Tetrazolyl derivatives

Abstract

The present invention relates to substituted tetrazole derivatives. These compounds are useful for the prevention and / or treatment of several medical conditions, including hyperproliferative disorders and diseases.

Description

Technical Field

[0001] The present invention relates to substituted tetrazole derivatives. These compounds are useful for inhibiting acetyl-CoA synthetase 2 (ACSS2) and for preventing and / or treating several medical conditions, including hyperproliferative disorders and diseases affected by ACSS2 activity. Background Art

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

[0003] In recent years, the effect of acetate metabolism on cancer cell proliferation has become more and more concerned in the development of cancer research and cancer therapy. It has been shown that some tumors mainly utilize acetate to produce energy, while other tumors mainly utilize acetate to synthesize lipids (i.e. biomass) or regulate histone acetylation and therefore gene transcription (ZTSchug, et al., Nature Reviews Cancer 16,707-717 (2016)). In all these processes, acetate is converted into acetyl-CoA by acetyl-CoA synthetase ACSS through the ACSS1 of mitochondrial positioning or the ACSS2 of nuclear cytoplasm positioning. Therefore, acetyl-CoA is an important metabolite of cancer cells, not only related to the energy production in mitochondria, but also related to lipid and fatty acid synthesis in cancer cell cytosol and histone acetylation in nucleus.

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

[0005] Prior art

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

[0007] WO 2020 / 252407 A1 discloses certain benzimidazole derivatives as inhibitors of ACSS2. Summary of the invention

[0008] It is an object of the present invention to provide compounds useful for the prevention and / or treatment of medical conditions, disorders and / or diseases, in particular hyperproliferative disorders / diseases, which compounds are inhibitors of ACSS2.

[0009] This object is unexpectedly solved by the compounds of the present invention. The present invention provides tetrazole derivatives of formula Ia, Ib or Ic

[0010]

[0011] Which independently

[0012] R 1 Ar A or Hetar A ;

[0013] R 2 Ar B or Hetar B ;

[0014] R 3 Represents C 1-6 -Aliphatic or -OC 1-6 - aliphatic;

[0015] R 4 Indicates H, D, C 1-6 -Aliphatic or -OC 1-6 - aliphatic;

[0016] R 5 Indicates H, D, C 1-6 -Aliphatic, -OC 1-6 - aliphatic or halogen;

[0017] Ar A is a monoaryl or diaryl group having 5, 6, 7, 8, 9, 10 or 11 ring carbon atoms, wherein the aryl group may be unsubstituted or substituted by the same or different substituents R A1 , R A2 , R A3 , R A4 and / or R A5 replace;

[0018] Ar B is a monoaryl or diaryl group having 5, 6, 7, 8, 9, 10 or 11 ring carbon atoms, wherein the aryl group may be unsubstituted or substituted by the same or different substituents R B1 , R B2 , R B3 , R B4 and / or R B5 replace;

[0019] HetarA 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 heteroatoms selected from N, O and / or S and the rest are carbon atoms, wherein the heteroaryl may be unsubstituted or substituted by substituents R which may be the same or different A1 , R A2 , R A3 , R A4 and / or R A5 replace;

[0020] 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 heteroatoms selected from N, O and / or S and the rest are carbon atoms, wherein the heteroaryl may be unsubstituted or substituted by substituents R which may be the same or different B1 , R B2 , R B3 , R B4 and / or R B5 replace;

[0021] R A1 , R A2 , R A3 , R A4 , R A5 , R B1 , R B2 , R B3 , R B4 , R B5 are independently H, D, halogen, C 1-6 -Aliphatic, -OC 1-6 - aliphatic;

[0022] Halogen means F, Cl, Br or I;

[0023] or 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.

[0024] In general, all residues, free radicals, substituents, groups, moieties etc. which occur more than once may be identical or different, i.e. independent of one another. Unless expressly indicated otherwise, the residues and parameters above and below have the meanings indicated for formula Ia, Ib or Ic. Therefore, the present invention particularly relates to compounds of formula Ia, Ib or Ic, wherein at least one of the residues, free radicals, substituents has one of the preferred meanings indicated below.

[0025] Unless otherwise indicated, any of those particular or even preferred embodiments of the invention as specified below or in the claims refers not only to the specified compounds of formula Ia, Ib or Ic, but also to derivatives, N-oxides, prodrugs, solvates, tautomers or stereoisomers thereof and pharmaceutically acceptable salts of each of the foregoing, also including mixtures thereof in all ratios.

[0026] In a specific embodiment PE1, the compound of the invention is a tetrazole 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 means that, for example, if R 1 Ar A , then R 2 Ar B , which in turn represents the same as for R 1 The same Ar A , that is, it is the same substituent; similarly, if R 1 Hetar A , then R 2 Hetar B , which in turn refers to the same 1 Same Hetar A (ie, it is the same substituent).

[0027] Other specific embodiments of the present invention (designated PE2) are tetrazoles 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 In this embodiment, the substituent R 1 and R 2 For example, if R 1 represents 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 the Ar attached to the carbon atom substituted with the hydroxyl group. A The attachment point is at the 2-methyl group, and the other is hydrogen), then R 2 May be Hetar as defined hereinB or Ar other than 2-methylphenyl B .

[0028] It must be recognized that any tetrazole derivative of PE2 carrying different substituents R 1 and R 2 has a chiral center at the carbon atom of because that carbon atom will then be substituted by four different substituents.

[0029] In yet another specific embodiment of the present invention (designated PE3), the tetrazole derivative of the present invention is a tetrazole 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 the substituent R 1 and R 2 are all independently monocyclic, that is,

[0030] Ar A is phenyl, which may be unsubstituted or substituted by R A1 , R A2 , R A3 , R A4 , R A5 mono-, di-, tri-, tetra- or pentasubstituted;

[0031] Ar B is phenyl, which may be unsubstituted or substituted by R B1 , R B2 , R B3 , R B4 , R B5 mono-, di-, tri-, tetra- or pentasubstituted;

[0032] Hetar A is a monocyclic heteroaryl group having 5 or 6 ring atoms, wherein 1 or 2 of the ring atoms are heteroatoms selected from N, O and / or S and the rest are carbon atoms, wherein the heteroaryl group may be unsubstituted or replaced by R A1 , R A2 , R A3 , R A4 , R A5 mono-, di-, tri-, tetra- or pentasubstituted;

[0033] Hetar B is a monocyclic heteroaryl group having 5 or 6 ring atoms, wherein 1 or 2 of the ring atoms are heteroatoms selected from N, O and / or S and the rest are carbon atoms, wherein the heteroaryl group may be unsubstituted or replaced by R B1 , R B2 , R B3 , RB4 , R B5 mono-, di-, tri-, tetra- or pentasubstituted;

[0034] 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 Can be the same or different.

[0035] If R 1 and R 2 The same, that is, has the same meaning, then PE3 is also within the scope of PE1. Similarly, if R 1 and R 2 Do not have the same meaning, PE3 is within the scope of PE2.

[0036] In a preferred specific embodiment PE3a of PE3,

[0037] Ar A is phenyl, which may be unsubstituted or substituted by R A1 and / or R A2 mono- or disubstituted;

[0038] Ar B is phenyl, which may be unsubstituted or substituted by R B1 and / or R B2 mono- or disubstituted;

[0039] Hetar A is a monocyclic heteroaryl group having 5 or 6 ring atoms, wherein 1 or 2 of the ring atoms are heteroatoms selected from N, O and / or S and the rest are carbon atoms, wherein the heteroaryl group may be unsubstituted or substituted by substituents R which may be identical or different A1 and / or R A2 replace;

[0040] Hetar B is a monocyclic heteroaryl group having 5 or 6 ring atoms, wherein 1 or 2 of the ring atoms are heteroatoms selected from N, O and / or S and the rest are carbon atoms, wherein the heteroaryl group may be unsubstituted or substituted by substituents R which may be identical or different B1 and / or R B2 replace.

[0041] In yet another preferred particular embodiment PE3b of PE3a,

[0042] R A1 , R A2 , R B1 , R B2 H, F, Cl, C independently of each other 1-4 -Aliphatic, -OC 1-4 -Aliphatic.

[0043] If the substituent Ar is a phenyl group in PE3a A Substituted group R A1 or R A2 Monosubstituted, the substituent R A1 or R A2 Preferably, it is located at the 2-position or 4-position of the benzene ring. A By R A1 and R A2 If disubstituted, the two substituents, which may be identical or different, are preferably located in the 2-position and 4-position of the phenyl ring.

[0044] Similarly, if the phenyl substituent Ar in PE3a B Substituted group R B1 or R B2 Monosubstituted, the substituent R B1 or R B2 Preferably, it is located at the 2-position or 4-position of the benzene ring. B By R B1 and R B2 If disubstituted, the two substituents, which may be identical or different, are preferably located in the 2-position and 4-position of the phenyl ring.

[0045] In yet another specific embodiment PE4, the tetrazole derivative of the present invention is a tetrazole 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 independently of one another

[0046] R 3 Represents C 1-4 -alkyl, preferably C 1-2 -alkyl, which is unsubstituted or monosubstituted by -OH or -NH2;

[0047] R 4 Indicates H;

[0048] R 5 Indicates H, C 1-4 -alkyl, -OC 1-4 -alkyl, F or Cl; preferably H, C 1-2 -alkyl, -OC 1-2 -alkyl, F or Cl;

[0049] and, wherein the remaining radicals, residues, groups or substituents are as defined above generally for Formulas Ia, Ib and Ic or for any other specific embodiments described above (ie, PE1, PE2, PE3, PE3a, PE3b).

[0050] In yet another specific embodiment PE5, the tetrazole derivative of the present invention is a tetrazole 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 independently of one another

[0051] R 1 Ar A or Hetar A ;

[0052] R 2 Ar B or Hetar B ;

[0053] R 3 represents methyl, ethyl, 2-aminoethyl or 2-hydroxyethyl;

[0054] R 4 Indicates H;

[0055] R 5 represents H, methyl, ethyl, methoxy, F or Cl;

[0056] Ar A is phenyl; deuterated phenyl, preferably pentadeuterated phenyl; fluorophenyl, preferably 2-fluorophenyl; methylphenyl (tolyl), preferably 2-methylphenyl; difluoromethoxy, preferably 4-difluoromethoxy; 4-difluoromethoxy-2-fluorophenyl;

[0057] Ar B is phenyl; deuterated phenyl, preferably pentadeuterated phenyl; fluorophenyl, preferably 2-fluorophenyl; methylphenyl (tolyl), preferably 2-methylphenyl; difluoromethoxy, preferably 4-difluoromethoxy; 4-difluoromethoxy-2-fluorophenyl;

[0058] Hetar A is methylpyrazolyl, preferably 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl; thiophene-2-yl, thiophene-3-yl; methylthiophene, preferably 5-methylthiophene-2-yl; thiazolyl, preferably 1,3-thiazol-2-yl; pyridin-2-yl, pyridin-3-yl, pyridin-4-yl; pyrimidinyl, preferably pyrimidin-2-yl, pyrimidin-4-yl; pyridazinyl, preferably pyridazin-3-yl;

[0059] HetarB It is methylpyrazolyl, preferably 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl; thiophene-2-yl, thiophene-3-yl; methylthiophene, preferably 5-methylthiophene-2-yl; thiazolyl, preferably 1,3-thiazol-2-yl; pyridin-2-yl, pyridin-3-yl, pyridin-4-yl; pyrimidinyl, preferably pyrimidin-2-yl, pyrimidin-4-yl; pyridazinyl, preferably pyridazin-3-yl.

[0060] If R 1 and R 2 is the same, i.e. has the same meaning, then this is another specific embodiment PE5a of PE5. Similarly, if R 1 and R 2 Not having the same meaning, this is yet another specific embodiment PE5b of PE5.

[0061] In yet another specific embodiment PE6, the tetrazole derivative of the present invention is selected from the compounds of formula Ia (i.e., 1H-imidazo[4,5-b]pyridine derivatives), or any derivatives, N-oxides, prodrugs, solvates, tautomers or stereoisomers thereof and / or any pharmaceutically acceptable salts of each of the foregoing, including mixtures thereof in all ratios, wherein R 1 , R 2 , R 3 , R 4 and R 5 As defined in claim 1 or for any of the specific embodiments PE1, PE2, PE3, PE3a, PE3b, PE4, PE5, PE5a, PE5b. In a specific specific embodiment PE6a of PE6,

[0062] R 1 represents phenyl, 2-methylphenyl, 2-fluorophenyl, 1-methylpyrazol-4-yl, thiophen-2-yl, thiophen-3-yl, 1,3-thiazol-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl; pyrimidin-2-yl, pyrimidin-4-yl, pyridazin-3-yl, 4-difluoromethoxy; 4-difluoromethoxy-2-fluorophenyl;

[0063] R 2 represents phenyl, 2-methylphenyl, 2-fluorophenyl, thiophen-2-yl, thiophen-3-yl;

[0064] R 3 represents methyl, ethyl, 2-aminoethyl, 2-hydroxyethyl; preferably methyl or ethyl;

[0065] R 4 is H;

[0066] R 5It is H, methyl, methoxy, Cl; preferably methoxy.

[0067] In another specific embodiment PE6b of PE6 or PE6a, R 1 and R 2 In another specific embodiment PE6c of PE6 or PE6a, R 1 and R 2 are different.

[0068] In yet another specific embodiment PE7, the tetrazole derivative of the present invention is selected from the compounds of formula Ib (i.e., pyrazolo[1,5]a]pyridine derivatives), or any derivatives, N-oxides, prodrugs, solvates, tautomers or stereoisomers thereof and / or any pharmaceutically acceptable salts of each of the foregoing, including mixtures thereof in all ratios, wherein R 1 , R 2 , R 3 , R 4 and R 5 As defined in claim 1 or for any of the specific embodiments PE1, PE2, PE3, PE3a, PE3b, PE4, PE5, PE5a, PE5b. In a specific specific embodiment PE7a of PE7,

[0069] R 1 represents phenyl, 2-fluorophenyl;

[0070] R 2 represents phenyl, 2-fluorophenyl;

[0071] R 3 represents ethyl;

[0072] R 4 is H;

[0073] R 5 are H, methoxy, F, Cl;

[0074] In another specific embodiment PE7b of PE7 or PE7a, R 1 and R 2 In another specific embodiment PE7c of PE7 or PE7a, R 1 and R 2 are different.

[0075] In yet another specific embodiment PE8, the tetrazole derivative of the present invention is selected from the compounds of formula Ic (i.e., imidazo[1,2-a]pyridine derivatives), or any derivative, N-oxide, prodrug, solvate, tautomer or stereoisomer thereof and / or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios, wherein R 1 , R 2 , R 3 , R 4 and R 5 As defined in claim 1 or for any of the specific embodiments PE1, PE2, PE3, PE3a, PE3b, PE4, PE5, PE5a, PE5b. In a specific specific embodiment PE8a of PE8,

[0076] R 1 represents phenyl, 2-fluorophenyl, 1-methylpyrazol-3-yl, 5-methylthiophen-2-yl, 1,3-thiazol-2-yl, pyridin-2-yl, pyrimidin-2-yl;

[0077] R 2 represents phenyl, 2-fluorophenyl;

[0078] R 3 represents ethyl;

[0079] R 4 is H;

[0080] R 5 It is ethyl, methoxy, F, Cl; preferably methoxy.

[0081] In another specific embodiment PE8b of PE8 or PE8a, R 1 and R 2 In another specific embodiment PE8c of PE8 or PE8a, R 1 and R 2 are different.

[0082] In yet another specific embodiment PE9, the tetrazole derivative of formula Ia, Ib or Ic is selected from the compounds shown in Table 1 (which is divided into Tables 1a, 1b, 1c, 1d, 1e, 1f, 1g, 1h, 1i and 1j) 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.

[0083] As used herein, the following definitions shall apply to a particular substituent, radical, residue, group or moiety unless stated otherwise or specifically defined elsewhere in the specification and / or claims.

[0084] As used herein, the term "aliphatic" or "aliphatic group" refers to a straight (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain, which is fully saturated or contains one or more unsaturated units, or a monocyclic hydrocarbon, a bicyclic hydrocarbon, or a tricyclic hydrocarbon, which is fully saturated or contains one or more unsaturated units, such as one or more C=C double bonds and / or C≡C triple bonds, but is not aromatic (also referred to herein as "carbocycle", "alicyclic" or "cycloalkyl"), which generally and if not otherwise defined in this specification or the appended claims, has 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, an aliphatic group contains 1-3 aliphatic carbon atoms, and in yet other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "alicyclic" ("cycloalkyl") refers to a monocyclic C3-C7 hydrocarbon that is fully saturated or contains one or more unsaturated units, but 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 alicyclic ring system that is fused to an aromatic, heteroaromatic or heterocyclic ring or ring system via 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, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0085] The term "alkyl" generally refers to saturated aliphatic and acyclic moieties, while the term "alkenyl" generally refers to unsaturated aliphatic and acyclic moieties having one or more C=C double bonds, and the term "alkynyl" generally refers to aliphatic and acyclic moieties having one or more C≡C triple bonds. Exemplary aliphatic groups are straight or branched, substituted or unsubstituted C 1-8 -alkyl, C 1-6 -alkyl, C 1-4 -alkyl, C 2-8 -Alkenyl, C 2-6 -Alkenyl, C 2-8 -Alkynyl, C 2-6 -alkynyl and its hybrids, for example (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0086] In particular, the term "C 1-3 "-alkyl" refers to an alkyl group having 1, 2 or 3 carbon atoms, i.e., a saturated acyclic aliphatic group. Exemplary C1-3 -alkyl is methyl, ethyl, propyl and isopropyl. The term "C 1-4 "-alkyl" refers to an alkyl group having 1, 2, 3 or 4 carbon atoms. Exemplary C 1-4 Alkyl is 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 is 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 is 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 (except for C1-alkyl and C2-alkyl) branched and may be unsubstituted or substituted with 1, 2 or 3 substituents which may be the same or different and, if not otherwise specified elsewhere in the specification, are selected from halogen, hydroxy, alkoxy, unsubstituted or mono- or disubstituted amino.

[0087] In some cases, C 1-3 -alkyl, C 1-4 -alkyl, C 1-6 -alkyl, C 1-8 -Alkyl groups may also comprise residues in which one or two of the non-terminal and non-adjacent -CH2-(methylene) groups are replaced by -O-, -S- and / or one or two of the non-terminal and non-adjacent -CH2- or -CH- groups are replaced by -NH- or -N-. These replacements result, for example, in (modified) alkyl groups such as -CH2-CH2-O-CH3, -CH2-CH2-CH2-S-CH3, CH2-CH2-NH-CH2-CH3, CH2-CH2-O-CH2-CH2-O-CH3, CH2-CH2-N(CH3)-CH2-CH3, etc. For specific alkyl substituents or free radicals elsewhere in the specification and / or claims, further and / or different replacements of -CH- and -CH2- groups may be defined.

[0088] The term "C 3-7 "-Cycloalkyl" refers to alicyclic hydrocarbons as defined above having 3, 4, 5, 6 or 7 ring carbon atoms. 3-7-Cycloalkyl may be unsubstituted or substituted by 1, 2 or 3 substituents (unless specified differently elsewhere in the specification), which substituents may be the same or different and, unless specified differently elsewhere in the specification, are selected from C 1-6 -Alkyl, OC 1-6 -alkyl (alkoxy), halogen, hydroxy, unsubstituted or mono- or di-substituted amino. 3-7 -Cycloalkyl is cyclopropyl, 2-methyl-cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl.

