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WO2024028169A1 - Nouveaux composés thiophénoliques à substitution spécifique - Google Patents

Nouveaux composés thiophénoliques à substitution spécifique Download PDF

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Publication number
WO2024028169A1
WO2024028169A1 PCT/EP2023/070611 EP2023070611W WO2024028169A1 WO 2024028169 A1 WO2024028169 A1 WO 2024028169A1 EP 2023070611 W EP2023070611 W EP 2023070611W WO 2024028169 A1 WO2024028169 A1 WO 2024028169A1
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Prior art keywords
alkyl
replaced
hal
hydrogen atoms
perhaloalkyl
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PCT/EP2023/070611
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English (en)
Inventor
Gianluca Mariano Enrico Papeo
Daniela Silvia ASA
Laura BUFFA
Marina Caldarelli
Giovanni Cervi
Riccardo Colombo
Markus Klein
Andrea UNZUE-LOPEZ
Christian Sirrenberg
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Nerviano Medical Sciences S.R.L.
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Publication of WO2024028169A1 publication Critical patent/WO2024028169A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel, preferably specifically substituted, thiophenolic compounds which preferably are useful in the treatment of diseases, preferably proliferative and/or hyper- proliferative diseases.
  • the compounds of the present invention comprise activity in inhibiting one or more helicases, preferably including Werner helicase (WRN).
  • WRN Werner helicase
  • the instant invention preferably relates to the use of the compounds according to the invention to inhibit the activity of one or more helicases, preferably including Werner Helicase (WRN).
  • WRN Werner syndrome protein
  • RECQL2 Werner syndrome protein
  • WRN was initially identified as the defective protein responsible for a rare autosomal recessive genetic disorder called Werner Syndrome, characterized by the onset of premature aging and multiple age-related diseases.
  • WRN is an ATP dependent DNA helicase which also possesses exonuclease activity and plays important roles in DNA metabolism, including DNA replication, recombination, repair, and transcription and in maintaining genomic stability via telomere regulation.
  • WRN is crucial for the recovery of stalled replication forks and promotes repair of double-strand breaks. Moreover, loss of WRN function deregulates DNA metabolism, resulting in detrimental consequences for various cellular processes, ultimately causing chromosomal aberrations, replication fork stalling and prolonged S phase triggering/activation of DNA damage checkpoints, leading to G2 arrest. Finally, WRN depleted cells were found to be more sensitive to DNA damaging agents as compared with WRN wild type cells. The role of WRN in DNA repair regulation, together with the fact that this enzyme has been found to be upregulated in a subset of tumors, suggest a possible role of this helicase in promoting cancer and therefore the hypothesis that direct inhibition of this target could lead to anti-tumoral effects in determined genetic contexts.
  • the helicase translocates in a directionally specific manner (3’ to 5’ or 5’ to 3’) along the strand it predominantly interacts with.
  • DNA helicases are classified according to their amino acid sequence homology in the ATPase/helicase core domain into two larger (SF1 and SF2) and four smaller superfamilies (1).
  • SF1 and SF2 Two larger
  • SF1 and SF2 Two larger
  • WRN also known as RECQL2
  • WRN belongs to a conserved RecQ DNA helicase sub-family consisting of RECQL1, RECQL4, RECQL5 and BLM (4-6).
  • helicases take part in all stages of DNA replication, comprising unwinding, Okazaki fragment maturation, initiation and extension of lagging and leading-strands.
  • these “genome guardians” participate in DNA G-quadruplex and Holliday junction resolution (7) as well as in other replication-related processes, such as replication re-initiation, telomere lengthening, translesion synthesis and DNA damage signaling, many of which might represent interesting targets for cancer therapy (4-6).
  • RecQ helicases can therefore be considered as “caretaker” genes that maintain genomic stability (8) and, due to their important roles in DNA metabolism, some of these helicases are implicated in rare heritable human autosomal recessive disorders characterized by genomic instability, developmental abnormalities and premature aging.
  • WRN inactivation is the cause of Werner syndrome (WS), characterized by increased incidence of premature aging related diseases beginning in the second decade of life (3).
  • WRN is the largest protein in the RecQ family, it localizes predominantly to the nucleolus but, after DNA damage, it rapidly mobilizes to other nuclear regions (9) where it regulates DNA strand displacement, normal progression of replication forks, recovery of stalled replication forks induced by DNA damage, proofreading activity and base excision repair regulation via its ATP dependent 3′ to 5′ DNA helicase and DNA exonucleolytic activities, the latter being unique among the RecQ family members (4-5; 10-11).
  • WS cells deficient in functional WRN exhibit replication stress due to irreparable mutations, translesions and damaged DNA forks, that normally occur during cell life (12- 15). These DNA lesions stall DNA replication, making WRN dependent reactivation of stalled replication forks a major challenge for DNA replication machinery, ultimately leading to highly toxic DNA double strand breaks (DSBs) which are mainly repaired by NHEJ and HR pathways. Improperly repaired DSBs are the cause of genome instability (16-17). WRN-knockout mice have no overt pathology and fail to recapitulate features of clinical WS (18-20) whereas, in contrast to WS cells which lack functional WRN, many types of cancers and cell lines display increased levels of the helicase.
  • DSBs DNA double strand breaks
  • High level of helicase is also induced by c-Myc and by the presence of several translocations including BCR/ABL (6; 21- ,23). Accordingly, high levels of WRN are beneficial to cell cycle progression and proliferation of cancer cells (4-5). By contrast, low levels of the helicase-nuclease due to targeted inhibition led to replication stress, owing to the formation of translesions, stalled DNA forks and genome fragility, all of which can trigger cell death (24-25). WRN was recently reported to be required for the proper proliferation of cancer cell lines characterized by microsatellite instability (MSI) caused by mismatch repair pathway deficiencies and this synthetic lethality requires the helicase/ATPase activity of the enzyme (26-29).
  • MSI microsatellite instability
  • the present invention provides new compounds which are endowed with inhibitory activity against Werner helicase protein (WRN, RECQL2) and are thus useful in the therapy or treatment of disorders, preferably disorders as described herein, and especially in the therapy or treatment of cancer.
  • the object of the present invention is to provide a compound of formula (I): wherein: Cy 1 is selected from the group consisting of P 1 and/or or P 2; P 1 is selected from optionally substituted monocyclic residues, selected from the group consisting of C 3 -C 8 cycloalkyl residues, optionally substituted phenyl residues, optionally substituted saturated or ethylenically unsaturated 4-to-8 membered heterocyclic residues, and/or optionally substituted aromatic 5-to-6-membered heterocyclic residues, wherein each of said substituted monocyclic residues is mono- , di-, tri-, tetra- or penta-substituted and wherein each substituent is preferably selected independently from each other from Hal,
  • the present invention provides a compound of formula (I) and/or compound of one or more of subformulae (Ia) to (Ik) and/or (Ir) to Iu), preferably as defined in more detail above and/or below, wherein: X is preferably independently selected from the group consisting of S, SO and SO 2 ; Y is preferably independently selected from the group consisting of wherein each residue R a is preferably in each case independently selected from the group consisting of hydrogen, COR 7 , a linear or branched C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 - C 6 alkynyl, C 3 -C 7 cycloalkyl, heterocyclyl, aryl, heteroaryl group, in all of which one or more of the hydrogen atoms may be replaced by halogen, preferably halogen selected from the group consisting of F, Cl, Br and I, or R a , together with another Residue R 1 to R 11 other
  • the compounds according to formula (I), the compounds according to one or more of sub-formulae (Ia) to (If), the compounds according to one or more of sub-formulae (Ig) to (Ij), the compounds according to sub-formula (Ik) and/or the compounds according one or more of sub-formulae (Ir) to (Iu) comprise at least one residue R 1 . More preferably, at least one of said residues R 1 is other than hydrogen (or hydrogen atom or H).
  • the compounds according to formula (I), the compounds according to one or more of sub-formulae (Ia) to (If), the compounds according to one or more of sub- formulae (Ig) to (Ij), the compounds according to sub-formula (Ik) and/or the compounds according one or more of sub-formulae (Ir) to (Iu) comprise at least one residue R 1 other than hydrogen (or hydrogen atom or H), which is preferably selected from the meanings given for R 1 other than hydrogen hereinabove and/or hereinbelow.
  • one residue R 1 is located in the para-position relative to group Y (or the group that Y stands for) on Cy 2 (or the group that Cy 2 stands for).
  • compounds according to formula (I), the compounds according to one or more of sub-formulae (Ia) to (If), the compounds according to one or more of sub- formulae (Ig) to (Ij), the compounds according to sub-formula (Ik) and/or the compounds according one or more of sub-formulae (Ir) to (Iu) which comprise at least one residue R 1 other than hydrogen on the cyclic residue that Cy 2 stands, wherein one residue R 1 other than hydrogen is located in the para position relative to Y.
  • Cy 2 comprises or consists of a 6-membered cyclic group or residue, preferably a 6-membered cyclic residue as defined herein above and/or hereinbelow for Cy 2 .
  • both said R 1 (other than hydrogen) and said group Y are preferably located in para-position to each other.
  • compounds of formula (I) as described above and/or below in more detail, but that are selected from one or more subformulae (Ia) to (If):
  • R 1 , R 2 , R 3 , R 4 , and/or R a preferably are as defined above and /or below, Cy 1 -R and/or Cy 1 -(R)m are as defined above and/or below and especially Cy 1 -R is as defined above and/or below, and wherein R c , R c‘ and/or R c’’ are independently from each other selected from hydrogen, halogen atom, cyano, SR 5 , OR 5 , COR 7 , R 5 R 6 N-C 1 -C 6 alkyl, R 5 O-C 1 -C 6 alkyl, a linear or branched C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, heterocyclyl, aryl, heteroaryl group wherein 1 to 12 H atoms may be independently replaced by F, or, taken together with the atoms
  • a reference to a compound of formula (Ia) and/or subformula (Ia) shall preferably always include a reference to a compound of formula (Ia’).
  • compounds of formula (Ib) as described above and/or below in more detail that are selected from subformula (Ib’): .
  • a reference to a compound of formula (Ib) and/or subformula (Ib) shall preferably always include a reference to a compound of formula (Ib’).
  • R 1 is preferably selected from the meanings given for R 1 above and/or below other than hydrogen, and is especially preferably selected, preferably in each case independently, from the group consisting of: methyl and/or methyl in which 1, 2 or 3 of the hydrogen atoms may be replaced by Hal, preferably F and/or Cl, ethyl and/or ethyl in which one or more or all of the hydrogen atoms may be replaced by Hal, preferably F and/or Cl, propan-1-yl and/or propan-1-yl in which one or more or all of the hydrogen atoms may be replaced by Hal, preferably F and/or Cl,
  • R c and/or R c’ is in each case independently selected from the group consisting of: Hydrogen, hydrogen atom or H; Hal or halogen, preferably F or Cl; methyl and/or methyl in which 1, 2 or 3 of the hydrogen atoms may be replaced by Hal, preferably F and/or Cl; and/or nitril or CN.
  • R c and/or R c’ is other than hydrogen. Even more preferably, R c is preferably other than hydrogen.
  • R 1 and/or R is preferably as defined above and/or below, Z 1 , Z 2 , Z 3 and/or Z 4 is independently selected from N and/or CR Z , wherein each R Z is independently selected from the meanings given for R 8 and/or R 9 , or is independently selected from the group consisting of H, C 1 -C 4 -alkyl, C 1 -C 6 -cycloalkyl, C 1 -C 4 -hydroxyalkyl, C 1 -C 4 -Halo-alkyl and C 1 -C 4 - perhaloalkyl, or selected from one or more of the following residues: methyl and/or methyl in which 1, 2 or 3 of the hydrogen atoms may be replaced by Hal, preferably F and/or Cl, ethyl and/or e
  • R 1 and/or R c is preferably as defined above and/or below, Z 2 selected from N and/or C-F, R is as defined as defined above and/or below, and especially is selected from from one or more of the following residues: methyl and/or methyl in which 1, 2 or 3 of the hydrogen atoms may be replaced by Hal, preferably F and/or Cl, ethyl and/or ethyl in which one or more or all of the hydrogen atoms may be replaced by Hal, preferably F and/or Cl, propan-1-yl and/or propan-1-yl in which one or more or all of the hydrogen atoms may be replaced by Hal, preferably F and/or Cl, propan-2-yl and/or propan-2-yl in which one or more or all of the hydrogen atoms may be replaced by Hal, preferably F and/or Cl,
  • each R Z is independently selected from the meanings given for R 8 and/or R 9 , or is independently selected from the group consisting of H, C 1 -C 4 -alkyl, C 1 -C 6 -cycloalkyl, C 1 -C 4 - hydroxyalkyl, C 1 -C 4 -halo-alkyl and C 1 -C 4 -perhaloalkyl, or selected from one or more of the following residues: methyl and/or methyl in which 1, 2 or 3 of the hydrogen atoms may be replaced by Hal, preferably F and/or Cl, ethyl and/or
  • Compound according to one or more of the preceding claims as a WRN inhibitor.
  • a preferred aspect is a pharmaceutical composition, characterized in that it contains one or more compounds, preferably compounds of formula (I), preferably as described herein above and/or herein below.
  • a preferred aspect is a pharmaceutical composition, preferably as described herein above and/or below, characterized in that it contains one or more compounds according to the instant invention, preferably compounds of formula (I), preferably as described herein above and/or below.
  • a preferred aspect is a pharmaceutical composition, preferably as described herein above and/or below, characterized in that it contains a) one or more compounds according to the instant invention, preferably compounds of formula (I), preferably as described herein above and/or below, b) one or more additional compounds, selected from the group consisting of physiologically acceptable excipients, auxiliaries, adjuvants, carriers and pharmaceutical active ingredients other than the compounds according to the instant invention, preferably compounds of formula (I), preferably as described herein above and/or below.
  • a preferred aspect is a process for the manufacture of a pharmaceutical composition, preferably a pharmaceutical composition, preferably as described herein above and/or below, characterized in that one or more compounds according to the instant invention, preferably compounds of formula (I), preferably as described herein above and/or below, and one or more compounds selected from the group consisting of carriers, excipients, auxiliaries and pharmaceutical active ingredients (other than the compounds according to the instant invention, preferably compounds of formula (I), preferably as described herein above and/or below), is processed by mechanical means into a pharmaceutical composition that is suitable as dosage form for application and/or administration to a patient.
  • a preferred aspect is the use of a compound according to the instant invention, preferably a compound of formula (I), preferably as described herein above and/or below, as a pharmaceutical.
  • a preferred aspect is the use of a compound according to the instant invention, preferably a compound of formula (I), preferably as described herein above and/or below, in the treatment and/or prophylaxis of disorders.
  • a preferred aspect is the use of a compound according to the instant invention, preferably a compound of formula (I), preferably as described herein above and/or below, for producing a pharmaceutical composition for the treatment and/or prophylaxis of disorders.
  • a preferred aspect is the use of a compound according to the instant invention, preferably a compound of formula (I), preferably as described herein above and/or below, for producing a pharmaceutical composition for the treatment and/or prophylaxis of disorders, wherein the disorders are selected from the group consisting of hyperproliferative and non- hyperproliferative disorders.
  • a preferred aspect is a compound for use, preferably as described herein above and/or below, and/or a method of treatment using a compound of formula (I), preferably as described herein above and/or below, characterized in that the disorders are selected from the group consisting of hyperproliferative and non-hyperproliferative disorders.
  • a preferred aspect is a compound for use, preferably as described herein above and/or below, and/or a method of treatment using a compound of formula (I), preferably as described herein above and/or below, characterized in that the disorder is cancer.
  • a preferred aspect is a compound for use, preferably as described herein above and/or below, and/or a method of treatment using a compound of formula (I), preferably as described herein above and/or below, wherein the disorder is additionally having assay detectable Microsatellite Instability (MSI).
  • MSI Microsatellite Instability
  • the disorder is selected from the group consisting of hyperproliferative and non- hyperproliferative disorders, preferably hyperproliferative disorders. More preferably, the disorder is cancer.
  • the disorder is additionally having assay detectable Microsatellite Instability (MSI).
