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BR-112020009729-B1 - ACSS2 inhibitors and methods of their use.

BR112020009729B1BR 112020009729 B1BR112020009729 B1BR 112020009729B1BR-112020009729-B1

Abstract

ACSS2 INHIBITORS AND METHODS OF USE THEREOF The present invention relates to novel ACSS2 inhibitors exhibiting activity as an anti-cancer therapy, treatment of alcoholism and viral infection (e.g., CMV), composition and methods of preparation thereof, and uses thereof for the treatment of viral infection, alcoholism, alcoholic steatohepatitis (ASH), non-alcoholic steatohepatitis (NASH), obesity/weight gain, anxiety, depression, post-traumatic stress disorder, inflammatory/autoimmune conditions and cancer, including metastatic cancer, advanced cancer and drug-resistant cancer of various types.

Inventors

  • Philippe Nakache
  • Omri Erez
  • Simone BOTTI
  • Andreas Goutopoulos
  • Marc Labelle

Assignees

  • METABOMED LTD

Dates

Publication Date
20260317
Application Date
20181115
Priority Date
20171115

Claims (8)

  1. 1. Compound, characterized by being represented by the formula structure (I): in which: ring A is an aromatic or heteroaromatic ring system selected from phenyl, naphthyl, pyridinyl (2-, 3- and 4-pyridinyl), quinolinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, 1-methylimidazole, pyrazolyl, pyrrolyl, furanyl, thiophenyl, quinolinyl, isoquinolinyl, 2,3-dihydroindenyl, indenyl, tetrahydronaphthyl, 3,4-dihydro-2H-benzo[b][1,4]dioxepin, benzodioxolyl,benzo[d][1,3]dioxol, tetrahydronaphthyl, indolyl, 1H-indole, isoindolyl, anthracenyl, benzimidazolyl, 2,3-dihydro-1H-benzo[d]imidazolyl, indazolyl, 2H-indazole, triazolyl, 4,5,6,7-tetrahydro-2H-indazole, 3H-indol-3-one, purinyl, benzoxazolyl, 1,3-benzoxazolyl, benzisoxazolyl, benzothiazolyl, 1,3-benzothiazol, 4,5,6,7-tetrahydro-1,3- benzothiazole, quinazolinyl, quinoxalinyl, 1,2,3,4- tetrahydroquinoxaline, 1-(pyridin-1(2H)-yl)ethanone, cinolinyl, phthalazinyl, quinolinyl, isoquinolinyl, acridinyl, benzofuranyl, 1-benzofuran, isobenzofuranil, benzofuran-2(3H)-one, benzothiophenyl, benzoxadiazole, benzo[c][1,2,5]oxadiazolyl, benzo[c]thiophenyl, benzodioxolyl, thiadiazolyl, [1,3]oxazolo[4,5-b]pyridine, oxadiazolyl, imidazo[2,1-b][1,3]thiazole, 4H,5H,6H-cyclopenta[d][1,3]thiazole, 5H,6H,7H,8H-imidazo[1,2- a]pyridine, 7-oxo-6H,7H-[1,3]thiazolo[4,5-d]pyrimidine, [1,3]thiazolo[5,4-b]pyridine, 2H,3H-imidazo[2,1- b][1,3]thiazole, thieno[3,2-d]pyrimidin-4(3H)-one, 4-oxo- 4H-thieno[3,2-d][1,3]thiazin, imidazo[1,2-a]pyridine, 1H- imidazo[4,5-b]pyridine, 1H-imidazo[4,5-c]pyridine, 3H- imidazo[4,5-c]pyridine, pyrazolo[1,5-a]pyridine, imidazo[1,2-a]pyrazine, imidazo[1,2-a]pyrimidine, 1H-pyrrolo[2,3-b]pyridine, pyrido[2,3-b]pyrazine, pyrido[2,3-b]pyrazin-3(4H)-one, 4H-thieno[3,2-b]pyrrole, quinoxalin-2(1H)-one, 1H-pyrrolo[3,2-b]pyridine, 7H- pyrrolo[2,3-d]pyrimidine, oxazolo[5,4-b]pyridine, thiazolo[5,4-b]pyridine, thieno[3,2-c]pyridine; a C3-C10- cycloalkyl; or a C3-C10-heterocyclic ring; ring B is an aromatic or heteroaromatic ring system selected from phenyl, naphthyl, pyridinyl (2-, 3- and 4-pyridinyl), quinolinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, 1-methylimidazole, pyrazolyl, pyrrolyl, furanyl, thiophenyl, quinolinyl, isoquinolinyl, 