[0089] The term "aliphatic oxy" refers to a saturated or unsaturated aliphatic group or substituent as defined above, attached to another moiety via an oxygen atom (-O-). The term "alkoxy" refers to a specific subset of saturated aliphatic oxy groups, namely alkyl substituents and residues attached to another moiety via an oxygen atom (-O-). Sometimes, it is also referred to as "O-alkyl", and more specifically "OC 1-4 -alkyl", "OC 1-6 -alkyl", "OC 1-8 -O-C1-alkyl". Like similar alkyl groups, it may be linear or (except for -O-C1-alkyl and -O-C2-alkyl) branched, and may be unsubstituted or substituted with 1, 2 or 3 substituents which may be the same or different and, if not specified differently elsewhere in the specification, are selected from halogen, unsubstituted or mono- or di-substituted amino. Exemplary alkoxy groups are methoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy.

[0090] The term "alkylene" refers to a divalent aliphatic group, and in particular a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) x -, wherein x is a positive integer, preferably 1, 2, 3, 4, 5 or 6. In the context of the present invention, "C 1-3 "-alkylene" refers to an alkylene moiety having 1, 2, and 3 -CH2- groups, respectively; however, the term "alkylene" includes not only straight-chain alkylene, i.e., "alkylene chain", but also branched-chain alkylene. The term "C 1-6 "-alkylene" refers to an alkylene moiety which is linear, i.e., an alkylene chain, or branched and has 1, 2, 3, 4, 5, or 6 carbon atoms. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced by a substituent (or substituted by a substituent). Suitable substituents include those described herein for substituted alkyl groups. In some cases, 1 or 2 methylene groups of the alkylene chain may be replaced by, for example, O, S and / or NH or NC1-4 Exemplary alkylene groups are -CH2-, -CH2-CH2-, -CH2-CH2-CH2-CH2-, -O-CH2-O-, -O-CH2-CH2-O-, -O-CH2-CH2-CH2-O-, -CH2-NH-CH2-CH2-, -CH2-N(CH3)-CH2-CH2-.

[0091] The term "alkenylene" refers to a divalent alkenyl group. Substituted alkenylene chains are polymethylene groups containing at least one double bond in which one or more hydrogen atoms are replaced by substituents. Suitable substituents include those described herein for substituted aliphatic groups.

[0092] 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 by a substituent. Suitable substituents include those described herein for substituted aliphatic groups.

[0093] The term "halogen" refers to F, Cl, Br or I.

[0094] The term "heteroatom" refers to one or more of oxygen (O), sulfur (S) or nitrogen (N), including any oxidized form of nitrogen or sulfur, such as N-oxide, sulfoxide and sulfone; any basic nitrogen or quaternized form of a 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, where SUB is a suitable substituent (as in N-substituted pyrrolidinyl).

[0095] The term "aryl", used alone or as part of a larger moiety such as "aralkyl", "aralkyloxy" or "aryloxyalkyl", refers to monocyclic, bicyclic and tricyclic ring systems having a total of 5-14 ring members, the ring members being carbon atoms, wherein at least one ring in the system is aromatic, i.e., it has (4n+2)π (π) electrons (wherein n is an integer selected from 0, 1, 2, 3), the electrons being delocalized on the system, and wherein each ring in the system contains 3-7 ring members. Preferably, all rings in the aryl system or the entire ring system is aromatic. The term "aryl" is used interchangeably with the term "aromatic ring". In certain embodiments of the present invention, "aryl" refers to an "aromatic ring system". More specifically, those aromatic ring systems may be monocyclic, bicyclic or tricyclic rings having 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 ring carbon atoms. Even more specifically, those aromatic ring systems can be monocyclic or bicyclic with 6, 7, 8, 9, 10 ring carbon atoms. The term "monoaryl" refers to monocyclic aromatic groups. The term "biaryl" refers to bicyclic aromatic groups. Exemplary aromatic groups are phenyl, biphenyl, naphthyl, anthracenyl, etc., which can 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 used herein are groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, etc. In the latter case, the "aryl" or substituent is attached to its side group via the aromatic portion of the ring system.

[0096] The term "benzo" refers to a six-membered aromatic ring (having carbon ring atoms) fused to another ring via two adjacent carbon atoms, which is alicyclic, aromatic, heteroaromatic or heterocyclic (heteroaliphatic) ring; the result is a ring system having at least two rings, wherein the benzo ring shares two common carbon atoms with the other ring to which it is fused. For example, if a benzo ring is fused to a benzene ring, a naphthalene ring system is formed, while fusion of a benzo ring to pyridine provides quinoline or isoquinoline.

[0097] The terms "heteroaryl" and "heteroar-", used alone or as part of a larger moiety such as "heteroaralkyl" or "heteroaralkoxy", refer to groups having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 ring atoms (the atoms being carbon and heteroatoms), preferably 5, 6, 9 or 10 ring atoms; sharing 6, 10 or 14 π (pi) electrons in a cyclic array; and having 1, 2, 3, 4 or 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl includes, but is not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, furazanyl, pyridinyl (pyridyl), pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl and pyrrolopyridinyl, particularly pyrrolo[2,3-b]pyridinyl. As used herein, the terms "heteroaryl" and "heteroar-" also include groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic or heterocyclyl rings, wherein the radical or point of attachment is preferably on the heteroaromatic, or, if present, on the aryl ring. Non-limiting examples include indolyl, isoindolyl, benzothiophenyl (benzothienyl), benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, 9H-carbazolyl, dibenzofuranyl and pyrido [2,3-b] -1,4-oxazine -3 (4H) -one. For example, the indolyl ring can be attached via one ring atom of a six-membered aryl ring or via one ring atom of a five-membered heteroaryl ring. The heteroaryl group is optionally monocyclic, bicyclic or tricyclic. The term "heteroaryl" is used interchangeably with the terms "heteroaryl ring", "heteroaryl" or "heteroaromatic", any of which include rings that are unsubstituted or substituted with one or more substituents that are the same or different. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group, wherein the alkyl and heteroaryl portions are independently optionally substituted.

[0098] The heteroaryl ring may be attached to its pendant group at any heteroatom or carbon ring atom thereof where such attachment results in a stable structure or molecule: any ring atom may be unsubstituted or substituted.

[0099] The structures of typical examples of "heteroaryl" substituents used in the present invention are shown below:

[0100]

[0101]

[0102]

[0103] Those heteroaryl substituents may be attached to any pendant group via any ring atom which is suitable for such attachment.

[0104] When used in reference to a ring atom of a heterocyclic ring, 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, nitrogen is N (such as in 3,4-dihydro-2H-pyrrolyl), NH (such as in pyrrolidinyl) or N-SUB, wherein SUB is a suitable substituent (such as in N-substituted pyrrolidinyl).

[0105] As used herein, the term "unsaturated" means that a moiety or group or substituent has one or more units of unsaturation.

[0106] The terms "bicyclic", "bicyclic ring" or "bicyclic ring system" as used herein refer to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or having one or more unsaturated units (i.e., partially unsaturated) or aromatic, with one or more common atoms between the two rings of the ring system. Therefore, the term includes any permissible ring fusion, such as ortho-fusion or spirocyclic. The term "heterobicyclic" as used herein is a subset of "bicyclic", which requires that one or more heteroatoms are present in one or both rings of the bicyclic ring. Such heteroatoms may be present at the ring junction and are optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms, such as sulfones and sulfonates), phosphorus (including oxidized forms, such as phosphates), boron, etc. In some embodiments, the bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Likewise, the term "tricyclic", "tricyclic ring" or "tricyclic system" refers to any tricyclic system, i.e., carbocyclic or heterocyclic, saturated and or with one or more unsaturated units (i.e., partially unsaturated) or aromatic, wherein a bicyclic system (as defined above) is fused to another third ring. Therefore, the term includes any permissible ring fusion. The term "heterotricyclic" as used herein is a subset of "tricyclic", which requires that one or more heteroatoms are present in one or two rings of the tricyclic. Such heteroatoms may be present at the ring junction and 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, the tricyclic group has 10-14 ring members and 0-5 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0107] As described herein, certain compounds of the present invention contain "substituted" or "optionally substituted" moieties. In general, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. "Substituted" applies to one or more hydrogens, either explicitly or implicitly from the structure. Unless otherwise specified, a "substituted" or "optionally substituted" group has a suitable substituent at each substitutable position of the group, and when more than one position in any given structure is substituted with more than one substituent selected from the designated group, the substituents are the same or different at each position. If a group, substituent, moiety or radical is "monosubstituted", it carries one (1) substituent. If it is "disubstituted", it carries two (2) substituents that are the same or different; if it is "trisubstituted", it carries three (3) substituents, all three of which are the same, or two are the same and the third is different, or all three are different from each other. Combinations of substituents contemplated by the 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 not substantially altered when subjected to conditions that allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0108] If not otherwise stated elsewhere in the specification or appended claims, it is understood that each optional substituent on a substitutable carbon is independently selected from the following monovalent substituents: halogen; -(CH2) 0-4 R o ; -(CH2) 0- 4OR o ; -O(CH2) 0-4 R o ,-O-(CH2) 0-4 C(O)OR o ; -(CH2) 0-4 CH(OR o )2; -(CH2) 0-4 SR o ; -(CH2) 0-4 Ph, which can be represented by one or more R o Substitution; -(CH2) 0-4 O(CH2) 0-1 Ph, which can be represented by one or more R o Substituted; -CH=CHPh, which may be replaced by one or more R o Substitution; -(CH2) 0-4 O(CH2) 0-1 -pyridyl, which may be replaced by one or more R o Substitution; -NO2; -CN; -N3; ​​-(CH2)0-4 N(R o )2;-(CH2) 0-4 N(R o )C(O)R o ;-N(R o )C(S)R o ;-(CH2) 0-4 N(R o )C(O)NR o 2;-N(R o )C(S)NR o 2;-(CH2) 0-4 N(R o )C(O)OR o ;-N(R o )N(R o )C(O)R o ;-N(R o )N(R o )C(O)NR o 2;-N(R o )N(R o )C(O)OR o ;-(CH2) 0-4 C(O)R o ;-C(S)R o ;-(CH2) 0-4 C(O)OR o ;-(CH2) 0-4 C(O)SR o ;-(CH2) 0-4 C(O)OSiR o 3;-(CH2) 0-4 OC(O)R o ;-OC(O)(CH2) 0-4 SR-;SC(S)SR o ;-(CH2) 0-4 SC(O)R o ;-(CH2) 0-4 C(O)NR o 2;-C(S)NR o 2;-C(S)SR o ;-SC(S)SR o ,-(CH2) 0-4 OC(O)NR o 2;-C(O)N(OR o )R o ;-C(O)C(O)R o ;-C(O)CH2C(O)R o ;-C(NOR o )Ro ; -(CH2) 0-4 SSR o ; -(CH2) 0-4 S(O)2R o ; -(CH2) 0-4 S(O)2OR o ; -(CH2) 0-4 OS(O)2R o ; -S(O)2NR o 2; -S(O)(NR o )R o ; -S(O)2N=C(NR o 2)2;-(CH2) 0-4 S(O)R o ;-N(R o )S(O)2NR o 2;-N(R o )S(O)2R o ;-N(OR o )R o ; -C(NH)NR o 2;-P(O)2R o ;-P(O)R o 2;-OP(O)R o 2;-OP(O)(OR o )2;SiR o 3;-(C 1-4 Straight or branched alkylene)ON(R o )2; or -(C 1-4 Straight or branched alkylene)C(O)ON(R o )2. It is understood that "Ph" means phenyl; and "-(CH2) 0-4 ” refers to the absence of an alkylene group (if the subscript is “0” (zero)) or an alkylene group having 1, 2, 3 or 4 CH2 units.

[0109] Each R o are independently hydrogen, halogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -CH2-(5-6 membered heteroaryl ring) or a 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, notwithstanding the above definitions, two independent occurrences of R o Together with their one or more intervening atoms, they form a 3-12 membered saturated, partially unsaturated or aromatic monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be selected from =O and =S. oA divalent substituent on a saturated carbon atom; or each R o Optionally substituted with monovalent substituents independently selected from: halogen, -(CH2) 0-2 R · 、-(haloR · )、-(CH2) 0-2 OH, -(CH2) 0-2 OR · 、-(CH2) 0-2 CH(OR · )2. -O(haloR · )、-CN、-N3、-(CH2) 0-2 C(O)R · 、-(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR · 、-(CH2) 0-2 SR · 、-(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR · 、-(CH2) 0-2 NR · 2. -NO2, -SiR · 3. -OSiR · 3. -C(O)SR · 、-(C 1-4 Straight or branched alkylene)C(O)OR · or -SSR · It is understood that "Ph" refers to phenyl; "halo" refers to halogen; and "-(CH2) 0-2 ” means that there is no alkylene group (if the subscript is “0” (zero)) or an alkylene group having 1 or 2 CH2 units.

[0110] Each R · Independently selected from C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph or a 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, and wherein each R · is unsubstituted or, when preceded by halo, substituted only by one or more halogens; or wherein the optional substituents on the saturated carbon are divalent substituents 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 the divalent substituent bonded to the adjacent substitutable carbon of the "optionally substituted" group is -O(CR * 2) 2-3 O-, where each independent occurrence of R * Selected from hydrogen, C 1-6 An aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0111] When R * C 1-6 When aliphatic, R * Optionally halogen, -R · 、-(haloR · ), -OH, -OR · 、-O(haloR · )、-CN、-C(O)OH、-C(O)OR · 、-NH2、-NHR · 、-NR · 2, or -NO2 substituted, wherein each R · Independently selected from C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph or a 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, and wherein each R · is unsubstituted or, when preceded by halo, substituted only by one or more halogens.

[0112] The optional substituents on the substitutable nitrogen are independently Each of these are independently hydrogen, C 1-6 aliphatic, unsubstituted -OPh, or an unsubstituted 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or two independent occurrences of Together with their one or more intervening atoms, they form an unsubstituted 3-12-membered saturated, partially unsaturated or aromatic monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; wherein when C 1-6 When aliphatic, Optionally halogen, -R · 、-(haloR · ), -OH, -OR · 、-O(haloR · )、-CN、-C(O)OH、-C(O)OR · 、-NH2、-NHR · 、-NR · 2 or -NO2, where each R · Independently selected from C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, and wherein each R · is unsubstituted or, when preceded by halo, substituted only by one or more halogens. It is understood that "Ph" means phenyl; and "halo" means halogen.

[0113] In the context of the present invention, the term "derivative" refers to any non-toxic salt, ester, salt of an ester or other derivative of a compound of the present invention which, upon administration to a recipient, is capable of directly or indirectly providing a compound of the present invention or an inhibitory metabolite or residue thereof.

[0114] Compound of the present invention can be in the form of prodrug compound. "Prodrug" and "prodrug compound" refer to the derivatives of the bioactive compounds according to the present invention that are converted under physiological conditions in the living body, such as by oxidation, reduction, hydrolysis, etc., wherein each is enzymatically carried out, or without enzyme participation. The example of prodrug is such compound, wherein the amino in the compound of the present invention is acylated, alkylated or phosphorylated, such as eicosanoylamino, alanylamino, pivaloyloxymethylamino, or wherein hydroxyl is acylated, alkylated, phosphorylated or converted into borate, such as acetoxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, alanyloxy, or wherein carboxyl is esterified or amidated, or wherein sulfhydryl and carrier molecule (such as peptide) form disulfide bridges, and drug selectivity can be delivered to the cytosol of target and / or cell by the carrier molecule. These compounds can be produced by the compound of the present invention according to known methods. Other examples of prodrug are such compounds, wherein the carboxylate in the compound of the present invention is for example converted into alkyl-, aryl-, choline-, amino-, acyloxymethyl esters, linolenoyl ester.

[0115] The term "solvate" refers to an addition form of a compound of the invention with a solvent, preferably a pharmaceutically acceptable solvent containing a stoichiometric or non-stoichiometric amount of the solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water, the solvate formed is a hydrate, such as a monohydrate or a dihydrate. If the solvent is an alcohol, the solvate formed is an alcoholate, such as a methanolate or an ethanolate. If the solvent is an ether, the solvate formed is an etherate, such as an etherate.

[0116] The term "N-oxide" refers to compounds of the present invention that contain an amine oxide moiety, ie, an oxide of a tertiary amine group.

[0117] The compounds of formula Ia, Ib or Ic may have one or more chiral centers. Therefore, they may exist in various enantiomeric and diastereomeric forms, as the case may be, and may be racemic or optically active forms. Therefore, the present invention also relates to optically active forms, enantiomers, racemates, diastereomers, mixtures of all ratios thereof, for purposes of the present invention, collectively referred to as "stereoisomers" of these compounds. Since the pharmaceutical activity of the racemate or stereoisomer of the compound according to the present invention may be different, it may be desirable to use a specific stereoisomer, such as a specific enantiomer or diastereomer. In these cases, the compounds according to the present invention obtained as racemates or even their intermediates may be separated into stereoisomers (enantiomers, diastereomers) compounds by chemical or physical measures known to those skilled in the art. Another method that can be used to obtain one or more specific stereoisomers of the compounds of the present invention in enriched or pure form utilizes stereoselective synthesis procedures, such as the use of starting materials in stereoisomerically enriched or pure form (e.g., using pure or enriched (R)- or (S)-enantiomers of specific starting materials with chiral centers) or the use of chiral reagents or catalysts, particularly enzymes. In the context of the present invention, the term "pure enantiomer" generally refers to a relative purity of one enantiomer relative to the other enantiomer (the enantiomer thereof) equal to or greater than 95%, preferably ≥98%, more preferably ≥98.5%, and even more preferably ≥99%.

[0118] Thus, for example, compounds of the invention which have one or more chiral centers and 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. Separation of the compounds of the invention can be carried out by chromatography, for example column separation on a chiral or non-chiral phase, or by recrystallization from an optional optically active solvent or by using an optically active acid or base or by derivatization with an optically active reagent (e.g. an optically active alcohol), and subsequent elimination of free radicals.

[0119] In the context of the present invention, the term "tautomer" refers to compounds of the present invention that can exist in tautomeric form and exhibit tautomerism; for example, carbonyl compounds can exist in their keto and / or their enol form and exhibit keto-enol tautomerism. These tautomers can exist in their individual forms, such as keto or enol form, or as mixtures thereof, and can be claimed individually and together as mixtures in any ratio. The same applies to cis / trans isomers, E / Z isomers, conformational isomers, etc.

[0120] In one embodiment, the compounds of the present invention are in the form of free base or acid, as the case may be, i.e., their non-salt (or salt-free) forms. In another embodiment, the compounds of the present invention are in the form of pharmaceutically acceptable salts, pharmaceutically acceptable solvates, or pharmaceutically acceptable solvates of pharmaceutically acceptable salts.

