WO2016202935A1 - Glucose transport inhibitors - Google Patents
Glucose transport inhibitors Download PDFInfo
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- WO2016202935A1 WO2016202935A1 PCT/EP2016/063918 EP2016063918W WO2016202935A1 WO 2016202935 A1 WO2016202935 A1 WO 2016202935A1 EP 2016063918 W EP2016063918 W EP 2016063918W WO 2016202935 A1 WO2016202935 A1 WO 2016202935A1
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- 0 *c1cnn[n]1I* Chemical compound *c1cnn[n]1I* 0.000 description 2
- AFPQCAAEYNZANJ-UHFFFAOYSA-N CCc1c(NC(c2cc(C(N)=O)nc3c2cccc3)=O)nn[n]1Cc(cc1)ccc1F Chemical compound CCc1c(NC(c2cc(C(N)=O)nc3c2cccc3)=O)nn[n]1Cc(cc1)ccc1F AFPQCAAEYNZANJ-UHFFFAOYSA-N 0.000 description 1
- RDOXTESZEPMUJZ-UHFFFAOYSA-N COc1ccccc1 Chemical compound COc1ccccc1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 1
- CTXJQWPRMXRJQJ-UHFFFAOYSA-N Cc1c(N)[s]c(Cc(cc2)ccc2F)n1 Chemical compound Cc1c(N)[s]c(Cc(cc2)ccc2F)n1 CTXJQWPRMXRJQJ-UHFFFAOYSA-N 0.000 description 1
- KCMIWIAVVQYLIT-UHFFFAOYSA-N Cc1c(NC(c2cc(C(N)=O)nc(cc3F)c2cc3Cl)=O)nn[n]1Cc(cc1)ccc1OC(F)(F)F Chemical compound Cc1c(NC(c2cc(C(N)=O)nc(cc3F)c2cc3Cl)=O)nn[n]1Cc(cc1)ccc1OC(F)(F)F KCMIWIAVVQYLIT-UHFFFAOYSA-N 0.000 description 1
- MMSWTNWGYNRFDO-UHFFFAOYSA-N Cc1c(NC(c2cc(C(N)=O)nc3c2ccc(F)c3)=O)[s]c(Cc2ccc(C)cc2)n1 Chemical compound Cc1c(NC(c2cc(C(N)=O)nc3c2ccc(F)c3)=O)[s]c(Cc2ccc(C)cc2)n1 MMSWTNWGYNRFDO-UHFFFAOYSA-N 0.000 description 1
- VGIMAULRNWKPRP-UHFFFAOYSA-N Cc1c(NC(c2cc(C(N)=O)nc3c2ccc(F)c3)=O)[s]c(Oc(cc2)ccc2F)n1 Chemical compound Cc1c(NC(c2cc(C(N)=O)nc3c2ccc(F)c3)=O)[s]c(Oc(cc2)ccc2F)n1 VGIMAULRNWKPRP-UHFFFAOYSA-N 0.000 description 1
- WGBSJVRXCOQYDC-UHFFFAOYSA-N Cc1c(NC(c2cc(C3CC3)nc(cc3)c2cc3Br)=O)[s]c(Oc2cc(C)ccc2)n1 Chemical compound Cc1c(NC(c2cc(C3CC3)nc(cc3)c2cc3Br)=O)[s]c(Oc2cc(C)ccc2)n1 WGBSJVRXCOQYDC-UHFFFAOYSA-N 0.000 description 1
- MOFFWQQMJWWQKH-UHFFFAOYSA-N Cc1cc(C[n]2nnc(NC(c3cc(C(N)=O)nc(cc4F)c3cc4Cl)=O)c2C)n[o]1 Chemical compound Cc1cc(C[n]2nnc(NC(c3cc(C(N)=O)nc(cc4F)c3cc4Cl)=O)c2C)n[o]1 MOFFWQQMJWWQKH-UHFFFAOYSA-N 0.000 description 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Cc1ccccc1 Chemical compound Cc1ccccc1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 1
- GQHWSLKNULCZGI-UHFFFAOYSA-N FC(Oc1ccccc1)(F)F Chemical compound FC(Oc1ccccc1)(F)F GQHWSLKNULCZGI-UHFFFAOYSA-N 0.000 description 1
- UETQZKWPDOEBTG-UHFFFAOYSA-N N#Cc1ccc(Cc2nc(C(F)(F)F)c(NC(c3cc(Cl)nc4ccccc34)=O)[s]2)cc1 Chemical compound N#Cc1ccc(Cc2nc(C(F)(F)F)c(NC(c3cc(Cl)nc4ccccc34)=O)[s]2)cc1 UETQZKWPDOEBTG-UHFFFAOYSA-N 0.000 description 1
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- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
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- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The present invention relates to quinoline-4-carboxamide derivatives of Formula (I) that selectively inhibit glucose transporter 1 (GLUT1), to methods of preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds, to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, as well as to intermediate compounds useful in the preparation of said compounds.
Description
GLUCOSE TRANSPORT INHIBITORS The present invention relates to chemical compounds that selectively inhibit glucose transporter 1 (GLUT1), to methods of preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds, to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, as well as to intermediate compounds useful in the preparation of said compounds.
BACKGROUND OF THE INVENTION
Glucose is an essential substrate for metabolism in most cells. Because glucose is a polar molecule, transport through biological membranes requires specific transport proteins. Transport of glucose through the apical membrane of intestinal and kidney epithelial cells depends on the presence of secondary active Na+/glucose symporters, SGLT-1 and SGLT-2, which concentrate glucose inside the cells, using the energy provided by co-transport of Na+ ions down their electrochemical gradient. Facilitated diffusion of glucose through the cellular membrane is otherwise catalyzed by glucose carriers (protein symbol GLUT, gene symbol SLC2 for Solute Carrier Family 2) that belong to a superfamily of transport facilitators (major facilitator superfamily) including organic anion and cation transporters, yeast hexose transporter, plant hexose/proton symporters, and bacterial sugar/proton symporters. Basal glucose transporters (GLUTs) function as glucose channels and are required for maintaining the basic glucose needs of cells. These GLUTs are constitutively expressed and functional in cells and are not regulated by (or sensitive to) insulin. All cells use both glycolysis and oxidative phosphorylation in mitochondria but rely overwhelmingly on oxidative phosphorylation when oxygen is abundant, switching to glycolysis at times of oxygen deprivation (hypoxia), as it occurs in cancer. In glycolysis, glucose is converted to pyruvate
and two ATP molecules are generated in the process. Cancer cells, because of their faster proliferation rates, are predominantly in a hypoxic (low oxygen) state. Therefore, cancer cells use glycolysis (lactate formation) as their predominant glucose metabolism pathway. Such a glycolytic switch not only gives cancer higher potentials for metastasis and invasiveness, but also increases cancer's vulnerability to external interference in glycolysis. The reduction of basal glucose transport is likely to restrict glucose supply to cancer cells, leading to glucose deprivation that forces cancer cells to slow down growth or to starve.