  • MSI Microsatellite Instability
  • the disorder is a cancerous disorder, selected from the group consisting of melanoma, brain cancer, lung cancer, squamous cell cancer, bladder cancer, gastric cancer, pancreatic cancer, hepatic cancer, renal cancer, colorectal cancer, breast cancer, head cancer, neck cancer, esophageal cancer, gynecological cancer, ovarian cancer, uterine cancer, prostate cancer, thyroid cancer, lymphoma, chronic leukemia and/or acute leukemia.
  • the disorder is a cancerous disorder, selected from the group consisting of melanoma, brain cancer, lung cancer, squamous cell cancer, bladder cancer, gastric cancer, pancreatic cancer, hepatic cancer, renal cancer, colorectal cancer, breast cancer, head cancer, neck cancer, esophageal cancer, gynaecological cancer, ovarian cancer, uterine cancer, prostate cancer, thyroid cancer, lymphoma, chronic leukemia and/or acute leukemia, wherein the disorder is additionally having assay detectable Microsatellite Instability (MSI).
  • MSI Microsatellite Instability
  • a preferred aspect is a compound for use, preferably as described herein above and/or below, and/or a method of treatment using a compound of formula (I), preferably as described herein above and/or below, wherein the disorder is additionally having assay detectable Microsatellite Instability (MSI).
  • MSI Microsatellite Instability
  • a preferred aspect is a compound for use, preferably as described herein above and/or below, and/or a method of treatment using a compound of formula (I), preferably as described herein above and/or below, wherein the cancerous disorders are selected from the group consisting of melanoma, brain cancer, lung cancer, squamous cell cancer, bladder cancer, gastric cancer, pancreatic cancer, hepatic cancer, renal cancer, colorectal cancer, breast cancer, head cancer, neck cancer, esophageal cancer, gynecological cancer, ovarian cancer, uterine cancer, prostate cancer, thyroid cancer, lymphoma, chronic leukemia and/or acute leukemia, preferably wherein the disorder is additionally having assay detectable Microsatellite Instability (MSI).
  • MSI Microsatellite Instability
  • the disorder is selected from the group consisting of endometrial cancer, colon cancer, colorectal cancer (CRC), gastric cancer, glioblastoma, and/or glioblastoma multiforme (GBM).
  • the disorder is selected from the group consisting of Uterine Corpus Endometrial Carcinoma (UCEC), Stomach adenocarcinoma (STAD), Rectum adenocarcinoma (READ), Adrenocortical carcinoma (ACC), Uterine Carcinosarcoma (UCS), Cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), Wilms Tumor Syndromes (WT), Mesothelioma (MESO), Esophageal carcinoma (ESCA), Breast Cancer (BC), Kidney renal clear cell carcinoma (KIRC), Ovarian serous cystadenocarcinoma (OV), Cholangiocarcinoma (CHOL), Thymoma (TH)
  • the disorders are selected from the group consisting of arthritis, restenosis; fibrotic disorders; mesangial cell proliferative disorders, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes, organ transplant rejection, glomerulopathies, metabolic disorders, inflammation, solid tumors, rheumatic arthritis, diabetic retinopathy, and neurodegenerative diseases.
  • disorders as described herein above and/or below, wherein disorder is additionally having assay detectable Microsatellite Instability (MSI).
  • MSI Microsatellite Instability
  • a method for the treatment and/or prophylaxis of disorders characterized in that one or more of the compounds according to the instant invention, preferably one or more compounds of formula (I), preferably as described herein above and/or below, is/are administered to a patient in need of such a treatment.
  • the following definitions shall apply unless otherwise indicated or defined specifically elsewhere in the description and/or the claims for specific substituents, radicals, residues, groups or moieties.
  • aliphatic groups contain 1-8 or 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms.
  • “cycloaliphatic” (“cycloalkyl”) refers to a monocyclic C 3 -C 7 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule.
  • the term “carbocycle” refers to a monocyclic or bicyclic cycloaliphatic ring system which is fused to an aromatic, heteroaromatic or heterocyclic ring or ring system via two adjacent ring atoms of that aromatic, heteroaromatic or heterocyclic ring or ring system; in other words, such carbocycle shares two ring atoms with the ring or ring system to which it is fused thereby having two points of attachment to the rest of the molecule.
  • Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
  • alkyl usually refers to a saturated aliphatic and acyclic moiety
  • alkynyl usually refers to an aliphatic and acyclic moiety with one or more C ⁇ C triple bonds.
  • Exemplary aliphatic groups are linear 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 groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
  • C 1-3 -alkyl refers to alkyl groups, i.e., saturated acyclic aliphatic groups, having 1, 2 or 3 carbon atoms.
  • Exemplary C 1 -3-alkyl groups are methyl, ethyl, propyl and isopropyl.
  • the term “C 1-4 -alkyl” refers to alkyl groups having 1, 2, 3 or 4 carbon atoms.
  • ExemplaryC 1-4 -alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.
  • C 1-6 -alkyl refers to alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • C 1-6 -alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, 2- pentyl, n-hexyl, and 2-hexyl.
  • C 1-8 -alkyl refers to alkyl groups having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms.
  • Exemplary C 1-8 -alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, 2-hexyl n-heptyl, 2-heptyl, n-octyl, 2-octyl, and 2,2,4-trimethylpentyl.
  • Each of these alkyl groups may be straight-chain or – except for C 1 -alkyl and C 2 -alkyl – branched and may be unsubstituted or substituted with 1, 2 or 3 substituents that may be the same or different and are, if not specified differently elsewhere in this specification, selected from the group comprising halogen, hydroxy, alkoxy, unsubstituted or mono- or di-substituted amino.
  • C 1 -3-alkyl, C 1-4 -alkyl, C 1-6 -alkyl, C 1-8 -alkyl groups may also comprise those residues in which 1 or 2 of non-terminal and non-adjacent –CH 2 - (methylene) groups are replaced by –O-, -S- and/or 1 or 2 non-terminal and non-adjacent –CH 2 - or –CH- groups are replaced by –NH- or –N-.
  • C 3-7 -cycloalkyl refers to a cycloaliphatic hydrocarbon, as defined above, with 3, 4, 5, 6 or 7 ring carbon atoms.
  • C 3-7 -cycloalkyl groups may be unsubstituted or substituted with – unless specified differently elsewhere in this specification – 1, 2 or 3 substituents that may be the same of different and are – unless specified differently elsewhere in this specification – selected from the group comprising C 1-6 -alkyl, O-C 1-6 -alkyl (alkoxy), halogen, hydroxy, unsubstituted or mono- or di-substituted amino.
  • Exemplary C 3-7 -cycloalkyl groups are cyclopropyl, 2-methyl-cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl.
  • the term “aliphatoxy” refers to saturated or unsaturated aliphatic groups or substituents as defined above that are connected to another structural moiety via an oxygen atom (-O-).
  • alkoxy refers to a particular subgroup of saturated aliphatoxy, i.e., to alkyl substituents and residues that are connected to another structural moiety via an oxygen atom (-O-). Sometimes, it is also referred to as “O-alkyl” and more specifically as “O-C 1-4 -alkyl”, “O-C 1-6 - alkyl”, “O-C 1-8 -alkyl”.
  • alkyl groups may be straight-chain or – except for –O- C 1 -alkyl and –O-C 2 -alkyl – branched and may be unsubstituted or substituted with 1, 2 or 3 substituents that may be the same or different and are, if not specified differently elsewhere in this specification, selected from the group comprising halogen, unsubstituted or mono- or di- substituted amino.
  • substituents are methoxy, trifluoromethoxy, ethoxy, 2,2,2- trifluoroethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy.
  • alkylene refers to a divalent aliphatic group and in particular a divalent alkyl group.
  • An “alkylene chain” is a polymethylene group, i.e., –(CH 2 )x–, wherein x is a positive integer, preferably 1, 2, 3, 4, 5 or 6.
  • x is a positive integer, preferably 1, 2, 3, 4, 5 or 6.
  • C 1 -3-alkylene refers to an alkylene moiety with 1, 2 and 3, respectively, -CH 2 - groups; the term “alkylene”, however, not only comprises linear alkylene groups, i.e. "alkylene chains", but branched alkylene groups as well.
  • C 1-6 -alkylene refers to an alkylene moiety that is either 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 (or with) a substituent. Suitable substituents include those described herein for a substituted alkyl group. In some instances, 1 or 2 methylene groups of the alkylene chain may be replaced by, for instance, O, S and/or NH or N-C 1-4 -alkyl.
  • alkylene groups are —CH 2 -, –CH 2 – CH 2 -, –CH 2 –CH 2 –CH 2 -, -O–CH 2 -O-, -O–CH 2 –CH 2 -O-, -O–CH 2 –CH 2 –CH 2 -O-, –CH 2 -NH– CH 2 –CH 2 -, –CH 2 -N(CH 3 )–CH 2 –CH 2 -.
  • alkenylene refers to a bivalent alkenyl group.
  • a substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent.
  • Suitable substituents include those described herein for a substituted aliphatic group.
  • alkynylene refers to a bivalent alkynyl group.
  • a substituted alkynylene chain is a polymethylene group containing at least one triple bond in which one or more hydrogen atoms are replaced with a substituent.
  • Suitable substituents include those described herein for a substituted aliphatic group.
  • halogen means F, Cl, Br, or I.
  • heteroatom means one or more of oxygen (O), sulfur (S), or nitrogen (N), including, any oxidized form of nitrogen or sulfur, e.g.
  • N-oxides, sulfoxides and sulfones the quaternarized form of any basic nitrogen or a substitutable nitrogen of a heterocyclic or heteroaromatic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or N- SUB with SUB being a suitable substituent (as in N-substituted pyrrolidinyl).
  • aryl used alone or as part of a larger moiety as in “arylalkyl”, “arylalkoxy”, or “aryloxyalkyl”, refers to monocyclic, bicyclic and tricyclic ring systems having a total of five to fourteen ring members, that ring members being carbon atoms, wherein at least one ring in the system is aromatic, i.e., it has (4n+2) ⁇ (pi) electrons (with n being an integer selected from 0, 1, 2, 3), which electrons are delocalized over the system, and wherein each ring in the system contains three to seven ring members.
  • all rings in the aryl system or the entire ring system are aromatic.
  • aryl is used interchangeably with the term “aryl ring”.
  • aryl refers to an “aromatic ring system”. More specifically, those aromatic ring systems may be mono-, bi- or tricyclic with 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 ring carbon atoms. Even more specifically, those aromatic ring systems may be mono- or bicyclic with 6, 7, 8, 9, 10 ring carbon atoms.
  • monoaryl refers to a monocyclic aryl.
  • biasryl refers to a bicyclic aryl.
  • aryl groups are phenyl, biphenyl, naphthyl, anthracenyl and the like, which may be unsubstituted or substituted with one or more identical or different substituents.
  • aryl or aromatic ring system is a group in which an aromatic ring is fused to one or more non–aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like. In the latter case the "aryl” group or substituent is attached to its pendant group via the aromatic part of the ring system.
  • benzo refers to a six-membered aromatic ring (with carbon ring atoms) that is fused via two adjacent carbon atoms to another ring, being it a cycloaliphatic, aromatic, heteroaromatic or heterocyclic (heteroaliphatic) ring; as a result a ring system with at least two rings is formed in which 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 phenyl ring, a naphthalin ring system is formed, while fusing a benzo ring to a pyridine provides for either a quinoline or an isoquinoline.
  • heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternarized form of a basic nitrogen.
  • Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, furazanyl, pyridyl (pyridinyl), pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, and pyrrolopyridinyl, in particular pyrrolo[2,3-b]pyridinyl.
  • heteroaryl and “heteroar—”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is preferably on the heteroaromatic or, if present, the aryl ring.
  • Nonlimiting examples include indolyl, isoindolyl, benzothienyl (benzothiophenyl), benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, 9H-carbazolyl, dibenzofuranyl and pyrido[2,3–b]–1,4–oxazin–3(4H)–one.
  • an indolyl ring may be attached via one of the ring atoms of the six-membered aryl ring or via one of the ring atoms of the five-membered heteroaryl ring.
  • a heteroaryl group is optionally mono-, bi- or tricyclic.
  • heteroaryl is used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”, any of which terms include rings that are unsubstituted or substituted with one or more identical or different substituents.
  • heteroarylkyl refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.
  • a heteroaryl ring can be attached to its pendant group at any of its hetero or carbon ring atoms which attachment results in a stable structure or molecule: any of the ring atoms may be unsubstituted or substituted.
  • the structures of typical examples of "heteroaryl" substituents as used in the present invention are depicted below:
  • heteroaryl substituents can be attached to any pendant group via any of its ring atoms suitable for such an attachment.
  • nitrogen includes a substituted nitrogen.
  • the nitrogen is N (as in 3,4–dihydro–2H– pyrrolyl), NH (as in pyrrolidinyl), or N-SUB with SUB being a suitable substituent (as in N– substituted pyrrolidinyl).
  • unsaturated means that a moiety or group or substituent has one or more units of unsaturation.
  • the term “bicyclic”, “bicyclic ring” or “bicyclic ring system” refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or having one or more units of unsaturation, i.e., being partially unsaturated or aromatic, having one or more atoms in common between the two rings of the ring system.
  • the term includes any permissible ring fusion, such as ortho-fused or spirocyclic.
  • heterocyclic is a subset of “bicyclic” that requires that one or more heteroatoms are present in one or both rings of the bicycle. Such heteroatoms may be present at ring junctions and are optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfoxides, sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc.
  • a bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • tricyclic refers to any tricyclic ring system, i.e., carbocyclic or heterocyclic, saturated or having one or more units of unsaturation, i.e., being partially unsaturated or aromatic, in which a bicyclic ring system (as defined above) is fused with another, third ring.
  • a bicyclic ring system as defined above
  • the term includes any permissible ring fusion.
  • heterotricyclic is a subset of “tricyclic” that requires that one or more heteroatoms are present in one, two or all rings of the tricycle.
  • Such heteroatoms may be present at ring junctions and are optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfoxides, sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc.
  • a tricyclic group has 10-14 ring members and 0-5 heteroatoms independently selected from nitrogen, oxygen or sulfur.
  • certain compounds of the invention contain “substituted” or “optionally substituted” moieties.
  • substituted means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. “Substituted” applies to one or more hydrogens that are either explicit or implicit from the structure. Unless otherwise indicated, 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 a specified group, the substituent is either the same or different at every position. If a certain group, substituent, moiety or radical is "mono-substituted", it bears one (1) substituent.
  • substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
  • Ph means phenyl
  • halo means halogen
  • —(CH 2 ) 0-2 means that there is either no alkylene group if the subscript is “0” (zero) or an alkylene group with 1 or 2 CH 2 units.
  • R * is C 1 –6 aliphatic
  • R * is optionally substituted with halogen, –R ⁇ , -(haloR ⁇ ), -OH, –OR ⁇ , –O(haloR ⁇ ), –CN, –C(O)OH, –C(O)OR ⁇ , –NH 2 , –NHR ⁇ , –NR ⁇ 2 , or –NO 2
  • each R ⁇ is independently selected from C 1–4 aliphatic, –CH 2 Ph, –O(CH 2 ) 0–1 Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R ⁇ is unsubstituted or where preceded by halo is substituted only with one or more halogens.
  • An optional substituent on a substitutable nitrogen is independently –R ⁇ , –NR ⁇ 2 , –C(O)R ⁇ , – C(O)OR ⁇ , –C(O)C(O)R ⁇ , –C(O)CH 2 C(O)R ⁇ , -S(O) 2 R ⁇ , -S(O) 2 NR ⁇ 2 , –C(S)NR ⁇ 2 , –C(NH)NR ⁇ 2 , or –N(R ⁇ )S(O) 2 R ⁇ ; wherein each R ⁇ is independently hydrogen, C 1 –6 aliphatic, unsubstituted – OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur or, two independent occurrences of R ⁇ , taken together with their intervening atom(s) form an
  • “Ph” means phenyl; and “halo” means halogen.
  • derivative means any non-toxic salt, ester, salt of an ester or other derivative of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitory active metabolite or residue thereof.