[0121] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable base or acid, including an inorganic base or acid and an organic base or acid. In the case where the compound of the present invention contains one or more acidic or basic groups, the present invention also includes their corresponding pharmaceutically acceptable salts. Therefore, the compound of the present invention containing an acidic group (e.g., carboxyl) can exist in the form of a salt and can be used, for example, as an alkali metal salt, an alkaline earth metal salt, an aluminum salt or an ammonium salt according to the present invention. More precise examples of such salts include lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, barium salts or salts with ammonia or an organic amine (e.g., ethylamine, ethanolamine, diethanolamine, triethanolamine, piperidine, N-methylglutamine or an amino acid). These salts are readily available, for example, by reacting a compound with 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 alkali salts of the compound of the present invention include but are not limited to copper (I), copper (II), iron (II), iron (III), manganese (II) and zinc salts. The compound of the present invention containing one or more basic groups (for example, groups that can be protonated) can exist in salt form, and can be used in the form of addition salts with inorganic or organic acids according to the present invention. The example of suitable acid includes hydrogen chloride, hydrogen bromide, hydrogen iodide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalene disulfonic 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, pamoic 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 well known to those skilled in the art. The salt formed is especially hydrochloride, chloride, hydrobromide, bromide, iodide, sulfate, phosphate, mesylate (mesylate), toluenesulfonate, carbonate, bicarbonate, formates, acetate, sulfoacetate, trifluoromethanesulfonate, oxalate, malonate, maleate, succinate, tartrate, malate, pamoate, mandelate, fumarate, lactate, citrate, glutarate, stearate, aspartate and glutamate. In addition, the stoichiometry of the salt formed by the compounds of the present invention can be an integer multiple or a non-integer multiple of one.

[0122] Compounds of the invention containing basic nitrogen-containing groups may be quaternized using agents such as (C1-C4) alkyl halides, such as methyl, ethyl, isopropyl and tert-butyl chlorides, bromides and iodides; di(C1-C4) alkyl sulfates, such as dimethyl, diethyl and diamyl sulfates; (C1-C4) alkyl halides, such as methyl, ethyl, isopropyl and tert-butyl chlorides, bromides and iodides; 10 -C 18) alkyl halides, such as decyl, dodecyl, tetradecyl and octadecyl chlorides, bromides and iodides; and aryl (C1-C4) alkyl halides, such as benzyl chloride and phenethyl bromide. Both water-soluble and oil-soluble compounds according to the present invention can be prepared using such salts.

[0123] If the compound of the present invention contains both acidic and basic groups in the molecule, the present invention also includes inner salts or betaines (zwitterions) in addition to the salt forms described. The corresponding salts can be obtained by conventional methods known to those skilled in the art, for example by contacting these with organic or inorganic acids or bases in solvents or dispersants, or by anion exchange or cation exchange with other salts. The present invention also includes all salts of the compounds of the present invention, which are not directly suitable for use in medicines due to their low physiological compatibility, but which can be used, for example, as intermediates in chemical reactions or for the preparation of pharmaceutically acceptable salts.

[0124] Therefore, the following items also conform to the present invention:

[0125] (a) all stereoisomers or tautomers of the compounds, including mixtures thereof in all ratios;

[0126] (b) prodrugs of the compounds, or stereoisomers or tautomers of these prodrugs;

[0127] (c) the compounds and pharmaceutically acceptable salts of the items mentioned in (a) and (b);

[0128] (d) pharmaceutically acceptable solvates of the compounds and items mentioned in (a), (b) and (c);

[0129] (e) Compounds and N-oxides of the items mentioned in (a), (b), (c) and (d).

[0130] It should be understood that all references above and below to compounds are meant to include these items, in particular pharmaceutically acceptable solvates of the compounds, or pharmaceutically acceptable salts thereof.

[0131] In addition, it is intended that the compounds of the present invention include isotopically labeled forms thereof. An isotopically labeled form of a compound of Formula Ia, Ib or Ic is identical to such a compound except that one or more atoms of the compound are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally occurring in nature. Examples of isotopes that are readily commercially available and can be incorporated into the compounds of the present invention by known methods include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, respectively, such as 2 H(D), 3 H. 13 C. 14 C.15 N. 18 O. 17 O. 31 P. 32 P. 33 S. 34 S. 35 S. 36 S. 18 F and 36 Cl. Compounds of Formula Ia, Ib or Ic or pharmaceutically acceptable salts thereof containing 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 Formula Ia, Ib or Ic can be used in a number of beneficial ways. For example, compounds into which, for example, a radioactive isotope (e.g. 3 H or 14 C) of the present invention are suitable for drug and / or substrate tissue distribution assays. These radioactive isotopes (i.e., tritium ( 3 H) and carbon-14 ( 14 C)) is particularly preferred due to its simple preparation and excellent detectability. Heavier isotopes (e.g. deuterium ( 2 H)) incorporation into a compound of Formula Ia, Ib or Ic has therapeutic advantages due to the higher metabolic stability of the isotopically labeled compound. Higher metabolic stability directly translates into increased in vivo half-life or lower dosage, which in most cases represents a preferred embodiment of the present invention. Isotopically labeled compounds of Formula Ia, Ib or Ic can generally be prepared by following the procedures disclosed in the synthetic schemes and related descriptions in the Examples section and the Preparation section herein, substituting readily available isotopically labeled reactants for non-isotopically labeled reactants.

[0132] deuterium( 2 H; D) 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 a change in the rate of a chemical reaction caused by the exchange of isotopic nuclei, which in turn is caused by a change in the ground state energy required to form a covalent bond after the isotope exchange. The exchange of heavier isotopes generally results in a decrease in the ground state energy of the chemical bond and therefore causes a decrease in the rate of rate-limiting bond breaking. If the bond breaking occurs in or near the saddle point region along the coordinates of the multi-product reaction, the product distribution ratio can be significantly changed. To explain: if deuterium is bonded to a carbon atom in a non-exchangeable position, the typical rate difference is k M / k D= 2-7. If this rate difference is successfully applied to oxidation-sensitive compounds of formula Ia and Ib, the in vivo properties of the compounds may be significantly altered and lead to improved pharmacokinetic properties.

[0133] When discovering and developing therapeutic agents, those skilled in the art attempt to optimize pharmacokinetic parameters while maintaining desired in vitro properties. It is reasonable to assume that many compounds with poor pharmacokinetic properties are susceptible to oxidative metabolism. Currently available in vitro liver microsomal assays provide valuable information about this type of oxidative metabolic process, which in turn allows 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 properties of compounds of Formula Ia, Ib or Ic are thereby obtained, and can be tailored based on in vivo half-life (t1 / 2), maximum therapeutic concentration (C max ), increase in area under the dose-response curve (AUC), and F; and quantified in terms of reduced clearance, dose, and material cost.

[0134] The following is intended to illustrate the above: Compounds of formula Ia, Ib or Ic having multiple potential sites of attack for oxidative metabolism, such as benzylic hydrogen atoms and hydrogen atoms bonded to nitrogen atoms, are prepared as a series of analogs in which various combinations of hydrogen atoms are replaced by deuterium atoms, such that some, most or all of these hydrogen atoms are replaced by deuterium atoms. The half-life determination enables an advantageous and accurate determination of the degree of improvement in antioxidant metabolism. In this way, it was determined that the half-life of the parent compound can be extended by up to 100% due to this type of deuterium-hydrogen exchange.

[0135] Deuterium-hydrogen exchange in the compound of the present invention can also be used to realize the favorable modification of the metabolite spectrum of the starting compound, to reduce or eliminate undesirable toxic metabolites. For example, if toxic metabolites are produced by oxidative carbon-hydrogen (CH) bond rupture, it can be reasonably assumed that the deuterated analog will greatly reduce or eliminate the generation of unwanted metabolites, even if specific oxidation is not a rate-determining step. Further information about the prior art of deuterium-hydrogen exchange can be found in, for example, 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.

[0136] Furthermore, the present invention relates to a pharmaceutical composition comprising as an active ingredient at least one compound of formula Ia, Ib or Ic or a derivative, prodrug, solvate, tautomer or stereoisomer thereof and a pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios, and a pharmaceutically acceptable carrier.

[0137] For the purposes of the present invention, the term "pharmaceutical composition" (or "pharmaceutical preparation") refers to a composition or product comprising one or more active ingredients and one or more inert ingredients constituting a carrier, as well as any product produced directly or indirectly by the combination, complexation or aggregation of any two or more ingredients, or by the dissociation of one or more ingredients, or by other types of reactions or interactions of one or more ingredients. Therefore, the pharmaceutical composition of the present invention includes any composition prepared by mixing at least one compound of the present invention and a pharmaceutically acceptable carrier. It may further contain physiologically acceptable excipients, auxiliary agents, adjuvants, diluents and / or additional pharmaceutically active substances in addition to the compound of the present invention.

[0138] Pharmaceutical compositions include compositions and pharmaceutical preparations suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular and intravenous), ocular (eye), pulmonary (nasal or buccal inhalation) or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the condition being treated and the nature of the active ingredient. They may conveniently be presented in unit dosage form and prepared by any method well known in the art of pharmacy.

[0139] The pharmaceutical composition of the present invention may additionally include one or more other compounds as active ingredients (drugs), such as one or more other compounds of the present invention. In a particular embodiment, the pharmaceutical composition further includes a second active ingredient or a derivative thereof, a prodrug, a solvate, a tautomer or a stereoisomer and a pharmaceutically acceptable salt of each of the foregoing, including mixtures of all ratios thereof, wherein the second active ingredient is not a compound of formula Ia, Ib or Ic; preferably, the second active ingredient is a compound that can be used to treat, prevent, inhibit and / or improve a medical condition or pathology, and the compound of the present invention can also be used for the condition or pathology, and the condition or pathology is listed elsewhere above or below. Such a combination of two or more active ingredients or drugs can be safer or more effective than a single drug or active ingredient, or the combination is safer or more effective than expected based on the additive properties of a single drug. Such one or more other drugs can be administered by the route and amount that are usually used simultaneously or successively with the compound of the present invention. When the compound of the present invention is used simultaneously with one or more other drugs or active ingredients, it is preferably a combination product containing such one or more other drugs and the compound of the present invention, also referred to as a "fixed dose combination". However, combination therapy also includes therapies in which the compounds of the present invention and one or more other drugs are administered in different overlapping schedules. It is expected that when used in combination with other active ingredients, the compounds of the present invention or other active ingredients or both can be effectively used at lower doses than when each is used alone. Therefore, in addition to the compounds of the present invention, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients.

[0140] The compounds of the present invention or their derivatives, N-oxides, prodrugs, solvates, tautomers or stereoisomers and / or pharmaceutically acceptable salts of each of the foregoing (including mixtures of all ratios thereof) can be used as drugs. It has been found that they exhibit pharmacological activity by inhibiting acetyl-CoA synthetase (ACSS2). Compared with other ACSS2 inhibitors known in the art, they may also exhibit lower levels (if any) of CYP induction, particularly CYP3A4 induction. In addition, when tested for genotoxicity in the MNT (micronucleus) in vitro assay, they may exhibit improved properties, i.e., negative MNT assay readout, compared with the ACSS2 inhibitors of the prior art.

[0141] Therefore, the compounds of the present invention are particularly useful as ACSS2 inhibitors for the treatment, prevention, inhibition and / or amelioration of hyperproliferative disorders and cancers, particularly tumors, including solid tumors of the bladder, breast, colorectum, colon, kidney, liver, lung, head and neck, esophagus, bladder, gallbladder, ovary, pancreas, stomach, cervix, thyroid, prostate and skin, including 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 myeloid leukemia, myelodysplastic syndrome and promyelocytic leukemia; fibrosarcoma, rhabdomyosarcoma; mantle cell lymphoma, myeloma; astrocytoma, neuroblastoma, glioma, glioblastoma, malignant glioma, astrocytoma, hepatocellular carcinoma, gastrointestinal stromal tumor ("GIST") and schwannoma; melanoma, multiple myeloma, seminoma, teratoma, osteosarcoma, pigmented atopic dermatosis, keratoacanthoma, follicular thyroid carcinoma, endometrial carcinoma, gastrointestinal cancer and Kaposi's sarcoma; acanthoma, acinar cell carcinoma, acoustic neuroma, acral pigmented melanoma, apical spiral tumor, acute eosinophilic leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute myeloblastic leukemia with maturation, acute myeloid dendritic cell leukemia Blood disease, acute myeloid leukemia, acute promyelocytic leukemia, enamel epithelioma, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatous odontogenic tumor, adrenocortical carcinoma, adult T-cell leukemia, aggressive NK-cell leukemia, AIDS-related cancer, AIDS-related lymphoma, alveolar soft tissue sarcoma, ameloblastic fibroma, anal cancer, anaplastic large cell lymphoma, anaplastic thyroid cancer, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, appendix cancer, astrocytoma, atypical teratoid rhabdomyosarcoma, basal cell carcinoma, basaloid carcinoma, B-cell leukemia, B-cell lymphoma, renal tubule carcinoma, biliary tract cancer, bladder cancer, blastoma, bone cancer, bone tumor, brain stem glioma, brain tumor, breast cancer, ovarian fibroepithelioma , bronchiolar carcinoma, bronchioloalveolar carcinoma, brown tumor, Burkitt's lymphoma, carcinoid tumor, carcinoma, carcinosarcoma, giant lymphadenopathy, embryonal tumors of the central nervous system, cerebellar astrocytoma, cerebral astrocytoma, cervical cancer, bile duct cancer, chondroma, chondrosarcoma, chordoma, choriocarcinoma, choroid plexus papilloma, chronic lymphocytic leukemia, chronic monocytic leukemia, chronic myeloid leukemia, chronic myeloproliferative disorder, chronic neutrophilic leukemia, clear cell renal cell carcinoma, clear cell tumor, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, protuberant cutaneous fibrosarcoma, dermoid cyst, desmoplastic small round cell tumor, diffuse large B-cell lymphoma, dysembryoplastic neuroepithelioma, embryonal carcinoma,Endodermal sinus tumor, endometrial carcinoma, endometrial uterine carcinoma, endometrioid tumor, enteropathy-associated T-cell lymphoma, ependymoma, ependymoma, epithelioid sarcoma, erythroleukemia, esophageal cancer, sensory neuroblastoma, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, extramammary Paget's disease, fallopian tube cancer, fibroma, fibrosarcoma, follicular thyroid cancer, gallbladder cancer, ganglioglioma, ganglioneuroma, gastric cancer, gastric lymphoma, gastrointestinal cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, germ cell tumor, germ cell tumor, gestational choriocarcinoma, gestational trophoblastic tumor, giant cell tumor of bone, glioblastoma multiforme, glioma, glioma cerebri, glomus tumor, pancreatic hyperglycemia leukemia, gonadoblastoma, granulosa cell tumor, hairy cell leukemia, head and neck cancer, heart cancer, hemangioblastoma, hemangiopericytoma, angiosarcoma, hematological malignancies, hepatocellular carcinoma, hepatosplenic T-cell lymphoma, Hodgkin lymphoma, hypopharyngeal cancer, hypothalamic glioma, inflammatory breast cancer, intraocular melanoma, islet cell carcinoma, juvenile myelomonocytic leukemia, Kaposi's sarcoma, kidney cancer, Kraskin tumor, Krukenberg tumor, laryngeal cancer, malignant lentigo melanoma, leukemia, lip and oral cancer, liposarcoma, lung cancer, luteoma, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoid leukemia, lymphoma, macroglobulinemia, malignant fibrous histiocytoma, malignant glioma, malignant mesothelioma, malignant peripheral nerve sheath tumor, malignant rhabditis Tumor, malignant salamander tumor, malt lymphoma, mantle cell lymphoma, mast cell leukemia, mediastinal germ cell tumor, mediastinal tumor, medullary thyroid cancer, medulloblastoma, medulloepithelioma, melanoma, meningioma, Merkel cell carcinoma, mesothelioma, metastatic squamous neck cancer with occult primary cancer, metastatic urothelial carcinoma, mixed Mullerian tumor, monocytic leukemia, oral cancer, myxoma, multiple endocrine neoplasia syndrome, multiple myeloma, mycosis fungoides, myelodysplastic disease, myeloid leukemia, myeloid sarcoma, myeloproliferative disease, myxoma, nasal cancer, nasopharyngeal cancer, neoplasm, schwannoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, non-Hodgkin lymphoma, non-melanoma skin cancer, non Small cell lung cancer, ocular oncology, oligoastrocytoma, oligodendroglioma, large oncocytoma, optic nerve sheath meningioma, oral cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant tumor, Pankhurst tumor, pancreatic cancer, papillary thyroid cancer, papillomatosis, ganglioneuroma, paranasal sinus cancer, parathyroid cancer, penile cancer, perivascular epithelioid cell tumor, pharyngeal cancer, pheochromocytoma, intermediate differentiated pineal parenchymal tumor, pineoblastoma, pituitary cell tumor, pituitary adenoma, pituitary tumor, plasma cell neoplasm, pleuropulmonary blastoma, polyembryoma, precursor T-lymphoblastic lymphoma, primitive neuroectodermal tumor, prostate cancer, pseudomyxoma peritonei, rectal cancer, renal cell carcinoma,Retinoblastoma, rhabdomyosarcoma, rhabdomyosarcoma, Richter transformation, sacrococcygeal teratoma, salivary gland carcinoma, sarcoma, schwannomatosis, sebaceous gland carcinoma, secondary neoplasms, seminoma, serous tumor, Sertoli-Leydig cell tumor, germ cord-stromal tumor, Sesely syndrome, signet ring cell carcinoma, skin cancer, blue round cell tumor, small cell carcinoma, small cell lung cancer, small cell lymphoma, small intestinal cancer, soft tissue sarcoma, somatostatinoma, mottled wart tumor, spinal tumor, splenic marginal zone lymphoma, squamous cell carcinoma, gastric cancer, surface spreading melanoma, supratentorial primitive neuroectodermal tumor, surface 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, advanced lymphoma, testicular cancer, thecoma, laryngeal cancer, thymic cancer, thymoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter, transitional cell cancer, urachal cancer, urethral cancer, urogenital neoplasms, uterine sarcoma, uveal melanoma, vaginal cancer, Fermor syndrome, wart cancer, optic pathway glioma, vulvar cancer, Waldenstrom's macroglobulinemia, Warthin's tumor, Wilms' tumor, or any combination thereof. However, since the activity of ACSS2 also plays a role in acetyl-CoA synthesis in normal cells (i.e., non-cancer) cells, the compounds of the present invention can also be used to treat, prevent, inhibit and / or improve inflammatory conditions or diseases, in particular Crohn's disease, ulcerative colitis, idiopathic pulmonary fibrosis, muscular dystrophy, rheumatoid arthritis and systemic sclerosis (scleroderma); neurogenic conditions or diseases, in particular Huntington's disease; lipid metabolism conditions, such as NASH (non-alcoholic steatohepatitis), NAFLD (non-alcoholic fatty liver disease), fatty liver disease; viral infections, such as infection with cytomegalovirus; post-traumatic stress disorder (PTSD); bipolar disorder, depression, Tourette syndrome, schizophrenia, obsessive-compulsive disorder, anxiety, panic disorder, phobia, addiction, such as addiction to alcohol, tobacco, opioids, sedatives, hypnotics, anxiolytics, cocaine, marijuana, amphetamines, hallucinogens, inhalants, phencyclidine, impulse control disorders, behavioral addictions.

