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WO2025113806A1 - Dérivés de thiophène et de thiazole utilisés en tant qu'inhibiteurs de wip1 - Google Patents

Dérivés de thiophène et de thiazole utilisés en tant qu'inhibiteurs de wip1 Download PDF

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Publication number
WO2025113806A1
WO2025113806A1 PCT/EP2023/083804 EP2023083804W WO2025113806A1 WO 2025113806 A1 WO2025113806 A1 WO 2025113806A1 EP 2023083804 W EP2023083804 W EP 2023083804W WO 2025113806 A1 WO2025113806 A1 WO 2025113806A1
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Prior art keywords
amino
methyl
mmol
methylpyridin
chloro
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Inventor
Leonardus Wilhelmus Adriaan Van Berkom
Harald Matheas Henricus Gerardus ALBERS
Gruson KLAASSE
Rutger Henk Adriaan Folmer
Johan Jacobus Nicolaas VEERMAN
Gerhard Mueller
Roy Petrus Maria STORCKEN
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Anavo Therapeutics BV
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Anavo Therapeutics BV
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • C07D417/14—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 three or more hetero rings

Definitions

  • the present invention relates to compounds of formula (I) and salts, stereoisomer, tautomer, or N-oxide thereof that are useful as modulator or inhibitor of Wipl (PPM1D) phosphatase.
  • the present invention further relates to the compound of formula (I) for use as a medicament and to a pharmaceutical composition comprising said compounds.
  • the wild-type p53-induced phosphatase 1 (Wipl; also referred to as serine/threonine phosphatase PPM1D, protein phosphatase 2C delta (PP2C ⁇ T), PPMID, or IDDGIP) is a negative regulator of the tumor suppressor p53 and is overexpressed in several human (solid) tumors.
  • the Wipl gene (also known as PPMID gene) is located at 17q23. The expression of this gene is induced in a p53-dependent manner in response to various environmental threats, and plays an important role in homeostatic down-regulation of various stress response, cell cycle regulation, DNA damage repair and tumor cell metabolism. At present, Wipl has particularly been found to be amplified and overexpressed in various (human) tumors and is currently considered to be an oncogene.
  • Wipl is a member of the PP2C family of Ser/Thr protein phosphatase that are dependent on Mg 2+ or Mn 2+ for their catalytic activity and can be induced by various DNA damaging treatments including ionizing or UV irradiation in a P53 dependent manner (Fiscel la et al. PNAS 94, 6048-6053 (1997)). Upon its induction, Wipl acts upon multiple effectors of the DNA damage response pathway to dephosphorylate and consequently inactivate them.
  • UNG2 Li et al., Molecular Cell 15, 621-634 (2004)
  • MDM2 Li et al., Cancer Cell 12, 342-354 (2008)
  • MDMX Xinna et al., Journal of Biological Chemistry 281, 24847-24862 (2009)
  • ATM Shreeram et al., Journal of Experimental Medicine 203, 2793-2799 (2006)
  • yH2AX Choa et al., Cancer Research 70, 4112-4122 (2010)
  • p38MAPK Bulavin et al., Nature Genetics 36, 343-350 (2004)
  • Chk2 Flujimoto et al., Cell Death and Differentiation 13, 1170-1180 (2006)
  • KPNA2 P. Wang et al, .J. Cell. Biochem. (2019)
  • Chkl and p53 Li et al., Genes and Development 19, 1162-1174 ( 2005)
  • Wipl-/- mice also demonstrated tumor-resistance to both induced tumor models, using infection with MMTV driven ErbB2 or HRAS, as well as a decreased incidence of spontaneous leukemias and sarcomas. Similarly, Wipl-/- mice were relatively resistant to Ep-Myc induced lymphomas (Shreeram et al., Journal of Experimental Medicine 203, 2793-2799 (2006)).
  • Wipl Overexpression of Wipl is reported to result in delay or suppression of base-excision repair by inhibition of UNG2 and P53. Similarly, its overexpression suppresses DNA double- strand-break repair by inhibition of the ATM response, inhibiting repair by both homologous recombination and non-homologous end joining.
  • Wipl has been reported to elevate the activity of multiple stress response pathways, resulting in elevated levels of phospho-p38, phospho-p53(S15), p53 response genes p21/Waf, pl6INKAA, and ARF (Bulavin et al., Nature Genetics 36, 343-350 (2004)), and elevated y H2AX and DNA damage-associated nuclear foci (Moon et al., Journal of Biological Chemistry 285, 12935-1294 7 (2010)). Further, it is reported that Wipl overexpression predicts poor prognosis in esophageal squamous cell carcinoma ESCC (K. Li, Y. Liu et al., Pathol. Oncol. Res.: POR (2016)).
  • Wipl has also been proposed to promote tumorigenesis in multiple cancers by suppressing the regulatory activity of a host of its tumor suppressor substrates.
  • Amplification of the Wipl/PPMID gene locus on 17q23 has been reported in breast cancer (Li et al., Nature Genetics 31, 133-134 (2002)), ovarian clear cell carcinoma (Hirasawa et al., Clinical Cancer Research 9, 1995-2004 (2003)), neuroblastoma (Saito-Ohara et al., Journal of Experimental Medicine 203, 2793-2799 (2003)), and pancreatic adenocarcinoma (Loukopoulos et al., Cancer Science 98, 392-400 (2007)).
  • Wipl gene mutation exists in colon cancer, which lead to the persistent suppression of p53 and the occurrence of tumors (P. Kleiblova et al., J. Cell Biol., 201 (4), 511-521 (2013)).
  • Wipl mutations were associated with hematological diseases such as myelodysplastic syndrome, leukemia and lymphoma (M. Xie et al., Nat. Med., 20 (12), 1472-1478 (2014)), observed in a 3-year-old patient with glioblastoma multiforme (A.
  • Wipl can be expressed in lung cancer tissues and can also mediate the regulation of amyloid protein-binding protein 2 APPBP2 on lung cancer tissues as an intermediate molecule of pathway. Gong et al. observed an ectopic expression of APPBP2, Wipl and SPOP in human NSCLC tissues (H. Gong et al., EBioMedicine, 44 138- 149 (2019)).
  • Wipl is a target molecule for bladder cancer treatment (W. Wang et al., Braz. J. Med. Biol. Res., 47 (12) 1044-1049 (2014)).
  • Wipl mutations in Wipl are associated with multiple myeloma (Mouhieddine et al., Nat Commun., 11(1) (2020)). Wang et al. discloses that Wipl also has an important roles in cervical cancer (Oncol Res., 22(4) 225-233 (2014) and Zhang at al. report that Wipl regulates the proliferation and invasion of nasopharyngeal carcinoma (Tumour Biol., 35(8) 7651-7 (2014)).
  • Wipl is associated with osteosarcoma, Ewing's sarcoma (He et al., Eur Rev Med Pharmacol Sci., 25(1) 78-85 (2021), Long et al., J Cell Biochem., 120(4) 5652- 566 (2019)), Wilm’s tumor (Saliba et al., Pediatr Dev Pathol., 23(2) 167-171 (2020)), mesothelioma (Yu et al., Aging (Albany NY), 13(17) 21294-21308 (2021)), and melanoma (Wu et al., Br J Cancer, 118(4) 495-508 (2016)).
  • Wipl is associated with the treatment of amyotrophic lateral sclerosis (CN109876143A) and individual allergic asthma (CN105727295A), as well as with the regulation of the adipogenic differentiation capacity of mesenchymal stem cells (MSCs) (CN111118046A).
  • MSCs mesenchymal stem cells
  • compounds modulating or inhibiting Wipl are useful for treating one or more diseases such as cancer, pre-cancerous syndromes, autoimmune conditions, and neurological diseases.
  • Cancers may be in the form of solid tumors such as sarcomas, carcinomas, and lymphomas or in the form of liquid tumors, e.g. leukemia.
  • Compounds modulating or inhibiting Wipl are particularly useful for the treatment of amyotrophic lateral sclerosis, attention deficit hyperactivity disorder, autism, Bannayan- Zonana syndrome, bladder cancer, blood cancer, bone cancer, breast cancer (e.g.
  • breast cancer triple negative breast cancer (TNBC), and HER2+ breast cancer
  • brain cancer cervical cancer, colorectal cancer, Cowden disease, endometrial cancer, ependymoma, esophagus cancer, Ewing's sarcoma, gastric cancer, head and neck cancer, individual allergic asthma, kidney cancer, Lhermitte-Duclos disease, lung cancer, liver cancer, lymphoma, medulloblastoma, melanoma, mesothelioma, nasopharyngeal carcinoma, neuroblastoma, neurofibromatosis, ovarian cancer, osteosarcoma, pancreatic cancer, prostate cancer, Rhabdomyosarcoma, thyroid cancer, urothelial cancer, and Wilm's tumor.
  • TNBC triple negative breast cancer
  • HER2+ breast cancer brain cancer
  • cervical cancer colorectal cancer
  • Cowden disease endometrial cancer
  • ependymoma esophagus
  • Relevant blood cancers include leukemia, lymphoma and multiple myeloma.
  • Relevant leukemia include acute lymphocytic leukemia (ALL), Acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), and myelodysplastic syndromes (MDS).
  • ALL acute lymphocytic leukemia
  • AML Acute myeloid leukemia
  • CLL chronic lymphocytic leukemia
  • CML chronic myeloid leukemia
  • MDS myelodysplastic syndromes
  • AML AML.
  • Relevant brain cancers include glioblastoma, oligodendroglioma, diffuse intrinsic pontine glioma (DIPG), meningioma. Particularly relevant is glioblastoma.
  • Relevant lung cancers include small-cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Particularly relevant is NSCLC
  • liver cancer is hepatocellular carcinoma (HCC).
  • Compounds modulating or inhibiting Wipl may be especially useful in the treatment of amyotrophic lateral sclerosis, Bannayan-Zonana syndrome, bladder cancer, bone cancer, breast cancer, inflammatory breast cancer, brain cancer, especially glioblastoma, cervical cancer, colorectal cancer, Cowden disease, endometrial cancer, ependymoma, esophagus cancer, Ewing's sarcoma, gastric cancer, head and neck cancer, kidney cancer, leukemia, especially AML, Lhermitte- Duclos disease, lung cancer, especially NSCLC and SCLC, liver cancer, especially HCC, lymphoma, medulloblastoma, melanoma, mesothelioma, neuroblastoma, ovarian cancer, osteosarcoma, pancreatic cancer, prostate cancer, Rhabdomyosarcoma, thyroid cancer, and Wilm's tumor.
  • cancer especially the treatment of Bannayan-Zonana syndrome, bladder cancer, bone cancer
  • At least one of the above objects can be achieved by the compounds of formula (I) as defined herein as well as pharmaceutical compositions comprising the same, and by the medical uses thereof.
  • the compounds of formula (I) can be used as a medicament, in particular for the treatment of one or more diseases selected from the group consisting of amyotrophic lateral sclerosis, attention deficit hyperactivity disorder, autism, Bannayan-Zonana syndrome, bladder cancer, blood cancer, bone cancer, breast cancer, inflammatory breast cancer, brain cancer, cervical cancer, colorectal cancer, Cowden disease, endometrial cancer, ependymoma, esophagus cancer, Ewing's sarcoma, gastric cancer, head and neck cancer, individual allergic asthma, kidney cancer, Lhermitte- Duclos disease, lung cancer, liver cancer, lymphoma, medulloblastoma, melanoma, mesothelioma, nasopharyngeal carcinoma, neuroblastom
  • diseases selected from the group consisting of amyotrophic lateral sclerosis, attention deficit hyperactivity disorder, autism, Bannayan-Zonana syndrome, bladder cancer, blood cancer, bone cancer
  • the present invention relates to a compound of formula (I) or a salt, stereoisomer, tautomer, or N-oxide thereof, wherein
  • X 1 is CH or N
  • L 2 is CH 2 , CH 2 CH 2 , CHOH, CHOCH 3 or absent;
  • R 1 is H, C 1 -C 4 -al kyl, C 1 -C 4 -alkoxy, or 3- to 10-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, carbocyclylmethyl, heterocyclyl, or heterocyclylmethyl, wherein the aforementioned heterocyclic rings comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R x ;
  • R 2 is 5- to 10-membered aromatic carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R Y ;
  • R 4 is H, C 1 -C 2 -al kyl, 3- to 10-membered saturated or partially unsaturated carbocyclyl or heterocyclyl, or 4- to 12-membered saturated carbobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R z ;
  • R 5 is H or C 1 -C 2 -al kyl
  • R Y is halogen, CN, C 1 -C 4 -alkyl, Cj-C alkoxy, C ⁇ C ⁇ hal oa I kyl , Cj-C/j-haloalkoxy, or Cj-C 4 - hydroxyalkyl;
  • R z is halogen, CN, OH, C 1 -C 4 -alkyl, C 1 -C 4 - ha loa I ky I , C 1 -C 4 -haloalkoxy, or CJ-C J- hydroxyal kyl; or two R z attached to the same atom form a C 1 _C 3 -alkylene chain. with the proviso that at least one of the following conditions is met:
  • a 5- or 6-membered aromatic heterocyclyl or heterocyclylmethyl wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom is independently unsubstituted or substituted with one or more, same or different substituents R x ; or
  • a 9-membered aromatic heterocyclyl wherein the aforementioned heterocyclic rings comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R x ;
  • L 2 is CHOH or CH0CH 3 .