  • the compounds of the present invention can be in the form of a prodrug compound.
  • Prodrugs and “prodrug compound” mean a derivative that is converted into a biologically active compound according to the present invention under physiological conditions in the living body, e.g., by oxidation, reduction, hydrolysis or the like, each of which is carried out enzymatically, or without enzyme involvement.
  • Examples of prodrugs are compounds, in which the amino group in a compound of the present invention is acylated, alkylated or phosphorylated, e.g., eicosanoylamino, alanylamino, pivaloyloxymethylamino or in which the hydroxyl group is acylated, alkylated, phosphorylated or converted into the borate, e.g.
  • a carrier molecule e.g. a peptide
  • prodrugs are compounds, wherein the carboxylate in a compound of the present invention is for example converted into an alkyl-, aryl-, choline-, amino-, acyloxymethylester, linolenoyl-ester.
  • solvates means addition forms of the compounds of the present invention with solvents, preferably pharmaceutically acceptable solvents that contain either stoichiometric or non-stoichiometric amounts of 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, e.g., a mono- or dihydrate.
  • the solvate formed is an alcoholate, e.g., a methanolate or ethanolate. If the solvent is an ether, the solvate formed is an etherate, e.g., diethyl etherate.
  • N-oxides means such compounds of the present invention that contain an amine oxide moiety, i.e., the oxide of a tertiary amine group.
  • the compounds of formula (I) may have one or more asymmetric centers. They may accordingly occur in various enantiomeric and diastereomeric forms, as the case may be, and be in racemic or optically active form.
  • the invention therefore, also relates to the optically active forms, enantiomers, racemates, diastereomers, mixtures thereof in all ratios, collectively: “stereoisomers” for the purpose of the present invention, of these compounds.
  • stereoisomers for the purpose of the present invention, of these compounds.
  • the pharmaceutical activity of the racemates or stereoisomers of the compounds according to the invention may differ, it may be desirable to use a specific stereoisomer, e.g., one specific enantiomer or diastereomer.
  • a compound according to the present invention obtained as a racemate or even intermediates thereof – may be separated into the stereoisomeric (enantiomeric, diastereomeric) compounds by chemical or physical methods known to the person skilled in the art.
  • stereoselective synthetic procedures e.g. applying starting material in a stereoisomerically enriched or pure form (for instance using the pure or enriched (R)- or (S)- enantiomer of a particular starting material bearing a chiral center) or utilizing chiral reagents or catalysts, in particular enzymes.
  • the term "pure enantiomer” usually refers to a relative purity of one enantiomer over the other (its antipode) of equal to or greater than 95%, preferably ⁇ 98%, more preferably ⁇ 98.5%, still more preferably ⁇ 99%.
  • the compounds of the invention which have one or more centers of chirality and which occur as racemates or as mixtures of enantiomers or diastereomers can be fractionated or resolved by known methods into their optically pure or enriched isomers, i.e., enantiomers or diastereomers.
  • the separation of the compounds of the invention can take place by chromatographic methods, e.g., column separation on chiral or nonchiral phases, or by recrystallization from an optionally optically active solvent or by use of an optically active acid or base or by derivatization with an optically active reagent such as, for example, an optically active alcohol, and subsequent elimination of the radical.
  • tautomer refers to compounds of the present invention that may exist in tautomeric forms and show tautomerism; for instance, carbonyl compounds may be present in their keto and/or their enol form and show keto-enol tautomerism.
  • tautomers may occur in their individual forms, e.g., the keto or the enol form, or as mixtures thereof and are claimed separately and together as mixtures in any ratio.
  • the compounds of the present invention are in the form of free base or acid – as the case may be -, i.e., in their non-salt (or salt-free) form.
  • the compounds of the present invention are in the form of a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable bases or acids, including inorganic bases or acids and organic bases or acids.
  • the invention also comprises their corresponding pharmaceutically acceptable salts.
  • acidic groups such as carboxyl groups
  • the compounds of the present invention which contain acidic groups, such as carboxyl groups can be present in salt form, and can be used according to the invention, for example, as alkali metal salts, alkaline earth metal salts, aluminum salts or as ammonium salts.
  • salts include lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, barium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, diethanolamine, triethanolamine, piperidine, N- methylglutamine or amino acids.
  • a suitable base e.g., lithium hydroxide, sodium hydroxide, sodium propoxide, potassium hydroxide, potassium ethoxide, magnesium hydroxide, calcium hydroxide or barium hydroxide.
  • base salts of compounds of the present invention include but are not limited to copper(I), copper(II), iron(II), iron(III), manganese(II) and zinc salts.
  • Compounds of the present invention which contain one or more basic groups, e.g., groups which can be protonated, can be present in salt form, and can be used according to the invention in the form of their addition salts with inorganic or organic acids.
  • acids include hydrogen chloride, hydrogen bromide, hydrogen iodide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalene-2-sulfonic acid, sulfoacetic acid, trifluoroacetic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, carbonic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, malonic acid, maleic acid, malic acid, embonic acid, mandelic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, taurocholic acid, glutaric acid, stearic acid, glutamic acid or aspart
  • the salts which are formed are, inter alia, hydrochlorides, chlorides, hydrobromides, bromides, iodides, sulfates, phosphates, methanesulfonates (mesylates), tosylates, carbonates, bicarbonates, formates, acetates, sulfoacetates, triflates, oxalates, malonates, maleates, succinates, tartrates, malates, embonates, mandelates, fumarates, lactates, citrates, glutarates, stearates, aspartates and glutamates.
  • the stoichiometry of the salts formed from the compounds of the invention may moreover be an integral or non-integral multiple of one.
  • Compounds of the present invention which contain basic nitrogen-containing groups can be quaternarized using agents such as (C 1 C 4 )alkyl halides, for example methyl, ethyl, isopropyl and tert-butyl chloride, bromide and iodide; di(C 1 -C 4 )alkyl sulfates, for example dimethyl, diethyl and diamyl sulfate; (C 10 -C 18 )alkyl halides, for example decyl, dodecyl, lauryl, myristyl and stearyl chloride, bromide and iodide; and aryl(C 1 -C 4 )alkyl halides, for example benzyl chloride and phenethyl bromide.
  • agents such as (C 1
  • Both water- and oil-soluble compounds according to the invention can be prepared using such salts.
  • the invention also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions).
  • the respective salts can be obtained by customary methods which are known to a person skilled in the art, for example by contacting these with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts.
  • the present invention also includes all salts of the compounds of the present invention which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.
  • the following items are also in accordance with the invention: (a) all stereoisomers or tautomers of the compounds, including mixtures thereof in all ratios; (b) prodrugs of the compounds, or stereoisomers or tautomers of these prodrugs; (c) pharmaceutically acceptable salts of the compounds and of the items mentioned under (a) and (b); (d) pharmaceutically acceptable solvates of the compounds and of the items mentioned under (a), (b) and (c); (e) N-oxides of the compounds and of the items mentioned under (a), (b), (c), and (d).
  • a compound of the present invention includes isotope-labelled forms thereof.
  • An isotope-labelled form of a compound of the formula (I) is identical to this compound apart from the fact that one or more atoms of the compound have been replaced by an atom or atoms having an atomic mass or mass number which differs from the atomic mass or mass number of the atom which usually occurs naturally.
  • isotopes which are readily commercially available and which can be incorporated into a compound of the present invention by well-known methods include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, for example 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 CI, respectively.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof which contains one or more of the above-mentioned isotopes and/or other isotopes of other atoms is intended to be part of the present invention.
  • An isotope-labelled compound of formula (I) can be used in a number of beneficial ways.
  • an isotope-labelled compound of the present invention into which, for example, a radioisotope, such as 3 H or 14 C, has been incorporated is suitable for medicament and/or substrate tissue distribution assays.
  • radioisotopes i.e., tritium ( 3 H) and carbon-14 ( 14 C)
  • 3 H tritium
  • 14 C carbon-14
  • Incorporation of heavier isotopes, for example deuterium ( 2 H) into a compound of formula (I) has therapeutic advantages owing to the higher metabolic stability of this isotope-labelled compound. Higher metabolic stability translates directly into an increased in vivo half-life or lower dosages, which under most circumstances would represent a preferred embodiment of the present invention.
  • An isotope-labelled compound of formula (I) can usually be prepared by carrying out the procedures disclosed in the synthesis schemes and the related description, in the example part and in the preparation part in the present text, replacing a non-isotope-labelled reactant by a readily available isotope-labelled reactant.
  • Deuterium ( 2 H; D) can also be incorporated into a compound of formula (I) for the purpose of manipulating the oxidative metabolism of the compound by way of the primary kinetic isotope effect.
  • the primary kinetic isotope effect is a change of the rate for a chemical reaction that results from exchange of isotopic nuclei, which in turn is caused by the change in ground state energies necessary for covalent bond formation after this isotopic exchange.
  • Half-life determinations enable favorable and accurate determination of the extent to which the improvement in resistance to oxidative metabolism has improved. In this way, it is determined that the half-life of the parent compound can be extended by up to 100% as the result of deuterium-hydrogen exchange of this type.
  • Deuterium-hydrogen exchange in a compound of the present invention can also be used to achieve a favorable modification of the metabolite spectrum of the starting compound in order to diminish or eliminate undesired toxic metabolites.
  • the present invention relates to pharmaceutical compositions comprising at least one compound of formula (I), or its derivatives, prodrugs, solvates, tautomers or stereoisomers thereof as well as the pharmaceutically acceptable salts of each of the foregoing, including mixtures thereof in all ratios, as active ingredient, together with a pharmaceutically acceptable carrier.
  • the term “pharmaceutical composition” refers to a composition or product comprising one or more active ingredients, and one or more inert ingredients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • the pharmaceutical compositions of the present invention encompass any composition made by admixing at least one compound of the present invention and a pharmaceutically acceptable carrier.
  • compositions include compositions and pharmaceutical formulations suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well- known in the art of pharmacy.
  • a pharmaceutical composition of the present invention may additionally comprise one or more other compounds as active ingredients (drugs), such as one or more additional compounds of the present invention.
  • the pharmaceutical composition further comprises a second active ingredient or its derivatives, prodrugs, solvates, tautomers or stereoisomers thereof as well as the pharmaceutically acceptable salts of each of the foregoing, including mixtures thereof in all ratios, wherein that second active ingredient is other than a compound of formula (I); preferably, that second active ingredient is a compound that is useful in the treatment, prevention, suppression and/or amelioration of medicinal conditions or pathologies for which the compounds of the present invention are useful as well and which are listed elsewhere hereinbefore or hereinafter.
  • Such combination of two or more active ingredients or drugs may be safer or more effective than either drug or active ingredient alone, or the combination is safer or more effective than it would be expected based on the additive properties of the individual drugs.
  • Such other drug(s) may be administered, by a route and in an amount commonly used contemporaneously or sequentially with a compound of the invention.
  • a combination product containing such other drug(s) and the compound of the invention – also referred to as “fixed dose combination” – is preferred.
  • combination therapy also includes therapies in which the compound of the present invention and one or more other drugs are administered on different overlapping schedules.
  • the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of the invention.
  • the compounds of the present invention – or derivatives, N-oxides, prodrugs, solvates, tautomers or stereoisomers thereof and/or the pharmaceutically acceptable salts of each of the foregoing, including mixtures thereof in all ratios – can be used as medicaments. They have been found to exhibit pharmacological activity by inhibiting Werner Helicase (WRN).
  • WRN Werner Helicase
  • the compounds of the present invention being WRN inhibitors are useful in particular in the treatment, prevention, suppression and/or amelioration of hyperproliferative disorders and cancer, in particular tumors including solid tumors, of bladder, breast, colorectal, colon, kidney, liver, lung, head and neck, esophagus, 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, Burkitt lymphoma; chronic lymphocytic leukemia ("CLL”), acute and chronic myelogenous leukemia, myelodysplastic syndrome and promyelocyte leukemia; fibrosarcoma, rhab
  • the compounds of the present invention are useful also in the treatment, prevention, suppression and/or amelioration of an inflammatory disorder or disease, in particular Crohn's disease, ulcerative colitis, idiopathic pulmonary fibrosis, muscular dystrophy, rheumatoid arthritis, and systemic sclerosis (scleroderma); a neurogenerative disorder or disease, in particular Huntington’s disease; Lipid metabolism disorders, e.g. NASH (non-alcoholic steatohepatitis), NAFLD (non-alcoholic fatty liver disease), fatty liver disease; viral infections, e.g.
  • cytomegalovirus post-traumatic stress disorder (PTSD); bipolar disorder, depression, Tourette’s syndrome, schizophrenia, obsessive-compulsive disorder, anxiety disorder, panic disorders, phobias, addiction to e.g. alcohol, tobacco, opioids, sedatives, hypnotics, anxiolytics, cocaine, cannabis, amphetamines, hallucinogens, inhalants, phencyclidine, impulse control disorders, behavioral addictions.
  • the compounds of the present invention are for use in the prevention and/or treatment, especially in the treatment of any of the disorders or diseases listed above, preferably of cancer, in particular tumors including solid tumors, of the specific types of cancer disclosed in the previous paragraph; of an inflammatory disorder or disease, in particular Crohn's disease, ulcerative colitis, idiopathic pulmonary fibrosis, muscular dystrophy, rheumatoid arthritis, and systemic sclerosis (scleroderma); a neurogenerative disorder or disease, in particular Huntington’s disease; Lipid metabolism disorders, e.g. NASH (non-alcoholic steatohepatitis), NAFLD (non-alcoholic fatty liver disease), fatty liver disease; viral infections, e.g.
  • cytomegalovirus post-traumatic stress disorder (PTSD); bipolar disorder, depression, Tourette’s syndrome, schizophrenia, obsessive-compulsive disorder, anxiety disorder, panic disorders, phobias, addiction to e.g. alcohol, tobacco, opioids, sedatives, hypnotics, anxiolytics, cocaine, cannabis, amphetamines, hallucinogens, inhalants, phencyclidine, impulse control disorders, behavioral addictions.
  • Another particular 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 cancer, in particular tumors including solid tumors, of the specific types of cancer disclosed in the previous paragraphs; of an inflammatory disorder or disease, in particular Crohn's disease, ulcerative colitis, idiopathic pulmonary fibrosis, muscular dystrophy, rheumatoid arthritis, and systemic sclerosis (scleroderma); a neurogenerative disorder or disease, in particular Huntington’s disease; lipid metabolism disorders, e.g.
  • NASH non-alcoholic steatohepatitis
  • NAFLD non-alcoholic fatty liver disease
  • fatty liver disease e.g. with cytomegalovirus
  • viral infections e.g. with cytomegalovirus
  • post-traumatic stress disorder (PTSD) bipolar disorder, depression, Tourette’s syndrome
  • schizophrenia, obsessive- compulsive disorder, anxiety disorder, panic disorders, phobias addiction to e.g. alcohol, tobacco, opioids, sedatives, hypnotics, anxiolytics, cocaine, cannabis, amphetamines, hallucinogens, inhalants, phencyclidine, impulse control disorders, behavioral addictions.
  • Still another particular embodiment of the invention is the use of a compound of the present invention – or derivatives, N-oxides, prodrugs, solvates, tautomers or stereoisomers thereof and/or the pharmaceutically acceptable salts of each of the foregoing, including mixtures thereof in all ratios – for the manufacturing of a medicament, in particular for preventing and/or treating, preferably treating 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 previous paragraphs; of an inflammatory disorder or disease, in particular Crohn's disease, ulcerative colitis, idiopathic pulmonary fibrosis, muscular dystrophy, rheumatoid arthritis, and systemic sclerosis (scleroderma); a neurogenerative disorder or disease, in particular Huntington’s disease; Lipid metabolism disorders, e.g.
  • NASH non-alcoholic steatohepatitis
  • NAFLD non-alcoholic fatty liver disease
  • fatty liver disease e.g. with cytomegalovirus
  • viral infections e.g. with cytomegalovirus
  • post-traumatic stress disorder (PTSD) bipolar disorder, depression, Tourette’s syndrome
  • schizophrenia, obsessive-compulsive disorder, anxiety disorder, panic disorders, phobias addiction to e.g. alcohol, tobacco, opioids, sedatives, hypnotics, anxiolytics, cocaine, cannabis, amphetamines, hallucinogens, inhalants, phencyclidine, impulse control disorders, behavioral addictions.