[0142] In a particular embodiment, the compounds of the invention are used to prevent and / or treat (especially treat) any of the conditions or diseases listed above, preferably cancer, especially tumors, including solid tumors of the specific types of cancer disclosed in the preceding paragraphs; inflammatory conditions or diseases, especially Crohn's disease, ulcerative colitis, idiopathic pulmonary fibrosis, muscular dystrophy, rheumatoid arthritis and systemic sclerosis (scleroderma); neurogenic conditions or diseases, especially Huntington's disease; lipid metabolism conditions, such as NASH (non-alcoholic steatohepatitis), NAFLD (non-alcoholic fatty liver disease), fatty liver disease; viral infections, such as infection with cytomegalovirus; post-traumatic stress disorder (PTSD); bipolar disorder, depression, Tourette's syndrome, schizophrenia, obsessive-compulsive disorder, anxiety, panic disorder, phobia, addiction, addiction to, for example, alcohol, tobacco, opioids, sedatives, hypnotics, anxiolytics, cocaine, cannabis, amphetamines, hallucinogens, inhalants, phencyclidine, impulse control disorders, behavioral addictions.

[0143] Another specific embodiment of the present invention is a method for preventing and / or treating (preferably treating) a disorder or disease selected from the group consisting of: hyperproliferative disorders and cancers, in particular tumors, including solid tumors of the specific types of cancer disclosed in the preceding paragraphs; inflammatory disorders or diseases, in particular Crohn's disease, ulcerative colitis, idiopathic pulmonary fibrosis, muscular dystrophy, rheumatoid arthritis and systemic sclerosis (scleroderma); neurogenic disorders or diseases, in particular Huntington's disease; lipid metabolism disorders, such as NASH (non-alcoholic steatohepatitis), NAFLD (non-alcoholic fatty liver disease), fatty liver disease; viral infections, such as infection with cytomegalovirus; post-traumatic stress disorder (PTSD); bipolar disorder, depression, Tourette's syndrome, schizophrenia, obsessive-compulsive disorder, anxiety, panic disorder, phobia, addiction, addiction to, for example, alcohol, tobacco, opioids, sedatives, hypnotics, anxiolytics, cocaine, cannabis, amphetamines, hallucinogens, inhalants, phencyclidine, impulse control disorders, behavioral addictions.

[0144] Yet another particular embodiment of the present invention is the use of a compound of the present invention or a derivative, N-oxide, prodrug, solvate, tautomer or stereoisomer thereof and / or a pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios, for the manufacture of a medicament, in particular for the prevention and / or treatment (preferably treatment) of a disorder or disease selected from the group consisting of: hyperproliferative disorders and cancer, in particular tumors, including solid tumors of the specific types of cancer disclosed in the preceding paragraphs; inflammatory disorders or diseases, in particular Crohn's disease, ulcerative colitis, idiopathic pulmonary fibrosis, muscular dystrophy, rheumatoid arthritis and systemic sclerosis disorders or diseases of the nervous system, in particular Huntington's disease; disorders of lipid metabolism, such as NASH (non-alcoholic steatohepatitis), NAFLD (non-alcoholic fatty liver disease), fatty liver disease; viral infections, such as infection with cytomegalovirus; post-traumatic stress disorder (PTSD); bipolar disorder, depression, Tourette syndrome, schizophrenia, obsessive-compulsive disorder, anxiety disorders, panic disorders, phobias, addictions, such as addiction to alcohol, tobacco, opioids, sedatives, hypnotics, anxiolytics, cocaine, marijuana, amphetamines, hallucinogens, inhalants, phencyclidine, impulse control disorders, behavioral addictions.

[0145] Preferably, the present invention relates to a compound of the present invention for use in the prevention and / or treatment of a disease, or a method for the prevention and / or treatment of a disease by administering an effective amount of a compound of the present invention; or, in another alternative, the use of a compound of the present invention for the manufacture of a medicament for the prevention and / or treatment of a disease, wherein the disease is cancer, in particular a tumor, including solid tumors of the specific types of cancer disclosed in the preceding paragraphs; and more preferably, wherein the administration of the compound is carried out simultaneously, sequentially or alternatingly with the administration of at least one other active pharmaceutical agent.

[0146] The disclosed compounds of Formula Ia, Ib and Ic can be administered in combination with other known therapeutic agents, including anticancer agents. The term "anticancer agent" as used herein refers to any agent administered to a patient suffering from cancer for the purpose of treating cancer. The above defined anticancer treatment can be applied as a monotherapy, or can involve conventional surgery or radiotherapy or drug therapy in addition to the compounds of Formula Ia, Ib and Ic disclosed herein. Such drug therapy (e.g., chemotherapy or targeted therapy) can include one or more (but preferably one) of the following antineoplastic agents:

[0147] Alkylating agent

[0148] For example, altretamine, bendamustine, busulfan, carmustine, chlorambucil, nitrogen mustard, cyclophosphamide, dacarbazine, ifosfamide, improsulfan, p-toluenesulfonate, lomustine, melphalan, dibromomannitol, dibromodulanol, nimustine, ranimustine, temozolomide, thiotepa, trooxsulfan, nitrogen mustard, carboquinone, apaziquone, fotemustine, glufosfamide, palifosfamide, pipobroman, trofosfamide, uramustine, TH-302 4 、VAL-083 4 ;

[0149] Platinum compounds

[0150] For example, carboplatin, cisplatin, etaplatin, miplatin hydrate, oxaliplatin, lobaplatin, nedaplatin, picoplatin, satraplatin;

[0151] Lobaplatin, nedaplatin, picoplatin, satraplatin;

[0152] DNA altering agents

[0153] For example, amrubicin, bisantrene, decitabine, mitoxantrone, procarbazine, trabectedin, clofarabine;

[0154] amsacrine, brostallicin, pixenolone, laromustine 1,3 ;

[0155] Topoisomerase inhibitors

[0156] For example, etoposide, irinotecan, razoxane, sobuzoxane, teniposide, topotecan;

[0157] Aminafide, belotecan, elliptinium acetate, voreloxin;

[0158] Microtubule Modifiers

[0159] For example, cabazitaxel, docetaxel, eribulin, ixabepilone, paclitaxel, vinblastine, vincristine, vinorelbine, vindesine, vinflunine, fosbretabulin, tesetaxel;

[0160] Antimetabolites

[0161] For example, asparaginase 3, azacitidine, calcium leucovorin, capecitabine, cladribine, cytarabine, enocitabine, floxuridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine, methotrexate, nelarabine, pemetrexed, pralatrexate, azathioprine, thioguanine, carmofur, doxifluridine, elcirapine, raltitrexed, sapacitabine, tegafur 2,3 , trimetrexate;

[0162] anticancer antibiotics

[0163] For example, bleomycin, actinomycin D, doxorubicin, epirubicin, idarubicin, levamisole, miltefosine, mitomycin C, romidepsin, streptozocin, valrubicin, netastatin, daunorubicin, plicamycin; aclarubicin, peclorubicin, pirarubicin;

[0164] Hormones / antagonists

[0165] e.g. abarelix, abiraterone, bicalutamide, buserelin, calosterone, chlorethoxyquin, degarelix, dexamethasone, estradiol, fluocortolone, fluoxymesterone, flutamide, fulvestrant, goserelin, histrelin, leuprolide, megestrol acetate, mitotane, nafarelin, nandrolone, nilutamide, octreotide, prednisolone, raloxifene, tamoxifen, thyrotropin alfa, toremifene, trilostane, triptorelin, diethylstilbestrol, acolbifene, danazol, deslorelin, cyclothiodine, orteronel, enzalutamide 1,3 ;

[0166] Aromatase inhibitors

[0167] For example, aminoglutethimide, anastrozole, exemestane, fadrozole, letrozole, testolactone, formestane;

[0168] Small molecule kinase inhibitors

[0169] For example, crizotinib, dasatinib, erlotinib, imatinib, lapatinib, nilotinib, pazopanib, regorafenib, ruxolitinib, sorafenib, sunitinib, vandetanib, vemurafenib, bosutinib, gefitinib, axitinib, afatinib, alectinib, dabrafenib, dacomitinib, dinaciclib, dovitinib, ensartrinib, nintedanib, lenvatinib, linifanib, linsitinib, masitinib, midostaurin, motesanib, neratinib, orantinib, perifosine, ponatinib, radotinib, rigosertib, tepotinib, tipifarnib, tivantinib, tivozanib, trametinib, pimastinib, brivanib alaninate, cediranib, apatinib 4 , Cabozantinib S-malate 1,3 Ibrutinib 1,3 Icotinib 4 Bripalatinib 2 , ciprotinib 4 Cobimetinib 1,3 Alectinib 1,3 Fidatinib 1 XL-647 4 ;

[0170] Photosensitizer

[0171] For example, methoxsalen 3 ; Porfimer sodium, talaporfin, temoporfin;

[0172] Antibody

[0173] For example, alemtuzumab, bevacizumab, brentuximab, cetuximab, denosumab, ipilimumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, bevacizumab, pertuzumab 2,3 ; casotuzumab, elotuzumab, epratuzumab, farletuzumab, mokatuzumab, necituzumab, nimotuzumab, obinutuzumab, ocaratuzumab, ogavuzumab, 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 ;

[0174] Cytokines

[0175] For example, aldesleukin, interferon α 2 , interferon α2a3, interferon α2b 2,3 ;

[0176] Simoleukin, Tasonamine, Tesileukin, Oprelleukin 1,3 、Recombinant interferon beta-1a 4 ;

[0177] Drug conjugates

[0178] For example, denileukin, ibritumomab tiuxetan, iodobenzylguanidine I123, prednimustine, trastuzumab, estramustine, gemtuzumab ozogamicin, aflibercept, cintredekin besudotox, edutreotide, inotuzumabozogamicin, naptumomab estafenatox, oportuzumab monatox, technetium (99mTc) acitumomab 1,3 ,vintafolide 1,3 ;

[0179] vaccine

[0180] For example, sipuleucel 3 ;vitespen 3 、emepepimut-S 3 、oncoVAX 4 rindopepimut 3 troVax 4 、MGN-1601 4 、MGN-1703 4 ;

[0181] Miscellaneous

[0182] Alitretinoin, bexarotene, bortezomib, everolimus, ibandronic acid, imiquimod, lenalidomide, lentinan, methyltyrosine, mivastatin, pamidronate, pegaspargase, pentostatin, sipuleucel 3, sizofran, tamibarotene, temsirolimus, thalidomide, tretinoin, vismodegib, zoledronic acid, vorinostat, celecoxib, cilengitide, entinostat, etanidazole, ganadoxetine, iripadol, iniparib, ixazomib, lonidamine, nimorazole, panobinostat, dotretinoin, plitidepsin, pomalidomide, procodazole, tafoxilimus, taquimod, telotristat, thymalfasin, tirapazamine, tosedostat, trabedersen, ubenimex, valspodar, gendicine 4 , hemolytic streptococcal preparations 4 、reolysin 4 、retaspimycin hydrochloride 1,3 , trebananib 2,3 Virulqin 4 Carfilzomib 1,3 Endostatin 4 、immucothel 4 Belinostat 3 、MGN-1703 4 ;

[0183] PARP inhibitors

[0184] Olaparib, Veliparib.

[0185] MCT1 inhibitors

[0186] AZD3965 4 、BAY-8002 4 .

[0187] 1 Prop.INN (Proposed International Nonproprietary Name)

[0188] 2 Rec.INN (Recommended International Nonproprietary Name)

[0189] 3 USAN (United States adopted name)

[0190] 4 No INN.

[0191] A further embodiment of the present invention is a process for the manufacture of a pharmaceutical composition according to the invention, characterized in that one or more compounds according to the invention and one or more compounds other than the compounds according to the invention selected from solid, liquid or semi-liquid excipients, auxiliaries, adjuvants, diluents, carriers and pharmaceutically active agents are converted in a suitable dosage form.

[0192] In another aspect of the present invention, a kit or a reagent kit is provided, which comprises 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 other pharmacologically active substance other than the compound of the present invention. Preferably, the kit or reagent kit comprises the following individual packages:

[0193] a) an effective amount of a compound of formula Ia, Ib or Ic, or a derivative, prodrug, solvate, tautomer or stereoisomer thereof and a physiologically acceptable salt of each of the foregoing, including mixtures thereof in all ratios, and

[0194] b) an effective amount of another active ingredient which is not a compound of formula Ia, Ib or Ic.

[0195] The pharmaceutical composition (preparation) of the present invention can be administered in any manner to achieve its intended purpose. For example, administration can be via oral, parenteral, topical, enteral, intravenous, intramuscular, inhalation, nasal, intraarticular, intraspinal, transtracheal, transocular, subcutaneous, intraperitoneal, transdermal or buccal routes. Alternatively, or simultaneously, administration can be via oral routes. The dosage administered will depend on the age, health and weight of the recipient, the type of simultaneous treatment (if any), the frequency of treatment and the nature of the desired effect. Parenteral administration is preferred. Oral administration is particularly preferred.

[0196] Suitable dosage forms include, but are not limited to, capsules, tablets, pills, dragees, semisolids, powders, granules, suppositories, ointments, creams, lotions, inhalants, injections, pastes, gels, tapes, eye drops, solutions, syrups, aerosols, suspensions, emulsions, which can be prepared according to methods known in the art, for example as described below:

[0197] Tablets: One or more active ingredients are mixed with adjuvants and the mixture is compressed into tablets (direct compression), optionally part of the mixture is granulated before compression.

[0198] Capsules: One or more active ingredients and adjuvants are mixed to obtain a flowable powder, the powder is optionally granulated, the powder / granules are filled into open capsules, and the capsules are capped.

[0199] Semisolids (ointments, gels, creams): One or more active ingredients are dissolved / dispersed in an aqueous or fatty vehicle; the aqueous / fatty phase is subsequently mixed with a supplementary fatty / aqueous phase and homogenized (creams only).

[0200] Suppositories (rectal and vaginal): One or more active ingredients are dissolved / dispersed in a carrier material liquefied by heating (rectal: the carrier material is usually a wax; vaginal: the carrier is usually a heated solution of a gelling agent), the mixture is molded into a suppository form, annealed and the suppository removed from the form.

[0201] Aerosol: One or more active agents are dispersed / dissolved in a propellant and the mixture is bottled into a nebulizer.

[0202] Typically, non-chemical approaches for producing pharmaceutical compositions and / or pharmaceutical preparations include processing steps on suitable mechanical devices known in the art, which transfer one or more compounds of the present invention to a dosage form suitable for administering to patients in need of such treatment. Typically, transferring one or more compounds of the present invention to such a dosage form includes adding one or more compounds selected from carriers, excipients, adjuvants, and pharmaceutically active ingredients other than the compounds of the present invention. Suitable processing steps include, but are not limited to, combining, grinding, mixing, granulating, dissolving, dispersing, homogenizing, casting, and / or compressing the corresponding active and inactive ingredients. Mechanical devices for performing the processing steps are known in the art, such as those obtained from Ullmann's Encyclopedia of Industrial Chemistry, the 5th edition. In this regard, the active ingredient is preferably at least one compound of the present invention and optionally one or more additional compounds other than the compounds of the present invention, which exhibit valuable pharmaceutical properties, preferably those pharmaceutically active agents other than the compounds of the present invention disclosed herein.

[0203] 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, in addition there are suspensions, emulsions or implants, and suitable for topical use are ointments, creams or powders. The compound of the present invention can also be lyophilized, and the resulting lyophilized material is used, for example, to prepare injection preparations. The preparation can be sterile and / or include auxiliary agents, such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for regulating osmotic pressure, buffer substances, dyes, flavorings and / or a variety of other active ingredients, such as one or more vitamins.

[0204] Suitable excipients are organic or inorganic substances which are suitable for enteral (e.g. oral), parenteral or topical administration and which do not react with the compounds of the invention, for example water, vegetable oils, benzyl alcohol, alkylene glycols, polyethylene glycols, triacetin, gelatin, carbohydrates such as lactose, sucrose, mannitol, sorbitol or starch (corn starch, wheat starch, rice starch, potato starch), cellulose preparations and / or calcium phosphates (e.g. tricalcium phosphate or dibasic calcium phosphate), magnesium stearate, talc, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone and / or vaseline.

[0205] If desired, disintegrants can be added, such as the above-mentioned starch and carboxymethyl starch, cross-linked polyvinyl pyrrolidone, agar or alginic acid or its salt, such as sodium alginate. Auxiliary agents include but are not limited to flow regulators and lubricants, such as silicon dioxide, talcum, stearic acid or its salt, such as magnesium stearate or calcium stearate, and / or Polyethylene Glycol. The dragee core is provided with a suitable coating, and if desired, it can resist gastric juice. For this reason, concentrated sugar solution can be used, which can optionally contain gum arabic, talcum, polyvinyl pyrrolidone, Polyethylene Glycol and / or titanium dioxide, lacquer solution and suitable organic solvent or solvent mixture. In order to produce a coating resistant to gastric juice or to provide a dosage form with an extended effect advantage, tablets, dragees or pills can include inner dosage and outer dosage components, and the latter is the coating form of the former wrapped up. These two components can be separated by an enteric layer, which is used to resist disintegration in the stomach and allows the inner component to enter the duodenum intact or delay release. A variety of materials can be used for such enteric layers or coatings, such materials including a variety of polymeric acids and mixtures of polymeric acids with materials such as shellac, acetyl alcohol, solutions of suitable cellulose preparations such as acetylcellulose phthalate, cellulose acetate, or hydroxypropylmethylcellulose phthalate. Dyestuffs or pigments can be added to tablets or dragee coatings, for example, for identification or to characterize combinations of active compound doses.

[0206] Suitable carrier materials are organic or inorganic substances, which are suitable for enteral (e.g. oral) or parenteral administration or topical application and do not react with the novel compound, such as water, vegetable oil, benzyl alcohol, polyethylene glycol, gelatin, carbohydrates (e.g. lactose or starch), magnesium stearate, talc and vaseline. In particular, tablets, coated tablets, capsules, syrups, suspensions, drops or suppositories are used for enteral administration, solutions (preferably oily or aqueous solutions), in addition 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 lyophilized material obtained can be used for example to produce injection preparations.

[0207] Other pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, and soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules may contain the active compound in the form of granules, which may be mixed with fillers, such as lactose, binders, such as starches, 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 a fatty oil or liquid paraffin. In addition, stabilizers may be added.

[0208] The novel composition of the present invention can be incorporated into liquid forms for oral administration including aqueous solutions, syrups of suitable flavors, aqueous or oil suspensions and emulsions and elixirs and similar pharmaceutical vehicles with flavors of edible oils (e.g., cottonseed oil, sesame oil, coconut oil or peanut oil). Suitable dispersants or suspending agents for aqueous suspensions include synthetic and natural gums, such as tragacanth, gum arabic, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.

[0209] Preparations suitable for parenteral administration include aqueous solutions of the active compound in water-soluble form, such as water-soluble salts and alkaline solutions. In addition, suspensions of the active compound can be given 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 (the compound can be dissolved in PEG-400).

[0210] Aqueous injection suspensions may contain substances that increase the viscosity of the suspension including, for example, sodium carboxymethyl cellulose, sorbitol and / or dextran, and optionally, the suspension may also contain stabilizers.

[0211] For administration as an inhalation spray, sprays can be used in which the active ingredient is dissolved or suspended in a propellant gas or a propellant gas mixture (e.g. CO or chlorofluorocarbons). The active ingredient is advantageously used in micronized form, in which case one or more additional physiologically acceptable solvents, such as ethanol, may be present. Inhalation solutions can be administered with the aid of conventional inhalers.

