, rheumatoid arthritis, and systemic sclerosis (scleroderma); neurodegenerative 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. infectious diseases, for example, those caused by cytomegalovirus; post-traumatic stress disorder (PTSD); bipolar disorder, depression, Tourette's syndrome, schizophrenia, obsessive-compulsive disorder, anxiety disorder, panic disorder, phobias, for example, addiction to alcohol, tobacco, opioids, sedatives, hypnotics, anti-anxiety drugs, cocaine, cannabis, amphetamines, hallucinogens, inhalants, phencyclidine, impulse control disorders, and behavioral addictions.

[0090] Preferably, the present invention relates to a compound of the present invention for use in the prevention and / or treatment of a disease - or, alternatively, to 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, to 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, in particular tumors including solid tumors of the specific types of cancer disclosed in the preceding paragraph; more preferably, wherein the administration of the compound is simultaneous, sequential or alternating with the administration of at least one other active agent.

[0091] The disclosed compounds of Formulas Ia, Ib, and Ic can be administered in combination with other known therapeutic agents, including anti-cancer agents. As used herein, the term "anti-cancer agent" refers 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 monotherapy, or may involve, in addition to the compounds of Formulas Ia, Ib, and Ic disclosed herein, conventional surgery or radiation therapy or medicinal therapy. Such medicinal therapy (e.g., chemotherapy or targeted therapy) may include one or more, preferably one of the following anti-tumor agents:

[0092] Alkylating agents Altretamine, bendamustine, busulfan, carmustine, chlorambucil, chlormethine, cyclophosphamide, dacarbazine, ifosfamide, improsulfan, tosilate, lomustine, melphalan, mitobronitol, mitolactol, nimustine, ranimustine, temozolomide, thiotepa, treosulfan, mechlorethamine, carboquone; Apaziquone, fotemustine, glufosfamide, palifosfamide, pipobroman, trofosfamide, uramustine, TH-302 4 , VAL-083 4 etc;

[0093] platinum compound Carboplatin, cisplatin, eptaplatin, miriplatin hydrate, oxaliplatin, lobaplatin, nedaplatin, picoplatin, satraplatin; lobaplatin, nedaplatin, picoplatin, satraplatin, etc.; DNA modifying agents Amrubicin, bisantrene, decitabine, mitoxantrone, procarbazine, trabectedin, clofarabine; Amsacrine, brostallicin, pixantrone, laromustine1,3 etc;

[0094] Topoisomerase inhibitors Etoposide, irinotecan, razoxane, sobuzoxane, teniposide, topotecan; amonafide, belotecan, elliptinium acetate, voreloxin, etc.; microtubule modifier Cabazitaxel, docetaxel, eribulin, ixabepilone, paclitaxel, vinplastine, vincristine, vinorelbine, vindesine, vinflunine; Fosbretabline, tesetaxel, etc.

[0095] anti-metabolite Asparaginase 3 , azacitidine, levofolinate calcium, capecitabine, cladribine, cytarabine, enocitabine, floxuridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine, methotrexate, nelarabine, pemetrexed, pralatrexate, azathioprine, thioguanine, carmofur; Doxifluridine, elacitabine, raltitrexed, cepacitabine, tegafur 2,3 , trimethotrexate, etc.;

[0096] Anticancer antibiotics Bleomycin, dactinomycin, doxorubicin, epirubicin, idarubicin, levamisole, miltefosine, mitomycin C, romidepsin, streptozocin, valrubicin, zinostatin, zorubicin, daunorubicin, plicamycin; Aclarubicin, peplomycin, pirarubicin, etc.;

[0097] Hormones / antagonists Abarelix, abiraterone, bicalutamide, buserelin, calsterone, chlorotonianicene, degarelix, dexamethasone, estradiol, flutocortolone, fluoxymesterone, flutamide, fulvestrant, goserelin, histrelin, leuprorelin, megesterol, mitotane, nafarelin, nandrolone, nilutamide, octreotide, prednisolone, raloxifene, tamoxifen, thyrotropin alfa, toremifene, trilostane, triptorelin, diethylstilbestrol; Acolbifene, danazol, deslorelin, epithiostanol, orteronel, enzalutamide 1,3 etc;

[0098] Aromatase inhibitors Aminoglutethimide, anastrozole, exemestane, fadrozole, letrozole, testolactone; Holmestan, etc.;

[0099] Small Molecule Kinase Inhibitors Crizotinib, dasatinib, erlotinib, imatinib, lapatinib, nilotinib, pazopanib, regorafenib, ruxolitinib, sorafenib, sunitinib, vandetanib, vemurafenib, bosutinib, gefitinib, axitinib; Afatinib, alisertib, dabrafenib, dacomitinib, dinaciclib, dovitinib, enzastaurin, nintedanib, lenvatinib, linifanib, lincitinib, masitinib, midostaurin, motesanib, neratinib, orantinib, perifosine, ponatinib, radotinib, rigosertib, tepotinib, tipifanib, tivantinib, tivozanib, trametinib, pimasertib, brivanimab alaninate, cediranib, apatinib 4 , Cabozantinib S-malate 1,3 , ibrutinib 1,3 , icotinib 4 , buparlisib 2 , cipatinib 4 , cobimetinib 1,3 , idelalisib1,3 , fedratinib 1 , XL-647 4 etc;

[0100] Photosensitizers Methoxsalen 3 ; Porfimer sodium, talaporfin, temoporfin, etc.; antibody Alemtuzumab, besilesomab, brentuximab vedotin, cetuximab, denosumab, ipilimumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, bevacizumab, pertuzumab 2,3 ; Catumaxomab, elotuzumab, epratuzumab, farletuzumab, mogamulizumab, necitumumab, nimotuzumab, obinutuzumab, ocalatuzumab, 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 etc;

[0101] cytokines Aldesleukin, interferon alfa 2 , interferon alpha 2a 3 , interferon alfa-2b 2,3 ; Celmoleukin, tasonermin, teseleukin, operelvekin 1,3 , recombinant interferon beta-1a 4 etc; Drug conjugates Denileukin diftitox, ibritumomab tiuxetan, iobenguane I123, prednimustine, trastuzumab emtansine, estramustine, gemtuzumab, ozogamicin, aflibercept; Syntredequin besudotox, edotreotide, inotuzumab ozogamicin, naptumomab estafenatox, oportuzumab monatox, technitium (99mTc) arcitumomab 1,3 , vintaphorid 1,3 etc;

[0102] vaccine Sipuleucel 3 ;Vitespen 3 , Emepepimt-S 3 , OncoVAX 4 , Lindopepimt 3 , troVax 4 , MGN-1601 4 , MGN-1703 4 etc; others Alitretinoin, bexarotene, bortezomib, everolimus, ibandronate, imiquimod, lenalidomide, lentinan, metyrosine, mifamurtide, pamidronate, pegaspargase, pentostatin, sipuleucel 3 , sizofiran, tamibarotene, temsirolimus, thalidomide, tretinoin, vismodegib, zoledronic acid, vorinostat; Celecoxib, cilengitide, entinostat, etanidazole, ganetespib, idronoxyl, iniparib, ixazomib, lonidamine, nimorazole, parabinostat, peretinoin, plitidepsin, pomalidomide, procodazol, ridaforolimus, tasquinimod, telotristat, simalfasin, tirapazamine, tosedostat, travedelsen, ubenimex, valspodar, and gendicine 4 , Picibanil 4 , leiolysin 4 , letaspimycin hydrochloride1,3 , trebananib 2,3 , bilirudin 4 , carfilzomib 1,3 , endostatin 4 , Immucothel 4 , Belinostat 3 , MGN-1703 4 ;

[0103] PARP inhibitors Olaparib, veliparib. MCT1 inhibitors AZD3965 4 , BAY-8002 4 .

[0104] 1 Prop.INN (Proposed International Nonproprietary Name) 2 Rec.INN (Recommended International Nonproprietary Name) 3 USAN (United States Adopted Name) 4 No INN.

[0105] A further aspect of the present invention is a process for the preparation of the pharmaceutical composition of the present invention, characterized in that one or more compounds according to the present invention and one or more compounds selected from the group consisting of solid, liquid or semi-liquid excipients, auxiliaries, adjuvants, diluents, carriers and pharmaceutically active agents other than the compounds according to the present invention are converted into a suitable dosage form.

[0106] In another aspect of the present invention, there is provided a set or kit comprising a therapeutically effective amount of at least one compound of the present invention and / or at least one pharmaceutical composition as described herein, and a therapeutically effective amount of at least one additional pharmacologically active substance other than a compound of the present invention. The set or kit comprises: a) an effective amount of a compound of formula Ia, Ib, or Ic, or a derivative thereof, a prodrug, solvate, tautomer, or stereoisomer thereof, and a physiologically acceptable salt of each of the foregoing (including mixtures thereof in any ratio); and b) an effective amount of a further active ingredient which is not a compound of formula Ia, Ib, or Ic; Preferably, the pack comprises separate packs of:

[0107] The pharmaceutical compositions (formulations) of the present invention may be administered by any means that achieve their intended purpose. For example, administration may be via oral, parenteral, topical, enteral, intravenous, intramuscular, inhalation, nasal, intraarticular, intrathecal, tracheal, ocular, subcutaneous, intraperitoneal, transdermal, or buccal routes. Alternatively, or in parallel, administration may be via the oral route. The administered dosage will depend on the recipient's age, health, and weight, the type of current treatment (if any), the frequency of treatment, and the nature of the desired effect. Parenteral administration is preferred. Oral administration is particularly preferred.

[0108] Suitable dosage forms include, but are not limited to, capsules, tablets, pellets, dragees, semisolids, powders, granules, suppositories, ointments, creams, lotions, inhalants, injections, poultices, gels, tapes, eye drops, solutions, syrups, aerosols, suspensions, emulsions, which can be produced according to methods known in the art, for example, as described below:

[0109] Tablets: The active ingredient(s) are mixed with the auxiliaries and the mixture is compressed into tablets (direct compression), optionally granulating part of the mixture before compression.

[0110] Capsules: Mix the active ingredient(s) with the auxiliaries to obtain a free-flowing powder, optionally granulate the powder, fill the powder / granules into open capsules and cap the capsules.

[0111] Semi-solids (ointments, gels, creams): The active ingredient(s) are dissolved / dispersed in an aqueous or fatty carrier; the aqueous / fatty phase is then mixed with the complementary fatty / aqueous phase and homogenized (creams only).