  • the proviso applies that at least one of the following conditions is met:
  • R 1 is 5- or 6-membered aromatic heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom is independently unsubstituted or substituted with one or more, same or different substituents R x ; wherein
  • R x is F, CF 3 , or CH 3 ;
  • R z is F, CF 3 , or CH 3 ; or two R z attached to the same atom form a C 3 -alkylene chain; or
  • the proviso applies that at least one of the following conditions is met: R 1 is wherein the dotted line in each case marks the connection to the remainder of the molecule; or
  • L 2 and R 4 together form wherein the dotted line in each case marks the connection to the remainder of the molecule.
  • the proviso applies that at least one of the following conditions is met:
  • R 1 is wherein the dotted line in each case marks the connection to the remainder of the molecule;
  • L 2 and R 4 together form: wherein the dotted line marks the connection to the remainder of the molecule.
  • R 1 is wherein the dotted line in each case marks the connection to the remainder of the molecule
  • L 2 and R 4 together form: wherein the dotted line in each case marks the connection to the remainder of the molecule.
  • X 1 is N.
  • X 1 is CH.
  • L 1 is CH 2 ;
  • L 2 is CH 2 .
  • R 5 is H.
  • R 3 is H.
  • R 2 is any one of wherein the dotted line in each case marks the connection to the remainder of the molecule.
  • the compound according to formula (I) is selected from the group consisting of (S)-5-(((5-chloro-2-methylpyridin-3- yl)a min o) methyl) -N-(3 -eye Io pentyl- 1-oxo- l-(pyridin-3-ylamino) pro pan -2 -yl)th iophene -2- carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l- oxo-1 -(py rim id in -5-y lam i no) pro pan -2-yl) th iophene-2-carboxam ide, (S) -5-(((5-chloro-2- methylpyridin-3-yl)amino) methyl) -N-(3-cyclopent
  • the invention in a second aspect, relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to the first aspect and optionally a pharmaceutically acceptable carrier or excipient.
  • the invention relates to a compound according to the first aspect or a pharmaceutical composition according to the second aspect for use in medicine.
  • the invention relates to a compound according to the first aspect or a pharmaceutical composition according to the second aspect for use in the treatment of a disease selected from the group consisting of cancer, pre-cancerous syndromes, autoimmune conditions, neurological diseases, and viral disease, preferably selected from the group consisting of cancer, pre-cancerous syndromes, autoimmune conditions, and neurological diseases, more preferably selected from the group consisting of cancer, pre- cancerous syndromes, and neurological diseases.
  • a disease selected from the group consisting of cancer, pre-cancerous syndromes, autoimmune conditions, and viral disease, preferably selected from the group consisting of cancer, pre-cancerous syndromes, autoimmune conditions, and neurological diseases, more preferably selected from the group consisting of cancer, pre- cancerous syndromes, and neurological diseases.
  • the invention relates to a compound according to the first aspect or a pharmaceutical composition according to the second aspect for use in the treatment of cancer.
  • the invention relates to a compound according to the first aspect or a pharmaceutical composition according to the second aspect for use in the treatment of a disease selected from the group consisting of amyotrophic lateral sclerosis, attention deficit hyperactivity disorder, autism, Bannayan-Zonana syndrome, bladder cancer, blood cancer, bone cancer, breast cancer, inflammatory breast cancer, brain cancer, cervical cancer, colorectal cancer, Cowden disease, endometrial cancer, ependymoma, esophagus cancer, Ewing's sarcoma, gastric cancer, head and neck cancer, individual allergic asthma, kidney cancer, Lhermitte-Duclos disease, lung cancer, liver cancer, lymphoma, medulloblastoma, melanoma, mesothelioma, nasopharyngeal carcinoma, neuroblastoma, neurofibromatosis, ovarian cancer, osteosarcoma, pancreatic cancer, prostate cancer, Rhabdomyosarcom
  • the compounds according to the invention may be amorphous or may exist in one or more different crystalline states (polymorphs), which may have different macroscopic properties such as stability or show different biological properties such as activities.
  • the present invention relates to amorphous and crystalline forms of compounds of formula (I), mixtures of different crystalline states of the compounds of formula (I), as well as amorphous or crystalline salts thereof.
  • Salts of the compounds according to the invention are preferably pharmaceutically acceptable salts, such as those containing counterions present in drug products listed in the US FDA Orange Book database. They can be formed in a customary manner, e.g., by reacting the compound with an acid of the anion in question, if the compounds according to the invention have a basic functionality, or by reacting acidic compounds according to the invention with a suitable base.
  • Suitable cationic counterions are in particular the ions of the alkali metals, preferably lithium, sodium and potassium, of the alkaline earth metals, preferably calcium, magnesium and barium, and of the transition metals, preferably manganese, copper, silver, zinc and iron, and also ammonium (NH 4 + ) and substituted ammonium in which one to four of the hydrogen atoms are replaced by Cj- ⁇ -alkyl, Cj-C 4 - hyd roxya I ky I, Cj- ⁇ -alkoxy, Cj- ⁇ -alkoxy- Cj-Cj-al kyl, hydroxy-Cj- ⁇ -alkoxy-Cj- ⁇ -alkyl, phenyl or benzyl.
  • substituted ammonium ions comprise methylammonium, isopropylammonium, dimethylammonium, diisopropylammonium, trimethylammonium, tetramethylammonium, tetraethylammonium, tetra butylammonium, 2- hydroxyethylammonium, 2 -(2 -hydroxyethoxy) ethyl -ammonium, bis(2-hydroxyethyl)ammonium, benzyltrimethylammonium and benzyltriethylammonium, furthermore the cations of 1,4-piperazine, meglumine, benzathine and lysine.
  • Suitable anionic counterions are in particular chloride, bromide, hydrogensulfate, sulfate, dihydrogenphosphate, hydrogenphosphate, phosphate, nitrate, bicarbonate, carbonate, hexafluorosilicate, hexafluorophosphate, benzoate, and the anions of Cj- ⁇ -alkanoic acids, preferably formate, acetate, propionate and butyrate, furthermore lactate, gluconate, and the anions of poly acids such as succinate, oxalate, maleate, fumarate, malate, tartrate and citrate, furthermore sulfonate anions such as besylate (benzenesulfonate), tosylate (p- toluenesulfonate), napsylate (naphthalene-2-sulfonate), mesylate (methanesulfonate), esylate (ethanesulfonate), and ethanedisul
  • the compounds according to the invention may have one or more centres of chirality, including axial chirality.
  • the invention provides both, pure enantiomers or pure diastereomers, of the compounds according to the invention, and their mixtures, including racemic mixtures.
  • Suitable compounds according to the invention also include all possible geometrical stereoisomers (cis/trans isomers or E/Z isomers) and mixtures thereof.
  • E/Z- isomers may be present with respect to, e.g., an alkene, carbonnitrogen double-bond or amide group.
  • N-oxide includes any compound of the present invention which has at least one tertiary nitrogen atom that is oxidized to a N-oxide moiety.
  • substituted means that a hydrogen atom bonded to a designated atom is replaced with a specified substituent, provided that the substitution results in a stable or chemically feasible compound. Unless otherwise indicated, a substituted atom may have one or more substituents and each substituent is independently selected.
  • substituted when used in reference to a designated atom, means that attached to the atom is a hydrogen, which can be replaced with a suitable substituent.
  • substituents When it is referred to certain atoms or moieties being substituted with “one or more” substituents, the term “one or more” is intended to cover at least one substituent, e.g. 1 to 10 substituents, preferably 1, 2, 3, 4, or 5 substituents, more preferably 1, 2, or 3 substituents, most preferably 1, or 2 substituents.
  • substituents e.g. 1 to 10 substituents, preferably 1, 2, 3, 4, or 5 substituents, more preferably 1, 2, or 3 substituents, most preferably 1, or 2 substituents.
  • the organic moieties mentioned in the above definitions of the variables are - like the term halogen - collective terms for individual listings of the individual group members.
  • the prefix C n -C m indicates in each case the possible number of carbon atoms in the group.
  • alkyl denotes in each case a straight-chain or branched alkyl group having usually from 1 to 5 carbon atoms, preferably 1 to 4 carbon atoms, more preferably 1 to 3 or 1 or 2 carbon atoms. Examples of an alkyl group are methyl, ethyl, n - propyl, iso-propyl, n-butyl, 2-butyl, iso-butyl, tert-butyl, n-pentyl, 1-methylbutyl,
  • haloalkyl denotes in each case a straight-chain or branched alkyl group having usually from 1 to 4 carbon atoms, frequently 1 to 3 or 1 or 2 carbon atoms, wherein the hydrogen atoms of this group are partially or totally replaced with halogen atoms.
  • Preferred haloalkyl moieties are selected from Cj-C 4 - ha loa I ky I , more preferably from C 1 -C 3 - h a I oa I ky I or CJ-CJ- ha loa I ky I , in particular from Cj-Cj-fluoroalkyl such as fluoromethyl, difluoromethyl, trifluoromethyl, 1 -fluoroethyl, 2-f I uoroethyl, 2,2-d if I uoroethyl, 2,2,2-trif luoroethyl, pentafluoroethyl, and the like.
  • alkoxy denotes in each case a straight-chain or branched alkyl group which is bonded via an oxygen atom and has usually from 1 to 4 carbon atoms, preferably 1 to 2 carbon atoms, more preferably 1 carbon atom.
  • alkoxy group examples are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butyloxy, 2-butyloxy, iso-butyloxy, tert. -butyloxy, and the like.
  • haloalkoxy denotes in each case a straight-chain or branched alkoxy group having from 1 to 4 carbon atoms, preferably 1 to 2 carbon atoms, more preferably 1 carbon atom, wherein the hydrogen atoms of this group are partially or totally replaced with halogen atoms, in particular fluorine atoms.
  • Preferred haloalkoxy moieties include Cj-haloalkoxy, in particular Cj-fluoroalkoxy, such as trifluoromethoxy and the like.
  • hydroxyalkyl denotes in each case a straight-chain or branched alkyl group having usually from 1 to 4 carbon atoms, preferably from 1 to 3 carbon atoms and being further substituted with 1 to 5, preferably with 1 to 2 hydroxy grou ps, in particular with 1 hydroxy group.
  • the one hydroxy group is terminating the straight-chain or branched alkyl group so that the hydroxy group is bonded to an alkyl bridge, which is bonded to the remainder of the molecule.
  • hydroxyalkyl group examples include hydroxymethyl, hydroxyethyl, n-hydroxypropyl, 2-hydroxypropyl, n-hydroxybutyl, 2- hydroxybutyl, 2-hydroxy-2-methylpropyl, and n-hydroxypentyl. Hydroxymethyl, hydroxyethyl, hydroxypropyl, and hydroxybutyl, are preferred, in particular hydroxymethyl and hydroxyethyl.
  • Carbocyclic or “carbocyclyl” includes, unless otherwise indicated, in general a
  • the carbocycle may be saturated, partially or fully unsaturated, or aromatic, wherein saturated means that only single bonds are present, and partially or fully unsaturated means that one or more double bonds may be present in suitable positions, while the Huckel rule for aromaticity is not fulfilled, whereas aromatic means that the Huckel (4n + 2) rule is fulfilled.
  • Carbocylce or “carbocyclyl”, unless otherwise indicated, may therefore cover inter alia cycloalkyl, cycloalkenyl, as well as phenyl.
  • the term “carbocycle” covers cycloalkyl and cycloalkenyl groups, for example cyclopropane, cyclobutane, cyclopentane and cyclohexane rings.
  • cycloalkyl denotes in each case a monocyclic cycloaliphatic radical having usually from 3 to 10 or from 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl or cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • carbobicycle includes in general 6 to 14-membered, preferably 7- to 12-membered or 8- to 10-membered, more preferably 9- or 10-membered bicyclic rings comprising 6 to 14, preferably 7 to 12 or 8 to 10, more preferably 9 or 10 carbon atoms.
  • the carbobicycle may be saturated, partially or fully unsaturated, or aromatic, wherein saturated means that only single bonds are present, and partially or fully unsaturated means that one or more double bonds may be present in suitable positions, while the Huckel rule for aromaticity is not fulfilled, whereas aromatic means that the Huckel (4n + 2) rule is fulfilled.