[0212] Possible pharmaceutical preparations that can be used rectally include, for example, suppositories, which consist of a combination of one or more active compounds and a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides or paraffins. In addition, gelatin rectal capsules can also be used, which consist of a combination of an active compound and a base. Possible base materials include, for example, liquid triglycerides, polyethylene glycols or paraffins.

[0213] For use in medicine, the compound of the present invention can be in the form of a pharmaceutically acceptable salt. However, other salts can be used to prepare the compound of the present invention or its pharmaceutically acceptable salt. Suitable pharmaceutically acceptable salts of the compound of the present invention are those described above, and include acid addition salts, which can be formed, for example, by mixing a solution of a compound according to the present invention with a solution of a pharmaceutically acceptable acid (e.g., hydrochloric acid, sulfuric acid, methanesulfonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid). In addition, when the compound of the present invention carries an acidic part, its suitable pharmaceutically acceptable salt can include an alkali metal salt, such as a sodium salt or a potassium salt; an alkaline earth metal salt, such as a calcium salt or a magnesium salt; and a salt formed with a suitable organic base, such as a quaternary ammonium salt.

[0214] Pharmaceutical preparations can be used as drugs in human and veterinary medicine. The term "effective amount" as used herein refers to the amount of a drug or medicament that will cause a biological or medical response in a tissue, system, animal or human, which is sought by, for example, a researcher or clinician. In addition, the term "therapeutically effective amount" refers to any amount that results in improved treatment, healing, prevention or improvement of a disease, condition or side effect, or a reduction in the rate of progression of a disease or condition, compared to a corresponding subject that has not received such an amount. The term also includes within its scope an amount that effectively enhances normal physiological function. The therapeutically effective amount of one or more compounds of the present invention is known to professionals or can be easily determined by standard methods known in the art.

[0215] The compounds of the present invention and optional additional active substances are usually administered in a manner similar to commercial preparations. Typically, the appropriate dosage for treatment is between 0.0005 mg and 1000 mg per dosage unit, preferably between 0.005 mg and 500 mg, and especially between 0.5 mg and 100 mg. The daily dose is preferably between about 0.001 mg / kg and 10 mg / kg body weight.

[0216] Those skilled in the art will readily appreciate that dosage levels may vary with the specific compound, the severity of the symptoms, and the subject's susceptibility to side effects. Some specific compounds are more effective than other compounds. The preferred dosage of a given compound is readily determined by those skilled in the art in a variety of ways. The preferred way is to measure the physiological efficacy of a given compound.

[0217] However, the specific dosage for an individual patient, particularly for an individual human patient, depends on a variety of factors, such as the efficacy of the specific compound used, age, body weight, general health status, sex, type of diet, time and route of administration, rate of excretion, type and dosage form of administration, drug combination, and severity of the specific condition involved in the therapy. The specific therapeutically effective dosage for an individual patient can be readily determined by routine experimentation, such as by a physician or doctor who advises or participates in therapeutic treatment.

[0218] The compounds of the invention can be prepared according to the procedures of the following schemes and examples, using appropriate materials, and as further illustrated by the following specific examples. They can also be prepared by methods known per se, as described in the literature (e.g. in standard works, such as Houben-Weyl, Methoden der Organischen Chemie [Methods of Organic Chemistry], Georg Thieme Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc., New York), precisely under reaction conditions known and suitable for the reaction. Variants known per se but not mentioned in more detail here can also be used.

[0219] Equally, the raw material for preparing the compound of the present invention can be prepared by the method described in the examples or by methods known per se, as described in the literature of synthetic organic chemistry and methods known to the technician, or can be commercially available.If desired, the raw material for the method claimed and / or used can also be formed in situ by not separating them from the reaction mixture but immediately converting them further into compounds of the present invention or intermediate compounds.On the other hand, the reaction can usually be carried out step by step.

[0220] 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 ethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers such as ethylene glycol monomethyl ether or ethylene glycol monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones such as acetone or butanone; amides such as acetamide, dimethylacetamide, dimethylformamide (DMF) or N-methylpyrrolidone (NMP); nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide (DMSO); nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate, or mixtures of the solvents or mixtures with water.

[0221] The reaction temperature is between about -100°C and 300°C, depending on the reaction step and conditions used.

[0222] The reaction times is usually in the range of a fraction of a minute to several days, depending on the reactivity of the corresponding compound and corresponding reaction conditions. Suitable reaction times can be easily determined by methods known in the art such as reaction monitoring. Based on the temperature of reaction provided above, suitable reaction times is usually between 10 minutes and 48 hours.

[0223] In addition, by utilizing the procedures described herein, in combination with the ordinary skills in the art, other compounds of the present invention claimed herein can be easily prepared. However, the compounds illustrated in the examples should not be construed as forming the only species considered to be the present invention. The examples further describe the preparation of the compounds of the present invention in detail. Those skilled in the art will readily appreciate that known variations of the conditions and methods of the following preparation procedures can be used to prepare these compounds.

[0224] The present invention also relates to a process for the manufacture of a compound of formula Ia, Ib or Ic in its most general form and any of the specific embodiments PE1, PE2, PE3, PE3a, PE3b, PE4, PE5, PE5a, PE5b, PE6, PE6a, PE6b, PE6c, PE7, PE7a, PE7b, PE7c, PE8, PE8a, PE8b, PE8c, PE9 described herein, or a derivative, N-oxide, prodrug, solvate, tautomer or stereoisomer thereof and a pharmaceutically acceptable salt of each of the foregoing, characterized in that

[0225] (a) In the case of tetrazole-1H-imidazo[4.5-b]pyridine derivatives of formula Ia

[0226] Carbonitrile of general formula II-a

[0227]

[0228] Where R 1 , R 2 , R 3 , R 4 and R 5 As described above for Formula Ia and in the appended claims,

[0229] Optionally, subject to cyclization reaction with a suitable azide reagent such as sodium azide in the presence of a suitable catalyst such as zinc chloride to produce a tetrazole derivative of Formula Ia:

[0230]

[0231] Where R 1 , R 2 , R 3 , R 4 and R 5 As described above for Formula Ia and in the appended claims;

[0232] or

[0233] (b) In the case of tetrazole-1-pyrazolo[1,5-a]pyridine derivatives of formula Ib

[0234] Carbonitrile of general formula II-b

[0235]

[0236] Where R 1 , R 2 , R 3 , R 4 and R 5 As described above for Formula Ib and in the appended claims,

[0237] Optionally, subject to cyclization reaction with a suitable azide reagent such as sodium azide in the presence of a suitable catalyst such as zinc chloride to produce a tetrazole derivative of Formula Ib:

[0238]

[0239] Where R 1 , R 2 , R 3 , R 4 and R 5 As described above for Formula Ia and in the appended claims;

[0240] or

[0241] (c) In the case of tetrazole-imidazo[1,2-a]pyridine derivatives of formula Ic

[0242] Carbonitrile of general formula II-c

[0243]

[0244] Where R 1 , R 2 , R 3 , R 4 and R 5 As described above for Formula Ia and in the appended claims,

[0245] Optionally, subject to cyclization reaction with a suitable azide reagent such as sodium azide in the presence of a suitable catalyst such as zinc chloride to produce a tetrazole derivative of Formula Ia:

[0246]

[0247] Where R 1 , R 2 , R 3 , R 4 and R 5 As described above for Formula Ia and in the appended claims.

[0248] As will be appreciated by those skilled in the art of organic synthesis, the compounds of the present invention (particularly compounds of formula Ia, Ib or Ic) can be readily obtained by various synthetic routes, some of which are illustrated in the accompanying experimental section. In order to obtain the compounds of the present invention, in any particular case (wherever required or used), the technician will readily recognize which reagents and reaction conditions will be used and how to apply and adjust them. In addition, some compounds of the present invention can be easily synthesized by reacting other compounds of the present invention under suitable conditions, for example, by applying standard synthetic methods, such as reduction, oxidation, addition or substitution reactions, to convert a specific functional group present in a compound of the present invention or a suitable precursor molecule thereof into another; those methods are well known to the technician. Similarly, whenever necessary or useful, the technician will apply the synthetic protective (or protective) group; suitable protective groups and methods for introducing and removing them are well known to those skilled in the art of chemical synthesis, and are described in more detail in, for example, PGM Wuts, TW Greene, "Greene's Protective Groups in Organic Synthesis", 4th edition (2006) (John Wiley & Sons).

[0249] The following general synthetic routes that can be used to prepare compounds of the present invention are described in more detail in Schemes A to E:

[0250]

[0251] Plan A

[0252] Scheme A above describes a general synthetic route for preparing tetrazolyl compounds of Formula Ia. 2-amino-3-nitro-pyridine derivatives Aa (which can be readily obtained by utilizing known synthetic methods or through commercial sources) are converted to 5-bromo-substituted derivatives Ba by a suitable bromination reaction (step a), for example by using N-bromosuccinimide (NBS), preferably in a slight excess of about 1.05-1.15 equivalents relative to Aa, in a suitable solvent such as dimethylformamide (DMF). The nitro substituent of the bromo-substituted pyridine derivative Ba can then be converted to an amino group by a reduction reaction with gaseous hydrogen in the presence of a suitable metal catalyst such as a sponge nickel catalyst (step b), thereby providing 2,3-diamino-5-bromo-substituted pyridine derivatives Ca. The derivative can be isolated or, preferably, not isolated, reacted with a reaction partner suitable for the desired cyclization under sufficient reaction conditions to produce a 3H-imidazo[4.5-b]pyridine derivative of formula Da (step c); such reaction partner and conditions can be, for example, the addition of triethyl orthoformate and formic acid, respectively, and subsequent heating. After the usual work-up, compound Da is obtained, which can then be converted into 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 reaction of a suitable alkyl halide R in the presence of a strong base (e.g. sodium hydride). 3 -Hal (e.g. alkyl iodide), followed by neutralization with, for example, ammonium chloride solution. Typically, the desired regional isomer Ea is obtained as the major product, and the other isomer Ea-iso is obtained as a minor product, which is then separated by conventional techniques (e.g. silica gel chromatography). The 1H-imidazo[4.5-b]pyridine derivative Ea is then converted into a carbonitrile derivative of formula Fa by bromine / cyanide exchange (step e); this exchange can be achieved, for example, by adding K4[Fe(CN)6] and potassium acetate in a suitable solvent (e.g. dioxane), followed by addition of a suitable catalyst (e.g. a suitable palladium catalyst, such as tBuBrettPhos Pd G3), and then heating the resulting reaction mixture. Then, by reacting carbonitrile with a compound of formula R 1 -C(=O)-R 2 (where R 1 and R 2Carbonitrile Fa can be converted to tertiary alcohol II-a (step f) by reacting a ketone (as defined for tetrazoles of formula Ia and which may be the same or different) in the presence of a strong base (e.g. lithium dimethylsilylamide) in a suitable solvent (e.g. THF). In the final step (step g), the desired tetrazole derivative Ia can be obtained by subjecting the compound of formula II-a to a suitable azide reagent such as sodium azide in the presence of zinc chloride or azidotributylstannane.

[0253]

[0254] Plan B

[0255] Where R 1 and R 2 The same tetrazole compound of formula Ib is readily accessible via the synthetic route described in Scheme B above: 2-propyl-4-carbonitrile substituted pyridine derivative Ab (which can be obtained from commercial sources or via synthetic procedures well known to the skilled person) is converted into the corresponding 1-amino-pyridinium compound Bb by using a suitable reagent, such as 2,4,6-trimethylbenzene-1-sulfonic acid aminoester in dichloromethane (step a). Bb is then subjected to a cyclization reaction with an appropriate reaction partner such as ethyl oxalyl chloride (H5C2-OC(=O)-C(=O)-Cl) under typical conditions to produce a pyrazolo[1,5-a]pyridine derivative Cb (step b). This is then reacted with a suitable C-nucleophile, for example in the presence of, for example, R 1 -Mg-Cl (or R 2 In a classical Grignard reaction with 2-(4-(2-(4-nitrogen-2-ol)-1-(2 ...

[0256]

[0257] Plan C

[0258] Where R 1 and R 2Tetrazolyl compounds of formula Ib that are not identical but different can be readily obtained via the synthetic route described in Scheme C above: 2-propyl-4-bromo-substituted pyridine derivatives Eb (which can be obtained from commercial sources or via synthetic procedures well known to the skilled person) are converted into the corresponding 1-amino-pyridinium compounds Fb (step a) by using a suitable reagent (e.g. 2,4,6-trimethylbenzene-1-sulfonic acid amino ester in dichloromethane). Fb is then subjected to a cyclization reaction under typical conditions with a suitable reaction partner such as ethyl oxalyl chloride (H5C2-OC(=O)-C(=O)-Cl) to produce pyrazolo[1,5-a]pyridine derivatives Gb (step b). Gb is then converted to its carboxylic acid Hb under typical saponification conditions, for example by the addition of a base (e.g. LiOH, NaOH or KOH). The carboxylic acid Hb is then converted to the carboxamide Jb by reaction with methoxy(methyl)amine hydrochloride under appropriate conditions, for example in the presence of EDC N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, HOBt (1-hydroxybenzotriazole) and an amine base such as triethylamine. The carboxamide Jb can then be reacted with 1 equivalent of a suitable Grignard reagent R 1 -Mg-Hal reaction to provide ketone Kb (step e). Subsequent bromine-cyanide exchange (step f) by reacting Kb with, for example, Zn(CN)2 and a palladium catalyst such as Pd2(dba)3 and XantPhos in DMF produces carbonitrile Lb, which in turn reacts with an appropriate organometallic compound such as R 2 -Li, which can be obtained by making a suitable halide R 2 -Hal is reacted with a suitable lithium-organic base (e.g., n-butyllithium) to provide a tertiary alcohol II-b (step g). As described in Schemes A and B, the compound II-b is finally converted (step h) to the desired tetrazole derivative of formula Ib by reaction with an azide reagent such as sodium azide or in the presence of zinc chloride or azidotributylstannane.

[0259]

[0260] Plan D

[0261] Where R 1 and R 2 The same tetrazole compounds of formula Ic can be readily obtained via the synthetic route described in Scheme D above: under typical conditions, using an appropriate reaction partner such as a substituted α-halogen-ethyl oxalate (C2H5-OC(=O)-C(=O)-CHHal-R 3 , for example C2H5-OC(=O)-C(=O)-CHBr-C2H5, if Hal=Br and R3 =ethyl (Bc)), a 2-amino-5-bromo-substituted pyridine derivative Ac (which can be obtained from commercial sources or via synthetic procedures known to the skilled person) is subjected to a cyclization reaction to produce an imidazo[1,2-a]pyridine derivative Cc (step a). Cc is then reacted with a suitable C-nucleophile, for example, in a classical Grignard reaction with, for example, R 1 -Mg-Cl (or R 2 -Mg-Cl) to convert Cc to a tertiary alcohol Dc (step b). Subsequent bromine-cyanide exchange (step c) of Dc with, for example, Zn(CN)2 and a palladium catalyst such as Pd(PPh3)4 in DMF produces carbonitrile II-c, which is then converted (step d) to the desired tetrazole of formula Ic by reacting II-c with a suitable azide reagent such as sodium azide in the presence of zinc chloride or azidotributylstannane.

[0262]

[0263] Plan E

[0264] Where R 1 and R 2 Tetrazolyl compounds of formula Ic which are not identical but different can be readily obtained via the synthetic route described 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 the addition of a base such as LiOH, NaOH or KOH (step b). The carboxylic acid Ec is subsequently converted to a carboxamide Fc by reaction with methoxy(methyl)amine hydrochloride under appropriate conditions, for example in the presence of EDC N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, HOBt (1-hydroxybenzotriazole) and an amine base such as triethylamine (step c). The carboxamide Fc can then be reacted with 1 equivalent of a suitable Grignard reagent R 1 -Mg-Hal reaction to provide ketone Gc (step d). Subsequent bromine-cyanide exchange (step e) by reacting Kb with, for example, Zn(CN)2 in DMF in the presence of a palladium catalyst (such as Pd2(dba)3) and XantPhos produces carbonitrile Hc, which in turn reacts with a suitable organometallic compound (such as R 2 -Li, which can be obtained by making an appropriate halide R 2-Hal is reacted with a suitable lithium-organic base (e.g. n-butyllithium) to provide the tertiary alcohol II-c (step f). This compound II-c is finally converted (step g) to the desired tetrazole derivative of formula Ic by reaction with an azide reagent such as sodium azide or in the presence of zinc chloride or azidotributylstannane, as described for example for Schemes A and B.

[0265] The present invention also relates to carbononitriles of the formula II-a, II-b or II-c, which are useful intermediates for preparing tetrazoles of the present invention of the formula Ia, Ib or Ic, respectively:

[0266]

[0267] Where R 1 , R 2 , R 3 , R 4 and R 5 As defined above for Formulae Ia, Ib and Ic.

[0268] As used herein, "treating" or "treatment" refers to completely or partially alleviating the symptoms associated with a disorder or disease, or slowing or stopping the further progression or worsening of these symptoms, or preventing or prophylaxis of a disease or condition in a subject at risk of developing the disease or condition.

[0269] The term "effective amount" in relation to a tetrazole of Formula Ia, Ib or Ic refers to an amount (of a compound, a drug, a pharmaceutical composition, etc.) that is capable of alleviating, in whole or in part, the symptoms associated with the disorder or disease, or slowing or stopping the further progression or worsening of these symptoms, or preventing or providing prophylaxis for the disease or disorder in a subject suffering from a disease disclosed herein (e.g., an inflammatory condition, an immunological condition, a cancer, or a metabolic condition) or at risk of developing a disease disclosed herein.

[0270] It should be noted that, except where otherwise specified or where the context provides a different meaning, the number of terms (i.e., their singular and plural forms) is generally used and can be read interchangeably. For example, the singular form of the term "compound" may also include or refer to a plurality of compounds, and the plural form of the term "compound" may also include or refer to a singular compound.

[0271] Experimental Section

[0272] abbreviation

[0273] The compounds of the present invention can be prepared according to the procedures of the following schemes and examples, using appropriate materials, and are further illustrated by the following specific examples. The compounds are shown in Table 1, which is divided into Tables 1a, 1b, 1c, 1d, 1e, 1f, 1g, 1h, 1i and 1j. The analytical data of the compounds prepared according to the following examples are also shown in Table 1 (Tables 1a, 1b, 1c, 1d, 1e, 1f, 1g, 1h, 1i and 1j).

[0274] The invention will be illustrated by reference to the specific embodiments described in the following examples, but is not limited thereto. Unless otherwise indicated in the schemes, the variables have the same meanings as described above and in the claims.

[0275] Unless otherwise stated, all starting materials were obtained from commercial suppliers and used without further purification. Unless otherwise stated, all temperatures are expressed in °C and all reactions were performed at RT (room temperature). Compounds were purified by silica gel chromatography or preparative HPLC.