[0112] Suppositories (rectal and vaginal): The active ingredient(s) are dissolved / dispersed in a carrier material that has been liquefied by heating (rectal: the carrier material is usually a wax; vaginal: the carrier is usually a heated solution of a gelling agent), the mixture is molded into a suppository form, and the suppository is removed from the annealing mold.

[0113] Aerosol: The active ingredient(s) are dissolved / dispersed in a propellant and the mixture is loaded into an atomizer.

[0114] In general, non-chemical routes for producing pharmaceutical compositions and / or preparations involve processing steps by suitable mechanical means known in the art to convert one or more compounds of the present invention into a dosage form suitable for administration to patients in need of such treatment. Converting one or more compounds of the present invention into such a dosage form usually involves the addition of one or more compounds selected from the group consisting of 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, milling, mixing, granulating, dissolving, dispersing, homogenizing, molding, and / or compressing the active and inactive ingredients, respectively. Mechanical means for carrying out such processing steps are known in the art, for example, from Ullmann's Encyclopedia of Industrial Chemistry, 5th Edition. In this regard, the active ingredients are preferably at least one compound of the present invention and, optionally, one or more additional compounds other than the compounds of the present invention that exhibit valuable pharmaceutical properties, preferably those pharmaceutically active agents disclosed herein other than the compounds of the present invention.

[0115] 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, as well as suspensions, emulsions, or implants; suitable for topical use are ointments, creams, or powders. The compounds of the present invention may also be lyophilized, and the resulting lyophilizates are used, for example, to prepare injection preparations. The indicated preparations may be sterilized and / or contain lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for modifying osmotic pressure, buffer substances, dyes, flavors, and / or several additional active ingredients, such as one or more vitamins.

[0116] Suitable excipients are organic or inorganic substances suitable for enteral (e.g., oral), parenteral, or topical administration, which do not react with the compounds of the invention, such as water, vegetable oils, benzyl alcohol, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose, sucrose, mannitol, sorbitol, or starch (corn starch, wheat starch, rice starch, potato starch), cellulose preparations, and / or calcium phosphates, such as calcium triphosphate or calcium hydrogen phosphate, magnesium stearate, talc, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, and / or vaseline.

[0117] If desired, disintegrants may be added to the above-mentioned starches, such as carboxymethyl-starch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof (such as sodium alginate). Auxiliaries include, but are not limited to, flow-regulating agents and lubricants, such as silica, talc, stearic acid or a salt thereof (such as magnesium stearate or calcium stearate), and / or polyethylene glycol. Dragee cores are provided with suitable coatings, which, if desired, are resistant to gastric juices. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol, and / or titanium dioxide, a lacquer solution, and a suitable organic solvent or solvent mixture. To produce a coating resistant to gastric juices or to provide a dosage form offering the advantage of prolonged action, tablets, dragees, or pills can contain an inner dosage and an outer dosage component, the latter in the form of an envelope surrounding the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and allows the inner component to pass intact into the duodenum or be delayed in release. Various materials can be used for such enteric layers or coatings, including a number of polymeric acids, and mixtures of polymeric acids with materials such as shellac, acetyl alcohol, solutions of suitable cellulose preparations (such as acetyl-cellulose phthalate, cellulose acetate, or hydroxypropylmethyl-cellulose phthalate), etc. Dyes or pigments can be added to tablets or dragee coatings, for example, for identification or to characterize active compound dose combinations.

[0118] Suitable carrier materials are organic or inorganic substances suitable for enteral administration (e.g., oral administration) or parenteral administration or topical application that do not react with the novel compounds, such as water, vegetable oils, benzyl alcohol, polyethylene glycol, gelatin, carbohydrates (such as lactose or starch), magnesium stearate, talc, and yellow petroleum jelly. In particular, tablets, coated tablets, capsules, syrups, suspensions, drops, or suppositories are used for enteral administration, solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants are used for parenteral administration, and ointments, creams, or powders are used for topical application. The compounds of the present invention can also be lyophilized, and the resulting lyophilized products can be used, for example, to produce injection preparations.

[0119] Other pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, and soft sealed capsules made of gelatin and plasticizers (such as glycerol or sorbitol). Push-fit capsules can contain the active compound in the form of granules, which may 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 oils or liquid paraffin. In addition, stabilizers may also be added.

[0120] Liquid forms into which the novel compositions of the present invention may be incorporated for oral administration include aqueous solutions, suitably flavored syrups, aqueous or oil 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, for example, tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone, or gelatin.

[0121] Suitable formulations for parenteral administration include aqueous solutions of water-soluble forms of active compounds, such as water-soluble salts and alkaline solutions.In addition, suspensions of active compounds can also be administered as appropriate 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 (this compound is soluble in PEG-400).

[0122] Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, and / or dextran; optionally, the suspension may also contain stabilizers.

[0123] For administration as an inhalation spray, sprays can be used in which the active ingredient is dissolved or suspended in a propellant gas or propellant gas mixture (for example, CO or chlorofluorocarbon).The active ingredient is preferably used here in finely divided form, and in this case, one or more additional physiologically acceptable solvents, such as ethanol, may be present.The inhalation solution can be administered using a conventional inhaler.

[0124] The practicable pharmaceutical preparations that can be used rectally include, for example, suppositories, which are made up of one or more active compounds combined with a suppository base.Suitable suppository bases are, for example, natural or synthetic triglycerides or paraffin hydrocarbons.In addition, gelatin rectal capsules, which are made up of active compounds combined with a base, can also be used.Practicable bases include, for example, liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.

[0125] For use in medicine, the compounds of the present invention may be in the form of pharmaceutically acceptable salts. However, other salts may also be useful in preparing the compounds of the present invention or their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of the present invention are those previously described herein, including, for example, acid addition salts that may be formed by mixing a solution of a compound according to the present 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. Furthermore, when the compound of the present invention contains 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.

[0126] Pharmaceutical preparations can be employed as human medicines and veterinary medicines. As used herein, the term "effective amount" refers to the amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human (as illustrated by a researcher or clinician) that is being sought. Furthermore, the term "therapeutically effective amount" refers to any amount that results in improved treatment, cure, prevention, or amelioration of a disease, disorder, or side effect, or a reduction in the rate of progression of a disease or disorder, compared to a corresponding subject not receiving such amount. The term also encompasses within its scope an amount effective to enhance normal physiological function. The therapeutically effective amount of one or more compounds of the present invention will be known to those skilled in the art or can be readily determined by standard methods known in the art.

[0127] The compound of the present invention and any additional active substance are generally administered in the same manner as commercial preparations.The suitable dosage that is usually therapeutically effective is between 0.0005mg and 1000mg per dosage unit, preferably between 0.005mg and 500mg, particularly between 0.5mg and 100mg.The daily dosage is preferably between about 0.001mg / kg body weight and about 10mg / kg body weight.

[0128] Those skilled in the art will readily understand that dosage levels may vary depending on the specific compound, the severity of the symptoms, and the subject's susceptibility to side effects. Some specific compounds are more potent than others. The preferred dosage for a given compound can be easily determined by those skilled in the art by a variety of means. A preferred means is to measure the physiological potency of a given compound.

[0129] However, the specific dose for an individual patient, and in particular for an individual human patient, depends on numerous factors, such as the potency of the specific compound employed, age, weight, general state of health, sex, type of diet, time and route of administration, excretion rate, type of administration and dosage form administered, drug combination, and the severity of the specific disorder to be treated. The specific therapeutically effective dose for an individual patient can be readily determined by routine experimentation, for example, by the physician or doctor advising or participating in the therapeutic treatment.

[0130] The compounds of the present invention can be prepared according to the procedures of the following schemes and examples using appropriate materials, as further illustrated by the following specific examples. They can also be prepared by methods known per se, or precisely under known and suitable reaction conditions for the reaction, 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). Variants known per se, but not mentioned in more detail here, can also be used.

[0131] Similarly, the starting materials for the preparation of the compounds of the present invention can be prepared by methods as 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 obtained commercially. The starting materials for the claimed and / or utilized processes can also be formed in situ, if desired, not by isolating them from the reaction mixture, but instead by immediately converting them to further compounds of the present invention or intermediate compounds. On the other hand, in general, the reactions can also be carried out stepwise.

[0132] Preferably, the reaction of the compounds 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, tetrachloromethane, 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 or monoethyl ether, or ethylene glycol dimethyl ether (diglyme); ketones such as acetone or butanone; amides such as acetamide, dimethylacetamide, dimethylformamide (DMF), or N-methylpyrrolidinone (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 such solvents or mixtures with water.

[0133] The reaction temperature is between about -100°C and 300°C, depending on the reaction steps and conditions used.

[0134] The reaction time generally ranges from a few minutes to several days, depending on the reactivity of each compound and the reaction conditions. A suitable reaction time can be easily determined by methods known in the art, such as reaction monitoring. Based on the reaction temperature given above, a suitable reaction time generally ranges from 10 minutes to 48 hours.

[0135] Moreover, by utilizing the procedures described herein, in conjunction 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 genus that is considered the invention. The examples further provide details for the preparation of compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can also be used to prepare these compounds.