All known GLUT proteins contain 12 transmembrane domains and transport glucose by facilitating diffusion, an energy-independent process. GLUT1 transports glucose into cells probably by altemating its conformation. According to this model, GLUT1 exposes a single substrate-binding site toward either the outside or the inside of the cell. Binding of glucose to one site triggers a conformational change, releasing glucose to the other side of the membrane. Results of transgenic and knockout animal studies support an important role for these transporters in the control of glucose utilization, glucose storage and glucose sensing. The GLUT proteins differ in their kinetics and are tailored to the needs of the cell types they serve. Although more than one GLUT protein may be expressed by a particular cell type, cancers frequently overexpress GLUT1, which is a high affinity glucose transporter, and its expression level is correlated with invasiveness and metastasis potentials of cancers, indicating the importance of upregulation of glucose transport in cancer cell growth and in the severity of cancer malignancy. GLUT1 expression was also found to be significantly higher than that of any other glucose transporters. Evidence indicates that cancer cells are more sensitive to glucose deprivation than normal cells. Numerous studies strongly suggest that basal glucose transport inhibition induces apoptosis and blocks cancer cell growth. Anti-
angiogenesis has been shown to be a very effective way to restrict cancer growth and cause cancer ablation. Reduced GLUT1 expression following transfection of GLUT1 antisense cDNA into cancer cell lines has been shown to suppress cell growth in vitro and tumor growth in vivo, and to reduce in vitro invasiveness of cells (Noguchi Y. et al. Cancer Lett 154(2), 2000, 175–182; Ito S. et al. J Natl Cancer Inst 94(14), 2002, 1080–1091). It has been demonstrated that GLUT1 is the most highly expressed hexose transporter in ErbB2- and PyVMT-induced mouse mammary carcinoma models, and that reducing the level of GLUT1 using shRNA or Cre/lox results in reduced glucose usage, reduced growth on plastic and in soft agar, and impaired tumor growth in nude mice (Christian D. Young et al., PLoS ONE, August 2011, Volume 6, Issue 8, e23205, 1-12). Therefore, inhibition of GLUT1 represents a promising approach for the treatment of proliferative disorders including solid tumours such as carcinomas and sarcomas and leukaemias and lymphoid malignancies or other disorders associated with uncontrolled cellular proliferation. Different compounds have been disclosed in prior art which show an inhibitory effect on GLUT1. For example, WO2011/119866(A1) discloses composition and methods for glucose transport inhibition; WO2012/051117(A2) and WO2013/155338(A2) disclose substituted benzamides as GLUT1 inhibitors. Compounds showing a certain structural similarity to the compounds of the present invention are disclosed in prior art. WO97/36881(A1) discloses arylheteroaryl-containing compounds which inhibit farnesyl-protein transferase. WO00/07996(A2) discloses pyrazole estrogen receptor agonist and
antagonist compounds. WO 2000/002871(A1) discloses heteroaromatic inhibitors of tyrosine kinases as antiangiogenic agents. WO 2000/026197(A1) discloses organic compounds as inhibitors of Inosine monophosphate dehydrogenase (IMPDH). WO01/21160(A2) discloses carboxamide derivatives as inhibitors of herpesviridae. WO03/037274(A2) and WO2004/099154(A2) disclose pyrazole-amides as inhibitors of sodium channels. WO2004/098528(A2) discloses pyrazole derived compounds as inhibitors of p38 kinase. WO2006/132197(A1) discloses heterocyclic compounds as inhibitors of 11 - hydroxysteroid dehydrogenase type 1. WO2006/062249(A1) discloses compounds for the prevention, therapy or improvement of a disease to which the activation of a thrombopoietin receptor is effective. WO2008/126899(A1) discloses 5-membered heterocyclic compounds as inhibitors of xanthine oxidase. WO2008/008286(A2) discloses substituted pyrazoles as ghrelin receptor antagonists. WO2009/025793(A2) discloses compounds that function as bitter taste blockers. WO2009/027393(A2) and WO2010/034737(A1) disclose pyrazole compounds for controlling invertebrate pests. WO2009/099193(A1) discloses compounds having inhibitory action on melanin production. WO2009/119880(A1) discloses pyrazole derivatives having an androgen receptor antagonistic action. WO 2010/108115(A1) discloses heteroaromatic compounds as allosteric inhibitors of c-Jun-N-terminal kinases (JNK). WO2011/050305(A1) and WO2011/050316(A1) disclose pyrazole compounds as allosteric modulators of mGluR4 receptor activity. WO 2011/093352(A1) discloses thiazole derivatives as agonists of the GPR52 receptor. WO2011/126903(A2) discloses multisubstituted aromatic compounds including substituted pyrazolyl as thrombin inhibitors. WO 2011/143466(A1) discloses heteroaromatic compounds as allosteric modulators of mGluR4 receptor activity. WO2004/110350(A2) discloses compounds modulating amyloid beta. WO2009/055917(A1) discloses inhibitors of histone deacetylase. WO02/23986(A1) discloses 4- acylaminopyrazole derivatives exhibiting fungicidal activities. WO03/051833(A2) discloses heteroaryl substituted pyrazole compounds as
mGluR5 modulators. WO03/051315(A2) discloses triazole compounds as mGluR5 modulators. WO2009/076454(A2) discloses compounds which modulate the activity of store-operated calcium channels. WO99/32454(A1) discloses nitrogen containing heteroaromatics with ortho-substituted P1 groups as factor Xa inhibitors. WO2004/037248(A2) and WO2004/043951(A1) disclose compounds as modulators of the peroxisome proliferator activated receptors. WO 2013/109991(A1) discloses various heterocyclic compounds for the treatment of neurodegenerative diseases. WO 2014/031936(A2) and WO 2014/031936(A2) disclose heterocyclic compounds as modulators of HIF pathway activity. WO 2014/181287 (A1) discloses heterocyclyl compounds as inhibitors of Interleukine 17 (IL-17) and Tumor Necrosis Factor alpha (TNF-α). However, the state of the art described above does not specifically disclose the compounds of general formula (I) of the present invention, or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, as described and defined herein, and as hereinafter referred to as“compounds of the present invention”, or their pharmacological activity. SUMMARY of the INVENTION
The present invention covers compounds of general formula (I) : A
(I) in which :
A represents a group selected from:
* , * ;
wherein * represents the point of attachment to the nitrogen atom; R1 represents a C1-C3-alkyl-, halo-C1-C3-alkyl-, cyano-, -C(=O)O-R10 or -C(=O)N(R10a)R10b group; R2 represents a group selected from: aryl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ;
wherein said 5- to 6-membered heterocycloalkyl- group is optionally benzocondensed;
wherein said aryl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L2)p-R6; and wherein two -(L2)p-R6 groups, if being present ortho to each other on an aryl- or heteroaryl- group optionally represent a bridge selected from:
*-C3-C8-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*, *-O(CF2)O-*, *-CH 10a
2C(R10a)(R10b)O-*, *-C(=O)N(R )CH2-*, *-N(R10a)C(=O)CH2O-*, *-NHC(=O)NH-*; wherein each * represents the point of attachment to said aryl- or heteroaryl- group; R3 represents a hydrogen atom or group selected from: C1-C3-alkyl-,
C1-C3-alkoxy-(L2)-, hydroxy-C1-C3-alkyl-, aryl-(L2)-, heteroaryl-(L2)-;
R4a represents a hydrogen atom or a halogen atom or a group selected from: cyano-, hydroxy-, C1-C3-alkyl-, halo-C1-C3-alkyl-, C1-C3-alkoxy-, halo-C1-C3-alkoxy-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, -C(=O)-OR10, -C(=O)N(R10a)R10b,
-C(=O)-N(R10a)-S(=O)2-R10, -SR10, -S(=O)-R10, -S(=NR11)-R10, -S(=O)2-R10, -S(=O)2-N(R10a)R10b, -S(=O)(=NR11)-R10, -N(R10a)R10b; R4b represents a hydrogen atom or a group selected from: C1-C3-alkoxy-, C1-C3-alkyl-, cyano- ; or