[0276] 1 H NMR:

[0277] 1 H-NMR data are provided in Table 1 below. If not otherwise reported, they were typically obtained on a Bruker Avance DRX 500, Bruker Avance 400 or Bruker DPX 300 NMR spectrometer under standard conditions using TMS (tetramethylsilane) as an internal standard and DMSO-d6 as a standard solvent. 1 H NMR spectra. NS (number of scans): 32, SF (spectrometer frequency) as indicated. TE (temperature): 297 K. Chemical shifts (δ) are reported in ppm relative to the residual solvent signal (for 1 H NMR in DMSO-d6 δ = 2.5 ppm, for 1 H NMR in CDCl3 δ = 7.27 ppm, for methanol-d4 δ = 3.31 ppm). 1 H NMR data are reported as follows: chemical shift (multiplicity, coupling constant, and number of hydrogens). Multiplicity abbreviations are as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublet), tt (triplet of triplet), td (triplet of doublet), br (broad) and coupling constants (J) are reported in Hz.

[0278] HPLC-MS:

[0279] The HPLC-MS data provided in Table 1 are given in mass, in m / z. The results can be obtained by one of the following methods. HPLC-MS analysis was usually performed on a Shimadzu LCMS-2020, Shimadzu SP-M20A 2010EV or Shimadzu UFLC-MS 2010EV system using one of the following columns: Shim-pack VP-ODS, Shim-pack XR-ODS, KinetexXB-C18 100A, Xbridge BEH C18, Gemini-NX 3u C18 110A or ACE UltraCore 2.5SuperC18. Standard conditions applied:

[0280] Standard solvent gradient, using

[0281] A: water + 0.1 vol% formic acid, B: acetonitrile + 0.1 vol% formic acid; or

[0282] A: water + 0.05 volume % trifluoroacetic acid, B: acetonitrile + 0.05 volume % trifluoroacetic acid

[0283] Detection wavelength: 220nm, MS type: API-ES

[0284] General Synthesis 1

[0285]

[0286] Example 1

[0287] [3-Ethyl-7-methoxy-6-(1H-tetrazolyl-5-yl)-imidazo[1,2-a]pyridin-2-yl]-diphenyl-methanol

[0288]

[0289] a) Method A: A mixture of 5-bromo-4-methoxypyridin-2-amine (4g, 19.70mmol) and ethyl 3-bromo-2-oxopentanoate (8g, 35.86mmol) in EtOH (40mL) was stirred at 80°C for 16 hours. The reaction mixture was then cooled to room temperature and the pH was adjusted to 8 with NaHCO3. The mixture was diluted with water (100mL) and extracted with DCM (100mL×3). The combined organic phases were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography, eluting with EtOAc / petroleum ether (5% to 30% gradient) to produce ethyl 6-bromo-3-ethyl-7-methoxyimidazo[1,2-a]pyridine-2-carboxylate as a light yellow solid (2.8g, 38%). LC / MS: [M+H] +327.1 / 329.1.

[0290] b) Method B: PhMgBr (1M in THF, 11.9 mL, 11.9 mmol) was added dropwise to a solution of 6-bromo-3-ethyl-7-methoxyimidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (1.3 g, 3.97 mmol) in THF (130 mL) at 0°C. The resulting mixture was kept stirring at 0°C for 1 hour. The reaction mixture was then carefully quenched with saturated NH4Cl solution (20 mL) and diluted with water (100 mL). The aqueous phase was extracted with DCM (150 mL×2), and the 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 MeOH / DCM (1% to 5% gradient) to produce [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.

[0291] c) A mixture of [6-bromo-3-ethyl-7-methoxyimidazo[1,2-a]pyridin-2-yl]diphenylmethanol (100 mg, 0.22 mmol), Zn(CN)2 (27 mg, 0.23 mmol) and Pd(PPh3)4 (53 mg, 0.046 mmol) in DMF (5 mL) was stirred at 120 ° C under nitrogen atmosphere for 2 h. The reaction mixture was then diluted with water (20 mL) and extracted with DCM (30 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography, eluting with EtOAc / petroleum ether (20% to 80% gradient) to give 3-ethyl-2-(hydroxydiphenylmethyl)-7-methoxyimidazo[1,2-a]pyridine-6-carbonitrile as a yellow solid (50 mg, 57%). LC / MS [M+H] + 384.3.

[0292] d) [3-Ethyl-7-methoxy-6-(1H-1,2,3,4-tetrazol-5-yl)imidazo[1,2-a]pyridin-2-yl]diphenylmethanol was prepared from 3-ethyl-2-(hydroxydiphenylmethyl)-7-methoxyimidazo[1,2-a]pyridine-6-carbonitrile and azidotributylstannane using Method C. The final product was purified by preparative HPLC under the following conditions: XBridge ShieldRP18 OBD column, 30x 150mm, 5μm; mobile phase, MeCN / water (10mM NH4HCO3 and 0.1% NH3.H2O), 5% to 45% gradient, 8min; detector, UV 254 / 220nm, yielding [3-ethyl-7-methoxy-6-(1H-1,2,3,4-tetrazol-5-yl)imidazo[1,2-a]pyridin-2-yl]diphenylmethanol as a white solid (12.5mg, 22.5%). LC / MS [M+H] + 427.0.

[0293] Example 2

[0294] [3-Ethyl-7-methoxy-6-(1H-tetrazolyl-5-yl)-imidazo[1,2-a]pyridin-2-yl]-bis-(2-fluoro-phenyl)-methanol

[0295]

[0296] a) Method D: A mixture of 6-bromo-3-ethyl-7-methoxyimidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (1.5 g, 4.58 mmol), Zn(CN)2 (0.3 g, 2.51 mmol), Pd2(dba)3 (1.2 g, 1.3 mmol) and XantPhos (0.7 g, 1.3 mmol) in DMF (30 mL) was stirred at 90°C for 3 hours under nitrogen atmosphere. The reaction mixture was then diluted with water and extracted with CH2Cl2. 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 MeOH / DCM (1% to 7% gradient) to give 6-cyano-3-ethyl-7-methoxyimidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester as a yellow solid (1.2 g, 92%). LC / MS[M+H] + 274.1.

[0297] b) Method E: iPrMgCl LiCl (10.4 mL, 1.3 M in THF) was added dropwise to a solution of 1-bromo-2-fluorobenzene (2.37 g, 13.54 mmol) in THF (30 mL) at -15 ° C. The resulting mixture was stirred at -15 ° C for 2 hours, followed by the slow addition of a solution of 6-cyano-3-ethyl-7-methoxyimidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (1.2 g, 4.40 mmol) in THF (10 mL). The reaction mixture was kept stirring at -15 ° C for another 2 hours. 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 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 MeOH / 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.

[0298] c) [3-Ethyl-7-methoxy-6-(1H-1,2,3,4-tetrazol-5-yl)imidazo[1,2-a]pyridin-2-yl]bis(2-fluorophenyl)methanol was prepared from 2-[bis(2-fluorophenyl)(hydroxy)methyl]-3-ethyl-7-methoxyimidazo[1,2-a]pyridine-6-carbonitrile and azidotributylstannane using Method C. The final product was purified by preparative HPLC under the following conditions: column, XBridge Shield RP18 OBD column, 30 x 150 mm, 5 μm; mobile phase, MeCN / water (10 mM NH4HCO3 and 0.1% NH3.H2O), 15% to 45% gradient, 8 min; detector, UV 254 / 220 nm. [3-ethyl-7-methoxy-6-(1H-1,2,3,4-tetrazolyl-5-yl)imidazo[1,2-a]pyridin-2-yl]bis(2-fluorophenyl)methanol was obtained as a white solid (15 mg, 42%). LC / MS [M+H] + 463.0.

[0299] Example 3

[0300] [7-Chloro-3-ethyl-6-(1H-1,2,3,4-tetrazolyl-5-yl)imidazo[1,2-a]pyridin-2-yl](phenyl)(pyridin-2-yl)methanol

[0301]

[0302] Ethyl 6-bromo-7-chloro-3-ethylimidazo[1,2-a]pyridine-2-carboxylate was prepared using Method A from 5-bromo-4-chloropyridin-2-amine.

[0303] 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 H2O (10 mL) was added LiOH (632 mg, 26.4 mmol) in portions. The resulting mixture was stirred at room temperature for 16 hours. The pH of the reaction mixture was then carefully adjusted to 5-6 with 6M aqueous HCl. The organic solvent was removed under reduced pressure, and the resulting solid was collected by filtration. The solid was washed with water and dried under high vacuum to 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.

[0304] 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 CH2Cl2 (200 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (2.65 g, 13.8 mmol), 1-hydroxybenzotriazole (1.87 g, 13.8 mmol), NEt3 (2.8 g, 27.7 mmol) and methoxy(methyl)amine hydrochloride (2.02 g, 20.76 mmol). The reaction mixture was stirred at room temperature for 16 hours. It was then diluted with water and extracted with CH2Cl2. The combined organic phases were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc / petroleum ether (5% to 50% gradient) to give 6-bromo-7-chloro-3-ethyl-N-methoxy-N-methylimidazo[1,2-a]pyridine-2-carboxamide as a yellow solid (1.5 g, 63%). LC / MS [M+H] + 345.8 / 347.9.

[0305] c) Method F: PhMgBr (5.8 mL, 1 M in THF) was added dropwise to a solution of 6-bromo-7-chloro-3-ethyl-N-methoxy-N-methylimidazo[1,2-a]pyridine-2-carboxamide (1.5 g, 4.33 mmol) in THF (200 mL) at -78°C. The mixture was kept stirring at -78°C for 2 hours, then carefully quenched with saturated NH4Cl solution and diluted with water. The aqueous layer was extracted with CH2Cl2, and the combined organic phases were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography, eluting with EtOAc / petroleum ether (10% to 50% gradient) to give 2-benzoyl-6-bromo-7-chloro-3-ethylimidazo[1,2-a]pyridine as a yellow solid (1.2 g, 72%). LC / MS [M+H] + 362.9 / 364.9.

[0306] d) Preparation of 2-Benzoyl-7-chloro-3-ethylimidazo[1,2-a]pyridine-6-carbonitrile from 2-benzoyl-6-bromo-7-chloro-3-ethylimidazo[1,2-a]pyridine using Method D. LC / MS [M+H] + 310.0.

[0307] e) Method G: At -78 ° C, 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. The resulting mixture was kept stirring at -78 ° C for 1 hour, 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 kept stirring at -78 ° C for another 1 hour, followed by careful quenching with saturated NH4Cl solution and diluted with water. The aqueous layer was extracted with CH2Cl2, and the combined organic phases were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with MeOH / DCM (1% to 8% gradient) to yield 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.

[0308] f) [7-Chloro-3-ethyl-6-(1H-1,2,3,4-tetrazol-5-yl)imidazo[1,2-a]pyridin-2-yl](phenyl)(pyridin-2-yl)methanol was prepared from 7-chloro-3-ethyl-2-[hydroxy(phenyl)(pyridin-2-yl)methyl]imidazo[1,2-a]pyridine-6-carbonitrile and azidotributylstannane using Method C.

[0309] Example 4

[0310]

[0311] [3-Ethyl-7-methoxy-6-(1H-1,2,3,4-tetrazol-5-yl)imidazo[1,2-a]pyridin-2-yl](phenyl)(pyridin-2-yl)methanol was prepared from ethyl 6-cyano-3-ethyl-7-methoxyimidazo[1,2-a]pyridine-2-carboxylate using Methods F, G, and C.

[0312] Example 5

[0313]

[0314] a) To a solution of 3-iodo-1-methyl-1H-pyrazole (3.96 g, 19.0 mmol) in THF (100 mL) was added dropwise iPrMgCl·LiCl (11.6 mL, 1.3 M / THF) at -15°C. The mixture was stirred continuously at -15°C for 1 hour and then cooled to -70°C. 2-Benzoyl-3-ethyl-7-methoxyimidazo[1,2-a]pyridine-6-carbonitrile (2.00 g, 6.55 mmol) / THF (40 mL) was slowly added to the reaction mixture. The reaction was warmed to 0°C and stirred for 2 hours. The reaction was carefully quenched with saturated NH4Cl solution and diluted with water. The aqueous layer was extracted with CH2Cl2 and the combined organic phases were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with MeOH / CH2Cl2 (1% to 8% gradient) to give 3-ethyl-2-[hydroxy(1-methyl-1H-pyrazol-3-yl)phenylmethyl]-7-methoxyimidazo[1,2-a]pyridine-6-carbonitrile as a yellow solid (1.10 g, 40%). LC / MS [M+H] + 388.1.

[0315] b) [3-Ethyl-7-methoxy-6-(1H-1,2,3,4-tetrazol-5-yl)imidazo[1,2-a]pyridin-2-yl](1-methyl-1H-pyrazol-3-yl)phenylmethanol was prepared from 3-ethyl-2-[hydroxy(1-methyl-1H-pyrazol-3-yl)phenylmethyl]-7-methoxyimidazo[1,2-a]pyridine-6-carbonitrile using Method C.

[0316] General Synthesis 2

[0317]

[0318] Example 6

[0319] [3-Ethyl-6-methoxy-5-(1H-tetrazolyl-5-yl)-pyrazolo[1,5-a]pyridin-2-yl]-diphenylmethanol

[0320]

[0321] a) At -30 ° C, nBuLi (42.5 mL, 2.5 M) was added dropwise to a solution of 2,2,6,6-tetramethylpiperidine (15 g, 106.19 mmol) in THF (250 mL). The resulting mixture was stirred at -30 ° C for 30 minutes and then cooled to -78 ° C. A solution of 2-propylpyridine-4-carbonitrile (7.8 g, 53.36 mmol) in THF (20 mL) was slowly added to the mixture. The reaction mixture was stirred at -78 ° C for 30 minutes, and then hexachloroethane (25 g, 105.6 mmol) was slowly added. The reaction mixture was slowly warmed to room temperature and stirred at room temperature for 30 minutes. Then, the reaction mixture was carefully quenched with saturated NH4Cl solution (100 mL) and diluted with water (300 mL). The resulting mixture was extracted with EtOAc (300 mL × 3), and the organic phases were combined, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc / petroleum ether (1% to 10% gradient) to give 5-chloro-2-propylpyridine-4-carbonitrile as a brown oil (1 g, 10.4%). LC / MS [M+H] + 181.1.

[0322] 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 hours. 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, eluted with EtOAc / 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.

[0323] c) 2,4,6-trimethylbenzene-1-sulfonic acid amino ester (3.68 g, 17.08 mmol) was slowly added to a solution of 5-methoxy-2-propylpyridine-4-carbonitrile (650 mg, 3.69 mmol) in DCM (10 mL). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to produce 1-amino-4-cyano-5-methoxy-2-propylpyridin-1-ium 2,4,6-trimethylbenzene-1-sulfonate as a white solid (700 mg, 98%), which was used in the next step without further purification. LC / MS [M] + 192.1.

[0324] 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 oxalyl chloride (4.0 g, 27.8 mmol) in pyridine (10 mL) was stirred at 100 ° C for 2 hours. 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 Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography, eluting with EtOAc / petroleum ether (10% to 50% gradient) to produce 5-cyano-3-ethyl-6-methoxypyrazolo[1,5-a]pyridine-2-carboxylic acid ethyl ester as a yellow oil (500 mg). LC / MS[M+H] + 274.0.

[0325] e) Preparation of 2-[Bis(2-fluorophenyl)(hydroxy)methyl]-3-ethyl-6-methoxypyrazolo[1,5-a]pyridine-5-carbonitrile from ethyl 5-cyano-3-ethyl-6-methoxypyrazolo[1,5-a]pyridine-2-carboxylate using method E. LC / MS [M-OH] + 366.0.

[0326] f) Method C: A mixture of 2-[bis(2-fluorophenyl)(hydroxy)methyl]-3-ethyl-6-methoxypyrazolo[1,5-a]pyridine-5-carbonitrile (90 mg, 0.21 mmol) and azidotributylstannane (459.0 mg, 1.38 mmol) in toluene (3 mL) was stirred at 80° C. for 18 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC under the following conditions: column, Kinetex EVO C18 column, 21.2 x 150 mm, 5 μm; mobile phase, MeCN / water (10 mM NH4HCO3 and 0.1% NH3.H2O), 19% to 31% gradient, 13 min; detector, UV 254 / 220 nm. [3-ethyl-6-methoxy-5-(1H-1,2,3,4-tetrazolyl-5-yl)pyrazolo[1,5-a]pyridin-2-yl]bis(2-fluorophenyl)methanol was obtained as a light yellow solid (9.1 mg, 9.2%). LC / MS [M+H] + 463.1.

[0327] Example 7

[0328] [3-ethyl-6-methoxy-5-(1H-1,2,3,4-tetrazolyl-5-yl)pyrazolo[1,5-a]pyridin-2-yl]diphenylmethanol

[0329]

[0330] [3-Ethyl-6-methoxy-5-(1H-1,2,3,4-tetrazol-5-yl)pyrazolo[1,5-a]pyridin-2-yl]benzhydrol was prepared from ethyl 5-cyano-3-ethyl-6-methoxypyrazolo[1,5-a]pyridine-2-carboxylate, PhMgBr and azidotributylstannane using Method B and Method C. The final product was purified by preparative HPLC under the following conditions: column, XBridgePrep C18 OBD column, 19 x 150 mm, 5 μm; mobile phase, MeCN / water (10 mM NH4HCO3 and 0.1% NH3.H2O), 30% to 45% gradient, 8 min; detector, UV 254 / 220 nm. [3-ethyl-6-methoxy-5-(1H-1,2,3,4-tetrazolyl-5-yl)pyrazolo[1,5-a]pyridin-2-yl]diphenylmethanol was obtained as a light yellow solid (34.9 mg, 16.7%, two steps). LC / MS [M+H] + 427.1.

[0331] Example 8

[0332] [3-Ethyl-6-fluoro-5-(1H-tetrazolyl-5-yl)-pyrazolo[1,5-a]pyridin-2-yl]-diphenyl-methanol

[0333]

[0334] a) 2-Bromo-5-fluoropyridine-4-carbonitrile (1.00 g, 4.73 mmol, 1.00 equiv., 95%), tributyl(prop-2-en-1-yl)stannane (1.80 g, 5.16 mmol, 1.10 equiv., 90%), Pd(amphos)Cl2 (354 mg, 0.47 mmol, 0.10 equiv., 90%) / MeCN (50 mL) were placed in a flask under an inert atmosphere and the reaction mixture was stirred at 100° C. for 24 hours, then cooled to room temperature and concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (4:96) to give 500 mg (46%) of 5-fluoro-2-(prop-2-en-1-yl)pyridine-4-carbonitrile as a yellow oil (70% purity). LC / MS [M+H] + 163.0.

[0335] b) 5-Fluoro-2-(prop-2-en-1-yl)pyridine-4-carbonitrile (490 mg, 2.12 mmol, 1.00 equiv., 70% purity) and Pd / C (50 mg, 0.42 mmol, 0.15 equiv., 90%) / EtOAC (6 mL) were placed in a flask under an inert atmosphere. The reaction mixture was placed under a hydrogen atmosphere (8 mg, 3.77 mmol, 1.31 equiv.) and stirred at room temperature for 1 hour. The solid was filtered off and the solution was concentrated in vacuo. The residue was applied to a silica gel column (ethyl acetate / petroleum ether (1:100) to give 300 mg (82%) of 5-fluoro-2-propylpyridine-4-carbonitrile as a yellow liquid. LC / MS [M+H] + 165.1.

[0336] c)-f) [3-ethyl-6-fluoro-5-(1H-tetrazol-5-yl)-pyrazolo[1,5-a]pyridin-2-yl]-diphenyl-methanol was prepared using the same reaction sequence as in Example 6, ([3-ethyl-6-methoxy-5-(1H-tetrazol-5-yl)-pyrazolo[1,5-a]pyridin-2-yl]-diphenyl-methanol, starting from 5-fluoro-2-propylpyridine-4-carbonitrile. [M-OH] + 397.1.