[0136] The present invention also refers to processes for making compounds of formula Ia, Ib, or Ic in their most general form, as well as the 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, or any of their derivatives, N-oxides, prodrugs, solvates, tautomers, or stereoisomers, and pharmaceutically acceptable salts of each of the foregoing, which processes comprise: (a) In the case of amido-1H-imidazo[4.5-b]pyridine derivatives of formula Ia, [ka] (R in the formula 1 , R 2 , R 3 , R 4 , and R 5 is as described above for formula Ia and in the appended claims. is a carboxylic acid represented by formula III: R 6 -NH2(III) (R in the formula 6 is as defined 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 give a compound of formula Ia: [ka] (R in the formula 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is as described above for formula Ia and in the appended claims. An amide derivative represented by the formula: or (b) In the case of amido-1-pyrazolo[1,5-a]pyridine derivatives of formula Ib, [ka] (R in the formula 1 , R 2 , R 3 , R 4 , and R 5 is as described above for formula Ib and in the appended claims. is a carboxylic acid represented by formula III: R 6 -NH2(III) (R in the formula 6 is as defined 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 give a compound of formula Ib: [ka] (R in the formula 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is as described above for formula Ib and in the appended claims. An amide derivative represented by the formula: or (c) In the case of the amido-imidazo[1,2-a]pyridine derivatives of formula Ic, [ka] (R in the formula 1 , R 2 , R 3 , R 4 , and R 5 is as described above for formula Ic and in the appended claims) is a carboxylic acid represented by formula III: R 6 -NH2(III) (R in the formula 6 is as defined 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 give a compound of formula Ic [ka] (R in the formula 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is as described above for formula Ic and in the appended claims) The amide derivative represented by It is characterized by:

[0137] As will be appreciated by those skilled in the art of organic synthesis, the compounds of the present invention, particularly those represented by formula Ia, Ib, or Ic, are readily accessible by a variety of synthetic routes, some of which are exemplified in the accompanying experimental section. Those skilled in the art will readily recognize which types of reagents and reaction conditions to use and how to apply and adapt them in any particular case—wherever necessary or useful—to obtain the compounds of the present invention. Furthermore, certain compounds of the present invention can be readily synthesized by reacting other compounds of the present invention under suitable conditions, for example, by converting certain specific functional groups present in the compounds of the present invention, or suitable precursor molecules thereof, into other ones by applying standard synthetic methods such as reduction, oxidation, addition, or substitution reactions, which are well known to those skilled in the art. Likewise, those skilled in the art will be aware that - whenever necessary or useful - synthetic protecting (or protective) groups; the application of suitable protecting groups as well as 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).

[0138] The following general synthetic routes that may be utilized to prepare compounds of the invention are described in more detail in Schemes A-E: [ka]

[0139] Scheme A Scheme A above depicts a general synthetic route for preparing amide compounds represented by Formula Ia. The 2-amino-3-nitro-pyridine derivative Aa, readily available through well-known synthetic methods or commercial sources, is converted to the 5-bromo-substituted derivative Ba using a suitable bromination reaction (step a), illustratively by using N-bromosuccinimide (NBS) in a suitable solvent (e.g., dimethylformamide (DMF)), preferably in a slight excess of about 1.05 to 1.15 equivalents relative to Aa. The nitro-substituent of the bromo-substituted pyridine derivative Ba can then be converted to an amino group using a reduction reaction (step b) with gaseous hydrogen in the presence of a suitable metal catalyst (e.g., sponge nickel catalyst), thereby producing the 2,3-diamino-5-bromo-substituted pyridine derivative Ca. This derivative may be isolated, or preferably, without isolation, reacted with a suitable reaction partner for the desired cyclization under appropriate reaction conditions to produce a 3H-imidazo[4.5-b]pyridine derivative of formula Da (step c); such reaction partner and conditions may illustratively be the addition of triethyl orthoformate and formic acid, respectively, followed by heating. After customary work-up, compound Da is obtained, which can then be converted to a 1H-imidazo[4.5-b]pyridine derivative of formula Ea and its regioisomer Ea-iso (step d). An example of such a conversion to Ea (and Ea-iso) is the addition of a suitable alkyl halide R 3-Hal, illustratively alkylation with an alkyl iodide in the presence of a strong base (e.g., sodium hydride), followed by neutralization (e.g., neutralization with ammonium chloride solution). The desired regioisomer Ea is usually obtained as the major product, while the other isomer Ea-iso is obtained as a by-product, which is subsequently separated by conventional techniques, e.g., chromatography on silica gel. The 1H-imidazo[4.5-b]pyridine derivative Ea is then converted to the carbonitrile derivative of formula Fa by bromine / cyanide exchange (step e); this exchange can be achieved by adding K4[Fe(CN)6] and potassium acetate in a suitable solvent (e.g., dioxane), followed by the addition of a suitable catalyst (e.g., a suitable palladium catalyst such as tBuBrettPhos Pd G3), followed by heating the resulting reaction mixture. The carbonitrile Fa is then converted to the carbonitrile of formula R by bromine / cyanide exchange in a suitable solvent (e.g., THF) in the presence of a strong base (e.g., lithium dimethylsilylamide). 1 -C(=O)-R 2 (R in the formula 1 and R 2may be converted to the tertiary alcohol Ga by reacting with a ketone of formula Ia (which may be the same or different, as defined for the amide of formula Ia) (step f). The carbonitrile Ga may then be converted to the respective carboxylic acid II-a (step g) under conditions typical for the saponification of nitriles, for example by reacting it with a strong base such as sodium hydroxide in a suitable solvent (for example ethanol). In the final step (step h), the desired amide derivative Ia can be obtained by converting a compound of formula II-a to a compound of formula III (R 6 -NH2) (step h).

[0140] Alternatively, the bromide Ea can be converted to the respective carboxylic acid ester Ha (where R is alkyl), [ka] The carbonylation reaction may be carried out 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. The carboxylic acid ester Ha may then be used in place of carbonitrile Fa in the subsequent reaction step f (introduction of a tertiary alcohol and immediate hydrolysis of the carboxylic acid ester to provide the carboxylic acid Ja) and reaction step h (amidation) in which the amide derivative Ia is prepared, thereby saving one reaction step compared to the route utilizing carbonitrile Fa.

[0141] [ka]

[0142] Scheme B R 1 and R 2 The amide compounds of formula Ib, in which the formulas are identical, are readily accessible via the synthetic route depicted in Scheme B above: 2-propyl-4-carbonitrile-substituted pyridine derivatives Ab, available either from commercial sources or via synthetic procedures well known to those skilled in the art, are converted to 1-amino-pyridinium compounds Bb, respectively, by using a suitable reagent (e.g., amino 2,4,6-trimethylbenzene-1-sulfonate) in dichloromethane (Step a). Bb is then subjected to a cyclization reaction with a suitable reaction partner, such as ethyl oxalochloridate (H5C2-OC(=O)-C(=O)-Cl), under typical conditions, to produce pyrazolo[1,5-a]pyridine derivatives Cb (Step b). Cb can then be reacted with a suitable C-nucleophile, illustratively via a classical Grignard reaction (e.g., R 1 -Mg-Cl (or R 2In a similar manner to step g in Scheme A, carbonitrile II-b can be converted to carboxylic acid II-b (step d), which can then be similarly converted to amide derivative Ib (step e) under conditions similar to those described for step h in Scheme A.

[0143] [ka]

[0144] Scheme C R 1 and R 2Amide compounds of formula Ib, in which , are different but not identical, are readily available via the synthetic route depicted in Scheme C above: 2-propyl-4-bromo-substituted pyridine derivatives Eb, available either from commercial sources or via synthetic procedures well known to those skilled in the art, are converted to 1-amino-pyridinium compounds Fb, respectively, by using a suitable reagent (e.g., amino 2,4,6-trimethylbenzene-1-sulfonate) in dichloromethane (Step a). Fb is then subjected to a cyclization reaction with a suitable reaction partner, such as a substituted alpha-halogen-substituted oxalic acid ethyl ester (C2H5-OC(=O)-C(=O)-Hal, e.g., C2H5-OC(=O)-C(=O)-Hal when Hal=Cl), under typical conditions to produce pyrazolo[1,5-a]pyridine derivatives Gb (Step b). Gb is then converted to its carboxylic acid Hb under conventional saponification conditions, for example, by adding a base, illustratively LiOH, NaOH, or KOH. The carboxylic acid Hb is then converted to the carboxamide Jb in a reaction with methoxy(methyl)amine hydrochloride under appropriate conditions, illustratively in the presence of an amine base, such as EDC, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, HOBt (1-hydroxybenzotriazole), and triethylamine. The carboxamide Jb is then reacted with 1 equivalent of a suitable Grignard reagent R 1 -Mg-Hal to provide the ketone Kb (step e). Subsequent bromine-cyanide exchange (step f) by reacting Kb with, illustratively, Zn(CN) and a palladium catalyst such as Pd(dba) and XantPhos in DMF produces the carbonitrile Lb, which can then be reacted with a suitable organometallic compound, e.g., R 2 -Li - This is the appropriate halide R 2Reaction of Hal with -Hal, which may be prepared in situ by reacting with a suitable lithium-organic base (e.g., n-butyllithium), provides the tertiary alcohol Mb (Step g). Similar to Step g in Scheme A, the carbonitrile Mb is converted to the carboxylic acid II-b (Step h), which may then be similarly converted to the amide derivative Ib (Step i) under conditions similar to those described for Step h in Scheme A.

[0145] [ka]

[0146] In an alternative approach, the amide derivative Ib is reacted with a suitable organometallic compound, e.g., R 2 -Li - as in step g described above - can be used to convert the ketone Kb into the tertiary alcohol Nb; a subsequent carbonylation reaction (e.g., with gaseous carbon monoxide 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) produces the ester derivative Ob, which may then be converted into the amide derivative Ib using saponification and a subsequent amidation reaction.

[0147] [ka]

[0148] Scheme D R 1 and R 2The amide compounds of formula Ic, in which the formula Ic is identical, are readily available via the synthetic route depicted in Scheme D above: 2-amino-5-bromo-substituted pyridine derivatives Ac, available either from commercial sources or via synthetic procedures well known to those skilled in the art, can be converted under typical conditions to substituted alpha-halogen-oxalic acid ethyl esters (CH—OC(═O)—C(═O)—CHHal-R 3 For example, Hal = Br and R 3

[0044] The imidazo[1,2-a]pyridine derivative Cc can then be cyclized with a suitable reaction partner, such as C2H5-OC(=O)-C(=O)-CHBr-C2H5(Bc) when C2H5 is ethyl, to produce the imidazo[1,2-a]pyridine derivative Cc (step a). Cc can then be reacted with a suitable C-nucleophile, for example, in a classical Grignard reaction (e.g., R 1 -Mg-Cl (or R 2 In the reaction with Zn(CN) and Pd(PPh) in DMF (step b), Dc is converted to the tertiary alcohol Dc (step b). Subsequent bromide-cyanide exchange (step c) by reacting Dc with a palladium catalyst, illustratively Zn(CN) and Pd(PPh) in DMF, produces carbonitrile Ec, which is then converted to carboxylic acid II-c (step d) under conditions similar to those described for step g in Scheme A. Carboxylic acid II-c may then be converted to amide derivative Ic (step e) under conditions similar to those described for step h in Scheme A. [ka]

[0149] Alternatively, the amide derivatives Ic can be obtained by converting the bromo-substituted derivatives Dc to the corresponding esters Kc via a carbonylation reaction, followed by a saponification and amidation reaction.