R4a and together R4b represent a -C3-C5-alkylene- group; R5a, R5b, R5c, R5d
independently from each other represent a hydrogen atom, a halogen atom or a group selected from:
cyano-, -NO2, C1-C3-alkyl-, halo-C1-C3-alkyl-, C1-C3-alkoxy-, halo-C1-C3-alkoxy-, phenyl-, heteroaryl-, -C(=O)R10, -C(=O)N(H)R10, -C(=O)N(R10a)R10b, -C(=O)O-R10, -N(R10a)R10b, -N(H)C(=O)R10, -N(R10a)C(=O)R10b, -N(H)C(=O)N(R10a)R10b, -N(R10a)C(=O)N(R10b)R10c, -N(R10a)C(=O)C(=O)N(R10b)R10c, -N(H)C(=O)OR10, -N(R10a)C(=O)OR10b, -N(H)S(=O)2R10, -N(R10a)S(=O)2R10b, -OR10, -O(C=O)R10, -O(C=O)N(R10a)R10b, -O(C=O)OR10, -SR10, -S(=O)R10, -S(=O)2R10, -S(=O)2N(H)R10, -S(=O)2N(R10a)R10b or -S(=O)(=NR11)-R10 ,
said phenyl- and heteroaryl- group being optionally substituted one or more times, identically or differently, with a group selected from: halo-, cyano-, C1-C3-alkyl-, halo-C1-C3-alkyl-, C1-C3-alkoxy-; R6 represents a group selected from: oxo, C1-C6-alkyl-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, halo-C1-C4-alkyl-, hydroxy-C1-C4-
alkyl-, cyano-C1-C4-alkyl-, C2-C4-alkenyl-, C2-C4-alkynyl-, C1-C4-alkoxy-, halo-C1-C4-alkoxy-, -OH, -CN, halo-, -C(=O)R7, -C(=O)-O-R7, -C(=O)N(R8a)R8b, -N(R10a)R10b, -S(=O)2R7, -S(=O)(=NR11)-R10, phenyl-, 5- to 6-membered heteroaryl-; R7 represents a hydrogen atom or a C1-C6-alkyl-, halo-C1-C3-alkyl-, cyano- C1-C4-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, C3-C7-cycloalkyl-, phenyl-, 5- to 6-membered heteroaryl- or benzyl- group; R8a, R8b
represent, independently from each other, a hydrogen atom, or a C1-C10-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(L3)-, C3-C6-alkenyl-, C3-C6-alkynyl-, 4- to 10-membered heterocycloalkyl-,
(4- to 10-membered heterocycloalkyl)-(L3)-, phenyl-, heteroaryl-, phenyl-(L3)-, (phenyl)-O-(L3)-, heteroaryl-(L3)-, or
(aryl)-(4- to 10-membered heterocycloalkyl)- group; said C1-C10-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(L3)-, C3-C6-alkenyl-, C3-C6-alkynyl-, 4- to 10-membered heterocycloalkyl-, (4- to 10-membered heterocycloalkyl)-(L3)-, phenyl-, heteroaryl-, phenyl-(L3)-, (phenyl)-O-(L3)-, heteroaryl-(L3)-, and (aryl)-(4- to 10-membered heterocycloalkyl)- group being optionally substituted one or more times, identically or differently, with R9;
or
R8a and R8b, together with the nitrogen atom they are attached to,
represent a 4- to 10-membered heterocycloalkyl- group, said 4- to 10- membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R9;
R9 represents a halogen atom, or an oxo, C1-C3-alkyl-, halo-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, -CN, -C(=O)R10, -C(=O)N(H)R10, -C(=O)N(R10a)R10b, -C(=O)O-R10, -N(R10a)R10b, -NO2, -N(H)C(=O)R10, -N(R10a)C(=O)R10b, -N(H)C(=O)N(R10a)R10b, -N(R10a)C(=O)N(R10b)R10c, -N(H)C(=O)OR10, -N(R10a)C(=O)OR10b, -N(H)S(=O)2R10, -N(R10a)S(=O)2R10b, -OR10, -O(C=O)R10, -O(C=O)N(R10a)R10b, -O(C=O)OR10, -SR10, -S(=O)R10, -S(=O)2R10, -S(=O)2N(H)R10, -S(=O)2N(R10a)R10b, -S(=O)(=NR11)R10 or a tetrazolyl- group; or
two R9 groups present ortho to each other on a phenyl- or heteroaryl- ring represent a bridge selected from: *-C3-C5-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*, *-O(CF2)O-*, *-CH2C(R10a)(R10b)O-*, *-C(=O)N(R10a)CH2-*, *-N(R10a)C(=O)CH2O-*, *-NHC(=O)NH-*; wherein each * represents the point of attachment to said phenyl- or heteroaryl- ring; R10, R10a, R10b, R10c
represent, independently from each other, a hydrogen atom or a group selected from: C1-C3-alkyl-, halo-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, C3-C7-cycloalkyl-; or
R10a and R10b, together with the nitrogen atom they are attached to,
represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7- membered heterocycloalkyl-group being optionally substituted one or more times, identically or differently, with R12; R11 represents a hydrogen atom or a cyano-, C1-C3-alkyl-, -C(=O)R10, -C(=O)N(H)R10, -C(=O)N(R10a)R10b or -C(=O)O-R10 group;
R12 represents a halogen atom or a cyano, hydroxy, oxo, C1-C3-alkyl-, trifluoromethyl-, -C(=O)R10 or -C(=O)O-R10 group; R13 represents a hydrogen atom or a C1-C6-alkyl- or benzyl- group; L1 represents a group selected from: -C1-C4-alkylene-, -CH2-CH=CH-, -C(phenyl)(H)-, -CH2-CH2-O-, -CH2-C(=O)-N(H)-, -CH2-C(=O)-N(R10a)-; L2 represents a group selected from:–CH2-,–CH2–CH2-, -CH2-CH2-CH2-; L3 represents a -C1-C6-alkylene- group; L4 represents a group selected from: -C1-C4-alkylene-, -CH2-CH=CH-, -C(phenyl)(H)-, -CH2-CH2-O-, -CH2-C(=O)-N(H)-, -CH2-C(=O)-N(R10a)-, -O-, - N(R13)-; p is an integer of 0 or 1 ; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. The present invention further relates to methods of preparing compounds of general formula (I), to pharmaceutical compositions and combinations comprising said compounds, to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, as well as to intermediate compounds useful in the preparation of said compounds.
DETAILED DESCRIPTION of the INVENTION
The terms as mentioned in the present text have preferably the following meanings : The term“halogen atom” or“halo-” is to be understood as meaning a fluorine, chlorine, bromine or iodine atom, also referred to as fluoro-, chloro-, bromo- and iodo-. The term“oxo” is to be understood as preferably meaning an oxygen atom attached to an atom featuring suitable bonding valence, such as a saturated carbon atom or a sulfur atom, by a double bond, resulting in the formation e.g. of a carbonyl group -C(=O)- or a sulfonyl group -S(=O)2-. The term“C1-C10-alkyl-” is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, e.g. a methyl-, ethyl-, propyl-, butyl-, pentyl-, hexyl-, iso-propyl-, iso-butyl-, sec-butyl-, tert-butyl-, iso-pentyl-, 2-methylbutyl-, 1- methylbutyl-, 1-ethylpropyl-, 1,2-dimethylpropyl-, neo-pentyl-, 1,1- dimethylpropyl-, 4-methylpentyl-, 3-methylpentyl-, 2-methylpentyl-, 1- methylpentyl-, 2-ethylbutyl-, 1-ethylbutyl-, 3,3-dimethylbutyl-, 2,2- dimethylbutyl-, 1,1-dimethylbutyl-, 2,3-dimethylbutyl-, 1,3-dimethylbutyl-, or 1,2-dimethylbutyl-, heptyl-, octyl-, nonyl- or decyl- group, or an isomer thereof. Particularly, said group has 1, 2, 3, 4, 5 or 6 carbon atoms (“C1-C6- alkyl-”), more particularly 1, 2, 3 or 4 carbon atoms (“C1-C4-alkyl-”), e.g. a methyl-, ethyl-, propyl-, butyl-, iso-propyl-, iso-butyl-, sec-butyl-, tert-butyl- group, even more particularly 1, 2 or 3 carbon atoms (“C1-C3-alkyl-”), e.g. a methyl-, ethyl-, n-propyl- or iso-propyl- group. The term“-C1-C8-alkylene-” is understood as preferably meaning a linear or branched, saturated, divalent hydrocarbon chain (or“tether”) having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, e.g.–CH2- (“methylene” or“-C1-alkylene-”) or, for
example -CH2-CH2- (“ethylene” or“-C2-alkylene-”), -CH2-CH2-CH2-, -C(H)(CH3)- CH2- or -C(CH3)2-) (“propylene” or “-C3-alkylene-”), or, for example, –CH2-C(H)(CH3)-CH2-, –CH2-C(CH3)2-), -CH2-CH2-CH2-CH2- (“butylene” or “-C4-alkylene-”),“-C5-alkylene-”, e.g. -CH2-CH2-CH2-CH2-CH2- (“n-pentylene”), or “-C6-alkylene-”, e.g. –CH2-CH2-CH2-CH2-CH2-CH2- (“n-hexylene”) group. Particularly, said alkylene tether has 1, 2, 3, 4, or 5 carbon atoms ("-C1-C5- alkylene-"), more particularly 1 or 2 carbon atoms ("-C1-C2-alkylene-"), or, 3, 4, or 5 carbon atoms("-C3-C5-alkylene-"). The term“halo-C1-C4-alkyl-” is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group in which the term“C1- C4-alkyl-” is defined supra, and in which one or more of the hydrogen atoms is replaced, identically or differently, by a halogen atom. Preferred are halo-C1- C3-alkyl- groups. Particularly, said halogen atom is F, resulting in a group also referred to as“fluoro-C1-C3-alkyl-”. Said halo-C1-C3-alkyl- group or fluoro-C1-C3- alkyl- group is, for example, –CF3, -CHF2, -CH2F, -CF2CF3, or -CH2CF3. Particularly preferred is–CF3, also referred to as“trifluoromethyl-“. The term“cyano-C1-C4-alkyl-” is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group in which the term“C1-C4-alkyl-” is defined supra, and in which one or more of the hydrogen atoms is replaced by a cyano group. Said cyano-C1-C4-alkyl- group is, for example, -CH2CN, -CH2CH2-CN, -C(CN)H-CH3, -C(CN)H-CH2CN, or -CH2CH2CH2CH2-CN. The term“hydroxy-C1-C4-alkyl-” is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group in which the term“C1-C4-alkyl-” is defined supra, and in which one or more of the hydrogen atoms is replaced by a hydroxy group with the proviso that not more than one hydrogen atom attached to a single carbon atom is being replaced. Preferred