2,3-dihydroindenyl, indenyl, tetrahydronaphthyl, 3,4-dihydro-2H-benzo[b][1,4]dioxepin, benzodioxolyl, benzo[d][1,3]dioxol, tetrahydronaphthyl, indolyl, 1H-indole, isoindolyl, anthracenyl, benzimidazolyl, 2,3-dihydro-1H-benzo[d]imidazolyl, indazolyl, 2H-indazol, triazolyl, 4,5,6,7-tetrahydro-2H-indazole, 3H-indol-3-one, purinyl, benzoxazolyl, 1,3-benzoxazolyl, benzisoxazolyl, benzothiazolyl, 1,3-benzothiazole, 4,5,6,7-tetrahydro-1,3-benzothiazole, quinazolinyl, quinoxalinyl, 1,2,3,4-tetrahydroquinoxaline, 1-(pyridin-1(2H)-yl)ethanone, cinolinyl, phthalazinyl, quinolinyl, isoquinolinyl, acridinyl, benzofuranil, 1-benzofuran, isobenzofuranil, benzofuran-2(3H)-one, benzothiophenyl, benzoxadiazole, benzo[c][1,2,5]oxadiazolyl, benzo[c]thiophenyl,benzodioxolyl, thiadiazolyl, [1,3]oxazolo[4,5-b]pyridine, oxadiazolyl, imidazo[2,1-b][1,3]thiazole, 4H,5H,6H- cyclopenta[d][1,3]thiazole, 5H,6H,7H,8H-imidazo[1,2-a]pyridine, 7-oxo-6H,7H-[1,3]thiazolo[4,5-d]pyrimidine, [1,3]thiazolo[5,4-b]pyridine, 2H,3H-imidazo[2,1-b][1,3]thiazole, thieno[3,2-d]pyrimidin-4(3H)-one, 4-oxo- 4H-thieno[3,2-d][1,3]thiazin, imidazo[1,2-a]pyridine, 1H- imidazo[4,5-b]pyridine, 1H-imidazo[4,5-c]pyridine, 3H- imidazo[4,5-c]pyridine, pyrazolo[1,5-a]pyridine,imidazo[1,2-a]pyrazine, imidazo[1,2-a]pyrimidine, 1H-pyrrolo[2,3-b]pyridine, pyrido[2,3-b]pyrazine,pyrido[2,3-b]pyrazin-3(4H)-one, 4H-thieno[3,2-b]pyrrole, quinoxalin-2(1H)-one, 1H-pyrrolo[3,2-b]pyridine, 7H- pyrrolo[2,3-d]pyrimidine, oxazolo[5,4-b]pyridine, thiazolo[5,4-b]pyridine, thieno[3,2-c]pyridine;, or a C3C10- cycloalkyl; R1 and R2 are, each independently, H, F, Cl, Br, I, OH, SH, R8-OH, R8-SH, -R8- O-R10, CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, R8-N(R10)(R11), R9-R8-N(R10)(R11), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R10, NHCO-N(R10)(R11), COOH, -C(O)Ph, C(O)O-R10, R8-C(O)-R10, C(O)H, C(O)-R10, C1-C5-C(O)-halo-alkyl linear or branched, -C(O)NH2, C(O)NHR, C(O)N(R10)(R11), SO2R, SO2N(R10)(R11), C1-C5-alkyl linear or branched, C1-C5-halo-alkyl linear or branched, C1-C5-alkoxy linear, branched or cyclic, C1-C5-thioalkoxy linear or branched, C1-C5-halo-alkoxy linear or branched, C1-C5-alkoxy-alkyl linear or branched, C3-C8-cycloalkyl, ring C3-C8 heterocyclic, aryl (in which, when substituted, the substitutions are selected from the group comprising: F, Cl, Br, I, C1-C5 linear or branched alkyl, OH, alkoxy, N(R)2, CF3, CN or NO2), CH(CF3)(NH-R10); or R2 and R1 are joined together to form a 5- or 6-membered ring, aliphatic or aromatic, carbocyclic or heterocyclic; R3 is C1-C5-C(O)-haloalkyl linear or branched, CF2CH3, CH2CF3, CF2CH2CH3, CF2CH2CF3, CF2CH(CH3)2, CF(CH3)-CH(CH3)2, C3-C8 cycloalkyl, C3-C8 heterocyclic ring (in which, when substituted, the substitutions are selected from the group comprising: F, Cl, Br, I, C1-C5-linear or branched alkyl, OH, alkoxy, N(R)2, CF3, CN or NO2); R4 is H, F, Cl, Br, I, OH, SH, R8-OH, R8-SH, -R8-O-R10, CF3, NH2, NHR, N(R)2, R8-N(R10)(R11), R9-R8-N(R10)(R11), -OC(O)CF3, -OCH2Ph, -NHCO-R10, NHCO-N(R10)(R11), -C(O)Ph, C(O)O-R10, R8-C(O)-R10, C(O)-R10, C1-C5-C(O)-halo-linear or branched alkyl, SO2R, SO2N(R10)(R11), C1-C5 linear or branched alkyl, C1-C5 linear or branched haloalkyl, C1-C5 