[0150] [ka]

[0151] Scheme E R 1 and R 2 Amide compounds of formula Ic, in which the esters are different but not the same, are readily accessible via the synthetic route depicted in Scheme E above: As shown and described in Scheme D, a 2-amino-5-bromo-substituted pyridine derivative Ac is converted to an imidazo[1,2-a]pyridine derivative Cc (Step a). The ester Cc is then converted to its carboxylic acid Ec under conventional saponification conditions, for example, by adding a base, illustratively LiOH, NaOH, or KOH (Step b). The carboxylic acid Ec is then converted to a carboxamide Fc under appropriate conditions, illustratively in reaction with methoxy(methyl)amine hydrochloride in the presence of EDC, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, HOBt (1-hydroxybenzotriazole), and an amine base such as triethylamine (Step c). The carboxamide Fc is then reacted with one equivalent of a suitable Grignard reagent R 1 -Mg-Hal to provide the ketone Gc (step d). Subsequent bromine-cyanide exchange (step e) by reacting Kb with, illustratively, Zn(CN) in DMF in the presence of Pd(dba) and a palladium catalyst such as XantPhos, produces the carbonitrile Hc, which can then be reacted with a suitable organometallic compound, e.g., R 2 -Li - This is the appropriate halide R 2 Reaction of -Hal with a suitable lithium-organic base (e.g., n-butyllithium) to provide the tertiary alcohol Jc (Step f). Similar to Step g in Scheme A, compound Jc is converted to the carboxylic acid II-c (Step g), which can then be similarly converted to the amide derivative Ic (Step h) under conditions similar to those described for Step h in Scheme A.

[0152] Alternatively, the bromide Gc can be reacted with, for example, an organolithium compound R 2 -Li to the corresponding tertiary alcohol; subsequent carbonylation and amidation reactions to provide the respective alkyl esters would then produce the amide derivatives Ic.

[0153] The present invention also refers to carboxylic acids of formula II-a, II-b, or II-c, which are useful intermediates for making the amides of the present invention of formula Ia, Ib, or Ic, respectively: [ka] R in the formula 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is as defined above for Formulas Ia, Ib, and Ic.

[0154] "Treating" or "treatment," as used herein, means alleviating all or part of the symptoms associated with a disorder or disease, or slowing or halting the further progression or worsening of those symptoms, or preventing the prevention or prophylaxis of a disease or disorder in a subject at risk of developing the disease or disorder.

[0155] The term "effective amount" in reference to an amide of Formula Ia, Ib, or Ic refers to an amount (of a compound, drug, pharmaceutical composition, etc.) capable of alleviating, in whole or in part, the symptoms associated with a disorder or disease, or slowing or halting the further progression or worsening of those symptoms, or preventing a disease or disorder in a subject having or at risk of developing a disease disclosed herein, such as an inflammatory disease, immunological disease, cancer, or metabolic disease, or providing prophylaxis for said disease or disorder.

[0156] It should be noted that, in general, terms, i.e., the singular and plural forms thereof, may be used and read interchangeably - unless specifically stated or the context provides a different meaning. For example, the singular term "compound" may also include or refer to a plurality of compounds, while the plural term "compounds" may also include or refer to a singular compound.

[0157] Experimental Part Abbreviation The compounds of the present invention can be prepared according to the procedures and examples of the following schemes using appropriate materials and are further illustrated by the following specific examples. The compounds are presented in Table 1, which is divided into Tables 1a, 1b, 1c, and 1d. Analytical data for compounds made according to the following examples are also presented in Table 1 (Tables 1a, 1b, 1c, and 1d).

[0158] The present invention is illustrated, but not limited, by reference to the specific embodiments described in the following examples. Unless otherwise indicated in the schemes, the variables have the same meanings as described above and in the claims.

[0159] Unless otherwise specified, all starting materials were obtained from commercial suppliers and used without further purification. Unless otherwise specified, all temperatures are expressed in °C and all reactions were performed at rt (room temperature). Compounds were purified by either silica chromatography or preparative HPLC.

[0160] 1 H NMR: 1 H-NMR data is provided in Table 1 below. 1H NMR spectra were mostly acquired on a Bruker Avance DRX 500, Bruker Avance 400, or Bruker DPX 300 NMR spectrometer under standard conditions using TMS (tetramethylsilane) as the internal standard and DMSO-d6 as the standard solvent unless otherwise reported. NS (number of scans): 32, SF (spectrometer frequency) as indicated. TE (temperature): 297 K. Chemical shifts (δ) are relative to the residual solvent signal (in DMSO-d6). 1 H NMR δ = 2.5 ppm in CDCl 1 Reported in ppm relative to 1H NMR (δ=7.27 ppm for H NMR and δ=3.31 ppm for methanol-d4). 1 H NMR data are reported as follows: chemical shifts (multiplicities, coupling constants, and hydrogen numbers). Multiplicities are abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublets), tt (triplet of triplets), td (triplet of doublets), br (broad), and coupling constants (J) are reported in Hz.

[0161] HPLC-MS: The HPLC-MS data provided in Table 1 are given in mass in m / z units. Results can be obtained by one of the methods described below. HPLC-MS analyses were mostly carried out on a Shimadzu LCMS-2020 system, a Shimadzu SP-M20A 2010EV system, or a Shimadzu UFLC-MS 2010EV system, utilizing 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. Standard conditions applied: A: Water + 0.1 vol.% formic acid, B: Acetonitrile + 0.1 vol.% formic acid; or A: Water + 0.05 vol.% trifluoroacetic acid, B: Acetonitrile + 0.05 vol.% trifluoroacetic acid Standard solvent gradients using Detection wavelength: 220 nm, MS-Typ: API-ES

[0162] General synthesis 1 [ka]

[0163] Example 1 (carbonitrile precursor) 2-[bis(2-fluorophenyl)(hydroxy)methyl]-3-ethyl-6-methoxypyrazolo[1,5-a]pyridine-5-carbonitrile [ka]

[0164] a) To a solution of 2,2,6,6-tetramethylpiperidine (15 g, 106.19 mmol) in THF (250 mL) was added nBuLi (42.5 mL, 2.5 M) dropwise at −30° C. The resulting mixture was stirred at −30° C. for 30 min 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 min, after which 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 min. The reaction mixture was then carefully quenched with saturated NH4Cl solution (100 mL) and diluted with water (300 mL). The resulting mixture was extracted with EtOAc (300 mL x 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 EtOAc in 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.

[0165] b) To a solution of 5-chloro-2-propylpyridine-4-carbonitrile (500 mg, 2.77 mmol) in DMSO (8 mL) was slowly added NaOMe solution (30% wt in MeOH, 1.35 g, 9.1 mmol). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was then 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 in petroleum ether (5% to 50% gradient) to produce 5-methoxy-2-propylpyridine-4-carbonitrile as a yellow oil (700 mg, 90%). LC / MS [M+H] + 177.1.

[0166] c) To a solution of 5-methoxy-2-propylpyridine-4-carbonitrile (650 mg, 3.69 mmol) in DCM (10 mL) was slowly added amino 2,4,6-trimethylbenzene-1-sulfonate (3.68 g, 17.08 mmol). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to afford 1-amino-4-cyano-5-methoxy-2-propylpyridin-1-ium 2,4,6-trimethylbenzene-1-sulfonate as a white solid (700 mg), which was used in the next step without further purification. LC / MS [M] + 192.1.

[0167] d) A mixture of 1-amino-4-cyano-5-methoxy-2-propylpyridin-1-ium 2,4,6-trimethylbenzene-1-sulfonate (2.8 g, 6.16 mmol) and ethyl oxalochloridate (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 organic phases were combined, washed with brine, and dried over Na SO . The solvent was removed under reduced pressure, and the residue was purified by flash chromatography eluting with EtOAc in petroleum ether (10% to 50% gradient) to produce 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.

[0168] e) 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 using Method E described below for Example 5. LC / MS [M-OH] + 366.0.

[0169] Example 2 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 [ka]

[0170] a) Method A: 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 HO (1 mL) was slowly added NaOH (104 mg, 2.46 mmol). 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 6 M HCl solution. The resulting mixture was extracted with DCM, and the organic phases were combined, washed with brine, and dried over Na SO . The solvent was removed under reduced pressure to produce 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.

[0171] 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), ethyldi(propan-2-yl)amine 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 in 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.

[0172] General synthesis 2 [ka]

[0173] Example 3 – Bromo-substituted precursors [6-Bromo-3-ethyl-7-methoxyimidazo[1,2-a]pyridin-2-yl]diphenylmethanol [ka]

[0174] 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 phase was 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 in petroleum ether (5% to 30% gradient) to produce 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.

[0175] b) Method D: 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) was added PhMgBr (1 M in THF, 11.9 mL, 11.9 mmol) dropwise at 0 °C. The resulting mixture was kept stirring at 0 °C for 1 h. The reaction mixture was then carefully quenched with saturated NH Cl solution (20 mL) and diluted with water (100 mL). The aqueous phase was extracted with DCM (150 mL × 2), and the organic phases were combined, washed with brine, and dried over Na SO . The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with MeOH in 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.

[0176] Example 4 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 [ka]

[0177] 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)Cl (50 mg, 0.067 mmol), and triethylamine (208 mg, 2.06 mmol) in MeOH (13 mL) was stirred at 100 °C under an atmosphere of CO (10 atm) for 6 h. The reaction mixture was then diluted with water (40 mL) and extracted with DCM (40 mL × 3). The combined organic phase was washed with brine and dried over Na SO . The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with MeOH in DCM (1% to 5% gradient) to yield 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.

[0178] b) 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 HO (5 mL), LiOH (36 mg, 1.51 mmol) was slowly added. 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 organic phases were combined, washed with brine, and dried over NaSO. The solvent was removed under reduced pressure to produce 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.

[0179] c) 3-Ethyl-2-(hydroxydiphenylmethyl)-7-methoxyimidazo[1,2-a]pyridine-6-carboxylic acid (1-ethyl-1H-[1,2,4]triazol-3-yl)-amide was prepared from 3-ethyl-2-(hydroxydiphenylmethyl)-7-methoxyimidazo[1,2-a]pyridine-6-carboxylic acid using Method B. The product was purified by preparative HPLC under the following conditions: Column, XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm; Mobile phase, MeCN in water (with 10 mM NH4HCO3 and 0.1% NH3·H2O), 35% to 50% gradient over 8 min; Detector, UV 254 / 220 nm. 3-Ethyl-N-(1-ethyl-1H-1,2,4-triazol-3-yl)-2-(hydroxydiphenylmethyl)-7-methoxyimidazo[1,2-a]pyridine-6-carboxamide was obtained as a white solid (50 mg, 22%). LCMS [M+H] + 497.2.