are hydroxy-C1-C3-alkyl- groups. Said hydroxy-C1-C4-alkyl- group, or, preferably, hydroxy-C1-C3-alkyl- group is, for example, -CH2OH, -CH2CH2-OH, -C(OH)H-CH3, or -C(OH)H-CH2OH. The term“C1-C4-alkoxy-” is to be understood as preferably meaning a linear or branched, saturated, monovalent group of formula–O-(C1-C4-alkyl-), in which the term “C1-C4-alkyl-” is defined supra, e.g. a methoxy-, ethoxy-, n-propoxy-, iso-propoxy-, n-butoxy-, tert-butoxy. Preferred are C1-C3-alkoxy- groups. The term“halo-C1-C4-alkoxy-” is to be understood as preferably meaning a linear or branched, saturated, monovalent C1-C4-alkoxy- group, as defined supra, in which one or more of the hydrogen atoms is replaced, identically or differently, by a halogen atom. Preferred are halo-C1-C3-alkoxy-groups. Particularly, said halogen atom is F, resulting in a group also referred to as “fluoro-C1-C4-alkoxy-”, or, preferably“fluoro-C1-C3-alkoxy-”. Said halo-C1-C4- alkoxy- group or fluoro-C1-C4-alkoxy- group is, for example,–OCF3, -OCHF2, - OCH2F, -OCF2CF3, or -OCH2CF3. Particularly preferred is–OCF3, also referred to as“trifluoromethoxy-“. The term“C1-C3-alkoxy-C1-C3-alkyl-” is to be understood as preferably meaning a linear or branched, saturated, monovalent C1-C3-alkyl- group, as defined supra, in which one or more of the hydrogen atoms is replaced, identically or differently, by a C1-C3-alkoxy group, as defined supra, e.g. methoxyalkyl-, ethoxyalkyl-, propyloxyalkyl- or iso-propoxyalkyl-. The term“halo-C1-C3-alkoxy-C1-C3-alkyl-” is to be understood as preferably meaning a linear or branched, saturated, monovalent C1-C3-alkoxy-C1-C3-alkyl- group, as defined supra, in which one or more of the hydrogen atoms is replaced, in identically or differently, by a halogen atom. Particularly, said
halogen atom is F, resulting in a group also referred to as “fluoro-C1-C3-alkoxy-C1-C3-alkyl-”. Said halo-C1-C3-alkoxy-C1-C3-alkyl- group or fluoro-C1-C3-alkoxy-C1-C3-alkyl- group is, for example,–CH2CH2OCF3, -CH2CH2OCHF2, -CH2CH2OCH2F, -CH2CH2OCF2CF3, or -CH2CH2OCH2CF3. The term“C2-C6-alkenyl-” is to be understood as preferably meaning a linear or branched, monovalent hydrocarbon group, which contains one or more double bonds, and which has 2, 3, 4, 5 or 6 carbon atoms, particularly 3, 4, 5 or 6 carbon atoms (“C3-C6-alkenyl-”), more particularly 2 or 4 carbon atoms (“C2-C4-alkenyl-”), or 3 or 4 carbon atoms (“C3-C4-alkenyl-”), it being understood that in the case in which said alkenyl- group contains more than one double bond, then said double bonds may be isolated from, or conjugated with, each other. Said alkenyl- group is, for example, a vinyl-, allyl-, (E)-2-methylvinyl-, (Z)-2-methylvinyl-, homoallyl-, (E)-but-2-enyl-, (Z)-but-2-enyl-, (E)-but-1-enyl-, (Z)-but-1-enyl-, pent-4-enyl-, (E)-pent-3-enyl-, (Z)-pent-3-enyl-, (E)-pent-2-enyl-, (Z)-pent-2-enyl-, (E)-pent-1-enyl-, (Z)-pent-1-enyl-, hex-5-enyl-, (E)-hex-4-enyl-, (Z)-hex-4-enyl-, (E)-hex-3-enyl-, (Z)-hex-3-enyl-, (E)-hex-2-enyl-, (Z)-hex-2-enyl-, (E)-hex-1-enyl-, (Z)-hex-1-enyl-, iso-propenyl-, 2-methylprop-2-enyl-, 1-methylprop-2-enyl-, 2-methylprop-1-enyl-, (E)-1-methylprop-1-enyl-, (Z)-1-methylprop-1-enyl-, 3-methylbut-3-enyl-, 2-methylbut-3-enyl-, 1-methylbut-3-enyl-, 3-methylbut-2-enyl-, (E)-2-methylbut-2-enyl-, (Z)-2-methylbut-2-enyl-, (E)-1-methylbut-2-enyl-, (Z)-1-methylbut-2-enyl-, (E)-3-methylbut-1-enyl-, (Z)-3-methylbut-1-enyl-, (E)-2-methylbut-1-enyl-, (Z)-2-methylbut-1-enyl-, (E)-1-methylbut-1-enyl-, (Z)-1-methylbut-1-enyl-, 1,1-dimethylprop-2-enyl-, 1-ethylprop-1-enyl-, 1-propylvinyl-, 1-isopropylvinyl-, 4-methylpent-4-enyl-, 3-methylpent-4-enyl-, 2-methylpent-4-enyl-, 1-methylpent-4-enyl-, 4-methylpent-3-enyl-, (E)-3-methylpent-3-enyl-, (Z)-3-methylpent-3-enyl-, (E)-2-methylpent-3-enyl-, (Z)-2-methylpent-3-enyl-, (E)-1-methylpent-3-enyl-, (Z)-1-methylpent-3-enyl-, (E)-4-methylpent-2-enyl-, (Z)-4-methylpent-2-enyl-,
(E)-3-methylpent-2-enyl-, (Z)-3-methylpent-2-enyl-, (E)-2-methylpent-2-enyl-, (Z)-2-methylpent-2-enyl-, (E)-1-methylpent-2-enyl-, (Z)-1-methylpent-2-enyl-, (E)-4-methylpent-1-enyl-, (Z)-4-methylpent-1-enyl-, (E)-3-methylpent-1-enyl-, (Z)-3-methylpent-1-enyl-, (E)-2-methylpent-1-enyl-, (Z)-2-methylpent-1-enyl-, (E)-1-methylpent-1-enyl-, (Z)-1-methylpent-1-enyl-, 3-ethylbut-3-enyl-, 2-ethylbut-3-enyl-, 1-ethylbut-3-enyl-, (E)-3-ethylbut-2-enyl-, (Z)-3-ethylbut-2-enyl-, (E)-2-ethylbut-2-enyl-, (Z)-2-ethylbut-2-enyl-, (E)-1-ethylbut-2-enyl-, (Z)-1-ethylbut-2-enyl-, (E)-3-ethylbut-1-enyl-, (Z)-3-ethylbut-1-enyl-, 2-ethylbut-1-enyl-, (E)-1-ethylbut-1-enyl-, (Z)-1-ethylbut-1-enyl-, 2-propylprop-2-enyl-, 1-propylprop-2-enyl-, 2-isopropylprop-2-enyl-, 1-isopropylprop-2-enyl-, (E)-2-propylprop-1-enyl-, (Z)-2-propylprop-1-enyl-, (E)-1-propylprop-1-enyl-, (Z)-1-propylprop-1-enyl-, (E)-2-isopropylprop-1-enyl-, (Z)-2-isopropylprop-1-enyl-, (E)-1-isopropylprop-1-enyl-, (Z)-1-isopropylprop-1-enyl-, (E)-3,3-dimethylprop-1-enyl-, (Z)-3,3-dimethylprop-1-enyl-, 1-(1,1-dimethylethyl)ethenyl-, buta-1,3-dienyl-, penta-1,4-dienyl-, hexa-1,5-dienyl-, or methylhexadienyl- group. Particularly, said group is vinyl- or allyl-. The term“C2-C6-alkynyl-” is to be understood as preferably meaning a linear or branched, monovalent hydrocarbon group which contains one or more triple bonds, and which contains 2, 3, 4, 5 or 6 carbon atoms, particularly 3, 4, 5 or 6 carbon atoms (“C3-C6-alkynyl-”), more particularly 2 or 4 carbon atoms (“C2-C4-alkynyl-”), or 3 or 4 carbon atoms (“C3-C4-alkynyl-”). Said C2-C6-alkynyl- group is, for example, ethynyl-, prop-1-ynyl-, prop-2-ynyl-, but-1-ynyl-, but-2-ynyl-, but-3-ynyl-, pent-1-ynyl-, pent-2-ynyl-, pent-3-ynyl-, pent-4-ynyl-, hex-1-ynyl-, hex-2-ynyl-, hex-3-ynyl-, hex-4-ynyl-, hex-5-ynyl-, 1-methylprop-2-ynyl-, 2-methylbut-3-ynyl-, 1-methylbut-3-ynyl-, 1-methylbut-2-ynyl-, 3-methylbut-1-ynyl-, 1-ethylprop-2-ynyl-, 3-methylpent-4-ynyl-, 2-methylpent-4-ynyl-, 1-methylpent-4-ynyl-,
2-methylpent-3-ynyl-, 1-methylpent-3-ynyl-, 4-methylpent-2-ynyl-, 1-methyl- pent-2-ynyl-, 4-methylpent-1-ynyl-, 3-methylpent-1-ynyl-, 2-ethylbut-3-ynyl-, 1-ethylbut-3-ynyl-, 1-ethylbut-2-ynyl-, 1-propylprop-2-ynyl-, 1-isopropylprop-2-ynyl-,
2,2-dimethylbut-3-ynyl-, 1,1-dimethylbut-3-ynyl-, 1,1-dimethylbut-2-ynyl-, or 3,3-dimethylbut-1-ynyl- group. Particularly, said alkynyl- group is ethynyl-, prop-1-ynyl-, or prop-2-ynyl-. The term“C3-C7-cycloalkyl-” is to be understood as meaning a saturated, monovalent, monocyclic hydrocarbon ring which contains 3, 4, 5, 6 or 7 carbon atoms. Said C3-C7-cycloalkyl- group is for example a cyclopropyl-, cyclobutyl-, cyclopentyl-, cyclohexyl- or cycloheptyl- ring. Particularly, said ring contains 3, 4, 5 or 6 carbon atoms (“C3-C6-cycloalkyl-”), more particularly, said ring contains 5 or 6 carbon atoms (“C5-C6-cycloalkyl-”). The term“4- to 10-membered heterocycloalkyl-” is to be understood as meaning a saturated, monovalent, mono- or bicyclic hydrocarbon ring which contains 3, 4, 5, 6, 7, 8 or 9 carbon atoms, and one or more heteroatom-containing groups selected from -O-, -S-, -S(=O)-, -S(=O)2-, -NRa-, in which Ra represents a hydrogen atom or a C1-C6-alkyl- or C3-C7-cycloalkyl- group; it being possible for said heterocycloalkyl- group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, a nitrogen atom. Heterospirocycloalkyl-, heterobicycloalkyl- and bridged heterocycloalkyl-, as defined infra, are also included within the scope of this definition. The term "heterospirocycloalkyl-" is to be understood as meaning a saturated, monovalent bicyclic hydrocarbon radical in which the two rings share one common ring carbon atom, and wherein said bicyclic hydrocarbon radical contains 3, 4, 5, 6, 7, 8 or 9 carbon atoms, and one or more