  • aromatic in connection with the carbobicyclic ring means that both rings of the bicyclic moiety are aromatic, so that, e.g., 8 n electrons are present in case of a 10-membered aromatic carbobicyclic ring.
  • carbobicycle is a fused carbobicycle, which is preferably aromatic, for example naphthalene
  • heterocyclic or “heterocyclyl” includes, unless otherwise indicated, in general a 3- to 9-membered, preferably a 4- to 8-membered or 5- to 7-membered, more preferably 5- or 6-membered, in particular 6-membered monocyclic ring.
  • the heterocycle may be saturated, partially or fully unsaturated, or aromatic, wherein saturated means that only single bonds are present, and partially or fully unsaturated means that one or more double bonds may be present in suitable positions, while the Huckel rule for aromaticity is not fulfilled, whereas aromatic means that the Huckel (4n + 2) rule is fulfilled.
  • the heterocycle typically comprises one or more, e.g.
  • the heterocycle is an aromatic heterocycle, preferably a 5- or 6-membered aromatic heterocycle comprising one or more, e.g. 1, 2, 3, or 4, preferably 1, 2, or 3 heteroatoms selected from N, O and S as ring members, where S-atoms as ring members may be present as S, SO or SO 2 .
  • aromatic heterocycles are provided below in connection with the definition of “hetaryl”.
  • Hetaryls or “heteroaryls” are covered by the term “heterocycles”.
  • the saturated or partially or fully unsaturated heterocycles usually comprise 1, 2, 3, 4 or 5, preferably 1, 2 or 3 heteroatoms selected from N, O and S as ring members, where S-atoms as ring members may be present as S, SO or SO 2 .
  • S, SO or SO 2 is to be understood as follows:
  • Saturated heterocycles include, unless otherwise indicated, in general 3- to 9- membered, preferably 4- to 8-membered or 5- to 7-membered, more preferably 5- or 6- membered monocyclic rings comprising 3 to 9, preferably 4 to 8 or 5 to 7, more preferably 5 or 6 atoms comprising at least one heteroatom, such as pyrrolidine, tetrahydrothiophene, tetrahydrofuran, piperidine, tetrahydropyran, dioxane, morpholine or piperazine.
  • heteroatoms such as pyrrolidine, tetrahydrothiophene, tetrahydrofuran, piperidine, tetrahydropyran, dioxane, morpholine or piperazine.
  • heterocyclic or “heterobicyclyl” includes, unless otherwise indicated, in general 6 to 14-membered, preferably 7- to 12-membered or 8- to 10-membered, more preferably 9- or 10-membered bicyclic rings.
  • the heterobicycle may be saturated, partially or fully unsaturated, or aromatic, wherein saturated means that only single bonds are present, and partially or fully unsaturated means that one or more double bonds may be present in suitable positions, while the Huckel rule for aromaticity is not fulfilled, whereas aromatic means that the Huckel (4n + 2) rule is fulfilled.
  • aromatic means that the Huckel (4n + 2) rule is fulfilled.
  • both rings of the bicyclic moiety are aromatic, so that, e.g., 8 n electrons are present in case of a 9- or 10-membered aromatic heterobicyclic ring.
  • the heterobicycle typically comprises one or more, e.g. 1, 2, 3, or 4, preferably 1, 2, or 3 heteroatoms selected from N, 0 and S as ring members, where S-atoms as ring members may be present as S, SO or SO 2 .
  • the remaining ring members are carbon atoms.
  • heterobicycles examples include benzofuranyl, benzothienyl, indolyl, indazolyl, benzimidazolyl, benzoxathiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzoxazinyl, quinolinyl, isoquinolinyl, purinyl, 1 ,8 - na phthyridyl , pteridyl, pyrido[3,2-d] pyrimidyl, pyridoimidazolyl, triethylenediamine or quinuclidine and the like.
  • Preferred heterobicycles according to the invention are aromatic heterobicycles such as benzodiazole, benzothiazole, quinoline, and iso-quinoline.
  • heteroaryl or “heteroaryl” or “aromatic heterocycle” or “aromatic heterocyclic ring” includes monocyclic 5- or 6-membered aromatic heterocycles comprising as ring members 1, 2, 3 or 4 heteroatoms selected from N, 0 and S, where S-atoms as ring members may be present as S, SO or SO 2 .
  • 5- or 6-membered aromatic heterocycles include pyridyl (also referred to as pyridinyl), i.e. 2-, 3-, or 4-pyridyl, pyrimidinyl, i.e. 2-, 4- or 5- pyrimidinyl, pyrazinyl, pyridazinyl, i.e.
  • 5- [l,3,4]oxadiazolyl 4- or 5-(l,2,3-oxadiazol)yl, 3- or 5-(l,2,4-oxadiazol)yl, 2- or 5-(l,3,4- thiadiazol)yl, thiadiazolyl, e.g. 2- or 5-(l,3,4-thiadiazol)yl, 4- or 5-(l,2,3-thiadiazol)yl, 3- or 5- (l,2,4-thiadiazol)yl, triazolyl, e.g.
  • heterobicycles 1H-, 2H- or 3H-l,2,3-triazol-4-yl, 2H-triazol-3-yl, 1H-, 2H-, or 4H-l,2,4-triazolyl and tetrazolyl, i.e. 1H- or 2H-tetrazolyl.
  • heteroaryl further covers “aromatic heterobicycles” as defined above.
  • aryl or “aromatic carbocyclyl” preferably includes 6-membered aromatic carbocyclic rings based on carbon atoms as ring members. A preferred example is phenyl. Unless otherwise indicated, the term “aryl” further covers “aromatic carbobicycles” as defined above.
  • carbocyclylmethyl and “heterocyclylmethyl” refer to the corresponding groups, which are bonded to the remainder of the molecule via a (%-alkyl group. Preferred examples include benzyl (i.e. phenylmethyl), cyclohexylmethyl, pyridinylmethyl, and piperidinomethyl.
  • alkylene chain refers to a linking straight-chain or branched alkylene group having usually from 1 to 4 carbon atoms, e.g. 1, 2, 3, or 4 carbon atoms.
  • the alkylene group bridges a certain group to the remainder of the molecule.
  • Preferred alkylene groups include methylene (CH 2 ), ethylene (CH 2 CH 2 ), propylene (CH 2 CH 2 CH 2 ) and the like.
  • CH 2 ethylene
  • propylene CH 2 CH 2 CH 2
  • a skilled person understands that, if it is referred, e.g., to CH 2 that the carbon atom being tetravalent has two valences left for forming a bridge (-CH 2 -).
  • each carbon atom has one valence left for forming a bridge (-CH 2 CH 2 -).
  • each terminal carbon atom has one valence left for forming a bridge (-CH 2 CH 2 CH 2 -).
  • cyclic moiety can refer to any cyclic groups, which are present in the compounds of formula (I), and which are defined above, e.g., cycloalkyl, cycloalkenyl, carbocycle.
  • pharmaceutically acceptable excipient refers to compounds commonly comprised in pharmaceutical compositions, which are known to the skilled person. Examples of suitable excipients are exemplary listed below. Typically, a pharmaceutically acceptable excipient can be defined as being pharmaceutically inactive.
  • treatment is to be understood as also including the option of “prophylaxis”. Thus, whenever reference is made herein to a “treatment” or “treating”, this is to be understood as “treatment and/or prophylaxis” or “treating and/or preventing”.
  • half-life denotes the time it takes for a substance from its maximum concentration (Cmax) to half of its maximum concentration in e.g. the blood plasma and is typically abbreviated by t 1/2 .
  • Cmax maximum concentration
  • t 1/2 the half-life can be indicated as the elimination half-life, which is the time required to produce a 50% reduction in blood or plasma concentration.
  • the present invention relates in a first aspect to a compound of formula (I) wherein
  • X 1 is CH or N, and the remaining substituents are as defined above.
  • the compound of formula (I) may therefore be a compound of formula (la) or (lb) as shown below:
  • the compound of formula (I) is a compound of formula (la). In another preferred embodiment, the compound of formula (I) is a compound of formula (lb).
  • the proviso applies that at least one of the following conditions is met:
  • R 1 is (i) a 5- or 6-membered aromatic heterocyclyl or heterocyclylmethyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom is independently unsubstituted or substituted with one or more, same or different substituents R x ; or
  • a 9-membered aromatic heterocyclyl wherein the aforementioned heterocyclic rings comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R x ; wherein
  • R x is F, CF 3 , or CH 3 ;
  • R 4 is (i) cyclohexyl or cyclopentyl, wherein one or more substitutable carbon atoms in the aforementioned groups are independently substituted with one or more, same or different substituents R z ; or
  • R z is F, CF 3 , or CH 3 ; or two R z attached to the same atom form a C 3 -alkylene chain; or
  • the proviso applies that at least one of the following conditions is met:
  • R 1 is a 5- or 6-membered aromatic heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and/or S-atoms are independently oxidized or nonoxidized, and wherein each substitutable carbon or heteroatom is independently unsubstituted or substituted with one or more, same or different substituents R x ; wherein
  • R x is F, CF 3 , or CH 3 ;
  • R z is F, CF 3 , or CH 3 ; or two R z attached to the same atom form a C 3 -alkylene chain; or
  • the proviso applies that at least one of the following conditions is met: wherein the dotted line in each case marks the connection to the remainder of the molecule; or
  • L 2 and R 4 together form wherein the dotted line in each case marks the connection to the remainder of the molecule.
  • the proviso applies that at least one of the following conditions is met: R 1 is wherein the dotted line in each case marks the connection to the remainder of the molecule; or
  • L 2 and R 4 together form: wherein the dotted line marks the connection to the remainder of the molecule.
  • the proviso applies that at least one of the following conditions is met: R 1 is wherein the dotted line in each case marks the connection to the remainder of the molecule; or
  • L 2 and R 4 together form: wherein the dotted line marks the connection to the remainder of the molecule.
  • the provisos according to the invention are further il lustrated in the following compounds of formulae (Ic), (Id), (le), (If), (Ig), (Ih), and (li).
  • the compound of formula (I) is selected from the group of compounds of formulae (Ic), (Id), (le), (If), (Ig), (Ih), and (li).
  • the compound of formula (I) is a compound of formula (Ic) wherein
  • R 1A is a 5- or 6-membered aromatic heterocyclyl or heterocyclylmethyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom is independently unsubstituted or substituted with one or more, same or different substituents R x .
  • R x is halogen, CN, OH, NH 2 , C 1 -C 4 -alkyl, Cj-C alkoxy, Cj-C ⁇ i- haloa I ky I, or Cj-C 4 - hydroxyalkyl, preferably halogen, C ⁇ C ⁇ al kyl or Cj-C ⁇ i- ha loa I kyl , and in particular F, CF 3 , or CH 3 .
  • R 1A is a 5- or 6-membered aromatic heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and/or S-atoms are independently oxidized or nonoxidized, and wherein each substitutable carbon or heteroatom is independently unsubstituted or substituted with one or more, same or different substituents R x ; wherein
  • R x is halogen, OH, C 1 -C 4 -alkyl, C 1 -C 4 - ha loa I ky I, preferably F, CF 3 , or CH 3 .
  • R 1A is a 5- or 6-membered aromatic heterocyclylmethyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and/or S-atoms are independently oxidized or nonoxidized, and wherein each substitutable carbon or heteroatom is independently unsubstituted or substituted with one or more, same or different substituents R x ; wherein
  • R x is halogen, OH, C 1 -C 4 -alkyl, C 1 -C 4 - ha loa I ky I, preferably F, CF 3 , or CH 3 .
  • R 1A is wherein the dotted line in each case marks the connection to the remainder of the molecule. In a preferred embodiment, wherein the dotted line in each case marks the connection to the remainder of the molecule.
  • R 1A is wherein the dotted line in each case marks the connection to the remainder of the molecule
  • L 2 and R 4 together form: wherein the dotted line in each case marks the connection to the remainder of the molecule.
  • the compound of formula (I) is a compound of formula (Id) wherein
  • R 1B is a 9-membered aromatic heterocyclyl, wherein the aforementioned heterocyclic rings comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R x .
  • R x is halogen, CN, OH, NH 2 , C 1 -C 4 -alkyl, Cj-C alkoxy, Cj-C 4 - haloa I ky I, or Cj-C 4 - hydroxyalkyl, preferably halogen, Cj-C 4 -al kyl or Cj-C 4 - ha loa I kyl , and in particular F, CF 3 , or CH 3 .
  • R 1B is a 9-membered aromatic heterocyclyl, wherein the aforementioned heterocyclic rings comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R x ; wherein
  • R x is halogen, OH, C 1 -C 4 -alkyl, C 1 -C 4 - ha loa I ky I, preferably F, CF 3 , or CH 3 .