[0180] Example 5 – Carbonitrile Precursors 2-[bis(2-fluorophenyl)(hydroxy)methyl]-3-ethyl-7-methoxyimidazo[1,2-a]pyridine-6-carbonitrile [ka]

[0181] a) Method F: 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) (0.3 g, 2.51 mmol), Pd(dba) (1.2 g, 1.3 mmol), and XantPhos (0.7 g, 1.3 mmol) in DMF (30 mL) was stirred at 90 °C under a nitrogen atmosphere for 3 h. The reaction mixture was then diluted with water and extracted with CHCl. ​​The organic phases were combined, washed with brine, and dried over NaSO. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography eluting with MeOH in DCM (1% to 7% gradient) to afford 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.

[0182] b) Method E: To a solution of 1-bromo-2-fluorobenzene (2.37 g, 13.54 mmol) in THF (30 mL) was added iPrMgCl·LiCl (10.4 mL, 1.3 M in THF) dropwise at −15 °C. The resulting mixture was stirred at −15 °C for 2 h, after which 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 slowly added. The reaction mixture was continued to stir for another 2 h at −15 °C. The reaction mixture was then 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 in DCM (1% to 5% gradient) to yield 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.

[0183] Example 6 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 [ka]

[0184] 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 in water (with 10 mM NH₄HCO₃ and 0.1% NH₃·H₂O), 35%–40% 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)-7-methoxyimidazo[1,2-a]pyridine-6-carboxamide was obtained as a white solid (30 mg, 14%). LCMS [M+H] + 533.1.

[0185] Example 7 - R 1 R 2 Synthesis of carbonitrile precursors different from 7-Chloro-3-ethyl-2-[hydroxy(phenyl)(pyridin-2-yl)methyl]imidazo[1,2-a]pyridine-6-carbonitrile [ka]

[0186] Ethyl 6-bromo-7-chloro-3-ethylimidazo[1,2-a]pyridine-2-carboxylate was prepared from 5-bromo-4-chloropyridin-2-amine using Method C.

[0187] a) 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 HO (10 mL) was added LiOH (632 mg, 26.4 mmol) in portions. The resulting mixture was stirred at room temperature for 16 h. The pH of the reaction mixture was then carefully adjusted to 5-6 with 6 M HCl aq., 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 produce 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.

[0188] b) To a solution of 6-bromo-7-chloro-3-ethylimidazo[1,2-a]pyridine-2-carboxylic acid (2.1 g, 6.91 mmol) in CHCl (200 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (2.65 g, 13.8 mmol), 1-hydroxybenzotriazole (1.87 g, 13.8 mmol), NEt (2.8 g, 27.7 mmol), and methoxy(methyl)amine hydrochloride (2.02 g, 20.76 mmol). The reaction mixture was stirred at room temperature for 16 h. It was then diluted with water and extracted with CHCl. ​​The combined organic phase was washed with brine and dried over NaSO. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in petroleum ether (5% to 50% gradient) to afford 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.

[0189] c) Method G: 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) was added PhMgBr (5.8 mL, 1 M in THF) dropwise at −78° C. The mixture was stirred at −78° C. for 2 h, after which it was carefully quenched with saturated NH4Cl solution and diluted with water. The aqueous layer was extracted with CHCl2, 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 in petroleum ether (10% to 50% gradient) to produce 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.

[0190] d) 2-Benzoyl-7-chloro-3-ethylimidazo[1,2-a]pyridine-6-carbonitrile was prepared from 2-benzoyl-6-bromo-7-chloro-3-ethylimidazo[1,2-a]pyridine using Method F. LC / MS [M+H] + 310.0.

[0191] e) Method H: To a solution of 2-bromopyridine (893 mg, 5.65 mmol) in THF (100 mL) was added nBuLi (1.72 mL, 2.5 M in THF) dropwise at −78° C. The resulting mixture was stirred at −78° C. for 1 h, followed by the slow addition of 2-benzoyl-7-chloro-3-ethylimidazo[1,2-a]pyridine-6-carbonitrile (700 mg, 2.26 mmol) in THF (20 mL). The mixture was stirred at −78° C. for another 1 h, after which it was carefully quenched with saturated NH4Cl solution and diluted with water. The aqueous layer was extracted with CHCl2, 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 in DCM (1% to 8% gradient) to afford 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.

[0192] Substituent R 1 and R 2 The amide derivatives of the invention, which vary in size, can be prepared by starting from carbonitriles prepared according to or analogously to the procedure given in Example 7 and utilizing the methods described in Examples 2, 4, and 6.

[0193] Example 8 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 [ka]

[0194] a) Synthesis of 5-bromo-6-methoxy-3-nitro-pyridin-2-ylamine In a 1 L two-neck flask, 6-methoxy-3-nitro-pyridin-2-ylamine (50 g, 286.75 mmol) was dissolved in dry N,N-dimethylformamide (500 ml). N-Bromosuccinimide (56.40 g, 313.69 mmol) was added in portions over a 20 min time course at 14-18 °C. The reaction mixture was stirred at room temperature for 1 h, at which time complete conversion to the desired product was observed.

[0195] The reaction mixture was poured into 1.5 L of water and stirred at room temperature for an additional 30 min. The solid was filtered off with suction and washed with water. The remaining residue was dried under vacuum at 50 °C overnight to produce pure 5-bromo-6-methoxy-3-nitro-pyridin-2-ylamine (69.76 g, 280.14 mmol). [M+H] + =247.0~249.9 (single bromine isotope distribution).

[0196] b) 5-Bromo-6-methoxy-pyridine-2,3-diamine & c) Synthesis of 6-bromo-5-methoxy-3H-imidazo[4.5-b]pyridine 5-Bromo-6-methoxy-3-nitro-pyridin-2-ylamine (10 g, 40.32 mmol) was dissolved in tetrahydrofuran (100 mL). The reaction mixture was then treated with sponge nickel catalyst (3 g, neutral pH, THF) and hydrogen under standard pressure overnight (16 h) at room temperature. After filtration and rinsing 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. To the solution in a 1 L three-necked flask equipped with a condenser, triethyl orthoformate (219.75 mL) and formic acid (98-100% strength, 3.84 mL, 100.78 mmol) were added. The reaction mixture was then heated at 90 °C under an argon atmosphere for 3 h. For workup, the reaction mixture was evaporated in vacuo. The residue was then dissolved in methanol (approximately 150 ml), diluted with aqueous HCl solution (2.0 M strength, approximately 500 ml) and decalcified water (approximately 300 ml), followed by extraction with ethyl acetate (twice, 300 ml each). The organic layer was discarded. The aqueous layer was cooled in an ice bath and neutralized with aqueous KOH solution (47% strength, approximately 50 ml) while stirring over a period of 30 min to obtain a pH 6 solution. The precipitate formed was filtered off under suction, washed twice with decalcified water (50 ml each), and dried in a vacuum drying cabinet (65 °C for 63 h at approximately 60 mbar) to produce 6-bromo-5-methoxy-3H-imidazo[4.5-b]pyridine as a solid (6.39 g, 97.9% purity, 27.44 mmol, 68.1% yield). A second crop of the title product was obtained by extracting the remaining aqueous layer with ethyl acetate (twice, 200 mL each). The combined organic layers were dried over sodium sulfate, filtered under suction, and evaporated in vacuo to afford 6-bromo-5-methoxy-3H-imidazo[4.5-b]pyridine (1.17 g, 83.9% purity, 4.30 mmol, 10.7% yield). [M+H] + =228.0 / 230.0 (single bromine isotope distribution).

[0197] d) Synthesis of 6-bromo-1-ethyl-5-methoxy-1H-imidazo[4.5-b]pyridine 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 inertized with argon and cooled in an ice bath, maintaining the suspension at 0-5 °C. Sodium hydride suspension (60% strength in paraffin oil, 2.39 g, 59.82 mmol) was then added in portions (two portions, 1.20 g each; caution: hydrogen formation). After complete addition, the flask was again inertized with argon, and the suspension was stirred at 0-5 °C for 15 min. Iodoethane (4.54 mL, 55.04 mmol, silver-stabilized) was then added dropwise within 5 min, and stirring was continued for 30 min. Stirring was continued for 63 hours while the reaction mixture was allowed to warm up to room temperature (approximately 50% conversion). A second portion of sodium hydride suspension (60% strength in paraffin oil, 2.39 g, 59.82 mmol) was added in two portions (1.12 g each), stirring was continued for 15 minutes, and this was followed by the addition of iodoethane (4.54 mL, 55.04 mmol). After stirring at room temperature for 19 hours (approximately 32% of the starting material remained), the procedure was repeated a third time with sodium hydride suspension (60% strength in paraffin oil, 4.31 g, 107.68 mmol) and iodoethane (8.48 mL, 102.89 mmol), and the suspension was diluted with additional dry tetrahydrofuran (20.13 mL). After warming up to room temperature, stirring was continued for an additional 17 hours until the reaction was complete. For workup, the reaction mixture was quenched with saturated aqueous ammonium chloride solution (approximately 20 ml) while stirring, followed by dilution with demineralized water (approximately 300 ml) and ethyl acetate (approximately 500 ml). After stirring for an additional 30 min, the mixture was filtered and extracted twice with ethyl acetate (200 ml each). The combined organic layers were dried over sodium sulfate, filtered with suction, and evaporated to dryness.The resulting crude product was purified by flash chromatography on silica gel (330 g, solvent gradient dichloromethane / 0-0.6% vol. ethanol) to afford the title product 6-bromo-1-ethyl-5-methoxy-1H-imidazo[4.5-b]pyridine (7.95 g, 96.7% purity, 29.99 mmol, 62.7% yield, Rf 0.61 using HPTLC Silica Gel 60 F254, solvent mixture dichloromethane-ethanol 10:1, vol. / vol.) and the by-product 6-bromo-3-ethyl-5-methoxy-3H-imidazo[4.5-b]pyridine (2.40 g, 94.7% purity, 8.88 mmol, 18.6% yield) [M+H]. + =256.0 / 258.0 (single bromine isotope distribution).