  • the compounds according to formula (I), preferably including the compounds according to one or more of sub-formulae (Ia) to (If), the compounds according to one or more of sub-formulae (Ig) to (Ij), the compounds according to sub-formula (Ik) and/or the compounds according to one or more of sub-formulae (Ir) to (Iu), as described hereinabove and/or hereinbelow are preferably suitable for use and/or used for the treatment of disorders.
  • the compounds according to formula (I), preferably including the compounds according to one or more of sub-formulae (Ia) to (If), the compounds according to one or more of sub-formulae (Ig) to (Ij), the compounds according to sub-formula (Ik) and/or the compounds according to one or more of sub-formulae (Ir) to (Iu), as described hereinabove and/or hereinbelow, are preferably suitable for use and/or used as a medicament.
  • the compounds according to formula (I), preferably including the compounds according to one or more of sub-formulae (Ia) to (If), the compound according to one or more of sub-formulae (Ig) to (Ij), the compounds according to sub-formula (Ik) and/or the compounds according to one or more of sub-formulae (Ir) to (Iu), as described hereinabove and/or hereinbelow, are preferably suitable for use and/or used as a WRN inhibitor.
  • compositions preferably for use in the treatment as described hereinabove and/or hereinbelow, comprising one or more compounds described hereinabove and/or hereinbelow, preferably compounds according to formula (I), preferably including the compounds according to one or more of sub-formulae (Ia) to (If), the compound according to one or more of sub-formulae (Ig) to (Ij), the compounds according to sub-formula (Ik) and/or the compounds according to one or more of sub- formulae (Ir) to (Iu), preferably including one or more the compounds explicitly described in the Experimental Section provided hereinbelow.
  • compounds according to formula (I) preferably including the compounds according to one or more of sub-formulae (Ia) to (If), the compound according to one or more of sub-formulae (Ig) to (Ij), the compounds according to sub-formula (Ik) and/or the compounds according to one or more of sub- formulae (Ir) to (Iu), preferably including one
  • compositions as described hereinabove and/or hereinbelow, that contains one or more additional compounds, selected from the group consisting of physiologically acceptable excipients, auxiliaries, adjuvants, carriers and pharmaceutical active ingredients other than the compounds according to formula (I), preferably including the compounds according to one or more of sub-formulae (Ia) to (If), the compound according to one or more of sub-formulae (Ig) to (Ij), the compounds according to sub-formula (Ik) and/or the compounds according to one or more of sub- formulae (Ir) to (Iu), preferably including one or more the compounds explicitly described in the Experimental Section provided hereinbelow.
  • additional compounds selected from the group consisting of physiologically acceptable excipients, auxiliaries, adjuvants, carriers and pharmaceutical active ingredients other than the compounds according to formula (I), preferably including the compounds according to one or more of sub-formulae (Ia) to (If), the compound according to one or more of sub-formulae (Ig)
  • a process for the manufacture of a pharmaceutical composition characterized in that one or more compounds according to formula (I), preferably including the compounds according to one or more of sub-formulae (Ia) to (If), the compound according to one or more of sub-formulae (Ig) to (Ij), the compounds according to sub-formula (Ik) and/or the compounds according to one or more of sub- formulae (Ir) to (Iu), preferably including one or more the compounds explicitly described in the Experimental Section provided hereinbelow, and one or more compounds, selected from the group consisting of carriers, excipients, auxiliaries and pharmaceutical active ingredients other than the compounds according to formula (I), preferably including the compounds according to one or more of sub-formulae (Ia) to (If), the compound according to one or more of sub-formulae (Ig) to (Ij), the compounds according to sub- formula (Ik) and/or the compounds according to one or more of sub-formulae (Ir) to (
  • a compound according to formula (I) preferably including the compounds according to one or more of sub-formulae (Ia) to (If), the compound according to one or more of sub-formulae (Ig) to (Ij), the compounds according to sub-formula (Ik) and/or the compounds according to one or more of sub- formulae (Ir) to (Iu), preferably including one or more the compounds explicitly described in the Experimental Section provided hereinbelow, as a pharmaceutical.
  • a compound according to formula (I) preferably including the compounds according to one or more of sub-formulae (Ia) to (If), the compound according to one or more of sub-formulae (Ig) to (Ij), the compounds according to sub-formula (Ik) and/or the compounds according to one or more of sub- formulae (Ir) to (Iu), preferably including one or more the compounds explicitly described in the Experimental Section provided hereinbelow, in the treatment and/or prophylaxis of disorders, preferably disorders as described hereinabove and/or hereinbelow.
  • a compound according to formula (I) preferably including the compounds according to one or more of sub-formulae (Ia) to (If), the compound according to one or more of sub-formulae (Ig) to (Ij), the compounds according to sub-formula (Ik) and/or the compounds according to one or more of sub- formulae (Ir) to (Iu), preferably including one or more the compounds explicitly described in the Experimental Section provided hereinbelow, for producing a pharmaceutical composition for the treatment and/or prophylaxis of disorders, preferably disorders as described hereinabove and/or hereinbelow.
  • the disorders in this regard are selected from the group consisting of hyperproliferative and non-hyperproliferative disorders. More preferably, the disorders in this regard comprise cancerous disorders. Even more preferably, the preferred disorder in this regard is cancer, preferably cancer as described hereinabove and/or hereinbelow. Alternatively preferably, the disorder in this regard is selected from the group consisting of noncancerous disorders, preferably noncancerous disorders as described hereinabove and/or hereinbelow. Preferred disorders in this regard are disorders having or additionally having Microsatellite Instability (MSI), preferably assay detectable Microsatellite Instability (MSI).
  • MSI Microsatellite Instability
  • MSI Microsatellite Instability
  • the preferred cancerous disorders in this regard are selected from the group consisting of melanoma, brain cancer, lung cancer, squamous cell cancer, bladder cancer, gastric cancer, pancreatic cancer, hepatic cancer, renal cancer, colorectal cancer, breast cancer, head cancer, neck cancer, esophageal cancer, gynecological cancer, ovarian cancer, uterine cancer, prostate cancer, thyroid cancer, lymphoma, chronic leukemia and/or acute leukemia.
  • cancerous disorders are one or more disorders, selected from the group consisting of endometrial cancer, colon cancer, colorectal cancer (CRC), gastric cancer, glioblastoma, and/or glioblastoma multiforme (GBM).
  • endometrial cancer colon cancer
  • CRC colorectal cancer
  • gastric cancer gastric cancer
  • glioblastoma glioblastoma multiforme
  • GBM glioblastoma multiforme
  • cancerous disorders are disorders selected from the group consisting of Uterine Corpus Endometrial Carcinoma (UCEC), Stomach adenocarcinoma (STAD), Rectum adenocarcinoma (READ), Adrenocortical carcinoma (ACC), Uterine Carcinosarcoma (UCS), Cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), Wilms Tumor Syndromes (WT), Mesothelioma (MESO), Esophageal carcinoma (ESCA), Breast Cancer (BC), Kidney renal clear cell carcinoma (KIRC), Ovarian serous cystadenocarcinoma (OV), Cholangiocarcinoma (CHOL), Thymoma (THYM), Liver hepatocellular carcinoma (LIHC), Head and Neck squamous cell carcinoma (HNSC), Sarcoma (SARC), Lung squamous cell carcinoma (LUSC), Prostate adenocarcino
  • the disorders in this regard are one or more disorders, selected from the group consisting of arthritis, restenosis; fibrotic disorders; mesangial cell proliferative disorders, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes, organ transplant rejection, glomerulopathies, metabolic disorders, inflammation, solid tumors, rheumatic arthritis, diabetic retinopathy, and neurodegenerative diseases.
  • MSI Microsatellite Instability
  • MSI Microsatellite Instability
  • ⁇ especially preferred are methods for the treatment and/or prophylaxis of disorders, characterized in that one or more compounds compound according to formula (I), preferably including the compounds according to one or more of sub-formulae (Ia) to (If), the compound according to one or more of sub-formulae (Ig) to (Ij), the compounds according to sub-formula (Ik) and/or the compounds according to one or more of sub- formulae (Ir) to (Iu), preferably including one or more the compounds explicitly described in the Experimental Section provided hereinbelow, is administered to a patient in need of such a treatment, even more preferably such methods for the treatment and/or prophylaxis of disorders, wherein the disorders are as described hereinabove and/or hereinbelow.
  • one or more compounds compound according to formula (I) preferably including the compounds according to one or more of sub-formulae (Ia) to (If), the compound according to one or more of sub-formulae (Ig) to (Ij),
  • anticancer agent relates to any agent which is administered to a patient with cancer for the purposes of treating the cancer.
  • the anti-cancer treatment defined above may be applied as monotherapy or may involve, in addition to the herein disclosed compounds of formula (I), conventional surgery or radiotherapy or medicinal therapy.
  • Such medicinal therapy e.g., a chemotherapy or a targeted therapy, may include one or more, but preferably one, of the following anti-tumor agents: Alkylating agents such as altretamine, bendamustine, busulfan, carmustine, chlorambucil, chlormethine, cyclophosphamide, dacarbazine, ifosfamide, improsulfan, tosilate, lomustine, melphalan, mitobronitol, mitolactol, nimustine, ranimustine, temozolomide, thiotepa, treosulfan, mechloretamine, carboquone, apaziquone, fotemustine, glufosfamide, palifosfamide, pipobroman, trofosfamide
  • a further embodiment of the present invention is a process for the manufacture of the pharmaceutical compositions of the present invention, characterized in that one or more compounds according to the invention and one or more compounds selected from the group consisting of solid, liquid or semiliquid excipients, auxiliaries, adjuvants, diluents, carriers and pharmaceutically active agents other than the compounds according to the invention, are converted in a suitable dosage form.
  • a set or kit comprising a therapeutically effective amount of at least one compound of the invention and/or at least one pharmaceutical composition as described herein and a therapeutically effective amount of at least one further pharmacologically active substance other than the compounds of the invention. It is preferred that this set or kit comprises separate packs of a) an effective amount of a compound of formula (I), or its derivatives, prodrugs, solvates, tautomers or stereoisomers thereof as well as the physiologically acceptable salts of each of the foregoing, including mixtures thereof in all ratios, and b) an effective amount of a further active ingredient that further active ingredient not being a compound of formula (I).
  • compositions (formulations) of the present invention may be administered by any means that achieve their intended purpose.
  • administration may be via oral, parenteral, topical, enteral, intravenous, intramuscular, inhalant, nasal, intraarticular, intraspinal, transtracheal, transocular, subcutaneous, intraperitoneal, transdermal, or buccal routes.
  • administration may be via the oral route.
  • the dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired. Parenteral administration is preferred. Oral administration is especially preferred.
  • Suitable dosage forms include, but are not limited to capsules, tablets, pellets, dragees, semi- solids, powders, granules, suppositories, ointments, creams, lotions, inhalants, injections, cataplasms, gels, tapes, eye drops, solution, syrups, aerosols, suspension, emulsion, which can be produced according to methods known in the art, for example as described below: Tablets: mixing of active ingredient/s and auxiliaries, compression of said mixture into tablets (direct compression), optionally granulation of part of mixture before compression.
  • Capsules mixing of active ingredient/s and auxiliaries to obtain a flowable powder, optionally granulating powder, filling powders/granulate into opened capsules, capping of capsules.
  • Semi-solids (ointments, gels, creams): dissolving/dispersing active ingredient/s in an aqueous or fatty carrier; subsequent mixing of aqueous/fatty phase with complementary fatty/aqueous phase, homogenization (creams only).
  • Suppositories (rectal and vaginal): dissolving/dispersing active ingredient/s in carrier material liquified by heat (rectal: carrier material normally a wax; vaginal: carrier normally a heated solution of a gelling agent), casting said mixture into suppository forms, annealing and withdrawal suppositories from the forms.
  • Aerosols dispersing/dissolving active agent/s in a propellant, bottling said mixture into an atomizer.
  • non-chemical routes for the production of pharmaceutical compositions and/or pharmaceutical preparations comprise processing steps on suitable mechanical means known in the art that transfer one or more compounds of the invention into a dosage form suitable for administration to a patient in need of such a treatment.
  • the transfer of one or more compounds of the invention into such a dosage form comprises the addition of one or more compounds, selected from the group consisting of carriers, excipients, auxiliaries and pharmaceutical active ingredients other than the compounds of the invention.
  • Suitable processing steps include, but are not limited to combining, milling, mixing, granulating, dissolving, dispersing, homogenizing, casting and/or compressing the respective active and nonactive ingredients.
  • Mechanical means for performing said processing steps are known in the art, for example from Ullmann's Encyclopedia of Industrial Chemistry, 5th Edition.
  • active ingredients are preferably at least one compound of the invention and optionally one or more additional compounds other than the compounds of the invention, which show valuable pharmaceutical properties, preferably those pharmaceutical active agents other than the compounds of the invention, which are disclosed herein.
  • Particularly suitable for oral use are tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops, suitable for rectal use are suppositories, suitable for parenteral use are solutions, preferably oil-based or aqueous solutions, furthermore suspensions, emulsions or implants, and suitable for topical use are ointments, creams or powders.
  • the compounds of the invention may also be lyophilized and the resultant lyophilizates used, for example, for the preparation of injection preparations.
  • the preparations indicated may be sterilized and/or comprise assistants, such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for modifying the osmotic pressure, buffer substances, dyes, flavors and/or a plurality of further active ingredients, for example one or more vitamins.
  • assistants such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for modifying the osmotic pressure, buffer substances, dyes, flavors and/or a plurality of further active ingredients, for example one or more vitamins.
  • Suitable excipients are organic or inorganic substances, which are suitable for enteral (for example oral), parenteral or topical administration and do not react with the compounds of the invention, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatine, carbohydrates, such as lactose, sucrose, mannitol, sorbitol or starch (maize starch, wheat starch, rice starch, potato starch), cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, magnesium stearate, talc, gelatine, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, polyvinyl pyrrolidone and/or vaseline.
  • enteral for example oral
  • parenteral or topical administration do not react with the compounds of the invention
  • carbohydrates such as lactose, sucrose, mannitol
  • disintegrating agents may be added such as the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.
  • Auxiliaries include, without limitation, flow-regulating agents and lubricants, for example, silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol.
  • Dragee cores are provided with suitable coatings, which, if desired, are resistant to gastric juices.
  • concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures.
  • the tablet, dragee or pill can comprise an inner dosage and an outer dosage component the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer, which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, acetyl alcohol, solutions of suitable cellulose preparations such as acetyl-cellulose phthalate, cellulose acetate or hydroxypropylmethyl- cellulose phthalate, are used.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.
  • Suitable carrier substances 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 compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc and petroleum jelly.
  • enteral e.g., oral
  • parenteral administration e.g., parenteral administration or topical application
  • Suitable carrier substances 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 compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc and petroleum jelly.
  • solutions preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants, are used for parenteral administration, and ointments
  • the compounds of the invention can also be lyophilized and the lyophilizates obtained can be used, for example, for the production of injection preparations.
  • Other pharmaceutical preparations which can be used orally include push-fit capsules made of gelatine, as well as soft, sealed capsules made of gelatine and a plasticizer such as glycerol or sorbitol.
  • the push-fit capsules can contain the active compounds 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.
  • the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils, or liquid paraffin.
  • liquid forms in which the novel compositions of the present invention may be incorporated for administration orally include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatine.
  • Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble salts and alkaline solutions.
  • suspensions of the active compounds as appropriate oily injection suspensions may be administered.
  • Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides or polyethylene glycol-400 (the compounds are soluble in PEG-400).
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, including, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran,optionally, the suspension may also contain stabilizers.
  • inhalation sprays for administration as an inhalation spray, it is possible to use sprays in which the active ingredient is either dissolved or suspended in a propellant gas or propellant gas mixture (for example CO 2 or chlorofluorocarbons).