  • the compound of formula (I) is a compound of formula (le) wherein
  • R 4A is cyclohexyl or cyclopentyl, wherein one or more substitutable carbon atoms in the aforementioned groups are independently substituted with one or more, same or different substituents R z .
  • R 4A is cyclohexyl, wherein one or more substitutable carbon atoms in the aforementioned groups are independently substituted with one or more, same or different substituents R z , wherein
  • R z is halogen, OH, C 1 -C 4 -a I ky I , or C 1 -C 4 - ha loa I ky I ; or two R z attached to the same atom form a C Cg-alkylene chain, preferably F, CH 3 , or CF 3 .
  • R 4A is cyclopentyl, wherein one or more substitutable carbon atoms in the aforementioned groups are independently substituted with one or more, same or different substituents R z , wherein
  • R z is halogen, OH, C 1 -C 4 -al kyl, or C 1 -C 4 - ha loa I ky I ; or two R z attached to the same atom form a C 1 _C 3 -alkylene chain, preferably F, CH 3 , or CF 3 .
  • the compound of formula (I) is a compound of formula (If) wherein
  • R 4B is a 3- to 4- or 7- to 10-membered saturated carbocyclyl; wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R z .
  • R 4B is a 3- to 4-membered saturated carbocyclyl; wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R z .
  • R z is halogen, C 1 -C 4 -al kyl, or C 1 -C 4 -haloal ky; or two R z attached to the same atom form a C Cs-alkylene chain; preferably halogen or C 1 -C 4 -alkyl; or two R z attached to the same atom form a C Cg-alkylene chain.
  • R 4B is a 4-membered saturated carbocyclyl; wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R z , wherein
  • R z is C 1 -C 4 -al kyl or two R z attached to the same atom form a C Cg-alkylene chain.
  • R 4B preferably wherein the dotted line marks the connection to the remainder of the molecule.
  • the compound of formula (I) is a compound of formula (Ig) wherein R 4C is a 3- to 10-membered saturated heterocyclyl, or 4- to 12-membered saturated carbobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and/or S-atoms are independently oxidized or nonoxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R z .
  • R 4C is a 5- to 6-membered saturated heterocyclyl, wherein the aforementioned heterocyclic comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R z .
  • R 4C is a 5- to 6-membered saturated heterocyclyl, wherein the aforementioned heterocyclic comprises one oxygen heteroatoms, and wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R z .
  • R z is halogen, C 1 -C 4 -al kyl, or C 1 -C 4 -haloal ky; or two R z attached to the same atom form a C Cs-alkylene chain; preferably halogen or C 1 -C 4 -al kyl; or two R z attached to the same atom form a C ⁇ Cg-alkylene chain.
  • the com ound of formula (I) is a compound of formula (I h) wherein
  • R 4D is a 5- to 6-membered partially unsaturated carbocyclyl, wherein each substitutable carbon atom is independently unsubstituted or substituted with one or more, same or different substituents R z .
  • R 4D is a 6-membered partially unsaturated carbocyclyl, wherein each substitutable carbon atom is independently unsubstituted or substituted with one or more, same or different substituents R z .
  • R 4D is a 6-membered partially unsaturated carbocyclyl, wherein each substitutable carbon atom is independently unsubstituted or substituted with one or more, same or different substituents R z .
  • R 4D is O; wherein the dotted line marks the connection to the remainder of the molecule.
  • the compound of formula (I) is a compound of formula (li) wherein
  • R A is H or CH 3 .
  • R 1 is C 1 -C 4 -al kyl, Cj- ⁇ -alkoxy, or 3- to 10-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, carbocyclylmethyl, heterocyclyl, or heterocyclylmethyl, wherein the aforementioned heterocyclic rings comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R x .
  • R x is preferably halogen, CN, OH, NH 2 , C 1 -C 4 -alkyl, Cj-Cj-alkoxy, C 1 -C 4 -haloalkyl, or Cj-C ⁇ hydroxyalkyl, more preferably halogen, OH, C 1 -C 4 -alkyl or Cj-C ⁇ haloalkyl, and in particular F, OH, CF 3 , CH 3 , or OCH 3 .
  • R 1 is C 1 -C 4 -alkyl or 3- to 10-membered saturated or aromatic carbocyclyl, carbocyclylmethyl, heterocyclyl, or heterocyclylmethyl, wherein the aforementioned heterocyclic rings comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R x .
  • R 1 is 3- to 10-membered aromatic heterocyclyl or heterocyclylmethyl, wherein the aforementioned heterocyclic rings comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R x .
  • a 5- or 6-membered aromatic heterocyclyl or heterocyclylmethyl wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom is independently unsubstituted or substituted with one or more, same or different substituents R x ; or
  • a 9-membered aromatic heterocyclyl wherein the aforementioned heterocyclic rings comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R x .
  • R 1 is a 5- or 6-membered aromatic heterocyclyl or heterocyclylmethyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom is independently unsubstituted or substituted with one or more, same or different substituents R x .
  • R x is preferably halogen, CN, OH, NH 2 , C 1 -C 4 -a I ky I , Cj-C alkoxy, C 1 -C 4 -haloalkyl, or Cj-C/j-hydroxyalkyl, more preferably halogen, C ⁇ C ⁇ alkyl or Cj-C 4 - haloalkyl, and in particular F, CF 3 , or CH 3 .
  • R 1 is a 5- or 6-membered aromatic heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and/or S-atoms are independently oxidized or nonoxidized, and wherein each substitutable carbon or heteroatom is independently unsubstituted or substituted with one or more, same or different substituents R x ; wherein
  • R x is halogen, OH, C 1 -C 4 -alkyl, C 1 -C 4 - ha loa I ky I, preferably F, CF 3 , or CH 3 .
  • R 1 is a 5- or 6-membered aromatic heterocyclylmethyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and/or S-atoms are independently oxidized or nonoxidized, and wherein each substitutable carbon or heteroatom is independently unsubstituted or substituted with one or more, same or different substituents R x ; wherein
  • R x is halogen, OH, C 1 -C 4 -alkyl, C 1 -C 4 - ha loa I ky I, preferably F, CF 3 , or CH 3 .
  • R 1 is wherein the dotted line in each case marks the connection to the remainder of the molecule.
  • R 1 is wherein the dotted line in each case marks the connection to the remainder of the molecule
  • L 2 and R 4 together form: wherein the dotted line in each case marks the connection to the remainder of the molecule.
  • R 1 is a 9-membered aromatic heterocyclyl, wherein the aforementioned heterocyclic rings comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R x .
  • R x is preferably halogen, CN, OH, NH 2 , C 1 -C 4 -alkyl, Cj-C alkoxy, C 1 -C 4 -haloalkyl, or Cj-C/j-hydroxyalkyl, more preferably halogen, C 1 -C 4 -alkyl or Cj-C 4 - haloalkyl, and in particular F, CF 3 , or CH 3 .
  • R 1 is a 9-membered aromatic heterocyclyl, wherein the aforementioned heterocyclic rings comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R x ; wherein
  • R x is halogen, OH, C 1 -C 4 -alkyl, C 1 -C 4 - ha loa I ky I, preferably F, CF 3 , or CH 3 .
  • L 2 and R 4 together form: wherein the dotted line in each case marks the connection to the remainder of the molecule.
  • R 4 is C 1 -C 2 -alkyl, 3- to 10-membered saturated or partially unsaturated carbocyclyl or heterocyclyl, or 4- to 12-membered saturated carbobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R z .
  • R z is preferably halogen, OH, Cj- ⁇ -alkyl, or C 1 -C 4 - ha loa I ky I ; or two R z attached to the same atom form a C Cg-alkylene chain, more preferably F, OH, CH 3 , or CF 3 ; or two R z attached to the same atom form a C 1 _C 3 -alkylene chain.
  • R 4 is Cj-02-alkyl.
  • R 4 is 3- to 6-membered saturated or partially unsaturated carbocyclyl or heterocyclyl, or 4- to 12-membered saturated carbobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R z .
  • R 4 I S (i) cyclohexyl or cyclopentyl, wherein one or more substitutable carbon atoms in the aforementioned groups are independently substituted with one or more, same or different substituents R z ; or
  • R 4 is cyclohexyl or cyclopentyl, wherein one or more substitutable carbon atoms in the aforementioned groups are independently substituted with one or more, same or different substituents R z .
  • R z is preferably halogen, C 1 -C 4 -al kyl, or Cj-C 4 - haloa I ky I ; or two R z attached to the same atom form a C 1 _C 3 -alkylene chain, more preferably F, CH 3 , or CF 3 .
  • R 4 is cyclohexyl, wherein one or more substitutable carbon atoms in the aforementioned groups are independently substituted with one or more, same or different substituents R z , wherein
  • R z is halogen, C 1 -C 4 -al kyl, or C 1 -C 4 -haloal kyl; or two R z attached to the same atom form a C 1 _C 3 -alkylene chain, preferably F, CH 3 , or CF 3 .
  • R 4 is cyclopentyl, wherein one or more substitutable carbon atoms in the aforementioned groups are independently substituted with one or more, same or different substituents R z , wherein
  • R z is halogen, C 1 -C 4 -al kyl, or C 1 -C 4 -haloal kyl; or two R z attached to the same atom form a C 1 _C 3 -alkylene chain, preferably F, CH 3 , or CF 3 .
  • R 4 is a 3- to 4- or 7- to 10-membered saturated carbocyclyl; wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R z .
  • R z is preferably halogen, C 1 -C 4 -al kyl, or Cj-C 4 - haloa I ky I ; or two R z attached to the same atom form a C Cg-alkylene chain, more preferably halogen or Cj-C 4 - al kyl; or two R z attached to the same atom form a C Cg-alkylene chain, and in particular F or CH 3 ; or two R z attached to the same atom form a C 1 _C 3 -alkylene chain.
  • R 4 is a 3- to 4-membered saturated carbocyclyl; wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R z .
  • R 4 preferably wherein the dotted line marks the connection to the remainder of the molecule.
  • R 4 is a 4-membered saturated carbocyclyl; wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R z , wherein
  • R z is halogen or C 1 -C 4 -al kyl; or two R z attached to the same atom form a C 1 _C 3 -alkylene chain, preferably C 1 -C 4 -al kyl or two R z attached to the same atom form a C r C 3 - alkylene chain.
  • R 4 is a 3- to 10-membered saturated heterocyclyl, or 4- to 12-membered saturated carbobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclic or heterobicyclic ring comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and/or S-atoms are independently oxidized or nonoxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R z .
  • R z is preferably halogen, C 1 -C 4 -alkyl, or Cj-C 4 - ha loa I ky; or two R z attached to the same atom form a C Cg-alkylene chain; more preferably halogen or Cj-C 4 - alkyl; or two R z attached to the same atom form a C Cg-alkylene chain.
  • R 4 is a 5- to 6-membered saturated heterocyclyl, wherein the aforementioned heterocyclic comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R z .
  • R 4 is a 5- to 6-membered saturated heterocyclyl, wherein the aforementioned heterocyclic comprises one oxygen heteroatom, and wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R z .
  • R 4 is wherein the dotted line marks the connection to the remainder of the molecule.
  • R 4 is a 5- to 6-membered partially unsaturated carbocyclyl, wherein each substitutable carbon atom is independently unsubstituted or substituted with one or more, same or different substituents R z .
  • R 4 is a 6-membered partially unsaturated carbocyclyl, wherein each substitutable carbon atom is independently unsubstituted or substituted with one or more, same or different substituents R z .
  • R 4 is 3- to 10-membered, preferably 4-to 6-membered, saturated carbocyclyl, wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R z .
  • X 1 is N.
  • X 1 is CH.
  • L 1 is CH 2 , CHCH 3 , or CHCF 3 , preferably CH 2 .
  • L 2 is CH 2 , CHOH, or CHOCH 3 .
  • L 2 is CH 2 .
  • L 2 is CHOH or CHOCH 3 .
  • L 1 is CH 2 ;
  • L 2 is CH 2 .
  • L 1 is CH 2 ;
  • L 2 is CH 2 .
  • R 2 is a 5- to 6-membered aromatic carbocyclyl or heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R Y .
  • R Y is preferably halogen, C 1 -C 4 -alkyl, C ⁇ -Cs- hal oa I ky I , Cj- ⁇ -haloalkoxy, or Cj-C hydroxyalkyl.
  • R 2 is a 6-membered aromatic heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R Y .
  • R 2 is any one of wherein the dotted line in each case marks the connection to the remainder of the molecule.
  • R 2 is wherein the dotted line in each case marks the connection to the remainder of the molecule.
  • R 3 is H.
  • R 5 is H or methyl.
  • R 5 is H.