heteroatom-containing groups selected from -O-, -S-, -S(=O)-, -S(=O)2-, -NRa-, in which Ra represents a hydrogen atom or a C1-C6-alkyl-- or C3-C7-cycloalkyl- group; it being possible for said heterospirocycloalkyl- group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, a nitrogen atom. Said heterospirocycloalkyl- group is, for example, azaspiro[2.3]hexyl-, azaspiro[3.3]heptyl-, oxaazaspiro[3.3]heptyl-, thiaazaspiro[3.3]heptyl-, oxaspiro[3.3]heptyl-, oxazaspiro[5.3]nonyl-, oxazaspiro[4.3]octyl-, oxazaspiro[5.5]undecyl-, diazaspiro[3.3]heptyl-, thiazaspiro[3.3]heptyl-, thiazaspiro[4.3]octyl-, or azaspiro[5.5]decyl-. The term "heterobicycloalkyl-" is to be understood as meaning a saturated, monovalent bicyclic hydrocarbon radical in which the two rings share two immediately adjacent ring atoms, and wherein said bicyclic hydrocarbon radical contains 3, 4, 5, 6, 7, 8 or 9 carbon atoms, and one or more heteroatom-containing groups selected from -O-, -S-, -S(=O)-, -S(=O)2-, -NRa-, in which Ra represents a hydrogen atom or a C1-C6-alkyl- or C3-C7-cycloalkyl- group; it being possible for said heterobicycloalkyl- group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, a nitrogen atom. Said heterobicycoalkyl- group is, for example, azabicyclo[3.3.0]octyl-, azabicyclo[4.3.0]nonyl-, diazabicyclo[4.3.0]nonyl-, oxazabicyclo[4.3.0]nonyl-, thiazabicyclo[4.3.0]nonyl-, or azabicyclo[4.4.0]decyl-. The term "bridged heterocycloalkyl-" is to be understood as meaning a saturated, monovalent bicyclic hydrocarbon radical in which the two rings share two common ring atoms which are not immediately adjacent, and wherein said bicyclic hydrocarbon radical contains 3, 4, 5, 6, 7, 8 or 9 carbon atoms, and one or more heteroatom-containing groups selected from -O-, -S-, - S(=O)-, -S(=O)2-, -NRa-, in which Ra represents a hydrogen atom, or a
C1-C6-alkyl- or C3-C7-cycloalkyl- group; it being possible for said bridged
heterocycloalkyl- group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, a nitrogen atom. Said bridged
heterocycloalkyl- group is, for example,
azabicyclo[2.2.1]heptyl-, oxazabicyclo[2.2.1]heptyl-,
thiazabicyclo[2.2.1]heptyl-, diazabicyclo[2.2.1]heptyl-,
azabicyclo[2.2.2]octyl-, diazabicyclo[2.2.2]octyl-, oxazabicyclo[2.2.2]octyl-, thiazabicyclo[2.2.2]octyl-, azabicyclo[3.2.1]octyl-, diazabicyclo[3.2.1]octyl-, oxazabicyclo[3.2.1]octyl-, thiazabicyclo[3.2.1]octyl-, azabicyclo[3.3.1]nonyl-, diazabicyclo[3.3.1]nonyl-, oxazabicyclo[3.3.1]nonyl-,
thiazabicyclo[3.3.1]nonyl-, azabicyclo[4.2.1]nonyl-, diazabicyclo[4.2.1]nonyl-, oxazabicyclo[4.2.1]nonyl, thiazabicyclo[4.2.1]nonyl-, azabicyclo[3.3.2]decyl-, diazabicyclo[3.3.2]decyl-, oxazabicyclo[3.3.2]decyl-,
thiazabicyclo[3.3.2]decyl-, or azabicyclo[4.2.2]decyl-. Particularly, said 4- to 10-membered heterocycloalkyl- can contain 3, 4, 5 or 6 carbon atoms, and one or more of the above-mentioned heteroatom-containing groups (a“4- to 7-membered heterocycloalkyl-”), more particularly said heterocycloalkyl- can contain 4 or 5 carbon atoms, and one or more of the above-mentioned heteroatom-containing groups (a “5- to 6-membered heterocycloalkyl-”). Particularly, without being limited thereto, said heterocycloalkyl- can be a 4-membered ring, such as an azetidinyl-, oxetanyl-, or a 5-membered ring, such as tetrahydrofuranyl-, pyrrolidinyl-, imidazolidinyl-, pyrazolidinyl-, or a 6-membered ring, such as tetrahydropyranyl-, piperidinyl-, morpholinyl-, dithianyl-, thiomorpholinyl-, piperazinyl-, or trithianyl-, or a 7-membered ring, such as a diazepanyl- ring, for example. The term“aryl-” is to be understood as preferably meaning a monovalent, aromatic, mono-, or bi- or tricyclic hydrocarbon ring system having 6, 7, 8, 9,
10, 11, 12, 13 or 14 carbon atoms (a“C6-C14-aryl-” group), particularly a group having 6 carbon atoms (a“C6-aryl-” group), e.g. a phenyl- group; or a group having 9 carbon atoms (a“C9-aryl-” group), e.g. an indanyl- or indenyl- group, or a group having 10 carbon atoms (a“C10-aryl-” group), e.g. a tetralinyl-, dihydronaphthyl-, or naphthyl- group, or a biphenyl- group (a“C12-aryl-” group), or a group having 13 carbon atoms, (a“C13-aryl-” group), e.g. a fluorenyl- group, or a group having 14 carbon atoms, (a“C14-aryl-” group), e.g. an anthracenyl- group. Preferably, the aryl- group is a phenyl- group. The term“heteroaryl-” is understood as preferably meaning an“aryl-“ group as defined supra, in which at least one of the carbon ring atoms is replaced by a heteroatom selected from oxygen, nitrogen, and sulphur. The“heteroaryl-“ group contains 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms (a“5- to 14-membered heteroaryl-” group), particularly 5 or 6 or 9 or 10 ring atoms (a “5- to 10-membered heteroaryl-” group), more particularly 5 or 6 ring atoms (a “5- to 6-membered heteroaryl-” group). Particularly, heteroaryl- is selected from thienyl-, furanyl-, pyrrolyl-, oxazolyl-, thiazolyl-, imidazolyl-, pyrazolyl-, isoxazolyl-, isothiazolyl-, oxadiazolyl-, triazolyl-, thiadiazolyl-, thia-4H-pyrazolyl-, tetrazolyl-, etc., and benzo derivatives thereof, such as, for example, benzofuranyl-, benzothienyl-, benzoxazolyl-, benzisoxazolyl-, benzimidazolyl-, benzotriazolyl-, benzothiadiazolyl-, indazolyl-, indolyl-, isoindolyl-, etc.; or pyridyl-, pyridazinyl-, pyrimidyl-, pyrazinyl-, triazinyl-, etc., and benzo derivatives thereof, such as, for example, quinolinyl-, quinazolinyl-, isoquinolinyl-, etc.; or azocinyl-, indolizinyl-, purinyl-, etc., and benzo derivatives thereof; or cinnolinyl-, phthalazinyl-, quinazolinyl-, quinoxalinyl-, naphthpyridinyl-, pteridinyl-, carbazolyl-, acridinyl-, phenazinyl- , phenothiazinyl-, phenoxazinyl-, xanthenyl-, or oxepinyl-, and further bi- or tricyclic heteroaryl- groups featuring heteroatoms in more than one rings such as pyrrolopyrazolyl-, imidazopyrazolyl-, thienopyrrolyl-, pyrrolooxazolyl-,
pyrrolopyridyl-, thienopyrimidyl-, imidazopyrimidyl-, imidazopyridazinyl-, imidazopyridyl-, thiazolopyridyl-, pyrazolopyridyl-, pyrrolotriazinyl-, etc.. Particularly,“5- to 6-membered heteroaryl-” is selected from thienyl-, furanyl- , pyrrolyl-, oxazolyl-, thiazolyl-, imidazolyl-, pyrazolyl-, isoxazolyl-, isothiazolyl-, oxadiazolyl-, triazolyl-, thiadiazolyl-, thia-4H-pyrazolyl-, tetrazolyl-, pyridyl-, pyridazinyl-, pyrimidyl-, pyrazinyl-, triazinyl-, etc.. In general, and unless otherwise mentioned, the heteroarylic or heteroarylenic radicals include all the possible isomeric forms thereof, e.g. the positional isomers thereof. Thus, for some illustrative non-restricting example, the term pyridyl- includes pyridin-2-yl-, pyridin-3-yl-, and pyridin-4-yl-; or the term thienyl- includes thien-2-yl- and thien-3-yl-. Preferably, the heteroaryl- group is a pyridyl- group. The term“C1-C6”, as used throughout this text, e.g. in the context of the definition of “C1-C6-alkyl-” is to be understood as meaning an alkyl- group having a finite number of carbon atoms of 1 to 6, i.e. 1, 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term“C1-C6” is to be interpreted as any sub-range comprised therein, e.g. C1-C6 , C2-C5 , C3-C4 ,
C1-C2 , C1-C3 , C1-C4 , C1-C5 , C1-C6 ; particularly C1-C2 , C1-C3 , C1-C4 , C1-C5 , C1-C6 ; more particularly C1-C4 ; in the case of“C1-C3-haloalkyl-” or“halo-C1-C3-alkoxy- ” even more particularly C1-C2. Similarly, as used herein, the term“C2-C6”, as used throughout this text, e.g. in the context of the definitions of“C2-C6-alkenyl-” and“C2-C6-alkynyl-”, is to be understood as meaning an alkenyl- group or an alkynyl group having a finite number of carbon atoms of 2 to 6, i.e. 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term“C2-C6” is to be interpreted as any sub-range comprised therein, e.g. C2-C6 , C3-C5 , C3-C4 , C2-C3 , C2-C4 , C2-C5 ; particularly C2- C3.