[0198] e) Synthesis of 1-ethyl-5-methoxy-1H-imidazo[4,5-b]pyridine-6-carboxylic acid methyl ester 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). The reaction mixture was then treated with carbon monoxide (grade 3.7, 68 mL) at 3-5 bar CO pressure at 100 °C for 21.5 h. For workup, the resulting solution was neutralized with saturated aqueous ammonium chloride solution (5 mL), diluted with demineralized water (45 mL), and extracted four times with ethyl acetate (40 mL each). The combined organic layers were dried over sodium sulfate, filtered under suction, and evaporated to dryness. The crude product was purified by flash chromatography on silica gel (24 g, solvent gradient dichloromethane / 0-5% ethanol by volume) to afford solid 1-ethyl-5-methoxy-1H-imidazo[4,5-b]pyridine-6-carboxylic acid methyl ester (733.1 mg, 94.8% purity, 2.95 mmol, 96.2% yield). [M+H] + = 236.1, HPTLC: dichloromethane / ethanol 20:1 (vol. / vol.) R f 0.33.

[0199] f) Synthesis of 1-ethyl-2-(hydroxy-diphenyl-methyl)-5-methoxy-1H-imidazo[4,5-b]pyridine-6-carboxylic acid Under an argon atmosphere, 1-ethyl-5-methoxy-1H-imidazo[4,5-b]pyridine-6-carboxylic acid methyl ester (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. Lithium bis(trimethylsilyl)amide solution (1.0 M in THF, 1.77 mL, 1.77 mmol) was then added dropwise within 2 min, and the solution was stirred for another hour. Tetrahydrofuran (5.5 mL), decalcified water (3.55 mL), and lithium hydroxide (144 mg, 5.9 mmol) were then added, and stirring was continued for another 16 hours at room temperature. For workup, the reaction mixture was diluted with decalcified water (30 ml), basified to pH 14 with NaOH (2.0 M strength, 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% strength, approximately 8 ml) and extracted three times with ethyl acetate (40 ml each time). The combined organic layers were dried over sodium sulfate, filtered with 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, 82.9% purity, 0.94 mmol, 64.1% yield), which was used in the next step without further purification. [M+H] + =404.1.

[0200] 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 Under an argon atmosphere, 1-ethyl-2-(hydroxydiphenylmethyl)-5-methoxy-1H-imidazo[4,5-b]pyridine-6-carboxylic acid (140 mg, 82.9% purity, 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), followed by the addition of 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). 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 vol.% TFA / 15-33 vol.% acetonitrile + 0.1 vol.% TFA). The combined product fractions were basified with saturated sodium bicarbonate solution (5 mL) and subsequently extracted twice with ethyl acetate (40 mL each). The combined organic layers were dried over sodium sulfate, filtered with suction, and evaporated in vacuo. The remaining residue was then finally purified by flash chromatography on silica gel (4 g, solvent gradient: dichloromethane / 0-4.5 vol.% ethanol) to produce 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, 96.8% purity, 0.21 mmol, 73.6% yield). [M+H] + = 498.2, HPTLC: dichloromethane / ethanol 10:1, R f 0.46.

[0201] reference compound The reference compound 3-ethyl-2-[hydroxy(diphenyl)methyl]-N-[(2R)-2-hydroxypropyl]benzimidazole-5-carboxamide is available as described in WO 2015 / 175845 (compound number 79).

[0202] Table 1 Table 1, divided into Tables 1a, 1b, 1c, and 1d, lists exemplary compounds of the present invention. All compounds depicted in Table 1 (including its subtables 1a, 1b, 1c, and 1d) have been synthesized according to or analogously to the methods described above for General Syntheses 1-3 and Examples 1-8. Table 1a - Exemplary compounds of formula Ib [Table 1a-1]

[0203] [Table 1a-2]

[0204] [Table 1a-3]

[0205] [Table 1a-4]

[0206] [Table 1a-5]

[0207] Table 1b. Exemplary compounds of formula Ic [Table 1b-1]

[0208] [Table 1b-2]

[0209] [Table 1b-3]

[0210] Table 1b-4

[0211] Table 1b-5

[0212] Table 1b-6

[0213] Table 1c Exemplary compounds of Formula Ia and Table 1 Table 1c-1

[0214] Table 1c-2

[0215] Table 1d

Table 1d-1

[0216]

Table 1d-2

[0217]

Table 1d-3

[0218]

Table 1d-4

[0219]

Table 1d-5

[0220]

Table 1d-6

[0221] Table 1d-7

[0222]

Table 1d-8

[0223]

Table 1d-9

[0224]

Table 1d-10

[0225]

Table 1d-11

[0226]

Table 1d-12

[0227]

Table 1d-13

[0228]

Table 1d-14

[0229]

Table 1d-15

[0230]

Table 1d-16

[0231]

Table 1d-17

[0232]

Table 1d-18

[0233]

Table 1d-19

[0234]

Table 1d-20

[0235]

Table 1d-21

[0236]

Table 1d-22

[0237]

Table 1d-23

[0238]

Table 1d-24

[0239]

Table 1d-25

[0240]

Table 1d-26

[0241]

Table 1d-27

[0242]

Table 1d-28

[0243]

Table 1d-29

[0244]

Table 1d-30

[0245]

Table 1d-31

[0246] biological activity Biochemical activity ACSS2 assay (IC 50 ACSS2 biochemical substances) The biochemical activity assay for ACSS2 is based on the detection of released AMP using the AMP-Glo™ Assay kit (Promega, Madison). The assay is performed in three steps: an enzymatic reaction in which human recombinant (rec) ACSS2 activates acetate with ATP and coenzyme A as cosubstrates for acetyl-CoA, thereby releasing AMP; and an AMP detection reaction using the AMP Glo assay in which the generated AMP is converted to ATP after destruction of residual ATP with AMP Glo Reagent 1, which is measured in a luciferase assay system (detection reagent). ACSS2 activity correlates with the detected luminescence signal.

[0247] Assays were performed in Perkin Elmer 384-well white Proxiplates in a total volume of 8 μl.

[0248] 1 nM (fc) C-term myc-tagged ACSS2 (human, recombinant, Origene, Rockville, US) was incubated with a mixture of 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 MgCl, 150 mM NaCl, 1 mM DTT, 0.01% (w / v) BSA, 0.3% DMSO, pH 7.5) in the absence or presence of test compound (10 dilutions, starting concentration 30 μM) at 37°C for 180 min. The reaction was stopped, and residual ATP was destroyed by the addition of 1 μl AMP Glo reagent solution (Promega, Madison, US). After 1 h of incubation at room temperature, 2 μl of AMP Glo detection reagent was added, and the assay was incubated at room temperature for 0.75 h. The luminescence signal was measured at 700 nm in luminescence mode on an Envision multimode reader (Perkin Elmer LAS Germany GmbH). The full value used was the reaction without inhibitor. A pharmacological zero value was generated by adding an ACSS2 inhibitor (Ac-CoA Synthase Inhibitor - CAS 508186-14-9 - Calbiochem) at a final concentration of 5 μM. Inhibition values ​​(IC50) were determined using the program Assay Analyzer® from GeneData.

[0249] The experimental data in the IC50 ACSS2 biochemical assay for the compounds shown in Table 1 are shown in Table 2 below and are divided into the following groups: Group A IC 50 is in the range of 0.01nM to <1nM Group B IC 50 is in the range of 1nM to <10nM Group C IC 50 is in the range of 10nM to <100nM Group D IC 50 is in the range of 100nM to <10000nM

[0250] 14 A cellular assay for the incorporation of C acetate into fatty acids (IC 50 ACSS2 cellular lipids) This protocol is suitable for extracellularly administered radiolabeled 14 We describe a cellular assay that can quantify endogenous fatty acid synthesis activity in the human HCT-15 cancer cell line that has undergone C acetate incorporation using scintillation proximity-based output values ​​for extracted fatty acids.

[0251] 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 leave subconfluent, vital cultures. Working cell banks were prepared from 1 × 10 7 Aliquots containing viable cells were prepared. After thawing, the cells were immediately diluted 1:20 in pre-warmed (37°C) culture medium. The cells were collected by centrifugation at 200 × g for 5 min, and the supernatant was replaced with 30 mL of fresh culture medium per aliquot to obtain a cell suspension containing 350,000 cells / mL. 100 μL of this cell suspension was distributed into each well of a collagen-coated 96-well plate (black, clear bottom, PS, F-bottom, Greiner) and cultured for 24 h (37°C, 5% CO2). After incubation, the culture medium was removed, and the wells were filled with 100 μL PBS++ (Mg 2+ / Ca 2+ The plates are washed once with RPMI 1640 (supplemented with RPMI 1640, Gibco) and 50 μL of assay medium (RPMI 1640 + 10 mM HEPES) is added to each well.

[0252] Serial dilutions of compounds are prepared from a 10 mM stock solution in DMSO using a fixed dilution factor (usually 1:3). After preparing the dilution series in DMSO, each dilution is further diluted in assay medium. The working dilutions are prepared so that the concentration in the assay is 7x the final concentration. The highest DMSO concentration in the final assay is 0.1%.

[0253] To each well, 10 μL of working compound dilution or DMSO blank is added and cells are incubated for 2 h (37°C, 5% CO2). 14 Ten μL of AlamarBlue reagent (Invitrogen) containing C-acetate (Perkin Elmer) was added to each well (70 μL total volume), and the cells were again incubated for 2 h. Cell viability was verified by measuring AlamarBlue fluorescence (Tecan Safire, ex: 544 nm / em: 590 nm). After incubation, the culture medium was removed, and the wells were carefully washed once with 100 μL PBS++. For cell lysis and fatty acid recovery, 50 μL of 0.1 M NaOH and 0.1% Triton-X100 was added per well. The plate was sealed with PlateLoc (peelable transparent heat seal, Agilent) and incubated at 70°C for 16–24 h. After cooling to room temperature, the plate was centrifuged at 1000 rpm for 1 min, and the plate seal was removed. To acidify the wells, 150 μL of 0.1 M HCl was added and mixed, and 150 μL of the mixture was transferred into a 96-well FlashPlate (Perkin Elmer). The plate was sealed with TopSeal-A (Perkin Elmer). The plate was incubated at 70°C for 4 h to allow the fatty acids to bind to the well surface. After cooling to room temperature, the plate was centrifuged at 1000 rpm for 1 min and stored at room temperature in the dark for 0.5 to 2 h. 14 Radioactivity from the incorporation of C into fatty acids is measured as CPM counts in a MicroBeta scintillation counter (Perkin Elmer).