  • R 2 is a 6-membered aromatic heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R Y ;
  • R 5 is H or methyl
  • R Y is halogen, C 1 -C 4 -alkyl, C 1 -C 3 - ha loa I ky I , Cj-C ⁇ -haloalkoxy, or Cj-C ⁇ -hydroxyalkyl, preferably halogen.
  • L 1 is CH 2 , CHCH 3 , or CHCF 3 , preferably CH 2 ;
  • L 2 is CH 2 , CHOH, or CH0CH 3 , preferably CH 2 ;
  • R 2 is a 6-membered aromatic heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from 0, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R Y ;
  • R 5 is H or methyl
  • R Y is halogen, C 1 -C 4 -alkyl, C 1 -C 3 - ha loa I ky I , Cj- ⁇ -haloalkoxy, or Cj- ⁇ -hydroxyalkyl, preferably halogen.
  • R 2 is wherein the dotted line in each case marks the connection to the remainder of the molecule
  • R 5 is H or methyl.
  • L 1 is CH 2 , CHCH 3 , or CHCF 3 ;
  • L 2 is CH 2 , CHOH, or CHOCH 3 ;
  • R 2 is wherein the dotted line in each case marks the connection to the remainder of the molecule
  • R 5 is H or methyl.
  • L 1 is CH 2 ;
  • L 2 is CH 2 ;
  • R 2 is wherein the dotted line in each case marks the connection to the remainder of the molecule
  • R 3 is H
  • R 5 is H.
  • R 5 is H or methyl.
  • R 5 is H or methyl.
  • R 3 is H
  • R 5 is H.
  • the compound according to formula (I) is selected from the group consisting of (S)-N-(5-chloro-2-methylpyridin-3-yl)-N-((5-((3-cyclopentyl-l- (cyc lop ropy lam i no) -1 -oxopropan -2-yl) carbamoyl) th io phen -2 -y I) methyl) glycine, 5-(l-((5- chloro-2-methylpyridin-3-yl)amino)ethyl)-N-((S)-3-cyclopentyl-l-(cyclopropylamino) -l- oxop ropa n -2 -y I) th iophene-2 -carboxamide, 5-(l-((5-chloro-2-methylpyridin-3-yl)amino) - 2,2,2-trifluoroethyl)-N
  • the compound according to formula (I) is selected from the group consisting of (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl) -N-(3-cyclopentyl- 1 -oxo-1 -(pyrid in -3-y lam i no) pro pan -2-yl) th iophene-2-carboxam ide, (S) -5 -(((5 -ch loro-2- methyl pyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-oxo-l-(pyrimidin-5-ylamino) propan- 2 -y I) th io phene-2 -carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3- cyclopenty 1-1 -oxo
  • the compound according to formula (I) is selected from the group consisting of 5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)-N-((lR,2S)-l- cyclopentyl-3-(cyclopropylamino)-l-hydroxy-3-oxopropan-2-yl)thiophene-2-carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl)- N-(l-(cyclopropylamino)-3-(4, 4- difluorocyclohexyl)-l-oxopropan-2-yl)thiophene-2-carboxamide, (S)-5-(((5-chloro-2- methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-((l-methyl-lH-pyrazol-4-yl)a
  • the compound according to formula (I) is selected from the group consisting of 5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-((lR,2S) -l- cyclopentyl-3-(cyclopropylamino)-l-hydroxy-3-oxopropan-2-yl)thiophene-2-carboxamide, (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl)- N-(l-(cyclopropylamino) -3-(4, 4- difluorocyclohexyl)-l-oxopropan-2-yl)thiophene-2-carboxamide, (S) -5-(((5-chloro-2- methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-((l-methyl-lH-pyrazol-4
  • the compound according to formula (I) is selected from the group consisting of (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl) -N-(3-cyclopentyl-
  • the compound according to formula (I) is selected from the group consisting of (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl) -N-(3-cyclopentyl-
  • the compound according to formula (I) is selected from the group consisting of (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl) -N-(3-cyclopentyl-
  • the compound according to formula (I) is selected from the group consisting of (S)-5-(((5-chloropyridin-3-yl)amino)methyl) -N-(3-cyclopentyl-l-((l- methyl-lH-pyrazol-4-yl)amino)-l-oxopropan-2-yl)thiophene-2-carboxamide, (S) -N-(3- cyclopentyl-l-((l-methyl-lH-pyrazol-4-yl)amino) -1-oxopropan -2-yl) -5-(((5- (difluoromethyl)-2-methylpyridin-3-yl)amino)methyl)thiophene-2-carboxamide, 5-(((5- chloro-2-methylpyridin-3-yl)amino) methyl) -N-((S)-1-((1 -methyl -lH-pyrazol
  • the invention relates in a second aspect to a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically effective amount of the above-outlined compounds and optionally a pharmaceutically acceptable carrier or excipient.
  • a pharmaceutical composition according to the present invention may be formulated for oral, buccal, nasal, rectal, topical, transdermal or parenteral application.
  • Preferred non - parenteral routes include mucosal (e.g., oral, vaginal, nasal, cervical, etc.) routes, of which the oral application may be preferred.
  • Preferred parenteral routes include but, are not limited to, one or more of subcutaneous, intravenous, intra-muscular, intraarterial, intradermal, intrathecal and epidural administrations.
  • Preferably administration is by subcutaneous, intra-tumoral or peri-tumoral routes. Particularly preferred is intratumoral administration.
  • the compound according to formula (I) should be applied in pharmaceutically effective amounts, for example in the amounts as set out herein below.
  • a pharmaceutical composition of the present invention may also be designated as formulation or dosage form.
  • a compound of formula (I) may also be designated in the following as (pharmaceutically) active agent or active compound.
  • compositions may be solid or liquid dosage forms or may have an intermediate, e.g. gel-like character depending inter alia on the route of administration.
  • inventive dosage forms can comprise various pharmaceutically acceptable excipients which will be selected depending on which functionality is to be achieved for the dosage form.
  • a “pharmaceutically acceptable excipient” in the meaning of the present invention can be any substance used for the preparation of pharmaceutical dosage forms, including coating materials, film-forming materials, fillers, disintegrating agents, releasemodifying materials, carrier materials, diluents, binding agents and other adjuvants.
  • Typical pharmaceutically acceptable excipients include substances like sucrose, mannitol, sorbitol, starch and starch derivatives, lactose, and lubricating agents such as magnesium stearate, disintegrants and buffering agents.
  • pharmaceutically acceptable carrier denotes pharmaceutically acceptable organic or inorganic carrier substances with which the active ingredient is combined to facilitate the application.
  • suitable pharmaceutically acceptable carriers include, for instance, water, aqueous salt solutions, alcohols, oils, preferably vegetable oils, propylene glycol, polyoxyethelene sorbitans, polyethylene-polypropylene block co-polymers such as poloxamer 188 or poloxamer 407, polyethylene glycols such as polyethylene glycol 200, 300, 400, 600, etc., gelatin, lactose, amylose, magnesium stearate, surfactants, perfume oil, fatty acid monoglycerides, diglycerides and triglycerides, polyoxyethylated medium or long chain fatty acids such as ricinoleic acid, and polyoxyethylated fatty acid mono-, di, and triglycerides such as capric or caprilic acids, petroethral fatty acid esters, hydroxymethyl celluloses such
  • the compounds of the present invention are administered in a pharmaceutical composition comprising of lipids, interbilayer crosslinked multilamellar vesicles, biodegradeable poly(D,L-lactic-co- glycolic acid) [PLGA]-based or poly anhydride-based nanoparticles or microparticles, nanoporous particle-supported lipid bilayers and as a conjugate with an antibody.
  • a pharmaceutical composition comprising of lipids, interbilayer crosslinked multilamellar vesicles, biodegradeable poly(D,L-lactic-co- glycolic acid) [PLGA]-based or poly anhydride-based nanoparticles or microparticles, nanoporous particle-supported lipid bilayers and as a conjugate with an antibody.
  • compositions can be sterile and, if desired, mixed with auxiliary agents, like lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavoring and/or aromatic substances and the like which do not deleteriously react with the active compound.
  • auxiliary agents like lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavoring and/or aromatic substances and the like which do not deleteriously react with the active compound.
  • auxiliary agents like lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavoring and/or aromatic substances and the like which do not deleteriously react with the active compound.
  • pharmaceutically acceptable carrier also covers an antibody that delivers the compound of formula (I).
  • liquid dosage forms can include pharmaceutically acceptable emulsions, solutions, suspensions and syrups containing inert diluents commonly used in the art such as water.
  • These dosage forms may contain e.g. microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer and sweeteners/flavoring agents.
  • suitable vehicles consist of solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants.
  • Pharmaceutical formulations for parenteral administration are particularly preferred and include aqueous solutions of the compounds of formula (I) in water-soluble form.
  • suspensions of the compounds of formula (I) may be prepared as appropriate oily injection suspensions.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • Particularly preferred dosage forms are injectable preparations of a compound of formula (I).
  • sterile injectable aqueous or oleaginous suspensions can for example be formulated according to the known art using suitable dispersing agents, wetting agents and/or suspending agents.
  • a sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent.
  • the acceptable vehicles and solvents that can be used are water and isotonic sodium chloride solution. Sterile oils are also conventionally used as solvent or suspending medium.
  • Preferred applications for injectable preparations comprising the compounds of the present invention are intravenous, intratumoral and peritumoral administration.
  • Suppositories for rectal administration of a compound of formula (I) can be prepared by e.g. mixing the compound with a suitable non-irritating excipient such as cocoa butter, synthetic triglycerides and polyethylene glycols which are solid at room temperature but liquid at rectal temperature such that they will melt in the rectum and release the compound according to formula (I) from said suppositories.
  • a suitable non-irritating excipient such as cocoa butter, synthetic triglycerides and polyethylene glycols which are solid at room temperature but liquid at rectal temperature such that they will melt in the rectum and release the compound according to formula (I) from said suppositories.
  • the compounds according to the present invention may be conveniently delivered in the form of an aerosol spray from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable
  • Oral dosage forms may be liquid or solid and include e.g. tablets, troches, pills, capsules, powders, effervescent formulations, dragees and granules.
  • Pharmaceutical preparations for oral use can be obtained as solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • the oral dosage forms may be formulated to ensure an immediate release of the compound of formula (I) or a sustained release of the compound of formula (I).
  • a solid dosage form may comprise a film coating.
  • the inventive dosage form may be in the form of a so-called film tablet.
  • a capsule of the invention may be a two-piece hard gelatin capsule, a two-piece hydroxypropylmethylcellulose capsule, a two-piece capsule made of vegetable or plant-based cellulose or a two-piece capsule made of polysaccharide.
  • the dosage form according to the invention may be formulated for topical application. Suitable pharmaceutical application forms for such an application may be a topical nasal spray, sublingual administration forms and controlled and/or sustained release skin patches.
  • the compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compositions may conveniently be presented in unit dosage forms and may be prepared by any of the methods well known in the art of pharmacy. The methods can include the step of bringing the compounds into association with a carrier, which constitutes one or more accessory ingredients.
  • the compositions are prepared by uniformly and intimately bringing the compounds into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product.
  • Liquid dose units are vials or ampoules. Solid dose units are tablets, capsules and suppositories.
  • an effective amount means an amount of compound (i.e. compound of formula (I)) that, when administered to a mammal in need of such treatment, is sufficient to treat or prevent a particular disease or condition.
  • the amount of the active compound administered will be dependent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician.
  • an effective amount is typically in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 0.01 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.07 to about 7000 mg/day, preferably about 0.7 to about 2500 mg/day.
  • dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be used without causing any harmful side effect, with such larger doses typically divided into several smaller doses for administration throughout the day.
  • the pharmaceutical composition may also contain the compound of formula (I) as a prodrug such as an ester or amide thereof.
  • a prodrug is any compound, which is converted under physiological conditions or by solvolysis to any of the compounds of the invention.
  • a prodrug may be inactive prior to administration but may be converted to an active compound of the invention in vivo.
  • the above-outlined compounds or an above-outlined pharmaceutical composition are suitable for use in medicine.
  • the compounds according to the present invention or the pharmaceutical composition according to the present invention are suitable for use in the treatment of a disease associated with Wipl.
  • the compounds according to the present invention or the pharmaceutical composition according to the present invention are capable to modulate or inhibit Wipl.
  • compounds according to the present invention or the pharmaceutical composition according to the present invention are suitable for use in the treatment of a disease selected from the group consisting of cancer, pre-cancerous syndromes, autoimmune conditions, neurological diseases, and viral disease, preferably selected from the group consisting of cancer, pre-cancerous syndromes, autoimmune conditions, and neurological diseases, more preferably selected from the group consisting of cancer, pre-cancerous syndromes, and neurological diseases.
  • compounds according to the present invention or the pharmaceutical composition according to the present invention are suitable for use in the treatment of a disease selected from the group consisting of cancer and pre-cancerous syndromes.