  • a propellant gas or propellant gas mixture for example CO 2 or chlorofluorocarbons.
  • the active ingredient is advantageously used here in micronized form, in which case one or more additional physiologically acceptable solvents may be present, for example ethanol.
  • Inhalation solutions can be administered with the aid of conventional inhalers.
  • Possible pharmaceutical preparations, which can be used rectally include, for example, suppositories, which consist of a combination of one or more of the active compounds with a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, or paraffin hydrocarbons.
  • gelatine rectal capsules which consist of a combination of the active compounds with a base.
  • Possible base materials include, for example, liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.
  • the compounds of the present invention may be in the form of pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds of the invention or of their pharmaceutically acceptable salts.
  • Suitable pharmaceutically acceptable salts of the compounds of this invention are those described hereinbefore and include acid addition salts which may, for example be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, methanesulfonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g.
  • the term "effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
  • therapeutically effective amount means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.
  • Said therapeutic effective amount of one or more of the compounds of the invention is known to the skilled artisan or can be easily determined by standard methods known in the art.
  • the compounds of the present invention and the optional additional active substances are generally administered analogously to commercial preparations.
  • suitable doses that are therapeutically effective lie in the range between 0.0005 mg and 1000 mg, preferably between 0.005 mg and 500 mg and especially between 0.5 mg and 100 mg per dose unit.
  • the daily dose is preferably between about 0.001 mg/kg and 10 mg/kg of body weight.
  • dose levels can vary as a function of the specific compound, the severity of the symptoms and the susceptibility of the subject to side effects. Some of the specific compounds are more potent than others.
  • Preferred dosages for a given compound are readily determinable by those of skill in the art by a variety of means.
  • a preferred means is to measure the physiological potency of a given compound.
  • the specific dose for the individual patient, in particular for the individual human patient depends, however, on the multitude of factors, for example on the efficacy of the specific compounds employed, on the age, body weight, general state of health, the sex, the kind of diet, on the time and route of administration, on the excretion rate, the kind of administration and the dosage form to be administered, the pharmaceutical combination and severity of the particular disorder to which the therapy relates.
  • the specific therapeutic effective dose for the individual patient can readily be determined by routine experimentation, for example by the doctor or physician, which advises or attends the therapeutic treatment.
  • the compounds of the present invention can be prepared according to the procedures of the following Schemes and Examples, using appropriate materials, and as further exemplified by the following specific examples. They may also be prepared by known methods, as described in the literature (for example 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). Use can also be made of synthetic variants which are known per se but are not mentioned here in greater detail. Likewise, the starting materials for the preparation of compounds of the present invention can be prepared by methods as described in the examples or by methods known per se, as described in the literature of synthetic organic chemistry and known to the skilled person or can be obtained commercially.
  • the starting materials for the processes claimed and/or utilized may, if desired, also be formed in situ by not isolating them from the reaction mixture, but instead immediately converting them further into the compounds of the invention or intermediate compounds.
  • the reaction stepwise it is possible to carry out the reaction stepwise.
  • the reaction of the compounds is carried out in the presence of a suitable solvent, which is preferably inert under the respective reaction conditions.
  • suitable solvents comprise but are not limited to hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichlorethylene, 1,2- dichloroethane, tetrachloromethane, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide, dimethylformamide (DMF) or N-methyl pyrrolidin
  • the reaction temperature is between about -100 °C and 300 °C, depending on the reaction step and the conditions used. Reaction times are generally in the range between a fraction of a minute and several days, depending on the reactivity of the respective compounds and the respective reaction conditions. Suitable reaction times are readily determinable by methods known in the art, for example reaction monitoring. Based on the reaction temperatures given above, suitable reaction times generally lie in the range between 10 minutes and 48 hours. Moreover, by utilizing the procedures described herein, in conjunction with ordinary skills in the art, additional compounds of the present invention claimed herein can be readily prepared. The compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention. The examples further illustrate details for the preparation of the compounds of the present invention.
  • the compounds of the present invention can readily be synthesized by reacting other compounds of the present invention under suitable conditions, for instance, by converting one particular functional group being present in a compound of the present invention, or a suitable precursor molecule thereof, into another one by applying standard synthetic methods, like reduction, oxidation, addition or substitution reactions; those methods are well known to the skilled person.
  • the skilled artisan will apply – whenever necessary or useful – synthetic protecting (or protective) groups; suitable protecting groups as well as methods for introducing and removing them are well-known to the person skilled in the art of chemical synthesis and are described, in more detail, in, e.g., P.G.M. Wuts, T.W.
  • Treating means an alleviation, in whole or in part, of symptoms associated with a disorder or disease, or slowing, or halting of further progression or worsening of those symptoms, or prevention or prophylaxis of the disease or disorder in a subject at risk for developing the disease or disorder.
  • disorder(s) and “disease(s)” as used herein are well-known and understood in the art. In the context of the present invention, they are preferably used as synonyms and thus are preferably interchangeable, if the context they are used herein does not strongly implicate otherwise.
  • fibrotic disorder(s) and “fibrotic disease(s)” as used herein are also well-known and understood in the art. In the context of the present invention, they are preferably used as synonyms and thus are preferably interchangeable, if the context they are used herein does not strongly implicate otherwise.
  • ⁇ in connection with a compound of formula (I) refers to an amount (of a compound, drug, pharmaceutical compositions, etc.) capable of alleviating, in whole or in part, symptoms associated with a disorder or disease, or slowing or halting further progression or worsening of those symptoms, or preventing or providing prophylaxis for the disease or disorder in a subject having or at risk for developing a disease disclosed herein, such as inflammatory conditions, immunological conditions, cancer or metabolic conditions.
  • ⁇ except for instances where it is specifically stated or the context provides for a different meaning – in general the number of a term, i.e., its singular and plural form, is used and can be read interchangeably.
  • the term “compound” in its singular form may also comprise or refer to a plurality of compounds, while the term “compounds” in its plural form may also comprise or refer to a singular compound.
  • Especially preferred according to the invention are subjects as described herein, wherein the characteristics of two or more preferred, more preferred and/or especially preferred embodiments, aspects and/or subjects are combined into one embodiment, aspect and/or subject.
  • preferred subjects or embodiments can be combined with other preferred subjects or embodiments; more preferred subjects or embodiments can be combined with other less preferred or even more preferred subjects or embodiments; especially preferred subjects or embodiments can be combined with other just preferred or just even more preferred subjects or embodiments, and the like.
  • “about” means +/- 10%, more preferably +/- 5% of the given specific value with respect to numbers, amounts, dosing, hours, times, timings, durations, and the like. Even more preferably, the term “about” includes a variance, deviation and/or variability of the respective number, figure, range and/or amount of at least plus/minus 5%, and especially a variance, deviation and/or variability of the respective number, figure, range and/or amount of plus/minus 5%. If not specified otherwise, amounts administered to a subject, human subject or patient given in "mg", such as in 500 mg, 1000 mg, or the like, are preferably intended to mean the respective amounts to be administered "flat", i.e.
  • the term "one or more” as used herein preferably means “one or more than one” and thus preferably includes “two or more” (or “two or more than two"), “three or more” (or “three or more than three") and/or “four more” (or “more or more than four”). Accordingly, the term “one or more” as used herein preferably includes the numbers one, two, three, four, five, six and/or higher numbers.
  • cancer co-therapeutic agents cancer chemotherapeutic agents
  • it especially preferably includes the numbers one, two, three, four and/or five, even more preferably the numbers one, two, three and/or four and especially the numbers one, two and/or three.
  • subjects and especially human subjects are preferably also referred to as patients.
  • the terms "disorder(s)” and “disease(s)” as used herein are well-known and understood in the art. In the context of the present invention, they are preferably used as synonyms and thus are preferably interchangeable, if the context they are used herein does not strongly implicate otherweise.
  • week In the medical context, including, but not limited to treatment regimens, dosing schedules and clinical trial designs, for convenience and/or ease of use by patients, medical staff and/or physicians, as well as reliability and/or reproducibility of results etc., the terms “week”/“a week”, “month”/“a month” and/or “year”/“a year” can used with slight deviations from the definitions of the Gregorian calendar. For example, in said medical context, a month is often referred to as 28 days, and a year is often referred to 48 weeks. Thus, in the context of the instant invention, the term “week” or “a week” preferably refers to a period of time of about 5, about 6 or about 7 days, more preferably about 7 days.
  • the term “month” or “a month” preferably refers to a period of time of about 28, about 29, about 30 or about 31 days, more preferably about 28, about 30 or about 31 days.
  • the term “year” or “a year” preferably refers to a period of time of about 12 months or to a period of time of about 48, about 50, or about 52 weeks, more preferably12 months, or about 48 or about 52 weeks.
  • Multiplicity is abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublets), tt (triplet of triplets), td (triplet of doublets) br (broad) and coupling constants (J) are reported in Hz.
  • HPLC-MS HPLC-MS data provided in Table 1 are given with mass in m/z. The results can be obtained by one of the methods described below.
  • HPLC-MS analyses were usually performed on a Shimadzu LCMS-2020, Shimadzu SP-M20A 2010EV or Shimadzu UFLC-MS 2010EV system utilizing one of the following columns: Shim-pack VP-ODS, Shim-pack XR-ODS, Kinetex XB- C18100A, Xbridge BEH C18, Gemini-NX 3u C18110A or ACE UltraCore 2.5 SuperC18.
  • Standard conditions applied Standard solvent gradients using A: Water + 0.1 vol.% formic acid, B: acetonitrile + 0.1 vol.% formic acid; or A: Water + 0.05 vol.% trifluoroacetic acid, B: acetonitrile + 0.05 vol.% trifluoroacetic acid Detection wavelength: 220 nm, MS-Typ: API-ES Methods: LC-MS: Method A: Agilent 1200 series LC-MS; Kinetex EVO C185.0 ⁇ m 50-4.6 mm; flow: 3.3 mL/min; 220 nm; T: 40 °C; buffer A: water + 0.05% formic acid; buffer B: acetonitrile + 0.04% formic acid; 1% - 99% B: 0 - 0.8 min
  • Method C Agilent 1200 series LC-MS; Kinetex EVO C185.0 ⁇ m 50-4.6 mm; flow: 3.3 mL/min; 220 nm; T: 40 °C; buffer A: water + 0.05% formic acid; buffer B: acetonitrile + 0.04% formic acid; 1% - 100% B: 0 - 1.8 min
  • Method D Titank C18, 1.7 ⁇ m 30-2.1 mm; flow: 0.8 mL/min; 254 nm; T: 40 °C; buffer A: water + 0.04% NH 4 OH; T: 40 °C; buffer B: ACN; Gradient: 10% B - 95% B in 2.1 min, hold 0.6 min.
  • Method E Kinetex 1.7 ⁇ m C18100A 30-2.1 mm; flow: 1.0 mL/min; 254 nm; T: 40 °C; buffer A: water + 0.05% TFA; buffer B: ACN + 0.05% TFA; gradient: 5% - 100% B in 1.2min, hold 0.6 min.
  • Method F HALO 2 ⁇ m 2.1-30 mm; flow: 1.5 mL/min; 254 nm; T: 45 °C; buffer A: water + 0.05% TFA; buffer B: ACN + 0.05% TFA; Gradient 5% B - 100% B in 1.2min, hold 0.4 min.
  • Method G HALO C182 ⁇ m 3.0-30 mm; flow: 1.5 mL/min; 254 nm; T: 40 °C; buffer A: water + 0.1% TFA; buffer B: Acetonitrile + 0.1% TFA; Gradient: 5% B - 100% B in 2.0 min.
  • Method H HALO 2 ⁇ m 3.0-30 mm; T: 40 °C; buffer A: water + 0.05% TFA; buffer B: ACN + 0.05% TFA; Gradient: 5% B - 100% B in 1.2 min, hold 0.5 min; 254 nm
  • Method I HALO C182.0 ⁇ m 3.0-30 mm; flow: 1.5 mL/min; 254 nm; T: 40 °C; buffer A: water + 0.1% FA; buffer B: ACN + 0.1% FA; flow: 1.5 mL/min; Gradient:5% B - 100% B in 1.2 min, hold 0.6 min.
  • Method J Exsil Mono 100 C181.7 ⁇ m 2.0-30 mm; flow: 0.8 mL/min; 254 nm; T: 45 °C; buffer A: water + 0.1% FA; buffer B: ACN + 0.1% FA; Gradient: 5% B - 100% B in 1.2 min, hold 0.6 min.
  • Method K Kinetex EVO C182.6 ⁇ m 3.0-50 mm; flow: 1.2 mL/min; 254 nm; T: 40 °C; buffer A: water (5mM NH 4 HCO 3 ); buffer B: ACN; Gradient: 10% B - 95% B in 2.1 min, hold 0.6 min.
  • Method L Agilent 70294979 - Chromolith Speed ROD RP-18e 50-4.6 mm; flow: 3.3 mL/min; 220 nm; T: 40 °C; buffer A: H 2 O + 0.05% HCOOH; buffer B: MeCN + 0.04% HCOOH + 1% H 2 O; 0% - 100% B: 0 – 2.0 min, 100% buffer B: 2.0 – 2.5 min
  • Method M Column: XBridge C8, 3.5 ⁇ m, 4.6 x 50 mm; Flow: 2 mL/min; Solvent A: water + 0.1% TFA; Solvent B: ACN + 0.1% TFA; Gradient: 0 min: 5% B, 8 min: 100% B, 8.1 min: 100% B, 8.5 min: 5% B, 10 min 5% B.
  • Method N Poroshell HPH C18; Solvent A: water + 10 mM NH 4 HCO 3 ; Solvent B: ACN; Flow: 1 mL/min; Gradient: 0 min: 5% B, 8 min: 100% B, 8.1 min: 100% B, 8.5 min: 5% B, 10 min 5% B.
  • Method O Shim-pack velox; Mobile phase A: Water/0.1% FA; Mobile phase B: Acetonitrile/0.1% FA
  • UPLC-MS Method A: Waters Acquity UPLC-MS; Kinetex EVO-C181.7 ⁇ m 50-2.1 mm; flow 0.9 mL/min; 220 nm; buffer A: water + 0.05% formic acid; buffer B: acetonitrile + 0.04% formic acid; T: 40 °C; 1-100% B: 0 - 1.0 min; 100% B: 1.0 -1.3 min
  • HPLC-MS Method A: Waters Alliance HT 2795 equipped with Waters 996 photodiode array detector and Waters micromass ZQ.
  • Solid phase YMC-TriaRt:C184.6 x 50 mm 3 ⁇ m.
  • Mobile phase solvent B water CH 3 COONH 4 5 mM pH 5.2: ACN 95:5; solvent C ACN: water 95:5; 10 to 90% of C in 5 min; flow 1.2 mL/min
  • Method B Waters Alliance HT 2795 equipped with Waters 996 photodiode array detector and Waters micromass ZQ.
  • Mobile phase solvent D 0.05%NH 3 /ACN 95:5; solvent C ACN: water 95:5; 10 to 90% of C in 5 min; flow 1.2 mL/min
  • Method C Waters Acquity Arc equipped with QDa detector and 2998 PDA detector.
  • Solid phase Phenomenex Gemini C18 4.6 x 50 mm 3 ⁇ m.
  • Mobile phase solvent B water CH 3 COONH 4 5 mM pH 5.2: ACN 95:5; solvent C ACN: water 95:5; 10 to 90% of C in 5 min; flow 1.2 mL/min
  • Method D Waters Acquity Arc equipped with QDa detector 2424 ELS detector and 2998 PDA detector.
  • Solid phase Phenomenex Gemini C184.6 x 50 mm 3 ⁇ m.
  • Mobile phase solvent B water CH3COONH 4 5 mM pH 5.2: ACN 95:5; solvent C ACN: water 95:5; 50 to 100% of C in 5 min; flow 1.2 mL/min Method
  • E Waters Acquity Arc equipped with QDa detector 2424 ELS detector and 2998 PDA detector.
  • Solid phase Phenomenex Gemini NX C184.6 x 50 mm 3 ⁇ m.