Further, as used herein, the term“C3-C7”, as used throughout this text, e.g. in the context of the definition of “C3-C7-cycloalkyl”, is to be understood as meaning a cycloalkyl group having a finite number of carbon atoms of 3 to 7, i.e. 3, 4, 5, 6 or 7 carbon atoms. It is to be understood further that said term “C3-C7” is to be interpreted as any sub-range comprised therein, e.g. C3-C6 , C4- C5 , C3-C5 , C3-C4 , C4-C6, C5-C7 ; particularly C3-C6. As used herein, the term“leaving group” refers to an atom or a group of atoms that is displaced in a chemical reaction as stable species taking with it the bonding electrons. The leaving group as used herein is suitable for nucleophilic aliphatic and/or aromatic substitution, e.g. a halogen atom, in particular chloro-, bromo- or iodo-, or a group selected from methanesulfonyloxy-, p-toluenesulfonyloxy-, trifluoromethanesulfonyloxy-, nonafluorobutanesulfonyloxy-, (4-bromo-benzene)sulfonyloxy-, (4-nitro-benzene)sulfonyloxy-, (2-nitro-benzene)-sulfonyloxy-, (4-isopropyl-benzene)sulfonyloxy-, (2,4,6-tri-isopropyl-benzene)-sulfonyloxy-, (2,4,6-trimethyl-benzene)sulfonyloxy-, (4-tert-butyl-benzene)sulfonyloxy-, benzenesulfonyloxy-, and (4-methoxy-benzene)sulfonyloxy-. As used herein, the term“protective group” is a protective group attached to a nitrogen in intermediates used for the preparation of compounds of the general formula (I). Such groups are introduced e.g. by chemical modification of the respective amino group in order to obtain chemoselectivity in a subsequent chemical reaction. Protective groups for amino groups are descibed for example in T.W. Greene and P.G.M. Wuts in Protective Groups in Organic Synthesis, 3rd edition, Wiley 1999; more specifically, said groups can be selected from substituted sulfonyl groups, such as mesyl-, tosyl- or phenylsulfonyl-, acyl groups such as benzoyl-, acetyl- or tetrahydropyranoyl-,
or carbamate based groups, such as tert.-butoxycarbonyl- (Boc), or can include silicon, as in e.g. 2-(trimethylsilyl)ethoxymethyl- (SEM). As used herein, the term“one or more times”, e.g. in the definition of the substituents of the compounds of the general formulae of the present invention, is understood as meaning“one, two, three, four or five times, particularly one, two, three or four times, more particularly one, two or three times, even more particularly one or two times”. Where the plural form of the word compounds, salts, polymorphs, hydrates, solvates and the like, is used herein, this is taken to mean also a single compound, salt, polymorph, isomer, hydrate, solvate or the like. The compounds of this invention contain one or more asymmetric centres, depending upon the location and nature of the various substituents desired. Asymmetric carbon atoms may be present in the (R) or (S) configuration. In certain instances, asymmetry may also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds. Substituents on a ring may also be present in either cis or trans form. It is intended that all such configurations are included within the scope of the present invention. Preferred compounds are those which produce the more desirable biological activity. Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of this invention are also included within the scope of the present invention. The purification and the separation of such materials can be accomplished by standard techniques known in the art.
The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers. Examples of appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, for example, by chromatography or fractional crystallisation. The optically active bases or acids are then liberated from the separated diastereomeric salts. A different process for separation of optical isomers involves the use of chiral chromatography (e.g., chiral HPLC columns), with or without conventional derivatisation, optimally chosen to maximise the separation of the enantiomers. Suitable chiral HPLC columns are manufactured by Diacel, e.g., Chiracel OD and Chiracel OJ among many others, all routinely selectable. Enzymatic separations, with or without derivatisation, are also useful. The optically active compounds of this invention can likewise be obtained by chiral syntheses utilizing optically active starting materials. In order to limit different types of isomers from each other reference is made to IUPAC Rules Section E (Pure Appl Chem 45, 11-30, 1976). The invention also includes all suitable isotopic variations of a compound of the invention. An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually or predominantly found in nature. Examples of isotopes that can be incorporated into a compound of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, chlorine, bromine and iodine, such as 2H (deuterium), 3H (tritium), 11C, 13C, 14C, 15N, 17O, 18O, 32P, 33P, 33S, 34S,
35S, 36S, 18F, 36Cl, 82Br, 123I, 124I, 129I and 131I, respectively. Certain isotopic variations of a compound of the invention, for example, those in which one or more radioactive isotopes such as 3H or 14C are incorporated, are useful in drug and/or substrate tissue distribution studies. Tritiated and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances. Isotopic variations of a compound of the invention can generally be prepared by conventional procedures known by a person skilled in the art such as by the illustrative methods or by the preparations described in the examples hereafter using appropriate isotopic variations of suitable reagents. The present invention includes all possible stereoisomers of the compounds of the present invention as single stereoisomers, or as any mixture of said stereoisomers, in any ratio. Isolation of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound of the present invention may be achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example. Further, the compounds of the present invention may exist as tautomers. For example, any compound of the present invention which contains a pyrazole moiety as a heteroaryl group for example can exist as a 1H tautomer, or a 2H tautomer, or even a mixture in any amount of the two tautomers, or a triazole moiety for example can exist as a 1H tautomer, a 2H tautomer, or a 4H tautomer, or even a mixture in any amount of said 1H, 2H and 4H tautomers, viz. :
1H-tautomer 2H-tautomer 4H-tautomer. The present invention includes all possible tautomers of the compounds of the present invention as single tautomers, or as any mixture of said tautomers, in any ratio. Further, the compounds of the present invention can exist as N-oxides, which are defined in that at least one nitrogen of the compounds of the present invention is oxidised. The present invention includes all such possible N-oxides. The present invention also relates to useful forms of the compounds as disclosed herein, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and co-precipitates. The compounds of the present invention can exist as a hydrate, or as a solvate, wherein the compounds of the present invention contain polar solvents, in particular water, methanol or ethanol for example as structural element of the crystal lattice of the compounds. The amount of polar solvents, in particular water, may exist in a stoichiometric or non-stoichiometric ratio. In the case of stoichiometric solvates, e.g. a hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri- , tetra-, penta- etc. solvates or hydrates, respectively, are possible. The present invention includes all such hydrates or solvates. Further, the compounds of the present invention can exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or can exist in the form of a salt. Said salt may be any salt, either an organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt, customarily used in pharmacy.