  • cancers may be in the form of solid tumors such as sarcomas, carcinomas, and lymphomas or in the form of liquid tumors, e.g. leukemia.
  • compounds according to the present invention or the pharmaceutical composition according to the present invention are suitable for use in the treatment of a disease selected from the group consisting of amyotrophic lateral sclerosis, amyotrophic lateral sclerosis, attention deficit hyperactivity disorder, autism, Bannayan - Zonana syndrome, bladder cancer, blood cancer, bone cancer, breast cancer, inflammatory breast cancer, brain cancer, cervical cancer, colorectal cancer, Cowden disease, endometrial cancer, ependymoma, esophagus cancer, Ewing's sarcoma, gastric cancer, head and neck cancer, individual allergic asthma, kidney cancer, Lhermitte-Duclos disease, lung cancer, liver cancer, lymphoma, medulloblastoma, melanoma, mesothelioma, nasopharyngeal carcinoma, neuroblastoma, neurofibromatosis, ovarian cancer, osteosarcoma, pancreatic cancer, prostate cancer, Rhab
  • compounds according to the present invention or the pharmaceutical composition according to the present invention are suitable for use in the treatment of breast cancer, preferably selected from the group consisting of inflammatory breast cancer, triple negative breast cancer (TNBC), and HER2+ breast cancer.
  • TNBC triple negative breast cancer
  • HER2+ breast cancer preferably selected from the group consisting of inflammatory breast cancer, triple negative breast cancer (TNBC), and HER2+ breast cancer.
  • compounds according to the present invention or the pharmaceutical composition according to the present invention are suitable for use in the treatment of blood cancers, preferably selected from the group consisting of leukemia, lymphoma and multiple myeloma.
  • leukemia include acute lymphocytic leukemia (ALL), Acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), and myelodysplastic syndromes (MDS). Of particular relevance is AML.
  • compounds according to the present invention or the pharmaceutical composition according to the present invention are suitable for use in the treatment of brain cancers, preferably selected from the group consisting of glioma, glioblastoma, oligodendroglioma, diffuse intrinsic pontine glioma (DIPG), meningioma. Particularly relevant is glioblastoma.
  • compounds according to the present invention or the pharmaceutical composition according to the present invention are suitable for use in the treatment of lung cancers, preferably selected from the group consisting of small-cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Particularly relevant is NSCLC.
  • SCLC small-cell lung cancer
  • NSCLC non-small cell lung cancer
  • compounds according to the present invention or the pharmaceutical composition according to the present invention are suitable for use in the treatment of liver cancer, preferably hepatocellular carcinoma (HCC).
  • liver cancer preferably hepatocellular carcinoma (HCC).
  • compounds according to the present invention or the pharmaceutical composition according to the present invention are suitable for use in the treatment of a disease selected from the group consisting of Bannayan-Zonana syndrome, bladder cancer, bone cancer, breast cancer, inflammatory breast cancer, brain cancer, especially glioblastoma and glioma, cervical cancer, colorectal cancer, Cowden disease, endometrial cancer, ependymoma, esophagus cancer, Ewing's sarcoma, gastric cancer, head and neck cancer, kidney cancer, leukemia, especially AML, Lhermitte-Duclos disease, lung cancer, especially NSCLC and SCLC, liver cancer, especially HCC, lymphoma, medulloblastoma, melanoma, mesothelioma, multiple myeloma, nasopharyngeal carcinoma, neuroblastoma, ovarian cancer, osteosarcoma, pancreatic cancer, prostate cancer, Rhabdomy
  • the compounds according to the present invention are administered in combination with antibodies, radiotherapy, surgical therapy, immunotherapy, chemotherapy, toxin therapy, gene therapy, or any other therapy known to those of ordinary skill in the art for treatment of a particular disease. This is particularly relevant in connection with the treatment of cancer.
  • Combination therapy may be achieved by use of a single pharmaceutical composition that includes both agents, or by administering two distinct compositions at the same time, wherein one composition includes a compound of the present invention, and the other includes the second agent(s).
  • the two therapies may be given in either order and may precede or follow the other treatment by intervals ranging from minutes to weeks.
  • the other agents are applied separately, one would generally ensure that a significant period of time did not expire between the time of each delivery, such that the agents would still be able to exert an advantageously combined effect on the patient.
  • the compound of the present invention is administered prior to administration of the distinct cancer treatment.
  • the distinct cancer treatment is administered prior to administration of the compound of the present invention.
  • Multiplicity is abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublets), dt (doublet of triplets), tt (triplet of triplets), td (triplet of doublets), qd (quartet of doublets), br (broad), hex (hextet).
  • Method A3 Apparatus: Waters ICIass; Bin. Pump: UPIBSM, SM: UPISMFTN with SO; UPCMA, PDA: UPPDATC, 210-320 nm, SQD: ACQ-SQD2 ESI; ELSD: gaspressure 40 psi, drift tube temp: 50 ° C; column: Waters XSelect CSH C18, 50x2.1 mm, 2.5 m, Temp: 25
  • Method A4 Apparatus: Waters ICIass; Bin. Pump: UPIBSM, SM: UPISMFTN with SO; UPCMA, PDA: UPPDATC, 210-320 nm, SQD: ACQ-SQD2 ESI; ELSD: gaspressure 40 psi, drift tube temp: 50 ° C; column: Waters XSelect CSH C18, 50x2.1 mm, 2.5 m, Temp: 40
  • Method B2 Instrument type: RevelerisTM prep MPLC; Column: Dr. Maisch Reprosil C18 150x25 mm, 10 ); Flow: 40 mL/min; Column temp: r.t.; Eluent A: 0.1% (v/v) formic acid in water, Eluent B: 0.1% (v/v) formic acid in MeCN; detection UV : 220, 254, 340 nm, ELSD. Appropriate fractions were combined and lyophilised.
  • HPLC instrument type Waters Modular Preparative HPLC System
  • column Waters XSelect (C18, 100x30 mm, 10pm); flow: 55 ml/min prep pump; column temp: r.t.
  • Method B4 MS instrument type: Agilent Technologies G6120AA Quadrupole; HPLC instrument type: Agilent Technologies 1200 preparative LC; Column: Waters XSelect CSH (C18, 100x30 mm, lOp); Flow: 55 ml/min; Column temp: r.t.; Eluent A: 0.1% formic acid in water; Eluent B: 100% MeCN; Detection: DAD (220-320 nm); Detection: MSD (ESI pos/neg) mass range: 100 - 1000; fraction collection based on MS and DAD
  • Method Cl Apparatus: Sepiatec Prep 250 SFC; Column: Phenomenex Lux i-Amylose-3 (250x21.2 mm, 5 pm); Column temp: 40 ° C; Flow: 100 ml/min; ABPR: 100 bar; Eluent A: CO 2 , Eluent B: 20 mM Ammonia in EtOH; Isocratic method: 30% B; Detection: UV 210 nm; Timed fraction collection.
  • Method C2 Apparatus: Waters Prep 100 SFC UV/MS directed system; Waters 2998 PDA Detector; Waters Acquity QDa MS detector; Waters 2767 Sample Manager; Column: Phenomenex Lux i-Amylose-3 (250x21.2 mm, 5 pm); Column temp: 35 ° C; Flow: 70 ml/min; ABPR: 120 bar; Eluent A: CO 2 , Eluent B: 20 mM Ammonia in EtOH; Isocratic method: 50% B; Detection: PDA (210-400 nm); Fraction collection based on PDA TIC.
  • Method C3 Apparatus: Sepiatec Prep 250 SFC; Column: Phenomenex Lux i -Cel lu lose-5 (250x21.2 mm, 5 pm); Column temp: 40 ° C; Flow: 100 ml/min; ABPR: 100 bar; Eluent A: CO 2 , Eluent B: 20 mM Ammonia in MeOH; Isocratic method: 10% B; Detection: UV 210 nm; Timed fraction collection.
  • Method C5 Apparatus: Sepiatec Prep 250 SFC; Column: Phenomenex Lux Amylose-1 (250x21.2 mm, 5 pm); Column temp: 40 ° C; Flow: 100 ml/min; ABPR: 100 bar; Eluent A: CO 2 , Eluent B: 20 mM Ammonia in MeOH; Isocratic method: 5% B; Detection: UV 215 nm; Timed fraction collection.
  • PDA Photodiode Array
  • Method C7 Apparatus: Waters Prep 100 SFC UV/MS directed system; Waters 2998 Photodiode Array (PDA) Detector; Waters Acquity QDa MS detector; Waters 2767 Sample Manager; Column: Diacel Phenomenex Lux i -Cel I u lose-5 (250x21mm, 5pm); Column temp: 35° C; Flow: 70 ml/min; ABPR: 120 bar; Eluent A: CO2, Eluent B: 20 mM Ammonia in MeOH; Isocratic method: 50% B for 9 min; Detection: PDA (210-400 nm); Timed fraction collection.
  • PDA Photodiode Array
  • Method C8 Apparatus: Sepiatec Prep 250 SFC; Column: Phenomenex Lux i -Cel lu lose-5 (250x21.2 mm, 5 pm); Column temp: 40 ° C; Flow: 100 ml/min; ABPR: 100 bar; Eluent A: CO 2 , Eluent B: 20 mM Ammonia in MeOH; Isocratic method: 5% B; Detection: UV 210 nm; Timed fraction collection.
  • Method C9 Apparatus: Sepiatec Prep 250 SFC; Column: Phenomenex Lux i-Amylose-3 (250x21.2 mm, 5 pm); Column temp: 40° C; Flow: 100 ml/min; ABPR: 100 bar; Eluent A: CO2, Eluent B: 20 mM Ammonia in Methanol; Isocratic method: 15 % B; Detection: UV 210 nm; Timed fraction collection.
  • PDA Photodiode Array
  • PDA Photodiode Array
  • Step 1 To an argon-sparged solution of (R)-2-isopropyl-3,6-dimethoxy-2,5- dihydropyrazine (1.0 equiv.) in anhydrous THF (0.3 M) at -78 ° C was added 2.5 M n-BuLi in hexanes (1.2 equiv.) over a period of 2 min at -78 ° C. The reaction mixture was stirred for 15 min. Then, a solution of a bromide (1.25 equiv.) in anhydrous THF (0.3 M) was added and the reaction was stirred at -78 ° C for 15 min. The reaction mixture was brought to r.t. and stirred for an additional 2h.
  • the reaction mixture was poured into a mixture of water/brine (1:1) and extracted with EtOAc. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The concentrate was purified by column chromatography on silica eluting with heptane:EtOAc (0-5%) affording the dihydropyrazine intermediate.
  • Step 2 The dihydropyrazine intermediate (1.0 equiv.) was dissolved in MeCN (0.2 M) to which was added 0.1 M TFA (3 equiv.) and the reaction was stirred at r.t. for 14h. The reaction was concentrated in vacuo. To the concentrate was added a saturated aqueous solution of NaHCO 3 (3 mL) and the product was extracted with EtOAc. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting amine intermediate was used as such in the next step.
  • Step 3 The amine intermediate (1.0 equiv.) was dissolved in DCM (0.05 M) and TEA (2.0 equiv.) and di-tert-butyl dicarbonate (1.0 equiv.) were added. The reaction mixture was stirred at r.t. for 14h. The reaction mixture was concentrated in vacuo. The concentrate was purified by column chromatography on silica eluting with heptane:EtOAc (0-100%) affording the Boc-protected intermediate.
  • Step 4 To a solution of Boc-protected intermediate (1.0 equiv.) in MeOH (0.5 M) was added a 2.5 M aqueous solution of NaOH (5 equiv.) at r.t.. The reaction was stirred at r.t. for 14-72h after which the reaction was acidified with a 4 M aqueous solution of HCI . The product was extracted with DCM. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo affording the intermediate Boc-protected amino acid which was used as such.
  • Step la To a solution of Boc-protected amino acid (1 equiv.) in DCM (0.15-0.4 M) was added TEA (2 equiv.) and HATU (1.2 equiv.). After stirring at r.t. for 10 min amine (1.2 equiv.) was added and stirring was continued at r.t. for 2-20h. The reaction mixture was purified by column chromatography on silica eluting with heptane:EtOAc (0-100%).
  • Step lb To (S)-2-((tert-butoxycarbonyl)amino)-3-cyclopentylpropanoic acid (1 equiv.) and amine (1.2 equiv.) was added anhydrous pyridine (0.39 M) and the resulting solution was cooled with a cooling bath to -12 ° C. Phosphorus oxychloride (1.7 equiv.) was added and after 30 min the temperature was raised to 0 ° C. The temperature was allowed to reach r.t. overnight. To the reaction mixture was added water (1.9 M), filtered and purified by reversed phase chromatography according to Method Bl.