  • Mobile phase solvent B water CH 3 COONH 4 5 mM pH 5.2: ACN 95:5; solvent C ACN: water 95:5; 10 to 90% of C in 5 min; flow 1.2 mL/min
  • Method F Waters Alliance LC 2795 equipped with a Waters PDA UV detector 2996 and a TOF Waters LCT Premier XE mass detector (ESI interface).
  • Solid phase Waters x Select 3.0 x 30 mm 3.5 ⁇ m.
  • Mobile phase solvent A 0.05% v/v formic acid and solvent B 70/25/5 (v/v/v) mixture of MeOH/iPrOH/H 2 O 0.035% v/v of formic acid; column 50 °C; 0% to 12% B in 4 min, 32% B in 4 min, 60% B in 4 min then 100% B in 4 min hold 100% B 1.4 min; flow 0.8 mL/min Method G: Waters Alliance HT 2795 equipped with Waters 996 photodiode array detector and Waters micromass ZQ. Solid phase: Gemini Phenyl C64.6 x 50 mm 3 ⁇ m.
  • Mobile phase solvent B water CH 3 COONH 4 5 mM pH 5.2: ACN 95:5; solvent C ACN: water 95:5; 10 to 90% of C in 5 min; flow 1.2 mL/min
  • Method H Waters Alliance HT 2795 equipped with Waters 996 photodiode array detector and Waters micromass ZQ.
  • Solid phase YMC-TriaRt:C184.6 x 50 mm 3 ⁇ m.
  • Mobile phase solvent B water CH 3 COONH 4 5 mM pH 5.2: ACN 95:5; solvent C ACN: water 95:5; 50 to 100% of C in 5 min; flow 1.2 mL/min
  • Method I Waters Alliance HT 2795 equipped with Waters 996 photodiode array detector and Waters micromass ZQ.
  • Solid phase GeminiPhenyl C64.6 x 50 mm 3 ⁇ m.
  • Mobile phase solvent A water 0.1% HCOOH: ACN 95:5; solvent C ACN: water 95:5; 50 to 100% of C in 5 min; flow 1.2 mL/min
  • Method L Waters Acquity Arc equipped with QDa detector 2424 ELS detector and 2998 PDA detector.
  • Solid phase Waters Cortecs C184.6 x 50 mm 2.7 ⁇ m.
  • Mobile phase solvent A water 0.1% HCOOH: ACN 95:5; solvent C ACN: water 95:5; 10 to 90% of C in 5 min; flow 1.2 mL/min Method M: Waters Acquity Arc equipped with QDa detector 2424 ELS detector and 2998 PDA detector.
  • Solid phase Sepachrom Robusta Phenyl 4.6 x 50 mm 3 ⁇ m.
  • Ester intermediate 1 methyl 2-[(1- ⁇ 2-[(4-methylbenzenesulfonyl)oxy]ethyl ⁇ -1H-1,2,3,4- tetrazol-5-yl)sulfanyl]-5-nitrobenzoate
  • Step 1 methyl 2- ⁇ [1-(2-hydroxyethyl)-1H-1,2,3,4-tetrazol-5-yl]sulfanyl ⁇ -5-nitrobenzoate
  • methyl 2-iodo-5-nitrobenzoate 0.2 g, 0.65 mmol, 1 eq.
  • 2-(5-sulfanyl-1H-1,2,3,4-tetrazol-1-yl)ethan-1-ol (0.107 g, 0.72 mmol, 1.1 eq.
  • Pd 2 (dba) 3 (0.03 g, 0.03 mmol, 0.05 eq.
  • xantphos 0.039 g, 0.07 mmol, 0.1 e
  • Step 1 methyl 2- ⁇ [1-(2-formamidoethyl)-1H-1,2,3,4-tetrazol-5-yl]sulfanyl ⁇ -5- nitrobenzoate
  • methyl 2-[(1- ⁇ 2-[(4-methylbenzenesulfonyl)oxy]ethyl ⁇ -1H-1,2,3,4- tetrazol-5-yl)sulfanyl]-5-nitrobenzoate 0.063 g, 0.13 mmol, 1 eq.
  • ACN 1.3 mL
  • sodium diformylamide 0.015 g, 0.16 mmol, 1.2 eq.
  • reaction mixture was stirred at room temperature for 1 h and 40 min. HPLC-MS analysis showed the presence of the desired product.
  • the solid was filtrated and the water was extracted five times with DCM, organic layer was washed with brine, dried on Na 2 SO 4 and evaporated. The two lots were put together, and the product was used in the next step without further purification (white solid, 0.02 g, 0.05 mmol, 93% yield, 89% purity).
  • Step 1 methyl 2-[(1-ethenyl-1H-1,2,3,4-tetrazol-5-yl)sulfanyl]-5-nitrobenzoate
  • methyl 2-[(1- ⁇ 2-[(4-methylbenzenesulfonyl)oxy]ethyl ⁇ -1H-1,2,3,4- tetrazol-5-yl)sulfanyl]-5-nitrobenzoate 0.063 g, 0.13 mmol, 1 eq.
  • ACN 1.3 mL
  • sodium diformylamide 0.015 g, 0.16 mmol, 1.2 eq.
  • reaction mixture was stirred at room temperature for 2 h. HPLC-MS analysis showed the presence of planned product.
  • the reaction mixture was evaporated, water was added, and the product was extracted with AcOEt 3 times, organic layers were combined and washed with brine, dried on Na 2 SO 4 and evaporated.
  • the crude was purified by chromatographic column using hexane/AcOEt (2/1) to afford the title compound as white solid (1.45 g, 5.59 mmol, 84% yield, 90% purity).
  • reaction mixture was stirred at room temperature for 1.5 h. HPLC-MS analysis showed the presence of target product.
  • the reaction mixture was evaporated to dryness, water was added and the product was extracted with AcOEt 3 times, organic layers were combined and washed with brine, dried on Na 2 SO 4 and evaporated.
  • the crude was used in the next step without further purification (white foam, 0.45 g, 1.57 mmol, 99% yield, 96% purity).
  • the reaction mixture was stirred at 0 °C for 30 min. After warming at room temperature, water was added and the product was extracted with DCM 3 times, organic layer was washed with brine, dried on Na 2 SO 4 and evaporated. The crude was purified by chromatographic column using hexane/AcOEt (9/1 to 1/1) to afford the target product as solid (0.56 g, 1.34 mmol, 85% yield, 100% purity).
  • reaction mixture was stirred at 60 °C for 4 h. HPLC-MS analysis showed the presence of the expected product.
  • the solid was filtrated and the product was used in the next step without further purification (0.12 g, 0.38 mmol, 60% yield, 90% purity).
  • HPLC/MS analysis showed partial conversion in the desired product (254 nm). The mixture was stirred for further 90 min at 80°C in microwave with slight conversion improvement. The reaction was stirred for a total time of 8h in CEM microwave reactor at 80°. HPLC/MS analysis showed, besides an improvement of the conversion, also the formation of the product of the ester hydrolysis of the final product.
  • the reaction mixture was dried (78 mg), dissolved in DCM and washed with NaHCO 3 saturated aqueous solution, the aqueous phase was ri-extracted twice with DCM.
  • the solution was stirred at rt for 16h.
  • the reaction was diluted with DCM and washed with a citric acid solution (1M), the organic phase was separated and the the acqueous phase was extracted twice with DCM.
  • the combined organic phases were collected dried over anhydrous Na 2 SO 4 , filtered and evaporated to dryness under reduced pressure affording 220 mg of yellow oil.
  • the crude was purified by flash chromatography (Silica): crude dissolved in minimum amount of DCM, eluant (hexane/AcOEt 8/2).
  • the aqueous phase was acidified to pH 2-3 with 1M HCl and extracted again five times with DCM.
  • the combined organic phases were dried over Na 2 SO 4 , filtered off and reduced to dryness to obtain 2-(cyclopent-1-en-1-yl)-5-nitrobenzoic acid (1.35 g; 5.46 mmol; 84% yield; 94% purity) as a beige solid.
  • Step 1 [2-(5-bromo-2-nitrophenoxy)ethyl]dimethylamine
  • 5-bromo-2-nitrophenol 500 mg; 2.18 mmol; 1.0 eq.
  • K 2 CO 3 792 mg; 5.45 mmol; 2.5 eq.
  • the reaction mixture was stirred in the microwave for 4 h at 140 °C.
  • the resulting mixture was diluted with water and extracted with DCM four times. The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • Step 1 2-(cyclopent-1-en-1-yl)-5-nitrobenzonitrile
  • 2-bromo-5-nitrobenzonitrile 500 mg; 2.09 mmol; 1.0 eq.
  • cyclopent-1-en- 1-ylboronic acid 370 mg; 3.14 mmol; 1.5 eq.
  • CH 2 Cl 2 90 mg, 0.11 mmol; 0.05 eq.
  • Step 1 methyl 2-nitro-5-cyclopentylbenzoate To a solution of methyl 5-bromo-2-nitrobenzoate (500 mg; 1.83 mmol; 1.0 eq.) and cyclopent- 1-en-1-ylboronic acid (323 mg; 2.74 mmol; 1.50 eq.) in 6.0 mL 1,4-dioxane, 4.0 mL EtOH and 2.0 mL H 2 O, K 2 CO 3 (797 mg; 5.48 mmol; 3.0 eq.) and Pd(dppf)Cl 2 . CH 2 Cl 2 (79 mg; 0.091 mmol; 0.05 eq.).
  • Step 1 4-(cyclopent-1-en-1-yl)-2-methoxy-1-nitrobenzene
  • 4-bromo-2-methoxy-1-nitrobenzene 500 mg; 2.05 mmol; 1.0 eq.
  • cyclopent-1-en-1-ylboronic acid 362 mg; 3.07 mmol; 1.50 eq.
  • K 2 CO 3 893 mg; 6.14 mmol; 3.0 eq.
  • Pd(dppf)Cl 2 Pd(dppf)Cl 2 .
  • Step 1 4-(cyclopent-1-en-1-yl)-2-fluoro-1-nitrobenzene 4-Bromo-2-fluoronitrobenzene, (200 mg; 0.88 mmol; 1.0 eq) was dissolved in 10.0 mL 1,4- dioxane.1-cyclopenteneboronic acid pinacol ester (270 mg; 1.32 mmol; 1.50 eq.), K 2 CO 3 (366 mg; 2,65 mmol; 3.0 eq), 1.9 mL EtOH and 0.7 mL H 2 O were added.
  • Step 1 5-(cyclopent-1-en-1-yl)-2-nitrobenzonitrile
  • 5-bromo-2-nitrobenzonitrile 500 mg; 2.09 mmol; 1.0 eq.
  • cyclopent-1-en-1- ylboronic acid 370 mg; 3.14 mmol; 1.50 eq.
  • K 2 CO 3 913 mg; 6.28 mmol; 3.0 eq.
  • the mixture was hydrogenated at room temperature for 2 h under a hydrogen atmosphere using a hydrogen balloon, filtered through a celite pad and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with PE/EtOAc (5/1) to afford 2-amino-5-cyclopentylbenzonitrile (160 mg; 0.81 mmol; 51% yield; 94% purity) as a light-yellow oil.
  • the light-yellow suspension was irritated with blue light for 21.5 h at room temperature.
  • the reaction was stopped and filtered through kieselguhr.
  • the filter cake was washed with EtOH and the filtrate was reduced to dryness under vacuo.
  • the residue was dissolved in DMSO, filtered through a syringe filter and purified by preparative HPLC (Sunfire RP18, water + 0.1% FA/10-80% ACN + 0.1% FA) giving 5-amino-2-(2,2- difluorocyclopentyl)benzamide (20.0 mg; 0.07 mmol; 17% yield; 89% purity) as a light brown solid.
  • the vial was purged with nitrogen and [1,1’’-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with DCM (49 mg; 0.060 mmol; 0.05 eq.) were added.
  • the vial was refilled with nitrogen and stirred in the microwave for 30 min at 110 °C.
  • the reaction mixture was diluted with water and extracted three times with EtOAc. The combined organic layers were dried over Na 2 SO 4 , filtered and evaporated.
  • the vial was purged with argon, then xantphos (102.6 mg; 0.177 mmol; 0.10 eq.) and tris(dibenzylideneacetone)dipalladium(0) (81.2 mg; 0.089 mmol; 0.05 eq.) were added.
  • the vial was closed with a septum and stirred in a microwave 30 min at 110 °C.
  • the vial was purged with argon, then xantphos (102.6 mg; 0.177 mmol; 0.10 eq.) and tris(dibenzylideneacetone)dipalladium(0) (81.2 mg; 0.089 mmol; 0.05 eq.) were added.
  • the vial was closed with a septum and stirred in a microwave 30 min at 110 °C.
  • potassium carbonate (1.8 g; 13,17 mmol; 3 eq.) and [1,1’’- bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with DCM (181.4 mg; 0.22 mmol; 0.050 eq.) were added, flushed with argon, closed with the septum and stirred in a microwave for 30 min at 100 °C. The mixture was filtered over Celite, and the filtrate was reduced to dryness.
  • Step 1 6,6-difluoro-2-(4-nitrophenyl)-2-azaspiro[3.3]heptane
  • 1-iodo-4-nitrobenzene (0.199 g, 0.80 mmol, 1 eq.)
  • 6,6-difluoro-2-azaspiro[3.3]heptane hydrochloride (0.171 g, 0.96 mmol, 1.2 eq.)
  • Pd 2 (dba) 3 0.037 g, 0.04 mmol, 0.05 eq.
  • xantphos 0.048 g, 0.08 mmol, 0.1 eq.
  • NaOtBu 0.238 g, 2.4 mmol, 3 eq.
  • 1,4-dioxane dry degassed (4.2 mL) were added.
  • Aniline intermediate 50 4-cyclopentyl-2-methylaniline
  • Step 1 4-(cyclopent-1-en-1-yl)-2-methylaniline 4-Bromo-2-methylaniline (0.201 g, 1.07 mmol, 1 eq.), (cyclopent-1-en-1-yl)boronic acid (0.247 g, 2.14 mmol, 2 eq.) and cesium carbonate (1.056 g, 3.21 mmol, 3 eq.) were suspended in toluene (7 mL) and H 2 O (2.3 mL) and three vacuum/argon cycles were performed.
  • H-cube hydrogenation was performed on Pd/C 10%, 60 bar, 1 mL/min at room temperature.
  • HPLC-MS analysis revealed the formation of the target product.
  • the reaction mixture was evaporated to dryness and the product was used in the next step without further purification (orange oil, 0.106 g, 0.60 mmol, 90% yield, 90% purity).
  • Aniline intermediate 51 4-cyclopentyl-2-fluoro-6-methylaniline
  • Step 1 4-(cyclopent-1-en-1-yl)-2-fluoro-6-methylaniline 4-Bromo-2-fluoro-6-methylaniline (0.200 g, 0.98 mmol, 1 eq.), (cyclopent-1-en-1-yl)boronic acid (0.226 g, 1.96 mmol, 2 eq.) and cesium carbonate (0.968 g, 2.94 mmol, 3 eq.) were suspended in toluene (6 mL) and H 2 O (2 mL) and three vacuum/argon cycles were performed.
  • H-cube hydrogenation was performed on Pd/C 10%, 60 bar, 1mL/min at room temperature.
  • HPLC-MS analysis revealed the formation of the target product.
  • the reaction mixture was evaporated to dryness and the product was used in the next step without further purification (orange oil, 0.081 g, 0.46 mmol, 55% yield, 89% purity).
  • the suspension was degassed with argon, then tetrakis(triphenylphosphine) palladium(0) (124 mg; 0.11 mmol) was added.
  • the vial was closed with a septum and irradiated at microwave 1.5 h at 130 °C.
  • the mixture was filtered over Celite, reduced to dryness and purified by chromatography (silica gel; n-heptane/AcOEt; gradient 0-100% AcOEt) to get 6-[4-(propan-2-yl)phenyl]-[1,2,4]triazolo[1,5- a]pyridin-2-amine (286 mg; 1.13 mmol; 63% yield; 99% purity) as a pale brown solid.