linear, branched or cyclic alkoxy, C1-C5 linear or branched haloalkoxy, C1-C5 linear or branched alkoxyalkyl, C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocyclic ring, aryl (wherein, when substituted, the substitutions are selected from the group comprising: F, Cl, Br, I, C1-C5 linear or branched alkyl, OH, alkoxy, N(R)2, CF3, CN or NO2), CH(CF3)(NH-R10);R5 is H, C1-C5 linear or branched alkyl, substituted or unsubstituted, C1-C5 linear or branched haloalkyl, R8-aryl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl unsubstituted (wherein the substitutions include: F, Cl, Br, I, linear or branched C1-C5 alkyl, OH, alkoxy, N(R)2, CF3, CN or NO2); R6 is H, linear or branched C1-C5 alkyl; R8 is [CH2]p, wherein p is between 1 and 10; R9 is [CH]q, [C]q, wherein q is between 2 and 10; R10 and R11 are, each independently, H, linear or branched C1-C5 alkyl, C(O)R or S(O)2R; R is H, linear or branched C1-C5 alkyl, linear or branched C1-C5 alkoxy, phenyl, aryl or heteroaryl, or two gem substituents R are joined together to form a 5- or 6-membered heterocyclic ring; m, n, and k are, independently, an integer between 0 and 1; 1 is 1; Q1 and Q2 are 0; or a pharmaceutically acceptable salt thereof.
  2. 2. Compound according to claim 1, characterized in that it is represented by the formula structure (II): wherein: R1, R2, R3, R4, R5, R6, R8, R10, R11, R, m, n, l, k, Q1 and Q2 are as defined in claim 1; X1, X2, X3, X4, X5, X6, X7, X8, X9 or X10 are each independently C or N.
  3. 3. Compound, according to claims 1 or 2, characterized by being represented by the formula structure (IV): wherein: R1, R2, R3, R4 and R5 are as defined in claim 1; and X3, X4, X7 and X8 are each independently C or N; wherein, if X3 is N, then R4 is absent; and wherein, if X8 is N, then R2 is absent.
  4. 4. Compound, according to claim 1, characterized by being selected from the following: or a pharmaceutically acceptable salt thereof.
  5. 5. A compound, according to any of the preceding claims, characterized by being an inhibitor of Member 2 of the Acyl-CoA synthetase Short Chain Family (ACSS2).
  6. 6. Pharmaceutical composition, characterized by comprising a compound as defined in any one of claims 1 to 5 and a pharmaceutically acceptable carrier.
  7. 7. In vitro method characterized by being for suppression, reduction or inhibition of lipid synthesis and/or regulation of acetylation and histone function in a cell, such as a cancer cell; or of suppression, reduction or inhibition of acetyl-CoA synthesis, such as ACSS2-mediated acetyl-CoA synthesis, from acetate in a cell such as a cancer cell; or of suppression, reduction or inhibition of acetate metabolism, such as ACSS2-mediated acetate metabolism, in a cancer cell, wherein the cancer cell is under hypoxic stress, the method comprising contacting the cell with a compound represented by the formula structure (I) as defined in claim 1.
  8. 8. In vitro method for linking an ACSS2 inhibitor compound to an ACSS2 enzyme, characterized by comprising the step of contacting an ACSS2 enzyme with an ACSS2 inhibitor compound represented by the formula structure (I) as defined in claim 1, in an amount effective to link the ACSS2 inhibitor compound to the ACSS2 enzyme.