[0337] General Scheme 3 and Example 9

[0338] Synthesis of 1-ethyl-5-methoxy-6-(1H-tetrazolyl-5-yl)-1H-imidazo[4.5-b]pyridin-2-yl]-diphenylmethanol

[0339]

[0340] a) Synthesis of 5-bromo-6-methoxy-3-nitro-pyridin-2-ylamine

[0341] In a 1L two-necked 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 period of 20 minutes at 14-18°C. The reaction mixture was stirred at room temperature for 1 hour, however, complete conversion to the desired product was observed.

[0342] The reaction mixture was poured into 1.5 L of water and stirred at room temperature for another 30 minutes. The solid was filtered off by 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 (mono-bromine isotope distribution).

[0343] b.5-Bromo-6-methoxy-pyridine-2,3-diamine and

[0344] c. Synthesis of 6-bromo-5-methoxy-3H-imidazo[4.5-b]pyridine

[0345] 5-bromo-6-methoxy-3-nitro-pyridine-2-ylamine (10g, 40.32mmol) is dissolved in tetrahydrofuran (100ml). Subsequently, under standard pressure and room temperature, with sponge nickel catalyst (3g, pH neutrality, THF) and hydrogen treatment reaction mixture overnight (16 hours). After filtering and filter cake with other tetrahydrofuran rinsing, obtain 5-bromo-6-methoxy-pyridine-2, the solution of 3-diamine (8.79g, 40.3mmol) in about 300mL THF, and be used for next step without further purification. In 1L three-necked flask with condenser, triethyl orthoformate (219.75ml) and formic acid (concentration 98-100%, 3.84ml, 100.78mmol) are added in the solution. Then, under argon atmosphere, reaction mixture is heated 3 hours at 90 ℃. For aftertreatment, reaction mixture is evaporated in vacuo. Subsequently, the residue was dissolved in methanol (about 150 ml), diluted with aqueous HCl solution (concentration 2.0 M, about 500 ml) and demineralized water (about 300 ml), and then extracted with ethyl acetate (twice, 300 ml each time). The organic layer was discarded. The aqueous layer was cooled in an ice bath and neutralized with aqueous KOH solution (concentration 47%, about 50 ml) under stirring for a time course of 30 minutes to obtain a solution with a pH of 6. The formed precipitate was filtered off by suction, washed twice with demineralized water (50 ml each time), and dried in a vacuum drying oven (about 60 mbar, at 65° C., 63 hours) to produce 6-bromo-5-methoxy-3H-imidazo[4.5-b]pyridine as a solid (6.39 g, purity 97.9%, 27.44 mmol, yield 68.1%). The second crop of the title product was obtained by extracting the remaining aqueous layer with ethyl acetate (twice, 200 ml each time). The combined organic layers were dried over sodium sulfate, suction filtered, and evaporated in vacuo to yield 6-bromo-5-methoxy-3H-imidazo[4.5-b]pyridine (1.17 g, purity 83.9%, 4.30 mmol, yield 10.7%). [M+H] + =228.0 / 230.0 (mono-bromine isotope distribution).

[0346] d. Synthesis of 6-bromo-1-ethyl-5-methoxy-1H-imidazo[4.5-b]pyridine

[0347] 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 the suspension was cooled in an ice bath while being maintained at 0-5° C. A sodium hydride suspension (60% concentration in paraffin oil, 2.39 g, 59.82 mmol) was subsequently added in portions (twice, 1.20 g each time, caution: hydrogen is formed). After the addition was complete, the flask was inertized again with argon and the suspension was stirred at a temperature of 0-5° C. for 15 minutes. Then, iodoethane (4.54 ml, 55.04 mmol, stabilized with silver) was added dropwise over 5 minutes and stirring was continued for 30 minutes. The reaction mixture was allowed to warm to room temperature while stirring was continued for 63 hours (about 50% conversion). The second crop of sodium hydride suspension (concentration 60%, in paraffin oil, 2.39g, 59.82mmol) was added in two portions (1.12g per portion), and stirring was continued for 15 minutes, followed by the addition of iodoethane (4.54ml, 55.04mmol). After stirring at room temperature for 19 hours (remaining about 32% of the raw material), the procedure was repeated for the third time with sodium hydride suspension (concentration 60%, in paraffin oil, 4.31g, 107.68mmol) and iodoethane (8.48ml, 102.89mmol), and the suspension was diluted with additional dry tetrahydrofuran (20.13ml). After warming to room temperature, stirring was continued for another 17 hours until the reaction was complete. For post-treatment, the reaction mixture was quenched with saturated aqueous ammonium chloride solution (about 20ml) under stirring, and then diluted with demineralized water (about 300ml) and ethyl acetate (about 500ml). After stirring for another 30 minutes, the mixture was filtered and extracted twice with ethyl acetate (each 200ml). The combined organic layer was dried over sodium sulfate, filtered with suction, and evaporated to dryness. The crude product obtained was purified by flash silica gel chromatography (330g, solvent gradient dichloromethane / 0-0.6 volume % ethanol), to produce title product 6-bromo-1-ethyl-5-methoxy-1H-imidazo [4.5-b] pyridine (7.95g, purity 96.7%, 29.99mmol, yield 62.7%, HPTLC silica gel 60F254, Rf 0.61, using solvent mixture dichloromethane-ethanol 10: 1, volume / volume) and by-product 6-bromo-3-ethyl-5-methoxy-3H imidazo [4.5-b] pyridine (2.40g, purity 94.7%, 8.88mmol, yield 18.6%). [M+H] + =256.0 / 258.0 (mono-bromine isotope distribution).

[0348] e. Synthesis of 1-ethyl-5-methoxy-1H-imidazo[4.5-b]pyridine-6-carbonitrile

[0349] In a 200 ml glass autoclave (Büchi), 6-bromo-1-ethyl-5-methoxy-1H-imidazo[4.5-b]pyridine (11.83 g, 46.21 mmol), K4[Fe(CN)6] (7.82 g, 18.51 mmol) and potassium acetate (570 mg, 5.81 mmol) were dissolved in dioxane (100 ml) and water (100 ml). The flask was then degassed by repeated cycles of vacuum and addition of argon. Thereafter, a suspension of the catalyst tBuBrettPhos Pd G3 (202 mg, 0.236 mmol) in dioxane (10 ml, oxygen-free; suspension treated in an ultrasonic bath) was added to the reaction mixture. The mixture was then heated to 114° C. (oil bath) for 22 h with stirring. For workup, the pale yellow mixture was diluted with demineralized water, ethyl acetate (200 ml each) and methanol (100 ml). The mixture was filtered through celite, and the aqueous layer was extracted with ethyl acetate three times (300 ml each time) until no more product was found in the aqueous layer. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1-ethyl-5-methoxy-1H-imidazo[4.5-b]pyridine-6-carbonitrile (7.80 g, purity 92.0%, 35.49 mmol, yield 73.9%). [M+H] + =203.

[0350] f. Synthesis of 1-ethyl-2-(hydroxy-diphenyl-methyl)-5-methoxy-1H-imidazo[4.5-b]pyridine-6-carbonitrile

[0351] Under argon atmosphere, 1-ethyl-5-methoxy-1H-imidazo[4.5-b]pyridine-6-carbonitrile (100 mg, 0.476 mmol) and benzophenone (109.48 mg, 0.595 mmol) were suspended in anhydrous tetrahydrofuran (1.5 ml) and cooled to 0-5 ° C in an ice bath. Subsequently, bis(trimethylsilyl)amide lithium solution (1.0 M / THF, 571 μl, 0.571 mmol) was added dropwise within 2 minutes and the resulting solution was further stirred for 1 hour. For post-treatment, the reaction mixture was diluted with saturated aqueous ammonium chloride solution (5 ml), then diluted with demineralized water (10 ml), and then extracted with ethyl acetate 3 times (10 ml each time). The combined organic layer was dried over sodium sulfate, filtered with suction, and evaporated to dryness. The remaining residue was purified by flash chromatography on silica gel (4 g, solvent gradient dichloromethane / 0-2 vol.% ethanol) to give 1-ethyl-2-(hydroxy-diphenyl-methyl)-5-methoxy-1H imidazo[4.5-b]pyridine-6-carbonitrile (166.4 mg, purity 97.1%, 0.42 mmol, yield 88.3%). [M+H] +=385.1; HPTLC: dichloromethane / ethanol (vol. / vol.20:1 / R f 0.68).

[0352] g. Synthesis of 1-ethyl-5-methoxy-6-(1H-tetrazolyl-5-yl)-1H-imidazo[4.5-b]pyridin-2-yl]-diphenylmethanol

[0353] Under argon atmosphere, 1-ethyl-2-(hydroxy-diphenyl-methyl)-5-methoxy-1H-imidazo[4.5-b]pyridine-6-carbonitrile (66 mg, 0.167 mmol), anhydrous zinc chloride (625.5 mg, 4.59 mmol) and sodium azide (361.4 mg, 5.50 mmol, ultrapure grade) were suspended in 1-propanol (9.8 ml). Subsequently, the reaction mixture was stirred at 100 ° C for 10 hours. For post-treatment, the mixture was poured into demineralized water (50 ml) and stirred for 30 minutes. The obtained precipitate was filtered off and rinsed 3 times with demineralized water (15 ml each time). Subsequently, the precipitate was dissolved in a mixture of HCl (2.0 M, 30 ml) and demineralized water (20 ml) and extracted 3 times with ethyl acetate (50 ml each time). The combined organic layer was dried over sodium sulfate, filtered and evaporated in vacuo. The crude product was purified by chromatography (pHPLC, solvent gradient: water + 0.1 vol.% TFA / 20-38 vol.% acetonitrile + 0.1 vol.% TFA) to give colorless [1-ethyl-5-methoxy-6-(1H-tetrazolyl-5-yl)-1H-imidazo[4.5-b]pyridin-2-yl]-diphenyl-methanol (Example 9, 400 mg, purity 99.4%, 0.93 mmol, yield 81.1%). [M+H] + =428.1; HPTLC: dichloromethane / ethanol 10:1 (vol. / vol.) R f 0.49.

[0354] Reference compounds

[0355] The reference compound 3-ethyl-2-[hydroxy(diphenyl)methyl]-N-[(2R)-2-hydroxypropyl]benzimidazole-5-carboxamide can be obtained as described in WO2015 / 175845 (Compound No. 79).

[0356] Table 1

[0357] Table 1 is divided into Tables 1a, 1b, 1c, 1d, 1e, 1f, 1g, 1h, 1i and 1j, which show exemplary compounds of the present invention.

[0358] Compounds of formula Ic which have been synthesized according to general synthesis 1 and according to or analogously to example 1 are shown in table 1a below.

[0359] Table 1a

[0360]

[0361]

[0362] Compounds of formula Ic which have been synthesized according to general synthesis 1 and according to or analogously to example 2 are shown in table 1b below.

[0363] Table 1b

[0364]

[0365]

[0366] Compounds of formula Ic which have been synthesized according to general synthesis 1 and according to or analogously to example 3 are shown in table 1c below.

[0367] Table 1c

[0368]

[0369]

[0370] Compounds of formula Ic which have been synthesized according to general synthesis 1 and according to or analogously to example 4 are shown in table 1d below.

[0371] Table 1d

[0372]

[0373]

[0374]

[0375] Compounds of formula Ic which have been synthesized according to general synthesis 1 and according to or analogously to example 5 are shown in table 1e below.

[0376] Table 1e

[0377]

[0378]

[0379]

[0380] Compounds of formula Ib which have been synthesized according to general synthesis 2 and according to or analogously to example 6 are shown in table 1f below.

[0381] Table 1f

[0382]

[0383] Compounds of formula Ib which have been synthesized according to general synthesis 2 and according to or analogously to example 7 are shown in table 1g below.

[0384] Table 1g

[0385]

[0386]

[0387] Compounds of formula Ib which have been synthesized according to general synthesis 2 and according to or analogously to example 8 are shown in table 1i below.

[0388] Table 1i

[0389]

[0390] Compounds of formula Ia which have been synthesized according to general synthesis 3 and according to or analogously to example 9 are shown in table 1j below.

[0391]

[0392]

[0393]

[0394]

[0395]

[0396]

[0397]

[0398]

[0399]

[0400]

[0401]

[0402]

[0403]

[0404]

[0405] Biological Activity

[0406] Biochemical activity of ACSS2 assay (IC 50 ACSS2 Biochemistry)

[0407] Biochemical activity assay of ACSS2 based on AMP-Glo TM Detection of released AMP by the assay kit (Promega, Madison). The assay was performed in three steps: an enzymatic reaction in which human rec ACSS2 activates acetate with ATP and coenzyme A as cosubstrates for vinyl-CoA to release AMP, and a detection reaction of AMP by the AMP Glo assay in which AMP produced by Glo reagent 1 is converted to ATP after destruction of residual ATP with AMP, which is measured in the luciferase assay system (detection reagent). ACSS2 activity is associated with the luminescent signal detected.

[0408] The assay was performed in a Perkin Elmer 384-well white Proxiplate in a total volume of 8 μl.

[0409] In the absence or presence of test compounds (10 dilution concentration, starting concentration 30 μM), a mixture of 1 nM (fc) C-term myc-tagged ACSS2 (human, recombinant, Origene, Rockville, US) and 100 μM (fc) ATP, 100 μM (fc) coenzyme A and 500 μM (fc) sodium acetate was incubated at 37° C. for 180 minutes in a total volume of 5 μl (50 mM Hepes, 1 mM magnesium chloride, 150 mM NaCl, 1 mM DTT, 0.01% (w / v) BSA, 0.3% DMSO, pH 7.5). The reaction was stopped and residual ATP was destroyed by adding 1 μl AMP Glo reagent solution (Promega, Madison, US). After incubation at room temperature for 1 hour, 2 μl AMP Glo detection reagent was added and the assay was incubated at room temperature for 0.75 hours. The luminescent signal was measured in luminescence mode at 700 nm using an Envision multimode reader (Perkin Elmer LAS Germany GmbH). The full value used was the reaction without inhibitor. A pharmacological zero value was generated by adding an ACSS2 inhibitor (Ac-CoA synthetase inhibitor-CAS508186-14-9-Calbiochem) at a final concentration of 5 μM. The program Assay from GeneData was used. The inhibition value (IC50) was determined.

[0410] The experimental data for the compounds shown in Table 1 in the IC50 ACSS2 biochemical assay are shown in Table 2 below and are classified into the following groups:

[0411] Group A IC 50 In the range of 0.01nM to <1nM

[0412] Group B IC50 In the range of 1nM to <10nM

[0413] Group C IC 50 In the range of 10nM to <100nM

[0414] Group D IC 50 In the range of 100nM to <10000nM

[0415] 14 Cellular assay for C acetate incorporation into fatty acids ( IC 50 ACSS2 Cellular lipids

[0416] This protocol describes a cellular assay that enables quantification of endogenous fatty acid synthesis activity in the human HCT-15 cancer cell line followed by incorporation of extracellularly administered radiolabeled 14 C acetate and scintillation proximity based readout on extracted fatty acids.

[0417] HCT-15 cells were grown in RPMI 1640 (Gibco) supplemented with 2 mM glutamine, 1 mM sodium pyruvate, 10 mM HEPES, and 10% FCS (heat inactivated) and passaged every 2-3 days to maintain subconfluent live cultures. 7 Working cell banks were prepared for each aliquot of viable cells. After thawing, the cells were immediately diluted 1:20 in preheated (37°C) culture medium. The cells were collected by centrifugation at 200×g for 5 minutes, and the supernatant was replaced with 30 mL of fresh culture medium per aliquot to obtain a cell suspension containing 350,000 cells / mL. From this cell suspension, 100 μL was dispersed into each well of a collagen-coated 96-well plate (black, transparent bottom, PS, F-bottom, Greiner) and cultured for 24 hours (37°C, 5% CO2). After incubation, the culture medium was removed and replaced with 100 μL PBS++ (supplemented with Mg 2+ / Ca 2+ Wells were washed once with RT-PCR (Sigma, Gibco) and 50 μL of assay medium (RPMI 1640 + 10 mM HEPES) was added to each well.

[0418] Compound serial dilutions were prepared from 10 mM DMSO stock solutions using a fixed dilution factor (usually 1:3). After preparing the serial dilutions in DMSO, each dilution was further diluted in assay medium. The working dilutions were prepared so that the concentration was 7 times the final concentration in the assay. The maximum DMSO concentration in the final assay was 0.1%.

[0419] 10 μL of compound working dilution or DMSO blank was added to each well, and the cells were incubated for 2 hours (37°C, 5% CO2). 14 10 μL AlamarBlue reagent (Invitrogen) of C-acetate (Perkin Elmer) is added to each well (70 μL total volume), and the cells are cultured again for 2 hours. Cell viability is verified by measuring AlamarBlue fluorescence (Tecan Safire, excitation: 544nm / emission: 590nm). After incubation, the culture medium is removed and the wells are carefully washed once with cold 100 μL PBS++. For cell lysis and fatty acid recovery, 50 μl 0.1M NaOH and 0.1% Triton-X100 are added to each well. The plate is sealed with PlateLoc (transparent peelable heat seal, Agilent) and incubated at 70°C for 16-24 hours. After cooling to room temperature, the plate is centrifuged at 1000rpm for 1 minute, and the plate seal is removed. For acidification, 150 μL 0.1M HCl is added to each well, mixed, and the 150 μL mixture is transferred to a 96-well Flashplate (Perkin Elmer). The plates were sealed with TopSeal-A (Perkin Elmer). To allow the fatty acids to bind to the well surface, the plates were incubated at 70°C for 4 hours. After cooling to room temperature, the plates were centrifuged at 1000 rpm for 1 minute and stored in the dark at room temperature for 0.5-2 hours. The number of scintillation markers in the wells was measured in a MicroBeta scintillation counter (Perkin Elmer). 14 The radioactivity incorporated into fatty acids was counted as CPM.

[0420] The compounds shown in Table 1 have 50 The experimental data in the ACSS2 cell lipid assay are shown in Table 2 below and are categorized into the following groups:

[0421] Group A IC 50 In the range of 0.01nM to <1nM

[0422] Group B IC 50 In the range of 1nM to <10nM

[0423] Group C IC 50 In the range of 10nM to <100nM

[0424] Group D IC 50 In the range of 100nM to <10000nM

[0425] 14 Cellular assay for C acetate incorporation into histones (IC 50 ACSS2 Cell Histones

[0426] This protocol describes a cellular assay that enables quantification of endogenous histone acetylation activity in the human HCT-15 cancer cell line followed by incorporation of extracellularly administered radiolabeled 14 C acetate and flash-based readout on acid-extracted histones.

[0427] HCT-15 cells were trypsinized, washed and suspended in DMEM medium supplemented with penicillin / streptomycin (100 U / mL), sodium pyruvate (1 mM) and 10% FBS.

[0428] Compound serial dilutions were prepared from 10 mM DMSO stock solutions in 96-well V-bottom microplates. 0.5 μl was transferred from these dilutions to fresh plates including pure DMSO as a negative control. Dilutions were prepared so that the final concentration in the assay was 1 / 400 of the concentration in the serial dilutions. The final DMSO concentration in the assay was 0.25%.