  • reaction suspension was diluted AcOEt, stirred for 5 min and filtrated over celite.
  • the filtrate was diluted with water and the aqueous phase was extracted 2 x with AcOEt.
  • the combined organic phase was washed with water and brine, dried over Na 2 SO 4 , filtrated and evaporated to get 5-amino-2-(1,1,2,2,3,3,3- heptafluoropropyl)benzamide (267 mg; 0.84 mmol; 19% yield; 95.8% purity) as a brown solid.
  • Step 1 5-(cyclopent-1-en-1-yl) pyrimidin-2-amine
  • 5-bromopyrimidin-2-amine 5.0 g; 27.30 mmol; 1.0 eq.
  • (cyclopent-1-en- 1-yl) boronic acid 3.86 g; 32.76 mmol; 1.2 eq.
  • 10.0 mL ethanol and 10.0 mL water were added followed by K 2 CO 3 (11.9 g; 81.90 mmol; 3.0 eq.) and Pd(dppf)Cl 2 .
  • CH 2 Cl 2 (1.17 g; 1.37 mmol; 0.05 eq.) under nitrogen atmosphere.
  • reaction mixture was stirred for 30 min at 110 °C.
  • the reaction mixture was quenched with water at room temperature and the aqueous layer was extracted with DCM three times.
  • the combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under vacuo.
  • the residue was purified by silica gel column chromatography, eluted with DCM/MeOH (1/1) to afford 5- (cyclopent-1-en-1-yl) pyrimidin-2-amine in pure form (4.0 g; 24.34 mmol; 89% yield; 98% purity) as a yellow solid.
  • reaction solution was cooled to 5 °C, a solution of isobutyl chloroformate (72.7 ⁇ L; 0.56 mmol; 1.2 eq.) in 1.0 mL THF was added dropwise and the mixture was stirred for 30 min at 5 °C. Then a solution of 5-cyclopentylpyrimidin-2-amine (79.4 mg; 0.49 mmol; 1.0 eq.) in 5.0 mL THF was added dropwise. The reaction mixture was stirred for 1 h at 5 °C and overnight at room temperature. The reaction mixture was diluted with a 5% aqueous NaHCO 3 solution and extracted with AcOEt twice.
  • Step 1 2-(cyclopent-1-en-1-yl)-5-nitrobenzonitrile 2-Bromo-5-nitrobenzonitrile (4.0 g; 17.1 mmol; 1.0 eq.), 1-cyclopenteneboronic acid pinacol ester (5.24 g; 25.6 mmol; 1.5 eq.), potassium carbonate (7.0 g; 51.3 mmol; 3.0 eq.) and [1,1‘‘- bis(diphenylphosphino)ferrocene] dichloropalladium(II) complex with DCM (760 mg; 0.92 mmol; 0.05 eq.) were suspended in 40 mL dried 1,4-dioxane, 20 mL EtOH and 10 mL demineralized water.
  • the vial was purged with nitrogen and stirred in a microwave for 30 min at 110 °C.
  • the reaction mixture was diluted with water and extracted three times with EtOAc.
  • the combined organic layers were dried over Na 2 SO 4 , filtered and evaporated.
  • the residue purified by flash chromatography (silica gel, eluent A: n-heptane; eluent B: n-heptane/EA 8/2; gradient 1-20%) to obtain 2-(cyclopent-1-en-1-yl)-5-nitrobenzonitrile (3.3 g; 15.4 mmol; 90% yield; 100% purity) as yellow oil which crystallized.
  • the brown reaction solution was stirred for 2 h at room temperature.
  • the brown reaction solution was poured into water and stirred for 5 min.
  • the formed precipitate was collected by vacuum filtration, washed with water and dried under vacuum.
  • the obtained solid was purified by using flash chromatography (heptane/EtOAc gradient 0 - 100%) to obtain 2-cyclopentyl-5-(2-iodo-5-nitrobenzamido)benzamide (176 mg; 0.36 mmol; 77% yield; 98% purity) as a light-yellow solid.
  • the dark orange reaction suspension was stirred at 120 °C for 4 h.
  • the reaction suspension was diluted with water and extracted 3x with DCM.
  • the organic phase was filtrated over celite, washed with brine, dried over Na 2 SO 4 , filtrated over celite and evaporated.
  • the residue was purified by flash chromatographie (40 g silica gel; heptane/0 - 50% AcOEt) to get 3-fluoro-5-(1,1,2,2,3,3,3- heptafluoropropyl)pyridin-2-amine (324 mg; 1.14 mmol; 56% yield; 99% purity) a a light beige solid.
  • the experiment was stirred at rt for 1.5 h.
  • the reaction mixture was quenched with DCM/water.
  • sat. NaHCO 3 solution was added until pH 8 was reached.
  • the org. layer was separated and washed with water and brine.
  • the organic layer was dried over Na 2 SO 4 , filtered and evaporated.
  • the cooling bath was removed, and the resulting mixture was stirred for 2 h at room temperature.
  • the reaction mixture was diluted with 200 mL of DCM, and then quenched with 250 mL of water.
  • the organic phase was collected, and then washed with 2x200 mL brine, and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc /PE (0 to 45% over 40 min).
  • the flask was purged and maintained with an atmosphere of H 2 , which was connected with a tire full of H 2 (10 L, about 2 atm). The resulting mixture was stirred for 2 h at room temperature. The reaction mixture was filtered through Celite. The filter cake was washed with 2x100 mL of THF, and the combined filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc/PE (0 to 40% over 30 min).
  • the reaction mixture was diluted with DCM, washed with water, 1N aqueous HCl and brine, dried on Na 2 SO 4 , filtered then solvent was evaporated.
  • the crude was purified by chromatographic column hexane/AcOEt (85/15 to 8/2) to give the planned compound (white solid, 0.64 g, 0.166 mmol, 51% yield, 100% purity).
  • the reaction mixture was diluted with DCM, washed with water, 1N aqueous HCl and brine, dried on Na 2 SO 4 , filtered and then solvent was evaporated.
  • the crude was purified by chromatographic column hexane/AcOEt (9/1 to 8/2) to give the title compound (0.532 g, 1.62 mmol, 81% yield, 99% purity).
  • the mixture was diluted with AcOEt and H 2 O.
  • the aqueous phase was extracted 2 times with AcOEt.
  • the organic extracts were combined, washed with a saturated aqueous solution of NaHCO 3 , 1N aqueous HCl and brine and dried over Na 2 SO 4 .
  • the solvent was evaporated under vacuum and the crude was purified by flash chromatography on silica gel eluting with hexane/AcOEt (8/2) to afford the target compound as a pale beige solid (0.200 g, 0.64 mmol, 67% yield, 92% purity).
  • the mixture was diluted with AcOEt and H 2 O.
  • the aqueous phase was extracted with AcOEt.
  • the organic extracts were washed with a saturated aqueous solution of NaHCO 3 , 1N aqueous HCl and brine and dried over Na 2 SO 4 .
  • the solvent was evaporated under vacuum and the crude was purified by flash chromatography on silica gel eluting with hexane/AcOEt (8/2) to afford the target compound as a beige solid (0.085 g, 0.26 mmol, 30% yield, 93% purity).
  • the mixture was diluted with DCM and H 2 O.
  • the aqueous phase was extracted with DCM.
  • the organic extracts were combined, washed with brine and dried over Na 2 SO 4 .
  • the solvent was evaporated under vacuum and the crude was used in the next step without further purification (0.120 g, 0.26 mmol, quantitative yield, 87% purity).
  • the mixture was diluted with DCM and H 2 O.
  • the aqueous phase was extracted with DCM.
  • the organic extracts were combined, washed with brine and dried over Na 2 SO 4 .
  • the solvent was evaporated under vacuum and the crude was purified by flash chromatography on silica gel eluting with hexane/AcOEt (8/2) to afford the target compound as a beige solid (2.9 g, 9.29 mmol, 93% yield, 91% purity).
  • the reaction mixture was cooled to room temperature, the solvent was evaporated under vacuum and the crude was purified by flash chromatography on silica gel eluting with hexane/AcOEt (7/3 to 6/4) to afford the target compound as an orange crystalline solid (0.855 g, 3.39 mmol, 30% yield, 89% purity).
  • the solid was filtrated and the product was used in next step without further purification (0.833 g, 3.02 mmol, 89% yield, 88% purity).
  • reaction mixture was stirred at 100 °C for 8 h then thionyl chloride (10 mL, 136.47 mmol, 5.05 eq.) was added and the reaction mixture was stirred at 100 °C for 1 h. After cooling to room temperature solvent was removed under reduced pressure and the compound was used in the next step without further purification (6 g, 24.69 mmol, 91% yield, 60% purity).
  • the mixture was diluted with DCM and H 2 O.
  • the aqueous phase was extracted with DCM.
  • the organic extracts were washed with brine and dried over Na 2 SO 4 .
  • the solvent was evaporated under vacuum and the crude was used in the next step without further purification (0.250 g, 0.54 mmol, 89% yield, 92% purity).
  • Triazol intermediate 1 tert-butyl N-methyl-N-[2-(5-sulfanylidene-4,5-dihydro-1H-1,2,4- triazol-4-yl)ethyl]carbamate
  • Step 1 tert-butyl N-(2-isothiocyanatoethyl)-N-methylcarbamate
  • 2-(N-Boc-N-methylamino)ethylamine (2.00 g; 10.90 mmol) and DIPEA (5.56 mL, 32.71 mL) were dissolved in 13 mL anhydrous DCM.
  • Step 3 tert-butyl N-methyl-N-[2-(5-sulfanylidene-4,5-dihydro-1H-1,2,4-triazol-4- yl)ethyl]carbamate
  • tert-butyl N- ⁇ 2-[(formohydrazidomethanethioyl)amino]ethyl ⁇ -N- methylcarbamate in 12 mL dry THF (1.70 g; 5.84 mmol), further diluted with 10 mL THF and 6 mL deionized water, was added potassium carbonate (1.70 g; 11.69 mmol).
  • the resulting mixture was cooled to room temperature and quenched with I2/sodium thiosulfate solution and extracted with DCM. Product stayed in the aqueous phase.
  • the volume of theaqeuous phase was concentrated under reduced pressure and purified by chromatography (reversed phase; water/ACN/0.1% HCOOH; gradient 5-70% ACN/0.1% HCOOH) to get tert-butyl N-[3-(5-sulfanylidene-4,5-dihydro-1H-1,2,3,4-tetrazol-1- yl)propyl]carbamate (567 mg; 2.13 mmol; 44% yield; 97% purity) as a yellow oil.
  • Tetrazole intermediate 6 2-methyl-2-(5-sulfanyltetrazol-1-yl)propan-1-ol
  • steps 2 were used to get 2-methyl-2-(5-sulfanyltetrazol-1-yl)propan-1-ol.
  • Tetrazole intermediate 7 (2R)-1-(5-sulfanyltetrazol-1-yl)propan-2-ol
  • 2R (2R)-1-(5-sulfanyltetrazol-1-yl)propan-2-ol
  • Tetrazole intermediate 8 (2S)-1-(5-sulfanyltetrazol-1-yl)propan-2-ol
  • 2S (2S)-1-(5-sulfanyltetrazol-1-yl)propan-2-ol
  • Tetrazole intermediate 9 (2R)-2-(5-sulfanyltetrazol-1-yl)propan-1-ol
  • 2R (2R)-2-(5-sulfanyltetrazol-1-yl)propan-1-ol
  • 2R (2R)-2-(5-sulfanyltetrazol-1- yl)propan-1-ol
  • Tetrazole intermediate 10 1-[(2-methyl-1,3-dioxolan-2-yl)methyl]tetrazole-5-thiol
  • tetrazole intermediate 3 The same methods as in tetrazole intermediate 3 was used to get 1-[(2-methyl-1,3-dioxolan-2- yl)methyl]tetrazole-5-thiol.
  • the corresponding amine (1.0 - 4.0 eq.), HATU (1.3 - 3.0 eq.) and 4-methylmorpholine (2.5 – 6.0 eq.) were then added.
  • the reaction solution was stirred between 1 and 72 h at room temperature.
  • the reaction mixture was poured into ice-cooled water and stirred for 20 min. A precipitate was formed which was filtered off under vacuo and washed with water.
  • the crude product was purified by reversed phase chromatography to obtain the desired amides in pure form.
  • the reaction mixture was diluted with AcOEt and extracted with water two or three times. The combined aqueous layers were washed with AcOEt. The combined organic layers were dried over Na 2 SO 4 , filtered and evaporated.
  • the crude product was purified by flash column or reversed phase chromatography to obtain the desired amides in pure form.
  • the crude product was purified by reversed phase chromatography to obtain the desired amides in pure form.
  • General procedure B for amide coupling The desired nitrobenzoic acid (1.0 eq.) was dissolved in dried DMF (0.1-0.15 M). The corresponding amine (1.1 eq.), HATU (1.5 eq.) and DBU (2.0 eq.) were then added. The reaction solution was stirred between 23 and 25 h at room temperature. The reaction mixture was diluted with an aqueous 5% NaHCO 3 solution and extracted twice with AcOEt.
  • reaction solution was stirred between 2 and 20 h at room temperature.
  • the reaction mixture was then diluted with DCM, washed with 1N aqueous NaOH or a saturated aqueous solution of NaHCO 3 , with1N aqueous HCl and brine.
  • the combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and evaporated.
  • the crude product was purified by flash chromatography (hexane/AcOEt or DCM/MeOH) or preparative HPLC. The evaporated fractions were lyophilized or diluted with Et 2 O, the solid was filtered off and dried at 65 °C under vacuo to afford the desired amides in pure form.
  • the crude product was purified by flash chromatography (hexane/AcOEt or DCM/MeOH) or preparative HPLC.
  • the evaporated fractions were lyophilized or diluted with Et 2 O, the solid was filtered off and dried at 65 °C under vacuo to afford the desired amides in pure form.
  • the product was precipitated with AcOEt/MeOH, the solid was filtered off and washed with Et 2 O, dried at 65 °C under vacuo to afford the desired amides in pure form.
  • the crude product was purified by flash chromatography (hexane/AcOEt or hexane/acetone) or by reversed phase chromatography to obtain the desired amides in pure form.
  • General procedure F for amide coupling The desired nitrobenzoic acid (1.0 eq.) was dissolved in dry pyridine (20 volumes), then phosphoryl chloride (1.1 eq.) was added and the mixture was stirred for 15 min at rt. After acid chloride formation, the correspondending amine (1.0 eq.), dissolved in anhydrous DCM (15 volumes), was added and the reaction mixture was stirred at rt for 2-24 h. The mixture was diluted with DCM and extracted with water. The organic phase was dried over Na 2 SO 4 and filtered off.
  • the crude product was purified by reversed phase chromatography to obtain the desired amides in pure form.
  • General procedure A for nucleophilic substitution The starting halide or triflate (1.0 eq.) was dissolved in dry DCM or dry ACN (0.02 – 0.18 M). The corresponding thiol (1.0 – 3.7 eq.) and DIPEA (1.2 – 2.0 eq.) or TEA (2.0 eq. – 9.0 eq.) were then added.
  • the reaction solution was stirred between 1 and 20 h at temperature between 25 °C to 80 °C or was stirred under microwave irradiations between 1 and 8 h at temperature between 70 °C to 130 °C.
  • the reaction mixture was diluted with AcOEt or DCM, washed with water and brine. The combined organic layers were dried over Na 2 SO 4 , filtered and evaporated.
  • the crude product was purified by flash chromatography (hexane/AcOEt or DCM/MeOH) or preparative HPLC. The evaporated fractions were lyophilized or diluted with Et 2 O, the solid was filtered off and dried at 65 °C under vacuo to afford the desired amides in pure form.
  • the reaction solution was stirred for 8 h at 110 °C or was stirred under microwave irradiation between 10 min and 1 h at temperature between 80 °C to 110 °C.
  • the reaction mixture was diluted with AcOEt, washed with water and brine. The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and evaporated.
  • the crude product was purified by flash chromatography (hexane/AcOEt). The evaporated fractions were lyophilized or diluted with Et 2 O, the solid was filtered off and dried at 65 °C under vacuo to afford the desired amides in pure form.