Description

FIELD OF THE INVENTION [0001] The present invention relates to novel ACSS2 inhibitors, their composition and methods of preparation, and their applications for the treatment of viral infection (e.g., CMV), alcoholism, alcoholic steatohepatitis (ASH), non-alcoholic steatohepatitis (NASH), metabolic disorders, including: obesity, weight gain and hepatic steatosis, neuropsychiatric diseases, including: anxiety, depression, schizophrenia, autism and post-traumatic stress disorder, inflammatory/autoimmune conditions and cancer, including metastatic cancer, advanced cancer and drug-resistant cancer of various types. HISTORY OF THE INVENTION [0002] Cancer is the second leading cause of death in the United States, surpassed only by heart disease. In the United States, cancer accounts for 1 in 4 deaths. The 5-year relative survival rate for all cancer patients diagnosed in 1996–2003 is 66%, compared to 50% in 1975–1977 (Cancer Facts & Figures American Cancer Society: Atlanta, GA (2008)). The rate of new cancer cases decreased by an average of 0.6% per year among men between 2000 and 2009 and remained the same for women. From 2000 to 2009, the death rates from all cancers combined decreased by an average of 1.8% per year among men and 1.4% per year among women. This improvement in survival reflects progress in early diagnosis and improvements in treatment. The discovery of highly effective anticancer agents with low toxicity is a primary goal in cancer research. [0003] Cell growth and proliferation are closely coordinated with metabolism. Potentially distinct metabolic differences between normal and cancerous cells have sparked renewed interest in targeting metabolic enzymes as an approach to discovering new anti-cancer therapies. [0004] It is now recognized that cancer cells within metabolically stressed microenvironments, defined here as those with low oxygen availability and low nutrient availability (i.e., hypoxic conditions), adopt many tumor-promoting characteristics, such as genomic instability, altered cellular bioenergetics, and invasive behavior. In addition, these cancer cells are often intrinsically resistant to cell death, and their physical isolation from the vasculature at the tumor site can compromise successful immune responses, drug delivery, and therapeutic efficiency, thereby promoting recurrence and metastasis, which ultimately translates into drastically reduced patient survival. Therefore, there is an absolute need to define therapeutic targets in metabolically stressed cancer cells and to develop new delivery techniques to increase therapeutic efficacy. For example, the particular metabolic dependence of cancer cells on alternative nutrients (such as acetate) to support energy and biomass production may offer opportunities for the development of new targeted therapies. Acetyl-CoA synthetase enzyme, ACSS2, as a target for cancer treatment. [0005] Acetyl-CoA represents a central node of carbon metabolism that plays a key role in bioenergetics, cell proliferation, and gene expression regulation. Highly glycolytic or hypoxic tumors must produce sufficient amounts of this metabolite to support cell growth and survival under nutrient-limiting conditions. Acetate is an important source of acetyl-CoA in hypoxia. Inhibition of acetate metabolism can impair tumor growth. The nucleocytosolic acetyl-CoA synthetase enzyme, ACSS2, supplies a key source of acetyl-CoA to tumors by capturing acetate as a carbon source. Despite not exhibiting gross growth or development deficits, adult mice lacking ACSS2 exhibit a significant reduction in tumor burden in two different hepatocellular carcinoma models. ACSS2 is expressed in a large proportion of human tumors, and its activity is responsible for most of the cellular acetate assimilation into both lipids and histones. Furthermore, ACSS2 was identified, in an unbiased functional genomic selection, as a critical enzyme for the growth and survival of breast and prostate cancer cells cultured under hypoxia in low serum. Elevated ACSS2 expression is frequently found in invasive ductal carcinomas of the breast, triple-negative breast cancer, glioblastoma, ovarian cancer, pancreatic cancer, and lung cancer, and often correlates directly with high-grade tumors and poorer survival compared to tumors exhibiting low ACSS2 expression. These observations may qualify ACSS2 as a steerable metabolic vulnerability of a broad spectrum of tumors. [0006] Due to the nature of tumorigenesis, cancer cells constantly encounter environments in which the availability of nutrients and oxygen is severely compromised. In order to survive these harsh conditions, the transformation of cancer cells is often coupled with major changes in metabolism to meet the energy and biomass demands imposed by continued cell proliferation. Several recent reports have found that acetate is used as an important nutritional source by some types of breast, prostate, liver, and brain tumors in an acetyl-CoA synthet