[0254] The IC of the compounds listed in Table 1 50 The experimental data in the ACSS2 cell lipid assay are displayed in Table 2 below and are divided into the following groups: Group A IC 50 is in the range of 0.01nM to <1nM Group B IC 50 is in the range of 1nM to <10nM Group C IC 50is in the range of 10nM to <100nM Group D IC 50 is in the range of 100nM to <10000nM

[0255] 14 A cellular assay for the incorporation of C acetate into histones (IC 50 ACSS2 Cell Histones) This protocol is suitable for extracellularly administered radiolabeled 14 We describe a cellular assay that can quantify endogenous histone acetyltransferase activity in the human HCT-15 cancer cell line after C-acetate incorporation using scintillation-based readouts on acid-extracted histones.

[0256] HCT-15 cells are trypsinized, washed, and suspended in DMEM culture medium supplemented with penicillin / streptomycin (100 U / mL), sodium pyruvate (1 mM), and 10% FBS.

[0257] Serial dilutions of compounds are prepared in a 96-well V-bottom microplate from a 10 mM stock solution in DMSO. 0.5 μl of these dilutions are transferred to a new plate containing pure DMSO as a negative control. Dilutions are prepared so that the final concentration in the assay is 1 / 400 of the concentration in the serial dilutions. The final DMSO concentration in the assay is 0.25%.

[0258] The cell suspension was diluted to 2 x 10 cells per 170 μl. 5 Cells are seeded into individual wells of a 96-well plate (each containing a 0.5 μl aliquot of serial compound dilutions) at a density of 0.5 μl per well and kept in a cell incubator for 1 h. Each well is dosed with 0.5 μl of 0.5 μl of Ci / mL. 14 30 μL of a mixture containing C-acetate with full medium is added, and the wells are then incubated in a cell incubator for 3 hours.

[0259] Further steps of the procedure are performed on ice or the instrument is pre-cooled to 4°C. Cells are deposited in a 96-well V-bottom microplate by centrifugation (Eppendorf 5804 R) at 1200 rpm for 5 min. The supernatant is removed, and the cells are washed twice with 200 μL of PBS-NaB (5 mM sodium butyrate) buffer by repeated resuspension and centrifugation. Finally, the cells are resuspended in 50 μL of TEB (PBS-NaB + 0.5% Triton X-100) and left on ice for 10 min. After centrifugation at 2300 rpm for 10 min at 4°C, the supernatant is removed, and the remaining pellet is suspended in 50 μL of 0.2 M HCl and incubated overnight at 4°C. After incubation, the well plate is shaken for 2 min on an MTP plate shaker set at 1200 rpm, then centrifuged at 3700 rpm for 10 min. The lysate is carefully aspirated (~43 μL) and transferred into a white MTP plate (Greiner bio-one 65509). 90 μL of Ultima Gold XR scintillation cocktail is added and the plate is sealed with clear cover tape before being mixed vigorously using a plate shaker set at 1200 rpm. 14 Radioactivity from C incorporation is measured as CPM counts in a MicroBeta Trilux luminescence counter.

[0260] The IC of the compounds listed in Table 1 50 The experimental data for the ACSS2 cell histone assay are displayed in Table 2 below and are categorized into the following groups: Group A IC 50 is in the range of 0.01nM to <1nM Group B IC 50 is in the range of 1nM to <10nM Group C IC 50 is in the range of 10nM to <100nM Group D IC 50 is in the range of 100nM to <10000nM

[0261] Micronucleus assay (MNT) The in vitro MNT assay is performed in CHO-K1 cells due to their stable and well-characterized karyotype, high sensitivity, and suitability for high-content imaging approaches: they have a basal spontaneous micronuclei frequency of 3-4%.

[0262] 24 hours after plating, CHO-K1 cells are treated with test compounds for 24 hours (in duplicate; fixed concentrations range from 0.2 μM to 100 μM in two-fold dilution steps). After changing the medium, cells are incubated with cytochalasin B for 24 hours to block cytokinesis, then fixed and visualized with a DNA stain for nuclei / micronuclei. Images are acquired with a Molecular Devices high-content imager IXU or IXM and analyzed with the dedicated MetaXpress software micronucleus module. The criteria for scoring micronuclei (MN) are as follows: The diameter of the MN should be less than 1 / 3 of the macronucleus. The MN is separated from or slightly overlaps the macronucleus (= no blebs) MNs should have similar staining to macronuclei

[0263] At least 1000 binucleated cells are evaluated for each treatment replicate. Mitomycin C is used as a reference stimulator for micronucleation. Cytotoxicity is assessed in parallel and defined by comparing the total nuclei counts in compound-treated samples to neutral control samples treated with vehicle (1% DMSO) only (100% cytotoxicity means all cells are dead or lost).

[0264] A test compound is considered positive if it can be observed at the same concentration that it produces micronuclei and exhibits less than 60% cytotoxicity (data values ​​are considered positive if they contain more micronuclei than the mean value of the neutral control plus 3 standard deviations).

[0265] A compound is reported as NEGATIVE if no micronuclei formation can be observed at concentrations that exhibit less than 60% cytotoxicity and at least one tested concentration gives more than 60% cytotoxicity. Compounds are reported as PN (presumed negative) if they do not produce micronuclei and exhibit less than 60% cytotoxicity at any concentration tested.

[0266] If a compound exhibits greater than 60% cytotoxicity at a concentration - regardless of whether it produces micronuclei - it is reported as ND (not determinable) at that concentration.

[0267] Compounds are scored only in the soluble concentration range. Experimental data in the MNT assay for the compounds listed in Table 1 are displayed in Table 2 below and are grouped into the following groups: Group A: Negative, presumed negative (micronuclei detected above the threshold of 60% cytotoxicity) Group B positive

[0268] Table 2 [Table 2-1]

[0269] [Table 2-2]

[0270] [Table 2-3]

[0271] [Table 2-4]

[0272] [Table 2-5]

[0273] [Table 2-6]

[0274] The following examples relate to pharmaceuticals: Example A: Injection vial A solution of 100 g of the active ingredient of formula Ia, Ib, or Ic and 5 g of disodium hydrogen phosphate in 3 L of double-distilled water is adjusted to pH 6.5 with 2 N hydrochloric acid, sterile filtered, transferred into injection vials, lyophilized under sterile conditions, and sealed under sterile conditions, each injection vial containing 5 mg of the active ingredient.

[0275] Example B: Suppositories A mixture of 20 g of an active ingredient of formula Ia, Ib, or Ic, 100 g of soybean lecithin, and 1400 g of cocoa butter is melted and poured into molds and allowed to cool. Each suppository contains 20 mg of the active ingredient.

[0276] Example C: Solution Prepare a solution of 1 g of the active ingredient of formula Ia, Ib, or Ic, 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. Adjust the pH to 6.8, make up to 1 L, and sterilize by irradiation. This solution can be used in the form of eye drops.

[0277] Example D: Ointment 500 mg of an active ingredient of Formula Ia, Ib, or Ic is mixed with 99.5 g of petrolatum under aseptic conditions.

[0278] Example E: Tablets A mixture of 1 kg of the active ingredient of Formula Ia, Ib, or Ic, 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 give tablets, each tablet containing 10 mg of the active ingredient.

[0279] Example F: Sugar-coated tablets Tablets are compressed similarly to Example E and then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth, and dye.

[0280] Example G: Capsule 2 kg of the active ingredient of formula Ia, Ib, or Ic is conventionally introduced into hard gelatin capsules, each containing 20 mg of the active ingredient.

[0281] Example H: Ampoule A solution of 1 kg of the active ingredient of formula Ia, Ib, or Ic in 60 L of double-distilled water is sterile-filtered into ampoules, lyophilized under sterile conditions, and sealed under sterile conditions, each ampoule containing 10 mg of the active ingredient.

Claims

1. Formula Ia, Ib, or Ic 【Chemistry 1】 wherein, independently of one another, R 1 Ar A or Hetar A Showing; R 2 Ar B or Hetar B Showing; R 3 is C 1～6 -Aliphatic or -OC 1～6 -indicating aliphatic; R 4 H, D, C 1～6 -Aliphatic, or -OC 1～6 -indicating aliphatic; R 5 H, D, C 1～6 -aliphatic, -OC 1～6 -Aliphatic, or halogen; R 6 Hetar C or -CH 2 -Hetar C Showing; Ar A is a mono- or biaryl having 5, 6, 7, 8, 9, 10, or 11 ring carbon atoms, where the aryl may be unsubstituted or may contain a substituent R A1 , R A2 , R A3 , R A4 , and / or R A5 and optionally substituted with, said substituents may be the same or different; Ar B is a mono- or biaryl having 5, 6, 7, 8, 9, 10, or 11 ring carbon atoms, where the aryl may be unsubstituted or may contain a substituent R B1 , R B2 , R B3 , R B4 , and / or R B5 and optionally substituted with, said substituents may be the same or different; 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 ring atoms are heteroatom(s) selected from N, O, and / or S, and the remainder are carbon atoms, wherein the heteroaryl may be unsubstituted or may contain a substituent R A1 , R A2 , R A3 , R A4 , and / or R A5 and optionally substituted with, said substituents may be the same or different; 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 ring atoms are heteroatom(s) selected from N, O, and / or S, and the remainder are carbon atoms, wherein the heteroaryl may be unsubstituted or may contain a substituent R B1 , R B2 , R B3 , R B4 , and / or R B5 and optionally substituted with, said substituents may be the same or different; 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 ring atoms are heteroatom(s) selected from N, O, and / or S, and the remainder are carbon atoms, wherein the heteroaryl may be unsubstituted or may contain a substituent R C1 , R C2 , R C3 , R C4 , and / or R C5 and optionally substituted with, said substituents may be the same or different; 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, independently of each other, H, D, halogen, C 1～6 -aliphatic, -OC 1～6 -Aliphatic; Halogen denotes F, Cl, Br, or I; or any N-oxide, solvate, tautomer, or stereoisomer, and / or any pharmaceutically acceptable salt of each of the above, and mixtures thereof in any ratio.

2. R in the formula 1 and R 2 has the same meaning, or any N-oxide, solvate, tautomer, or stereoisomer, and / or any pharmaceutically acceptable salt of each of the above, and mixtures thereof in any ratio.