  • Example 1 N-(4,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-2-[(1-methyl-1H- 1,2,3,4-tetrazol-5-yl)sulfanyl]-5-nitrobenzamide 2-[(1-methyl-1H-1,2,3,4-tetrazol-5-yl)sulfanyl]-5-nitrobenzoic acid (24 mg; 0.09 mmol; 1.0 eq.) was dissolved in 2 mL DMF.
  • the beige suspension was poured into water and stirred for 5 min.
  • the formed precipitate was collected by vacuum filtration, washed with water and dried under vacuum to get 2-[(1-methyl-1H-1,2,3,4-tetrazol-5-yl)sulfanyl]-5-nitro-N-[3-(propan-2-yl) phenyl] benzamide (45 mg; 0.11 mmol; 76% yield; 96% purity) as a beige solid.
  • the vial was purged with argon and tris(dibenzylideneacetone)dipalladium(0) (5.4 mg; 0.01 mmol; 0.05 eq.) and xantphos (6.8 mg; 0.01 mmol; 0.1 eq.) were added.
  • the vial was stirred in a microwave for 30 min at 110 °C.
  • Step 1 2-[(1-methyl-1H-1,2,3,4-tetrazol-5-yl)sulfanyl]-5-nitrobenzoyl chloride 2-[(1-Methyl-1H-1,2,3,4-tetrazol-5-yl)sulfanyl]-5-nitrobenzoic acid (220 mg; 0.78 mmol; 1.0 eq.) were suspended in 5 mL thionyl chloride and stirred at 70 °C for 2.5 h.
  • Step 2 2-[(1-methyl-1H-1,2,3,4-tetrazol-5-yl)sulfanyl]-5-nitro-N-[5-(propan-2-yl) pyridin- 2-yl] benzamide 2-[(1-Methyl-1H-1,2,3,4-tetrazol-5-yl)sulfanyl]-5-nitrobenzoyl chloride (121 mg; 0.38 mmol; 1.1 eq.) was dissolved in 3.5 mL dry DCM.
  • the reaction mixture was cooled to 0 °C and a solution of 2-amino-5-isopropylpyridine (50 mg; 0.35 mmol; 1.0 eq.) in 1.5 mL dry DCM and dry pyridine (56 ⁇ L; 0.70 mmol; 2.0 eq.) was added dropwise. The yellow suspension was stirred overnight at room temperature. The precipitate was filtered off and was washed with DCM.
  • the filtrate was purified by column chromatography (silica gel; n-heptane/0 - 70% EtOAc) to obtain 2-[(1- methyl-1H-1,2,3,4-tetrazol-5-yl)sulfanyl]-5-nitro-N-[5-(propan-2-yl)pyridin-2-yl]benzamide (30 mg; 0.07 mmol; 21% yield; 100% purity) as an off-white solid.
  • the colorless solution was stirred for 2 h at 5 °C and at room temperature for 3 days.
  • the mixture was diluted with DCM and was extracted twice with an aqueous sodium thiosulfate solution.
  • the organic phases were dried over Na 2 SO 4 , filtered and reduced to dryness.
  • the residue was purified by chromatography (C18; water + 0.1% HCOOH/gradient 5 - 80% ACN + 0.1% HCOOH) to obtain N-(4- cyclopentyl-2-fluorophenyl)-2-[(1-methyl-1H-1,2,3,4-tetrazol-5-yl)sulfinyl]-5-nitrobenzamide (12 mg; 0.02 mmol; 36% yield; 98% purity) as a white solid.
  • the reaction mixture was stirred overnight at room temperature under nitrogen atmosphere.
  • the reaction mixture was diluted with water and extracted with DCM four times.
  • the combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • the crude product was purified by chromatography (C18; water (10 mmol/L NH 4 HCO 3 + 0.1% NH 4 OH)/55 -85% ACN) to obtain N-(4-cyclopentylphenyl)-2-[(1-cyclopropyl- 1,2,3,4-tetrazol-5-yl)sulfanyl]-5-nitrobenzamide (8.2 mg; 0.02 mmol; 13% yield; 98% purity) as an off-white solid.
  • reaction mixture was stirred overnight at room temperature under nitrogen atmosphere, concentrated under reduced pressure and purified by chromatography (C18; water(10 mmol/L NH 4 HCO 3 + 0.1% NH 4 OH)/35 - 65% ACN) to obtain N-(4-isopropylphenyl)-3-methyl-2-[(1-methyl-1,2,3,4-tetrazol-5-yl)sulfanyl]-5-nitrobenzamide (2.8 mg; 0.01 mmol; 7% yield; 100% purity) as an off-white solid.
  • reaction mixture was stirred for 2 h at room temperature under nitrogen atmosphere, the solvent was removed under vacuum and the residue was purified by automated silica gel column chromatography, eluted with PE/AcOEt (1/1) to afford N-(5-cyclopentylpyrimidin-2-yl)-5-nitro- 2-(thiophen-2-ylsulfanyl)benzamide was obtained as a white solid (41 mg; 0.10 mmol; 11% yield; 100% purity).
  • the residue was purified first by automated flash chromatography (heptane/AcOEt; gradient: 0-50% AcOEt) followed by reversed phase chromatography (preparative HPLC (sunfire RP18; water + 0.1% TFA/ACN + 0.1% TFA; gradient: 5-100% ACN). Acetonitrile was removed and to the residual water phase a NaHCO 3 aqueous solution was added to adjust the pH to basic. The aqueous layer was extracted with DCM three times.
  • the vial was purged with argon, then xantphos (5.2 mg; 0.01 mmol; 0.1 eq.) and tris(dibezylideneacetone)dipalladium(0) (4.1 mg; 0.004 mmol; 0.05 eq.) were added.
  • the vial was closed with the septum and stirred in a microwave reactor for 30 min at 110 °C.
  • N-(5-cyclopentylpyrimidin-2-yl)-2-[(6- methylpyridin-2-yl)sulfanyl]-5-nitrobenzamide was obtained as a yellow solid (48 mg; 0.11 mmol; 41% yield; 99% purity).
  • reaction mixture was stirred in an open vial at 90 °C for 2 h and concentrated under reduced pressure.
  • residue was then diluted with aqueous 5% NaHCO 3 solution and extracted with AcOEt twice.
  • the combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and evaporated under reduced pressure.
  • reaction mixture was stirred in a closed vial at 80 °C for 30 min.
  • the reaction suspension was filtered off and evaporated under reduced pressure.
  • the residue was dissolved in EtOAc and extracted once with aqueous 5% NaHCO 3 solution and once with brine.
  • the organic layer was dried over anhydrous Na 2 SO 4 , filtered and evaporated under reduced pressure.
  • Step 1 4- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ -4H-1,2,4-triazole-3-thiol
  • mercaptotriazole (1.00 g; 9.39 mmol; 1.0 eq.) in 10.0 mL THF
  • 60% NaH (0.75 g; 18.79 mmol; 2.0 eq.
  • SEM-Cl (3.13 g; 18.77 mmol; 2.0 eq.) was added in portions at 0 °C.
  • the reaction mixture was stirred overnight at room temperature and the reaction was quenched by the addition of iced water at room temperature.
  • TEA 0.21 mmol; 300 mol%; 30 ⁇ lL
  • 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene 0.01 mmol; 10 mol%; 4 mg
  • tris(dibenzylideneacetone)dipalladium 5 mol%; 3 mg
  • TEA 0..99 mmol; 300 mol%; 137 ⁇ L
  • the vial was flushed with argon (approx. 2 min) and then 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (0.03 mmol; 10 mol%; 19 mg) and tris((1E,4E)-1,5-diphenylpenta-1,4-dien- 3-one)dipalladium (0.02 mmol; 5 mol%; 15 mg) were added.
  • the vial was closed with a septum and heated in a microwave reactor (100 °C; 30 min).
  • the vial was flushed with argon (approx. 2 min) and then 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.01 mmol; 10 mol%; 6 mg) and tris(dibenzylideneacetone)dipalladium(0) (0.01 mmol; 5 mol%; 5 mg) were added. The experiment was evaporated to residue.
  • reaction solution was evaporated and purified by preparative chromatography (C18; water 0.1% TFA/5 - 100% acetonitrile TFA 0.1%) to get N-[3-fluoro-5-(1,1,2,2,3,3,3- heptafluoropropyl)pyridin-2-yl]-2- ⁇ [4-(2-hydroxyethyl)-4H-1,2,4-triazol-3-yl]sulfanyl ⁇ -5- nitrobenzamide (8 mg; 26%; white solid).
  • Step 1 tert-butyl N- ⁇ 2-[3-( ⁇ 2-[(4-cyclopentyl-2,6-difluorophenyl)carbamoyl]-4- nitrophenyl ⁇ sulfanyl)-4H-1,2,4-triazol-4-yl]ethyl ⁇ -N-methylcarbamate Using the general precedure of the Buchwald reaction afforded tert-butyl N- ⁇ 2-[3-( ⁇ 2-[(4- cyclopentyl-2,6-difluorophenyl)carbamoyl]-4-nitrophenyl ⁇ sulfanyl)-4H-1,2,4-triazol-4-yl]ethyl ⁇ - N-methylcarbamate (95 mg; 0.15 mmol; 49% yield; 96% purity) as a beige solid.
  • TEA 80 ⁇ L; 0.58 mmol; 4 eq.
  • Xantphos 17 mg; 0.03 mmol; 0.2 eq.
  • tris(dibenzylideneacetone)dipalladium(0) 13 mg; 0.01 mmol; 0.1 eq.
  • the reaction mixture which appears as a beige-brown suspension, was cooled to 0 °C and POCl 3 (0.027 g, 0.18 mmol, 1.1 eq.) was slowly added. After 10 min the reaction turned to a pale-yellow solution; water was then added to quench the reaction. The mixture was extracted with DCM 3 times, organic layers were combined and washed with a 10% aqueous solution of citric acid and brine, dried on Na 2 SO 4 and evaporated. The crude was purified by column chromatography using hexane/AcOEt (8/2 to 3/7) to afford the target product as a white solid (0.031g, 0.07 mmol, 36% yield, 100% purity).
  • the reaction mixture (a beige-brown suspension) was cooled to 0 °C and POCl 3 (0.045 g, 0.29 mmol, 1.1 eq.) was slowly added. After 15 min a formation of an orange solution was observed and water was added to quench the reaction. The mixture was extracted with DCM 3 times, organic layers were combined and washed with a solution of 10% aqueous solution of citric acid and brine, dried on Na 2 SO 4 and evaporated. The product was precipitated with DCM/Et 2 O (1/1) to afford the title compound as a pale beige solid (0.076 g, 0.169 mmol, 63% yield, 96% purity).
  • N-(4-cyano-5-cyclopentylpyridin-2-yl)-2-[(1-methyl-1H-1,2,3,4-tetrazol-5- yl)sulfanyl]-5-nitrobenzamide (0.06 g, 0.13 mmol, 1 eq.)
  • acetaldehyde oxime (0.159 g, 2.66 mmol, 20 eq.)
  • indium(III) chloride 0.003 g, 0.01 mmol, 0.1 eq.
  • toluene 1.8 mL
  • the reaction mixture which appears as a beige-brown suspension, was then cooled to 0 °C and POCl 3 (0.015 g, 0.1 mmol, 1.1 eq.) was slowly added. The formation of an orange-red solution was then observed and after 15 min water was added to quench the reaction. The mixture was extracted with DCM 3 times, organic layers were combined and washed with a 10% aqueous solution of citric acid and brine, dried on Na 2 SO 4 and evaporated. The product was purified by column chromatography using hexane/acetone (8/2 to 6/4) to afford the title compound as a pale orange solid (0.01 g, 0.022 mmol, 24% yield, 92% purity).
  • reaction mixture was diluted with DCM, washed with saturated aqueous NaHCO 3 solution, 1N aqueous HCl, brine and then dried over Na 2 SO 4 , filtered. Finally, the solvent was evaporated and the crude was purified by chromatographic column hexane/AcOEt (6/4 to 2/8) to give the title compound as white solid (0.074 g, 0.17 mmol, 49% yield, 99.1% purity).
  • the reaction mixture was diluted with DCM, washed with 1N aqueous NaOH, 1N aqueous HCl and brine then dried on Na 2 SO 4 , filtered and the solvent evaporated.
  • the crude was purified by column chromatography using hexane/AcOEt (6/4 to 3/7) to give the target compound as light orange solid (0.023 g, 0.05 mmol, 33% yield, 94% purity).
  • reaction mixture was diluted with DCM, washed with saturated aqueous solution of NaHCO 3 , brine and dried on Na 2 SO 4 , filtered then solvent was evaporated.
  • the crude was purified by chromatographic column using hexane/AcOEt (8/2 to 4/6) to give the title compound as solid (0.025 g, 0.06 mmol, 40% yield, 95% purity).
  • the reaction mixture was diluted with DCM, washed with saturated aqueous solution of NaHCO 3 , 0.5N aqueous HCl, brine and dried on Na 2 SO 4 , filtered then solvent was evaporated.
  • the crude was purified by chromatographic column hexane/AcOEt (7/3 to 1/1) to give the title compound as light-yellow solid (0.070 g, 0.15 mmol, 83% yield, 91% purity).
  • the reaction mixture (a solution) was cooled to 0 °C and POCl 3 (0.009 g, 0.06 mmol, 1.1 eq.) was slowly added. After 15 min water was added to quench the reaction, resulting in an orange yellow suspension. The mixture was then extracted with DCM 3 times, organic layers were combined and washed with a 10% aqueous solution of citric acid and brine, dried on Na 2 SO 4 and evaporated. The resulting isonitrile was purified by chromatographic column using hexane/AcOEt (7/3 to 4/6) and by trituration with MeOH to obtain the title compound as a white solid (0.004 g, 0.008 mmol, 17% yield, 91% purity).
  • the reaction mixture (a yellow solution) was cooled to 0 °C and POCl3 (0.011 g, 0.07 mmol, 1.1 eq.) was slowly added. After 10 min water was added to quench the reaction, resulting in a yellow suspension. The mixture was then extracted with DCM 3 times, organic layers were combined and washed with a 10% aqueous solution of citric acid and brine, dried on Na 2 SO 4 and evaporated. The crude was purified by chromatographic column hexane/AcOEt (9/1 to 6/4) to give the target compound as a white solid (0.017 g, 0.037 mmol, 63% yield, 92% purity).
  • the solvent was evaporated under reduced pressure and, after dilution with AcOEt, the organic phase was washed with H 2 O and the aqueous layer was extracted with AcOEt. The combined organic layers were washed with a saturated aqueous solution of NaHCO 3 , H 2 O and brine. All the organics were dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • the crude was purified by flash chromatography on silica gel eluting with hexane/AcOEt (8/2) to afford the target compound as a white solid (0.093 g, 0.21 mmol, 59% yield, 100% purity).
  • the solvent was evaporated under reduced pressure and, after dilution with AcOEt, the organic phase was washed with H 2 O and the aqueous layer was extracted with AcOEt. The combined organic layers were washed with a saturated aqueous solution of NaHCO 3 , H 2 O and brine. All the organics were dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • the crude was purified by flash chromatography on silica gel eluting with hexane/AcOEt (8/2) to afford the target compound as a pale-yellow solid (0.048 g, 0.12 mmol, 68% yield, 100% purity).

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Abstract

La présente invention concerne de nouveaux composés thiophénoliques (I) qui sont utiles dans le traitement de maladies prolifératives et/ou hyper-prolifératives. De préférence, les composés de la présente invention présentent une activité inhibitrice contre la protéine hélicase Werner (WRN, RECQL2) et sont donc utiles dans la thérapie ou le traitement du cancer. En outre, l'invention concerne l'utilisation des composés selon l'invention pour inhiber l'activité d'une ou de plusieurs hélicases, y compris de préférence une hélicase Werner (WRN) et une composition pharmaceutique comprenant de tels composés. Formule (I).
PCT/EP2023/070611 2022-08-01 2023-07-25 Nouveaux composés thiophénoliques à substitution spécifique WO2024028169A1 (fr)

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