The term“pharmaceutically acceptable salt" refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention. For example, see S. M. Berge, et al.“Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1-19. The present invention includes all possible salts of the compounds of the present invention as single salts, or as any mixture of said salts, in any ratio. Furthermore, the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as single polymorphs, or as a mixture of more than one polymorphs, in any ratio. In accordance with a first aspect, the present invention relates to compounds of general formula (I-1) :
(I-1)
in which : R1 represents a C1-C3-alkyl-, halo-C1-C3-alkyl-, cyano-, -C(=O)O-R10 or -C(=O)N(R10a)R10b group;
R2 represents a group selected from: aryl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ;
wherein said 5- to 6-membered heterocycloalkyl- group is optionally benzocondensed;
wherein said aryl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L2)p-R6; and wherein two -(L2)p-R6 groups, if being present ortho to each other on an aryl- or heteroaryl- group optionally represent a bridge selected from:
*-C3-C8-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*, *-O(CF2)O-*, *-CH2C(R10a)(R10b)O-*, *-C(=O)N(R10a)CH2-*, *-N(R10a)C(=O)CH2O-*, *-NHC(=O)NH-*; wherein each * represents the point of attachment to said aryl- or heteroaryl- group; R3 represents a hydrogen atom or group selected from: C1-C3-alkyl-,
C1-C3-alkoxy-(L2)-, hydroxy-C1-C3-alkyl-, aryl-(L2)-, heteroaryl-(L2)-; R4a represents a hydrogen atom or a halogen atom or a group selected from: cyano-, hydroxy-, C1-C3-alkyl-, halo-C1-C3-alkyl-, C1-C3-alkoxy-, halo-C1-C3-alkoxy-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, -C(=O)-OR10, -C(=O)N(R10a)R10b,
-C(=O)-N(R10a)-S(=O)2-R10, -SR10, -S(=O)-R10, -S(=NR11)-R10, -S(=O)2-R10, -S(=O)2-N(R10a)R10b, -S(=O)(=NR11)-R10, -N(R10a)R10b; R4b represents a hydrogen atom or a group selected from: C1-C3-alkoxy-, C1-C3-alkyl-, cyano- ; or
R4a and together R4b represent a -C3-C5-alkylene- group; R5a, R5b, R5c, R5d
independently from each other represent a hydrogen atom, a halogen atom or a group selected from:
cyano-, -NO2, C1-C3-alkyl-, halo-C1-C3-alkyl-, C1-C3-alkoxy-, halo-C1-C3-alkoxy-, phenyl-, heteroaryl-, -C(=O)R10, -C(=O)N(H)R10, -C(=O)N(R10a)R10b, -C(=O)O-R10, -N(R10a)R10b, -N(H)C(=O)R10, -N(R10a)C(=O)R10b, -N(H)C(=O)N(R10a)R10b, -N(R10a)C(=O)N(R10b)R10c, -N(R10a)C(=O)C(=O)N(R10b)R10c, -N(H)C(=O)OR10, -N(R10a)C(=O)OR10b, -N(H)S(=O)2R10, -N(R10a)S(=O)2R10b, -OR10, -O(C=O)R10, -O(C=O)N(R10a)R10b, -O(C=O)OR10, -SR10, -S(=O)R10, -S(=O)2R10, -S(=O)2N(H)R10, -S(=O)2N(R10a)R10b or -S(=O)(=NR11)-R10 ,
said phenyl- and heteroaryl- group being optionally substituted one or more times, identically or differently, with a group selected from: halo-, cyano-, C1-C3-alkyl-, halo-C1-C3-alkyl-, C1-C3-alkoxy-; R6 represents a group selected from: oxo, C1-C6-alkyl-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, halo-C1-C4-alkyl-, hydroxy-C1-C4- alkyl-, cyano-C1-C4-alkyl-, C2-C4-alkenyl-, C2-C4-alkynyl-, C1-C4-alkoxy-, halo-C1-C4-alkoxy-, -OH, -CN, halo-, -C(=O)R7, -C(=O)-O-R7, -C(=O)N(R8a)R8b, -N(R10a)R10b, -S(=O)2R7, -S(=O)(=NR11)-R10, phenyl-, 5- to 6-membered heteroaryl-; R7 represents a hydrogen atom or a C1-C6-alkyl-, halo-C1-C3-alkyl-, cyano- C1-C4-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, C3-C7-cycloalkyl-, phenyl-, 5- to 6-membered heteroaryl- or benzyl- group; R8a, R8b
represent, independently from each other, a hydrogen atom, or a C1-C10-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(L3)-, C3-C6-alkenyl-, C3-C6-alkynyl-, 4- to 10-membered heterocycloalkyl-,
(4- to 10-membered heterocycloalkyl)-(L3)-, phenyl-, heteroaryl-, phenyl-(L3)-, (phenyl)-O-(L3)-, heteroaryl-(L3)-, or
(aryl)-(4- to 10-membered heterocycloalkyl)- group; said C1-C10-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(L3)-, C3-C6-alkenyl-, C3-C6-alkynyl-, 4- to 10-membered heterocycloalkyl-, (4- to 10-membered heterocycloalkyl)-(L3)-, phenyl-, heteroaryl-, phenyl-(L3)-, (phenyl)-O-(L3)-, heteroaryl-(L3)-, and (aryl)-(4- to 10-membered heterocycloalkyl)- group being optionally substituted one or more times, identically or differently, with R9;
or
R8a and R8b, together with the nitrogen atom they are attached to,
represent a 4- to 10-membered heterocycloalkyl- group, said 4- to 10- membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R9; R9 represents a halogen atom, or an oxo, C1-C3-alkyl-, halo-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, -CN, -C(=O)R10, -C(=O)N(H)R10, -C(=O)N(R10a)R10b, -C(=O)O-R10, -N(R10a)R10b, -NO2, -N(H)C(=O)R10, -N(R10a)C(=O)R10b, -N(H)C(=O)N(R10a)R10b, -N(R10a)C(=O)N(R10b)R10c, -N(H)C(=O)OR10, -N
-OR10, -O(C=O)R10, -O(C=O)N(R10a)R10b, -O(C=O)OR10, -SR10, -S(=O)R10, -S(=O)2R10, -S(=O) b
2N(H)R10, -S(=O)2N(R10a)R10 , -S(=O)(=NR11)R10 or a tetrazolyl- group; or
two R9 groups present ortho to each other on a phenyl- or heteroaryl- ring represent a bridge selected from: *-C3-C5-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*, *-O(CF2)O-*, *-CH2C(R10a)(R10b)O-*, *-C(=O)N(R10a)CH2-*, *-N(R10a)C(=O)CH2O-*, *-NHC(=O)NH-*; wherein each * represents the point of attachment to said phenyl- or heteroaryl- ring; R10, R10a, R10b, R10c
represent, independently from each other, a hydrogen atom or a group selected from: C1-C3-alkyl-, halo-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, C3-C7-cycloalkyl-; or
R10a and R10b, together with the nitrogen atom they are attached to,
represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7- membered heterocycloalkyl-group being optionally substituted one or more times, identically or differently, with R12; R11 represents a hydrogen atom or a cyano-, C1-C3-alkyl-, -C(=O)R10, -C(=O)N(H)R10, -C(=O)N(R10a)R10b or -C(=O)O-R10 group; R12 represents a halogen atom or a cyano, hydroxy, oxo, C1-C3-alkyl-, trifluoromethyl-, -C(=O)R10 or -C(=O)O-R10 group; L1 represents a group selected from: -C1-C4-alkylene-, -CH2-CH=CH-, -C(phenyl)(H)-, -CH2-CH2-O-, -CH2-C(=O)-N(H)-, -CH2-C(=O)-N(R10a)-; L2 represents a group selected from:–CH2-,–CH2–CH2-, -CH2-CH2-CH2-; L3 represents a -C1-C6-alkylene- group;
p is an integer of 0 or 1 ; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
In a preferred embodiment, the invention relates to compounds of formula (I- 1), supra, wherein R1 represents a C1-C3-alkyl-, halo-C1-C3-alkyl- or cyano- group. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R1 represents a C1-C3-alkyl- or halo-C1-C3-alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R1 represents a C1-C3-alkyl- or fluoro-C1-C3-alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R1 represents a C1-C3-alkyl- or trifluoromethyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R1 represents a C1-C3-alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R1 represents a methyl- or trifluoromethyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R1 represents a methyl- or ethyl- group.