3. R in the formula 1 and R 2 has a different meaning, or any N-oxide, solvate, tautomer, or stereoisomer, and / or any pharmaceutically acceptable salt of each of the above, and mixtures thereof in any ratio.

4. During the ceremony Ar A is unsubstituted, or R A1 and / or R A2 phenyl optionally mono- or di-substituted by R A1 and / or R A2 is as defined in any one of claims 1 to 3; or is trideuterophenyl, tetradeuterophenyl, or pentadeuterophenyl; Ar B is unsubstituted, or R B1 and / or R B2 phenyl optionally mono- or di-substituted by R B1 and / or R B2 is as defined in any one of claims 1 to 3; or is trideuterophenyl, tetradeuterophenyl, or pentadeuterophenyl; Hetar A is a monocyclic heteroaryl having 5 or 6 ring atoms, or a bicyclic heteroaryl having 10 ring atoms, wherein one or two of the ring atoms are heteroatom(s) selected from N, O, and / or S, and the remainder are carbon atoms, wherein the heteroaryl is unsubstituted or contains a substituent R A1 and / or R A2 and optionally substituted with, said substituents may be the same or different; Hetar B is a monocyclic heteroaryl having 5 or 6 ring atoms, wherein one or two of the ring atoms are heteroatom(s) selected from N, O, and / or S, and the remainder are carbon atoms, wherein the heteroaryl may be unsubstituted or may contain a substituent R B1 and / or R B2 wherein said substituents may be the same or different, An amide derivative according to any one of claims 1 to 3, or any N-oxide, solvate, tautomer or stereoisomer, and / or any pharmaceutically acceptable salt of each of the above, and mixtures thereof in all proportions.

5. R in the formula A1 , R A2 , R B1 , R B2 However, independently of each other, H, D, F, Cl, C 1～4 -aliphatic, -OC 1～4 - an amide derivative according to claim 4, or any N-oxide, solvate, tautomer or stereoisomer, and / or any pharmaceutically acceptable salt of each of the above, which is aliphatic, and mixtures thereof in all proportions.

6. wherein, independently of one another, R 3 is substituted or unsubstituted C 1～4 - denotes alkyl; R 4 indicates H; R 5 But H, C 1～4 -Alkyl, -OC 1～4 - denotes alkyl, F, or Cl, 6. The amide derivative according to any one of claims 1 to 5, or any N-oxide, solvate, tautomer or stereoisomer, and / or any pharmaceutically acceptable salt of each of the above, and mixtures thereof in all proportions.

7. During the ceremony R 6 But -CH 2 -Hetar C or Hetar C Showing; Hetar C is a monocyclic heteroaryl having 5 or 6 ring atoms, wherein 1, 2, or 3 of the ring atoms are heteroatom(s) selected from N, O, and / or S, and the remainder are carbon atoms, wherein the heteroaryl may be unsubstituted or may contain a substituent R C1 and / or R C2 and optionally substituted with, said substituents may be the same or different; R C1 , R C2 is H or substituted or unsubstituted C 1～4 -alkyl, where R C1 and R C2 At least one of them is not H, 7. The amide derivative according to any one of claims 1 to 6, or any N-oxide, solvate, tautomer or stereoisomer, and / or any pharmaceutically acceptable salt of each of the above, and mixtures thereof in all proportions.

8. During the ceremony R 6 But, Hetar C Showing; Hetar C is a monocyclic heteroaryl having five ring atoms, where two or three of the ring atoms are heteroatom(s) selected from N and / or O, and the remainder are carbon atoms, where the heteroaryl may be unsubstituted or may contain one substituent R C1 may be substituted with; R C1 represents ethyl, 2-aminoethyl, 2-hydroxyethyl, and 2-methoxyethyl; 8. The amide derivative according to any one of claims 1 to 7, or any N-oxide, solvate, tautomer or stereoisomer, and / or any pharmaceutically acceptable salt of each of the above, and mixtures thereof in all proportions.

9. wherein, independently of one another, R 3 denotes methyl, ethyl, 2-dimethylaminoethyl, 2-hydroxyethyl, 2-methoxyethyl; R 4 indicates H; R 5 denotes H, methyl, ethyl, methoxy, F, or Cl; R 6 But, Hetar C Showing; Ar A is phenyl; pentadeuterophenyl; 2-fluorophenyl; 2-methylphenyl; 2-methoxyphenyl; 4-difluoromethoxyphenyl; 4-difluoromethoxy-2-fluorophenyl; Ar B is phenyl; pentadeuterophenyl; 2-fluorophenyl; 2-methylphenyl; 4-difluoromethoxyphenyl; Hetar A are 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl; thien-2-yl, thien-3-yl; 5-methylthien-2-yl; 1,3-thiazol-2-yl; pyridin-2-yl; pyrimidin-4-yl; pyridazin-3-yl; quinolin-2-yl; Hetar B is thien-2-yl, thien-3-yl; 5-methylthien-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, 9. The amide derivative according to any one of claims 1 to 8, or any N-oxide, solvate, tautomer or stereoisomer, and / or any pharmaceutically acceptable salt of each of the above, and mixtures thereof in all proportions.

10. The amide derivative is the following compound: Table 1 Table 2 Table 3 Table 4 Table 5 Table 6 Table 7 Table 8 Table 9 Table 10 Table 11 Table 12 Table 13 Table 14 Table 15 Table 16 Table 17 Table 18 Table 19 Table 20 Table 21 Table 22 Table 23 Table 24 Table 25 Table 26 Table 27 Table 28 Table 29 Table 30 Table 31 Table 32 Table 33 Table 34 Table 35 Table 36 Table 37 Table 38 Table 39 Table 40 Table 41 Table 42 Table 43 Table 44 selected from the group consisting of 10. The amide derivative according to any one of claims 1 to 9, or any N-oxide, solvate, tautomer or stereoisomer, and / or any pharmaceutically acceptable salt of each of the above, and mixtures thereof in all proportions.

11. 11. A pharmaceutical composition comprising the amide derivative of any one of claims 1 to 10, or any N-oxide, solvate, tautomer, or stereoisomer, and / or any pharmaceutically acceptable salt of each of the above, and mixtures thereof in all ratios.

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, or any N-oxide, solvate, tautomer or stereoisomer, and / or any pharmaceutically acceptable salt of each of the above, and mixtures thereof in any ratio, for use in the prevention and / or treatment of a medical condition or disease that is affected by inhibiting ACSS2.

13. The following conditions are considered: cancer; inflammatory disorders or diseases, Crohn's disease, ulcerative colitis, idiopathic pulmonary fibrosis, muscular dystrophy, rheumatoid arthritis, and systemic sclerosis (scleroderma); neurodegenerative disorders or diseases, Huntington's disease; lipid metabolism disorders, NASH (non-alcoholic steatohepatitis), NAFLD (non-alcoholic fatty liver disease), fatty liver disease; viral infections; post-traumatic stress disorder (PTSD); bipolar disorder, depression, Tourette's syndrome, schizophrenia, obsessive-compulsive disorder, anxiety disorder, panic disorder, phobias, alcohol, tobacco, opioids 11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, or any N-oxide, solvate, tautomer, or stereoisomer, and / or any pharmaceutically acceptable salt of each of the above, and mixtures thereof in all ratios, for use in the prevention and / or treatment of a medical condition or disease selected from the group consisting of addictions including addiction to steroids, sedatives, hypnotics, anxiolytics, cocaine, cannabis, amphetamines, hallucinogens, inhalants, phencyclidine, impulse control disorders, behavioral addictions.

14. A pharmaceutical composition comprising at least one amide derivative according to any one of claims 1 to 10, or any N-oxide, solvate, tautomer or stereoisomer, and / or any pharmaceutically acceptable salt of each of the above, and mixtures thereof in any ratio, as an active ingredient together with a pharmaceutically acceptable carrier.

15. 15. The pharmaceutical composition of claim 14, further comprising a second active ingredient, or any of the N-oxides, solvates, tautomers, or stereoisomers, and pharmaceutically acceptable salts of each of the above, and mixtures thereof in any ratio, wherein the second active ingredient is other than the amide derivative of formula Ia, Ib, or Ic as defined in any one of claims 1 to 10.

16. a) an effective amount of an amide derivative of formula Ia, Ib, or Ic according to any one of claims 1 to 10, or any N-oxide, solvate, tautomer, or stereoisomer, and / or any pharmaceutically acceptable salt of each of the above, and mixtures thereof in any ratio; and b) an effective amount of a further active ingredient which is not an amide derivative of formula Ia, Ib or Ic as defined in any one of claims 1 to 10. Includes separate packs, sets (kits).

17. A process for the preparation of an amide derivative of formula Ia, Ib, or Ic according to any one of claims 1 to 10, or any N-oxide, solvate, tautomer, or stereoisomer, and / or any pharmaceutically acceptable salt of each of the above, comprising: (a) General formula II-a 【Chemistry 2】 (R in the formula 1 , R 2 , R 3 , R 4 , and R 5 is as defined in any one of claims 1 to 9) is a carboxylic acid represented by formula III: R 6 -NH 2 (III) (R in the formula 6 is as defined in any one of claims 1 to 9) to an amidation reaction with a compound of formula Ia: 【Transformation 3】 (R in the formula 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is as defined in any one of claims 1 to 9) An amide derivative represented by the formula: or (b) General formula II-b 【Chemistry 4】 (R in the formula 1 , R 2 , R 3 , R 4 , and R 5 is as defined in any one of claims 1 to 9), is a carboxylic acid represented by formula III: R 6 -NH 2 (III) (R in the formula 6 is as defined in any one of claims 1 to 9) to an amidation reaction with a compound of formula Ib: 【Transformation 5】 (R in the formula 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is as defined in any one of claims 1 to 9) An amide derivative represented by the formula: or (c) General formula II-c 【Transformation 6】 (R in the formula 1 , R 2 , R 3 , R 4 , and R 5 is as defined in any one of claims 1 to 9) is a carboxylic acid represented by formula III: R 6 -NH 2 (III) (R in the formula 6 is as defined in any one of claims 1 to 9) to an amidation reaction with a compound of formula Ic: 【Transformation 7】 (R in the formula 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is as defined in any one of claims 1 to 9) The amide derivative represented by The process characterized in that

18. Formula II-a, II-b, or II-c 【Transformation 8】 (R in the formula 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is as defined in any one of claims 1 to 9) A carboxylic acid represented by the formula:

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