  • Step lc A solution of the carboxylic acid (1 equiv.), TEA (1.2-3 equiv.) and HATU (1.0-1.2 equiv.) in DCM (0.1-0.2 M) was stirred at r.t. for 10 min before amine (1.0-1.2 equiv.) was added and stirring was continued for 2-20h. To the reaction mixture was added an aqueous saturated solution of NaHCO 3 and the layers were separated. The aqueous layer was extracted with DCM and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting concentrate was purified by column chromatography on silica eluting with heptane:EtOAc (0-100%) to obtain the corresponding amide.
  • Step 2 The Boc-protected amino acid was dissolved in DCM (0.02-0.1 M) and a solution of 4 M HCI in dioxane (15-20 equiv.) was added. After stirring at r.t. for l-24h the reaction mixture was concentrated in vacuo o afford the HCI salt intermediate.
  • Step 1 An argon-sparged solution of (R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (0.97 mL, 5.4 mmol) in anhydrous THF (6 mL) was cooled to -78° C. Next, 2.5 M n-BuLi in hexanes (2.4 mL, 6.0 mmol) was added over 10 min and the solution was stirred at -78 ° C. After 15 min a solution of cyclopentanecarbaldehyde (0.87 mL, 8.1 mmol) in anhydrous THF (3 mL) was added over 15 min.
  • reaction mixture was stirred at -78 ° C for 30 min and the temperature was raised to r.t. and stirring was continued for 2h.
  • the reaction mixture was quenched in a mixture of water/brine (1:1, 20 mL) and the water layer was extracted with EtOAc. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo.
  • Step 2 (R)-cyclopentyl((2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2- yl)methanol (520 mg, 1.84 mmol) was dissolved in MeCN (6 mL). Next, a 0.1 M aqueous solution of TFA (55 mL, 5.5 mmol) was added and the reaction mixture was stirred at r.t. for 17h. The reaction mixture was concentrated in vacuo and to the resulting concentrate was added a saturated aqueous solution of sodium hydrogen carbonate (5 mL) and the product was extracted with EtOAc. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude methyl (2S,3R)-2-amino-3- cyclopentyl-3-hydroxypropanoate (508 mg, crude) was used as such in the subsequent Boc protection step without purification.
  • Step 3 Crude methyl (2S,3R)-2-amino-3-cyclopentyl-3-hydroxypropanoate (508 mg, crude) was dissolved in MeCN (38 mL) and di-tert-butyl dicarbonate (592 mg, 2.72 mmol) and TEA (0.75 mL, 5.4 mmol) were added and the mixture was stirred at r.t. for 17h.
  • Step 4 Methyl (2S,3R)-2-((tert-butoxycarbonyl)amino)-3-cyclopentyl-3- hydroxypropanoate (157 mg, 0.546 mmol) was dissolved in a mixture of THF/water (2:1, 4 mL) and lithium hydroxide monohydrate (115 mg, 2.73 mmol) was added and the mixture was stirred at r.t. for 4h. The reaction mixture was diluted with water (5 mL) and a 1 M aqueous solution of HCI (5.5 mL, 5.5 mmol) was added.
  • Step 5 To a solution of (2S,3R)-2-((tert-butoxycarbonyl)amino)-3-cyclopentyl-3- hydroxypropanoic acid (50 mg, 0.18 mmol) and cyclopropylamine (14 pL, 0.20 mmol) in DCM (2 mL) was added TEA (38 pL, 0.27 mmol) and HATU (77 mg, 0.20 mmol) and the resulting suspension was stirred at r.t. for 17h. To the reaction mixture was added a saturated aqueous solution of NaHCO 3 . The layers were separated and the aqueous layer was extracted with DCM.
  • TEA 38 pL, 0.27 mmol
  • HATU 77 mg, 0.20 mmol
  • Step 1 (R)-cyclopentyl((2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2- y
  • methanol cyclopentyl((2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2- yl)methanol 201 mg, 0.712 mmol
  • sodium hydride (28.5 mg, 0.712 mmol) was added portion-wise and the reaction mixture was stirrred for 10 min at ambient temperature.
  • Step 2 (2S, 5 R) -2- ((R) -eye Io pentyl (meth oxy) methyl ) -5 -isop ropy 1-3, 6-di meth oxy-2,5 - dihydropyrazine (166 mg, 0.560 mmol) was dissolved in MeCN (3 mL). Next, 0.1 M aqueous TFA (16.8 ml, 1.68 mmol) was added and the reaction mixture was stirred at r.t. for 18h. The reaction mixture was concentrated in vacuo and to the resulting concentrate was added a saturated aqueous solution of NaHCO 3 (5 mL) and the product was extracted with EtOAc.
  • Step 3 Crude methyl (2S,3R)-2-amino-3-cyclopentyl-3-methoxypropanoate (146 mg, 0.725 mmol) was dissolved in MeCN (6 mL) and di-tert-butyl dicarbonate (158 mg, 0.725 mmol) and TEA (0.20 ml, 1.4 mmol) were added, and the mixture was stirred at r.t. for 18h.
  • Step 4 Methyl (2S,3R)-2-((tert-butoxycarbonyl)amino)-3-cyclopentyl-3- methoxypropanoate (143 mg, 0.474 mmol) was dissolved in a mixture of THF/water (2:1, 6 mL) and lithium hydroxide monohydrate (100 mg, 2.37 mmol) was added and the mixture was stirred at r.t. for 4h. The reaction mixture was diluted with water (5 mL) and a 1 M aqueous solution of potassium bisulfate (4.74 mL, 4.74 mmol) was added.
  • Step 5 To a solution of (2S,3R)-2-((tert-butoxycarbonyl)amino)-3-cyclopentyl-3- methoxypropanoic acid (68 mg, 0.237 mmol) and cyclopropylamine (0.018 ml, 0.26 mmol) in DCM (2 mL) was added TEA (0.049 ml, 0.36 mmol) and HATU (99 mg, 0.26 mmol) and the resulting suspension was stirred at r.t. for 17h. To the reaction mixture was added a saturated aqueous solution of NaHCO 3 (3 mL). The layers were separated and the aqueous layer was extracted with DCM.
  • TEA 0.049 ml, 0.36 mmol
  • HATU 99 mg, 0.26 mmol
  • Step 6 To a solution of tert-butyl tert-butyl ((lR,2S)-l-cyclopentyl-3-(cyclopropylamino)- l-methoxy-3-oxopropan-2-yl)carbamate (51 mg, 0.16 mmol) in DCM (2 mL) was added 4 M HCI in dioxane (0.60 ml, 2.3 mmol)and. The solution was stirred for 4 h at r.t.
  • step 2 3,6-dimethoxy-2,5-dihydropyrazine (550 mg, 2.99 mmol) and 6-(bromomethyl) -2,2- difluorospiro[3.3]heptane (1.00 g, 4.48 mmol).
  • step 2 after concentration the mixture was co-evaporated with toluene and DCM and extraction was performed with DCM instead of EtOAc.
  • step 4 lithium hydroxide monohydrate (5 equiv.) was used instead of NaOH and the reaction was performed in a mixture of THF/water (2:1, 0.2 M).
  • Step 1 To a nitrogen purged solution of methyl (tert-butoxycarbonyl)-L-tyrosinate (10.0 g, 33.9 mmol) in MeOH (200 mL) was added rhodium on carbon (5%) (2.8 g, 1.4 mmol). The reaction mixture was purged with hydrogen and was stirred under hydrogen atmosphere (5.5 bar) at 60 ° C for 72 h . Then, the reaction mixture was cooled to r.t., filtered and concentrated in vacuo.
  • Step 2 To a solution of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4- hydroxycyclohexyl)propanoate (11.4 g, 37.9 mmol) in DCM (350 mL) was added 3-oxo-H5- benzo[d] [1,2] iodaoxole-1 , 1, 1 (3 H) -triy I triacetate (19.3 g, 45.5 mmol). After stirring at r.t. for 18 h, the reaction mixture was diluted with water and DCM and filtered. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo.
  • Step 3 To a solution of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4- oxocyclohexyl)propanoate (10.1 g, 33.7 mmol) in DCM (130 mL) at 0 ° C was added a 50% solution of Deoxo-Fluor® in THF (29.3 mL, 67.5 mmol) in DCM (130 mL), followed by addition of EtOH (394 pL, 6.75 mmol). The reaction mixture was stirred at r.t. for 23h.
  • Step 1 To a solution of methyl (2S)-2-((tert-butoxycarbonyl)amino)-3-(4-fluorocyclohex- 3-en-l-yl)propanoate (100 mg, 0.332 mmol) in MeOH (3.0 mL) was added Evonik NOBLYST® P1126 5% Pd. The mixture was purged with hydrogen for 2 min and left to stir under a hydrogen atmosphere at r.t. for 4h to obtain a first batch.
  • Step 2 To a solution of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4- fluorocyclohexyl)propanoate (80 mg, 0.26 mmol) in THF (7.0 mL) and water (3.5 mL) was added lithium hydroxide monohydrate (55.3 mg, 1.32 mmol). After stirring at r.t. for 18h, the reaction mixture was acidified to pH ⁇ l with a 4 M aqueous solution of HCI and extracted with DCM.
  • step 4 only 0.37 mmol of the boc-protected intermediate was used out of 1.27 mmol, lithium hydroxide (5 equiv.) was used instead of NaOH, and the reaction was performed in a mixture of THF/water (2:1, 0.2 M) to afford (S) - 2-((tert-butoxycarbonyl)amino)-3-(cyclopent-3-en-l-yl)propanoic acid (95 mg, 0.37 mmol, 25% yield over four steps) as a clear oil.
  • step 1 (difluoromethyl)-l-methyl-lH-pyrazol-4-amine (55.0 mg, 0.374 mmol).
  • step 2 DMF was used instead of DCM and the reaction mixture was purified by reversed phase chromatography according to Method B3.
  • (S)-2-amino-3-cyclopentyl-N-(3-(difluoromethyl)- l-methyl-lH-pyrazol-4-yl)propanamide hydrochloride (82.1 mg, 0.284 mmol, 77% yield over two steps) was obtained as a yellow solid.
  • step 4 lithium hydroxide (5 equiv.) was used instead of NaOH, and the reaction was performed in a mixture of THF/water (2:1, 0.2 M) instead of MeOH.
  • (2S)-2-((tert- butoxycarbonyl)amino)-3-(3-fluorocyclopentyl)propanoic acid (331 mg, 1.20 mmol, 15% yield over four steps) was obtained as a clear oil and was used as such.
  • step 2 the reaction was performed in MeCN at a concentration of 0.06 M instead of 0.2 M, a 0.2 M aqueous solution of TFA (6 equiv.) was used instead of a 0.1 M aqueous solution of TFA (3 equiv.) and the aqueous layer was first extracted with EtOAc and then with 15% MeOH in EtOAc.
  • step 3 2 equiv. instead of 1 equiv. of di-tert-butyl dicarbonate was used.
  • I n step 4 lithium hydroxide was used instead of NaOH, and the reaction was performed in a mixture of THF/MeOH/water (2:1:1 , 0.02 M) instead of MeOH.
  • Step 1 To a mixture of benzyl (S)-2-(((benzyloxy)carbonyl)amino)-4-oxobutanoate (200 mg, 0.586 mmol) and molecular sieves (4 A) (400 mg, 0.586 mmol) in 1,3-propanediol (2.1 mL, 29 mmol) was added pyridinium p-toluenesulfonate (36.8 mg, 0.146 mmol). After stirring at 80 ° C for 18h, the reaction mixture was filtered over Celite® and the residue was washed with EtOAc. Water was added to the filtrate and the layers were separated .
  • Step 2 To a solution of benzyl (S)-2-(((benzyloxy)carbonyl)amino)-3-(l,3-dioxan-2- yl)propanoate (234 mg, 0.586 mmol) in THF (2.0 mL) and water (2.0 mL) was added NaOH (188 mg, 4.69 mmol). After stirring at r.t. for Ih, the reaction mixture was neutralized with formic acid (0.18 mL, 4.7 mmol) and purified by reversed phase chromatography according to Method B2.
  • Step 1 To a solution of (S)-2-(((benzyloxy)carbonyl)amino)-3-(l,3-dioxan-2-yl)propanoic acid (23 mg, 0.074 mmol), HATU (37 mg, 0.097 mmol) and DIPEA (65 pL, 0.37 mmol) in DMF (1.0 mL) was added cyclopropylamine (10 pL, 0.15 mmol). After stirring at r.t.
  • Step 2 To a solution of benzyl (S)-(l-(cyclopropylamino)-3-(l,3-dioxan-2-yl)-l- oxopropan-2-yl)carbamate (18 mg, 0.052 mmol) in THF (2.0 mL) was added 10% palladium on activated carbon (4 mg, 2 pmol). The reaction mixture was stirred under a hydrogen atmosphere at r.t. for 18h. The reaction mixture was filtered and concentrated in vacuo o obtain (S)-2-amino-N-cyclopropyl-3-(l,3-dioxan-2-yl)propanamide (12 mg, 0.056 mmol, quant, yield) as a colorless oil.