[0429] The cell suspension was diluted to 2 × 10 5 Cells were seeded at a density of 10 cells / 170 μL into individual wells of a 96-well plate, each well containing 0.5 μL aliquots of the compound serial dilutions and kept in a cell culture incubator for 1 hour. 30 μL of 0.5 mCi / mL of 14 Then, the wells were incubated in a cell culture incubator for 3 h.

[0430] The other steps of the procedure should be performed on ice or on an instrument precooled to 4°C. The cells were sedimented in a 96-well V-bottom microplate by centrifugation at 1200rpm (Eppendorf 5804R) for 5 minutes. The supernatant was removed and the cells were washed twice by repeated resuspension and centrifugation with 200μL PBS-NaB (5mM sodium butyrate) buffer. Finally, the cells were resuspended in 50μLTEB (PBS-NaB+0.5%Triton X-100) and placed on ice for 10 minutes. After centrifugation at 2300rpm for 10 minutes at 4°C, the supernatant was removed and the remaining precipitate was suspended in 50μL 0.2MHCl and incubated overnight at 4°C. After incubation, the well plate was shaken for 2 minutes in an MTP plate shaker set at 1200rpm and then centrifuged at 3700rpm for 10 minutes. Carefully aspirate the lysate (~43 μL) and transfer to a white MTP plate (Greiner bio-one 65509). Add 90 μL of UltimaGold XR scintillation cocktail and seal the plate with clear cover tape before vigorously mixing using a plate shaker set at 1200 rpm. Measure the scintillation rate in the wells in a MicroBeta Trilux scintillation counter. 14 The radioactivity incorporated by C was counted as CPM.

[0431] The compounds shown in Table 1 have 50 The experimental data in the ACSS2 cell histone assay are shown in Table 2 below and are classified into the following groups:

[0432] Group A IC 50 In the range of 0.01nM to <1nM

[0433] Group B IC 50 In the range of 1nM to <10nM

[0434] Group C IC 50 In the range of 10nM to <100nM

[0435] Group D IC 50 In the range of 100nM to <10000nM

[0436] Micronucleus assay (MNT)

[0437] In vitro MNT assays were performed in CHO-K1 cells due to their stable and well-characterized karyotype, high sensitivity, and suitability for high-content imaging methods. They have a basal spontaneous micronucleus frequency of 3-4%.

[0438] 24 hours after plating, CHO-K1 cells were treated with test compounds for 24 hours (in duplicate; fixed concentrations between 0.2 μM and 100 μM, in 2-fold dilution steps). After replacing the medium, the cells were incubated with cytochalasin B for 24 hours to block cytokinesis, and then the cells were fixed and the nuclei / micronuclei were visualized with a DNA stain. Images were acquired with a Molecular Devices high-content imager IXU or IXM and analyzed with the dedicated MetaXpress software micronucleus module. The criteria for micronucleus (MN) scoring are as follows:

[0439] The diameter of MN should be less than 1 / 3 of the main core

[0440] MN should be separated from the main nucleus or overlap it marginally (= no blebs)

[0441] MNs should have similar staining to the main nuclei

[0442] At least 1000 binucleated cells were evaluated in duplicate for each treatment. Mitomycin C was used as a reference stimulus for micronucleus formation. Cytotoxicity was evaluated in parallel and defined by comparing the total nuclear counts in compound-treated samples to neutral control samples treated with vehicle only (1% DMSO) (100% cytotoxicity means all cells are dead or lost).

[0443] A test compound was considered positive if it produced micronuclei and exhibited less than 60% cytotoxicity at the same concentration. (A data value was considered positive if it contained more micronuclei than the mean of the neutral control plus 3× standard deviation.)

[0444] If no micronuclei were observed at concentrations showing less than 60% cytotoxicity and at least one of the tested concentrations produced more than 60% cytotoxicity, the compound was reported as negative.

[0445] Compounds were reported as PN (presumptive negative) if they did not produce micronuclei and exhibited less than 60% cytotoxicity at any concentration tested.

[0446] A compound was reported as ND (not determined) if it exhibited more than 60% cytotoxicity at a certain concentration (independent of the generation of micronuclei).

[0447] Compounds were scored only within the soluble concentration range.

[0448] The experimental data for the compounds shown in Table 1 in the MNT assay are shown in Table 2 below and are classified into the following groups:

[0449] Group A negative, presumed negative (micronuclei detected exceeded 60% cytotoxicity threshold)

[0450] Group B positive

[0451] The QuantiGene Plex2.0 reagent system (branched DNA) from Affymetrix (Thermo Scientific) was used. CYP induction assay (CYP3A4 induction) was performed in HepaRG cells

[0452] The QuantiGene Plex 2.0 assay combines branched DNA (bDNA) signal amplification and multi-analyte characterization beads The xMAP system combines flow cytometry, fluorescently dyed microspheres (beads), lasers, and digital signal processing to allow up to 100 unique multiplex assays to be performed in a single sample.

[0453] The following analytes were assayed using a Luminex 200 analyzer and a 7-plex QuantiGene Plex 2.0 assay: CYP1A2 (NM_000761), CYP2B6 (NM_000767), CYP2C19 (NM_000769), CYP2C9 (NM_000771), CYP3A4 (NM_017460), HPRT1 (NM_000194), and TFRC (NM003234).

[0454] Human HepaRG cells (Thermo Scientific) were thawed and seeded in collagen pre-coated 96-well plates at a density of 0.72E6 cells / ml. After a 3-day adaptation period in the first Williams E medium (Gibco + thawing supplement, ThermoScientific), the medium was replaced with a second Williams E medium (Gibco + tox supplement, Thermo Scientific). From the 3rd to 10th day of culture, the test substances were treated with 4 concentrations every day for 48 hours. After 48 hours, the cells were lysed with 100 μl / well (lysis mixture, Affymetrix, diluted 1:2 with Williams E medium, Gibco, and a mixture of 5 μl proteinase K / ml was added, Affymetrix).

[0455] The QuantiGene Plex 2.0 assay uses fluorescent capture beads to capture specific RNA molecules. In order to hybridize and span the continuous sequence of the target RNA, a probe set containing 3 synthetic probes (capture extender, label extender and blocker) is incubated with the sample and beads at 54°C at 600rpm for 16-20 hours. Signal amplification is mediated by DNA amplification molecules hybridized to the tail of the label extender (overnight hybridization beads are incubated with pre-amplifier and amplifier reagent at 50°C for 1 hour, respectively, with washing steps in between). Each amplification unit contains multiple hybridization sites of biotin-labeled probes (incubated with label probe reagent at 50°C for 1 hour, with washing steps in between), which are bound to streptavidin-conjugated R-phycoerythrin (SAPE, 30 minutes final incubation step at room temperature). After SAPE incubation, a final wash step is performed using SAPE buffer (120μl remaining in the well). The resulting fluorescent signal associated with individual capture beads was detected on a Luminex 200 flow cytometer (parameters: volume 100 μl, timeout 45 seconds, DD-gate 5,000-25,000, bead events 50). The signal is reported as median fluorescence intensity (MFI) and is proportional to the number of target RNA molecules present in the sample.

[0456] To analyze the results, the mean and standard deviation of 3 technical replicates were calculated (acceptable %SD up to 30%). The mean of the blank was subtracted from the mean of the sample. Since the genes HPRT1 and TFRC are housekeeping genes, they are used to standardize the sample mean [(sample mean-blank) / housekeeping gene (mean-blank) = standardized value (HPRT1 or TFRC)]. The calculation of the fold change is performed by dividing the standardized sample value by the standardized mean of the DMSO control [(sample mean-blank) / housekeeping gene (mean-blank) = fc; (DMSO mean-blank) / housekeeping gene (mean-blank)].

[0457] Experimental data for the compounds shown in Table 1 in the CYP3A4 assay are shown in Table 2 below and are given in μM (significant induction above the 20% threshold; in brackets: lowest concentration resulting in at least a 2-fold induction):

[0458] Table 2

[0459]

[0460]

[0461]

[0462] The following examples relate to drugs:

[0463] Example A: Injection Vial

[0464] A solution of 100 g of the active ingredient of Formula Ia, Ib or Ic and 5 g of disodium hydrogen phosphate in 3 liters of double distilled water was adjusted to pH 6.5 using 2N hydrochloric acid, sterile filtered, transferred to injection vials, lyophilized under aseptic conditions and sealed under aseptic conditions. Each injection vial contains 5 mg of the active ingredient.

[0465] Example B: Suppository

[0466] A mixture of 20 g of the active ingredient of formula Ia, Ib or Ic with 100 g of soya lecithin and 1400 g of cocoa butter is melted, poured into a mold and cooled. Each suppository contains 20 mg of the active ingredient.

[0467] Example C: Solution

[0468] A solution is prepared from 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. The pH is adjusted to 6.8 and the solution is made up to 1 liter and sterilized by irradiation. The solution can be used in the form of eye drops.

[0469] Example D: Ointment

[0470] 500 mg of the active ingredient of Formula Ia, Ib or Ic are mixed with 99.5 g of petrolatum under aseptic conditions.

[0471] Example E: Tablets

[0472] A mixture of 1 kg of active ingredient of the 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 so that each tablet contains 10 mg of the active ingredient.

[0473] Example F: Dragees

[0474] Tablets are pressed analogously to Example E and subsequently coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and dye.

[0475] Example G: Capsules

[0476] 2 kg of active ingredient of the formula Ia, Ib or Ic are introduced into hard gelatine capsules in a customary manner so that each capsule contains 20 mg of active ingredient.

[0477] Example H: Ampoule

[0478] A solution of 1 kg of the active ingredient of formula Ia, Ib or Ic in 60 liters of double distilled water is sterile filtered, transferred into ampoules, lyophilized under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of the active ingredient.

Claims

1. Tetrazolyl derivatives of formula Ia, Ib or Ic Which independently R 1 Ar A or Hetar A ; R 2 Ar B or Hetar B ; R 3 Represents C 1-6 -alkyl or -OC 1-6 -alkyl; R 4 Indicates H, D, C 1-6 -alkyl or -OC 1-6 -alkyl; R 5 Indicates H, D, C 1-6 -alkyl, -OC 1-6 - alkyl or halogen; Ar A is a monoaryl radical having 5 or 6 ring carbon atoms, wherein the aryl radical is unsubstituted or substituted by the same or different substituents R A1 , R A2 , R A3 , R A4 and / or R A5 replace; Ar B is a monoaryl radical having 5 or 6 ring carbon atoms, wherein the aryl radical is unsubstituted or substituted by the same or different substituents R B1 , R B2 , R B3 , R B4 and / or R B5 replace; Hetar A is a monocyclic heteroaryl group having 5 or 6 ring atoms, wherein 1, 2, 3, 4, 5 of the ring atoms are heteroatoms selected from N, O and / or S and the rest are carbon atoms, wherein the heteroaryl group is unsubstituted or substituted by the same or different substituents R A1 , R A2 , R A3 , R A4 and / or R A5 replace; Hetar B is a monocyclic heteroaryl group having 5 or 6 ring atoms, wherein 1, 2, 3, 4, 5 of the ring atoms are heteroatoms selected from N, O and / or S and the rest are carbon atoms, wherein the heteroaryl group is unsubstituted or substituted by the same or different substituents R B1 , R B2 , R B3 , R B4 and / or R B5 replace; R A1 , R A2 , R A3 , R A4 , R A5 , R B1 , R B2 , R B3 , R B4 , R B5 are independently H, D, halogen, C 1-6 -alkyl, -OC 1-6 -alkyl; Halogen means F, Cl, Br or I; or any stereoisomer thereof and / or any pharmaceutically acceptable salt thereof.

2. The tetrazole derivative according to claim 1, or any stereoisomer thereof and / or any pharmaceutically acceptable salt thereof, in R 1 and R 2 Have the same meaning.

3. The tetrazole derivative according to claim 1, or any stereoisomer thereof and / or any pharmaceutically acceptable salt thereof, in R 1 and R 2 Have different meanings.

4. The tetrazole derivative according to claim 1, or any stereoisomer thereof and / or any pharmaceutically acceptable salt thereof, in Ar A is phenyl, which is unsubstituted or replaced by R A1 and / or R A2 mono- or disubstituted; Ar B is phenyl, which is unsubstituted or replaced by R B1 and / or R B2 mono- or disubstituted; Hetar A is a monocyclic heteroaryl group having 5 or 6 ring atoms, wherein 1 or 2 of the ring atoms are heteroatoms selected from N, O and / or S and the rest are carbon atoms, wherein the heteroaryl group is unsubstituted or substituted by identical or different substituents R A1 and / or R A2 replace; Hetar B is a monocyclic heteroaryl group having 5 or 6 ring atoms, wherein 1 or 2 of the ring atoms are heteroatoms selected from N, O and / or S and the rest are carbon atoms, wherein the heteroaryl group is unsubstituted or substituted by identical or different substituents R B1 and / or R B2 replace.

5. The tetrazole derivative according to claim 4, or any stereoisomer thereof and / or any pharmaceutically acceptable salt thereof, in R A1 , R A2 , R B1 , R B2 H, F, Cl, C independently of each other 1-4 -alkyl, -OC 1-4 -alkyl.

6. The tetrazole derivative according to claim 1, or any stereoisomer thereof and / or any pharmaceutically acceptable salt thereof, Which independently R 3 Indicates substituted or unsubstituted C 1-4 -alkyl; R 4 Indicates H; R 5 Indicates H, C 1-4 -alkyl, -OC 1-4 -alkyl, F or Cl.

7. The tetrazole derivative according to claim 1, or any stereoisomer thereof and / or any pharmaceutically acceptable salt thereof, Which independently R 3 represents methyl, ethyl, 2-aminoethyl or 2-hydroxyethyl; R 4 Indicates H; R 5 represents H, methyl, ethyl, methoxy, F or Cl; Ar A is phenyl; deuterated phenyl; fluorophenyl; methylphenyl; difluoromethoxyphenyl; 4-difluoromethoxy-2-fluorophenyl; Ar B is phenyl; deuterated phenyl; fluorophenyl; methylphenyl; difluoromethoxyphenyl; 4-difluoromethoxy-2-fluorophenyl; Hetar A is methylpyrazolyl; thiophen-2-yl, thiophen-3-yl; methylthiophenyl; thiazolyl; pyridin-2-yl, pyridin-3-yl, pyridin-4-yl; pyrimidinyl; pyridazinyl; Hetar B It is methylpyrazolyl; thiophen-2-yl, thiophen-3-yl; methylthiophenyl; thiazolyl; pyridin-2-yl, pyridin-3-yl, pyridin-4-yl; pyrimidinyl; pyridazinyl.

8. The tetrazole derivative according to claim 7, or any stereoisomer thereof and / or any pharmaceutically acceptable salt thereof, Which independently Ar A is phenyl; pentadeuteriophenyl; 2-fluorophenyl; 2-methylphenyl; 4-difluoromethoxyphenyl; 4-difluoromethoxy-2-fluorophenyl; Ar B is phenyl; pentadeuteriophenyl; 2-fluorophenyl; 2-methylphenyl; 4-difluoromethoxyphenyl; 4-difluoromethoxy-2-fluorophenyl; Hetar A 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl; thiophene-2-yl, thiophene-3-yl; 5-methylthiophene-2-yl; 1,3-thiazol-2-yl; pyridin-2-yl, pyridin-3-yl, pyridin-4-yl; pyrimidin-2-yl, pyrimidin-4-yl; pyridazin-3-yl; Hetar B It is 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl; thiophene-2-yl, thiophene-3-yl; 5-methylthiophene-2-yl; 1,3-thiazol-2-yl; pyridin-2-yl, pyridin-3-yl, pyridin-4-yl; pyrimidin-2-yl, pyrimidin-4-yl; pyridazin-3-yl.

9. The tetrazole derivative according to claim 1, or any stereoisomer thereof and / or any pharmaceutically acceptable salt thereof, Wherein the tetrazole derivative is selected from the compounds shown in Table 1, which is divided into Tables 1a, 1b, 1c, 1d, 1e, 1f, 1g, 1h, 1i and 1j.

10. Use of the tetrazole derivative according to any one of claims 1 to 9, or any stereoisomer thereof and / or any pharmaceutically acceptable salt thereof in the manufacture of a medicament for preventing and / or treating a disease affected by inhibiting ACSS2.

11. Use of a tetrazole derivative according to any one of claims 1 to 9, or any stereoisomer thereof and / or any pharmaceutically acceptable salt thereof in the manufacture of a medicament for preventing and / or treating a disease affected by inhibiting ACSS2 selected from the group consisting of cancer; lipid metabolism disorders; and viral infections.

12. Use of a tetrazole derivative according to any one of claims 1 to 9, or any stereoisomer thereof and / or any pharmaceutically acceptable salt thereof in the manufacture of a medicament for preventing and / or treating a disease affected by inhibiting ACSS2 selected from the group consisting of: solid tumors; fatty liver disease; and viral infection by cytomegalovirus.

13. A pharmaceutical composition comprising as an active ingredient at least one tetrazole derivative according to any one of claims 1 to 9, or any stereoisomer thereof and / or any pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

14. The pharmaceutical composition according to claim 13, further comprising a second active ingredient or any stereoisomer thereof and a pharmaceutically acceptable salt thereof, wherein the second active ingredient is not a tetrazole derivative of formula Ia, Ib or Ic as defined in any one of claims 1 to 9.

15. A set comprising the following individual packages: a) an effective amount of a tetrazole derivative of formula Ia, Ib or Ic according to any one of claims 1 to 9, or any stereoisomer thereof and / or any pharmaceutically acceptable salt thereof; and b) an effective amount of a further active ingredient which is not a tetrazole derivative of the formula Ia, Ib or Ic as defined in any one of claims 1 to 9.

16. A process for producing a tetrazole derivative of formula Ia, Ib or Ic according to any one of claims 1 to 9, or any stereoisomer thereof and / or any pharmaceutically acceptable salt thereof, characterized in that (a) Carbonitrile of general formula II-a Where R 1 , R 2 , R 3 , R 4 and R 5 As defined in any one of claims 1 to 9, Optionally, undergoing a cyclization reaction with a suitable azide reagent in the presence of a suitable catalyst to produce a tetrazole derivative of Formula Ia: Where R 1 , R 2 , R 3 , R 4 and R 5 As defined in any one of claims 1 to 9; or (b) Carbonitrile of general formula II-b Where R 1 , R 2 , R 3 , R 4 and R 5 As defined in any one of claims 1 to 9, Optionally, undergoing a cyclization reaction with a suitable azide reagent in the presence of a suitable catalyst to produce a tetrazole derivative of Formula Ib: Where R 1 , R 2 , R 3 , R 4 and R 5 As defined in any one of claims 1 to 9, or c) Carbonitrile of general formula II-c Where R 1 , R 2 , R 3 , R 4 and R 5 As defined in any one of claims 1 to 9, Optionally, undergoing a cyclization reaction with a suitable azide reagent in the presence of a suitable catalyst to produce a tetrazole derivative of Formula Ic: Where R 1 , R 2 , R 3 , R 4 and R 5 As defined in any one of claims 1 to 9.

17. Carbonitrile of formula II-a, II-b or II-c Where R 1 , R 2 , R 3 , R 4 and R 5 As defined in any one of claims 1 to 9.

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