  • Step 1 To a solution of (S)-2-(((benzyloxy)carbonyl)amino)-3-(l,3-dioxan-2-yl)propanoic acid (46 mg, 0.15 mmol), HATU (73.5 mg, 0.193 mmol) and DIPEA (0.13 mL, 0.74 mmol) in DMF (1.0 mL) was added l-methyl-lH-pyrazol-4-amine (25 pL, 0.30 mmol). After stirring at r.t.
  • Step 2 To a solution of benzyl (S)-(3-(l,3-dioxan-2-yl)-l-((l-methyl-lH-pyrazol-4- yl)amino)-l-oxopropan-2-yl)carbamate (52 mg, 0.13 mmol) in THF (2.0 mL) was added 10% palladium on activated carbon (10 mg, 4.7 pmol). The reaction mixture stirred under a hydrogen atmosphere at r.t. for 5h. Additional 10% palladium on activated carbon (10 mg, 4.7 pmol) was added and the reaction mixture was stirred under a hydrogen atmosphere at r.t. for 20h.
  • Step 1 A mixture of benzyl (S)-2-(((benzyloxy)carbonyl)amino)-4-oxobutanoate (100 mg, 0.293 mmol), molecular sieves (4 A) (300 mg, 0.293 mmol), 2,2-difluoropropane-l,3-diol (32.8 mg, 0.293 mmol) and p-toluenesulfonic acid monohydrate (8.4 mg, 0.044 mmol) in anhydrous toluene (1 mL) was stirred at 100 ° C for 3h. The reaction mixture was filtered over Celite® and the residue was washed with DCM. The resulting filtrate was concentrated in vacuo.
  • Step 2 To a solution of benzyl (S)-2-(((benzyloxy)carbonyl)amino)-3-(5,5-difluoro-l,3- dioxan-2-yl)propanoate (115 mg, 0.264 mmol) in THF (1.5 mL), MeOH (1.0 mL) and water (1.5 mL) was added sodium hydroxide (85 mg, 2.1 mmol). After stirring at r.t. for Ih, the reaction mixture was neutralized with formic acid (80 pL, 2.1 mmol) and purified by reversed phase chromatography according to Method B2.
  • Step 3 To a solution of (S)-2-(((benzyloxy)carbonyl)amino)-3-(5,5-difluoro-l,3-dioxan-2- yl)propanoic acid (62 mg, 0.18 mmol), HATU (89 mg, 0.23 mmol) and DIPEA (0.16 mL, 0.90 mmol) in DMF (2 mL) was added l-methyl-lH-pyrazol-4-amine (31 pL, 0.36 mmol). After stirring at r.t.
  • Step 4 To a solution of benzyl (S)-(3-(5,5-difluoro-l,3-dioxan-2-yl)-l-((l-methyl-lH- pyrazol-4-yl)amino)-l-oxopropan-2-yl)carbamate (52 mg, 0.12 mmol) in THF (2 mL) was added 10% palladium on activated carbon (20 mg, 9.4 pmol). The reaction mixture was stirred under a hydrogen atmosphere at r.t. for 2h.
  • the concentrate was suspended in THF (170 mL) and acetic acid (1.9 mL, 34 mmol) and sodium borohydride (1.41 g, 37.3 mmol) was added portion-wise. The mixture was stirred at 60 ° C for 2h, then at r.t. for 18h. The reaction mixture was concentrated in vacuo and the concentrate was suspended in a saturated aqueous solution of NaHCO 3 and the resulting mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo.
  • the reaction mixture was purified by reversed phase chromatography according to Method B2 to obtain 5-(((2-(tert-butoxy)-2-oxoethyl)(5-chloro-2-methylpyridin-3- yl)amino)methyl)thiophene-2-carboxylic acid (46.0 mg, 0.12 mmol, 47% yield) as a white solid.
  • Example 7 N -(l-(benzylami no) -l-oxo-3-(tetra hyd ro-2 H- pyran -4-yl) propan -2-yl) -5- (((5- ch loro-2-methy I py rid in-3-yl)amino) methyl) th io phene-2 -carboxamide
  • Example 8 5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(l-(cyclopropylamino) -l- oxo-3 - (tetra hyd ro-2 H - py ra n -4-y I) pro pan -2 -y I) th io phene -2 -carboxamide
  • Example 13 5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-(4, 4- d if I uorocyclohexy I)- 1 -oxo-1 - ((pyrid in -3-yl methyl) a mine) pro an -2 -y I) th iop he ne -2- carboxamide
  • Example 14 5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-(4, 4- dif lu orocyc I oh exyl) -l-((2 - m eth oxyethyl) ami no) -1-oxo pro pan -2 -yl) thio phene -2 -carboxamide
  • Example 16 (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l- oxo-1 -((pyrid in -4-yl methyl) ami no) pro pan -2-yl) th iophene-2-carboxam ide
  • Example 17 (S) -5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3 -cyclopentyl -1- oxo-1 -((pyrid in -2-yl methyl) ami no) propan -2-yl) th iophene-2-carboxam ide
  • Example 21 (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l- oxo-l-((l-(trifluoromethyl)-lH-pyrazol-4-yl)amino) pro pan -2 -y I) th iophene -2 -carboxamide
  • reaction mixture was purified by reversed phase chromatography according to Method B3 to afford 5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)-N-(3-cyclopentyl-l-oxo-l- (thiazol-2-ylamino)propan-2-yl)thiophene-2-carboxamide (5 mg, 0.01 mmol, 21% yield) as a light-yellow solid.
  • LCMS >95% (Method A3).
  • Example 24 5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-((5- methy I isoxazol -3-yl)amino)-l-oxopropan-2-y I) thiophene-2-carboxam ide
  • reaction mixture was purified by reversed phase chromatography according to Method B3 to afford 5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)-N-(3- cyclopentyl-1 -((5- methyl isoxazol -3-yl) ami no) -l-oxopropan-2-yl)thiophene-2-carboxam ide (10 mg, 0.019 mmol, 40% yield) as a light-yellow solid.
  • LCMS >95% (Method A3).
  • reaction mixture was purified by reversed phase chromatography according to Method B3 to afford 5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)-N-(3-cyclopentyl-l- (isoxazol-3-ylamino)-l-oxopropan-2-yl)thiophene-2-carboxamide (12 mg, 0.024 mmol, 50% yield) as a light-yellow solid.
  • LCMS >95% (Method A3).
  • Example 27 N-(l-((l,3,4-thiadiazol-2-yl)amino)-3-cyclopentyl-l-oxopropan-2-yl)-5-(((5- ch loro-2-methy I py rid in-3-yl)amino) methyl) th io phene-2 -carboxamide
  • Example 28 5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-((5- methylthiazol-2-yl)amino)-l-oxopropan-2-yl)thiophene-2-carboxamide
  • Example 30 5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-((l- methyl-lH-pyrazol-5-yl)amino)-l-oxopropan-2-yl)thiophene-2-carboxamide
  • Example 31 5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-((l- methyl-lH-imidazol-4-yl)amino)-l-oxopropan-2-yl)thiophene-2-carboxamide
  • reaction mixture was purified by reversed phase chromatography according to Method B3 to afford 5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)-N-(3- cyclopenty 1-1- ((1- methyl- IH-imidazol -4-yl) ami no)- 1 -oxopropan -2-yl) th iophene-2- carboxamide (4 mg, 0.007 mmol, 15% yield) as a light-yellow solid.
  • LCMS >95% (Method A4).
  • reaction mixture was purified by reversed phase chromatography according to Method B3 to afford 5-(((5-chloro-2-methylpyridin-3- yl)a min o) methyl) -N-(3 -eye I o pentyl- 1-oxo- 1-((5- (trifluoro methyl) -4 H- 1,2, 4 -triazo 1-3- yl)amino)propan-2-yl)thiophene-2-carboxamide (4 mg, 0.007 mmol, 14% yield) as a lightyellow solid.
  • LCMS >95% (Method A3).
  • Example 33 5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-((3- methy I pyrid in -4-yl)amino)-l -oxo pro pan -2-yl) th iophene-2-carboxam ide
  • Example 35 N - (1- ((1 H- benzo [d]imidazol-5-yl)ami no) -3-cyclopentyl-l -oxopropan -2-yl) -5- (((5 -ch loro-2- methy I pyrid in -3-yl) ami no) methyl) th iophene-2-carboxam ide
  • Example 37 5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l-((l- methyl-lH-benzo[d]imidazol-5-yl)amino)-l-oxopropan-2-yl)thiophene-2-carboxamide
  • reaction mixture was purified by reversed phase chromatography according to Method B3 to afford 5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)-N-(3- cyclopentyl-l-((l-methyl-lH-benzo[d]imidazol-5-yl)amino)-l-oxopropan-2-yl)thiophene-2- carboxamide (8 mg, 0.02 mmol, 30% yield) as a chestnut brown solid.
  • LCMS >90% (Method A3).
  • Example 38 (S)-N-(l-((lH-indol-5-yl)amino)-3-cyclopentyl-l-oxopropan-2-yl)-5-(((5- ch loro-2-methy I py rid in-3-yl)amino) methyl) th io phene-2 -carboxamide
  • Example 40 (S)-N-(3-(bicyclo[l.l.l] pentan-l-yl)-l-(cyclopropylamino) -l-oxopropan-2- yl)-5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)thiophene-2-carboxamide
  • Example 41 5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl) -N-((S)-3-(4,4- difluorocyclohexyl)-l-(((lr,3S)-3-hydroxycyclobutyl)amino)-l-oxopropan-2-yl)thiophene-2- carboxamide
  • Example 42 5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-((S)-3-(4, 4- difluorocyclohexyl)-l-(((lr,3S)-3-hydroxy-3-methylcyclobutyl)amino)-l-oxopropan-2- y I) th iophene-2 -carboxamide
  • Example 48 (S)-2-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l- oxo-1 - (py rid azin -4-y lam i no) pro pan -2-yl) th iazole-5-carboxam ide
  • Example 51 (S)-5-(((5-chloro-2-methyl yridin-3-yl)amino) methyl) -N-(3-cyclopentyl-l- oxo-1 -(py rim id in -4-y lam i no) pro pan -2-yl) th io hene-2-carboxam ide
  • Example 54 (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino) methyl) -N-(3-(4, 4- difluorocyclohexyl)-l-oxo-l-(pyridazin-4-ylamino)propan-2-yl)thiophene-2-carboxamide
  • Example 60 (S)-5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl) -N-(3-cyclopentyl-l- ((2-methyl-2H-l,2,3-triazol-4-yl)amino)-l-oxopropan-2-yl)thiophene-2-carboxamide

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Abstract

La présente invention concerne des composés de formule (I) et des sels, un stéréoisomère, un tautomère ou un N-oxyde de ceux-ci qui sont utiles en tant que modulateur ou inhibiteur de la phosphatase Wip1 (PPM1D). La présente invention concerne en outre le composé de formule (I) destiné à être utilisé en tant que médicament et une composition pharmaceutique comprenant lesdits composés.
PCT/EP2023/083804 2023-11-30 2023-11-30 Dérivés de thiophène et de thiazole utilisés en tant qu'inhibiteurs de wip1 Pending WO2025113806A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
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WO2012149102A1 (fr) 2011-04-29 2012-11-01 Glaxosmithkline Llc Nouveaux composés en tant qu'inhibiteurs de wip1
CN105727295A (zh) 2016-03-22 2016-07-06 中国科学院动物研究所 Wip1抑制剂的医学用途
JP2018024645A (ja) 2016-08-04 2018-02-15 学校法人中部大学 プロテインホスファターゼ阻害剤
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CN111118046A (zh) 2020-01-16 2020-05-08 中国人民解放军军事科学院军事医学研究院 一种能够调控MSCs成脂肪分化能力的基因及其衍生产品
JP2021138671A (ja) 2020-03-09 2021-09-16 国立大学法人北海道大学 Ｐｐｍ１ｄ阻害剤

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WO2012149102A1 (fr) 2011-04-29 2012-11-01 Glaxosmithkline Llc Nouveaux composés en tant qu'inhibiteurs de wip1
CN105727295A (zh) 2016-03-22 2016-07-06 中国科学院动物研究所 Wip1抑制剂的医学用途
JP2018024645A (ja) 2016-08-04 2018-02-15 学校法人中部大学 プロテインホスファターゼ阻害剤
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CN111118046A (zh) 2020-01-16 2020-05-08 中国人民解放军军事科学院军事医学研究院 一种能够调控MSCs成脂肪分化能力的基因及其衍生产品
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