In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R1 represents a methyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R1 represents an ethyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R1 represents a trifluoromethyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R2 represents a group selected from: phenyl-, 5- to 6-membered heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ;
wherein said phenyl-, 5- to 6-membered heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L2)p-R6;
and wherein two -(L2)p-R6 groups, if being present ortho to each other on a phenyl- or 5- to 6-membered heteroaryl- group optionally represent a bridge selected from: *-C3-C8-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*, *-O(CF2)O-*, *-CH2C(R10a)(R10b)O-*, *-C(=O)N(R10a)CH2-*, *-N(R10a)C(=O)CH2O-*, *-NHC(=O)NH-*; wherein each * represents the point of attachment to said phenyl- or 5- to 6-membered heteroaryl- group. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R2 represents a group selected from: phenyl-, 5- to 6-membered heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ;
wherein said phenyl-, 5- to 6-membered heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L2)p-R6;
and wherein two -(L2)p-R6 groups, if being present ortho to each other on a phenyl- or 5- to 6-membered heteroaryl- group optionally represent a bridge selected from: *-C3-C4-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*; wherein each * represents the point of attachment to said phenyl- or 5- to 6-membered heteroaryl- group. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R2 represents a group selected from: phenyl-, 5- to 6-membered heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ;
wherein said phenyl-, 5- to 6-membered heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L2)p-R6;
and wherein two -(L2)p-R6 groups, if being present ortho to each other on a phenyl- or 5- to 6-membered heteroaryl- group optionally represent a bridge selected from: *-C3-C4-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*; wherein each * represents the point of attachment to said phenyl- or 5- to 6-membered heteroaryl- group,
and in which compounds R1 represents a methyl- group, R3 represents a hydrogen atom, R4b represents a hydrogen atom and L1 represents a -CH2- group. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R2 represents a group selected from: phenyl-, 5- to 6-membered heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ;
wherein said phenyl-, 5- to 6-membered heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with R6. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R2 represents a group selected from: phenyl-, 5- to 6-membered heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ;
wherein said phenyl-, 5- to 6-membered heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with R6,
and in which compounds R1 represents a methyl- group, R3 represents a hydrogen atom, R4b represents a hydrogen atom and L1 represents a -CH2- group. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R2 represents a group selected from: phenyl-, 5- to 6-membered heteroaryl- and C5-C6-cyloalkyl- ;
wherein said phenyl-, 5- to 6-membered heteroaryl- and C5-C6-cyloalkyl- group is optionally substituted, one or more times, identically or differently, with– and wherein two -(L2)p-R6 groups, if being present ortho to each other on a phenyl- or 5- to 6-membered heteroaryl- group optionally represent a bridge selected from: *-C3-C4-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*; wherein each * represents the point of attachment to said phenyl- or 5- to 6-membered heteroaryl- group. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R2 represents a group selected from: phenyl-, 5- to 6-membered heteroaryl- and C5-C6-cyloalkyl- ;
wherein said phenyl-, 5- to 6-membered heteroaryl- and C5-C6-cyloalkyl- group is optionally substituted, one or more times, identically or differently, with– and wherein two -(L2)p-R6 groups, if being present ortho to each other on a phenyl- or 5- to 6-membered heteroaryl- group optionally represent a bridge selected from: *-C3-C4-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*; wherein each * represents the point of attachment to said phenyl- or 5- to 6-membered heteroaryl- group,
and in which compounds R1 represents a methyl- group, R3 represents a hydrogen atom, R4b represents a hydrogen atom and L1 represents a -CH2- group. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R2 represents a group selected from: phenyl-, 5- to 6-membered heteroaryl- and C5-C6-cyloalkyl- ;
wherein said phenyl- 5- to 6-membered heteroaryl- and C5-C6-cyloalkyl- group is optionally substituted, one or more times, identically or differently, with R6. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R2 represents a group selected from: phenyl-, 5- to 6-membered heteroaryl- and C5-C6-cyloalkyl- ;
wherein said phenyl- and 5- to 6-membered heteroaryl- group is optionally substituted, one or more times, identically or differently, with R6. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R2 represents a group selected from: phenyl-, 5- to 6-membered heteroaryl- and C5-C6-cyloalkyl- ;
wherein said phenyl- and 5- to 6-membered heteroaryl- group is optionally substituted, one or more times, identically or differently, with R6,
and in which compounds R1 represents a methyl- group, R3 represents a hydrogen atom, R4b represents a hydrogen atom and L1 represents a -CH2- group. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R2 represents a group selected from: phenyl-, isoxazolyl-, oxadiazolyl- and cyclopentyl-;
wherein said phenyl-, isoxazolyl- and oxadiazolyl- group is optionally substituted, one or two times, identically or differently, with R6 In another particularly preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R2 represents a phenyl- group ; wherein said phenyl- group is optionally substituted, one or more times, identically or differently, with R6. In another particularly preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R2 represents a phenyl- group ; wherein said phenyl- group is optionally substituted, one or more times, identically or differently, with R6,
and in which compounds R1 represents a methyl- group, R3 represents a hydrogen atom, R4b represents a hydrogen atom and L1 represents a -CH2- group. In another particularly preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R2 represents a phenyl- group ; wherein said phenyl- group is optionally substituted, one or two times, identically or differently, with R6. In another particularly preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R2 represents a phenyl- group ;
wherein said phenyl- group is optionally substituted once with R6. In another particularly preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R2 represents a phenyl- group ; wherein said phenyl- group is optionally substituted, one or more times, identically or differently, with a group selected from: -CN, halo-, C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-. In another particularly preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R2 represents a phenyl- group ; wherein said phenyl- group is optionally substituted, one or more times, identically or differently, with a group selected from: -CN, fluoro-, bromo-, methyl-, ethyl-, methoxy-, trifluoromethoxy-. In another particularly preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R2 represents a phenyl- group ; wherein said phenyl- group is substituted once with a group selected from: -CN, fluoro-, methyl-, methoxy-, trifluoromethoxy-. In another particularly preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R2 represents a phenyl- group ; wherein said phenyl- group is substituted once with a group selected from: -CN, fluoro-, methyl-, methoxy-, trifluoromethoxy-,
and in which compounds R1 represents a methyl- group, R3 represents a hydrogen atom, R4b represents a hydrogen atom and L1 represents a -CH2- group. In another particularly preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R2 represents a phenyl- group ;
wherein said phenyl- group is substituted once with a group selected from: fluoro-, methyl-, methoxy-, trifluoromethoxy-. In another particularly preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R2 represents a group selected from:
wherein * represents the point of attachment to L1. In another particularly preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R2 represents a group selected from:
* , *
,
wherein * represents the point of attachment to L1. In another particularly preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R2 represents a group selected from:
In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R3 represents a hydrogen atom or group selected from: C1-C3-alkyl-, C1-C3-alkoxy-(L2)-, hydroxy-C1-C3-alkyl-, aryl-(L2)-, heteroaryl-(L2)-, and wherein L2 represents -CH2- or -CH2CH2-. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R3 represents a hydrogen atom or group selected from: C1-C3-alkyl-, C1-C3-alkoxy-(L2)-, hydroxy-C1-C3-alkyl-, phenyl-(L2)-, and wherein L2 represents -CH2- or -CH2CH2-.
In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R3 represents a hydrogen atom or group selected from: C1-C3-alkyl-, phenyl-(L2)-, and wherein L2 represents -CH2- or -CH2CH2-. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R3 represents a hydrogen atom or group selected from: C1-C3-alkyl-, phenyl-(L2)-, and wherein L2 represents -CH2-. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R3 represents a hydrogen atom or a C1-C3-alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R3 represents a C1-C3-alkyl-group. In a particularly preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R3 represents a hydrogen atom. In a preferred embodiment, the invention relates to compounds of formula (I- 1), supra, wherein R4a represents a hydrogen atom or a halogen atom or a group selected from: cyano-, hydroxy-, methyl-, ethyl-, -trifluoromethyl-, methoxy-, ethoxy-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, -C(=O)N(R10a)R10b, -N(R10a)R10b,
or in which R4a together with R4b represents a -C3-C5-alkylene- group. In a preferred embodiment, the invention relates to compounds of formula (I- 1), supra, wherein R4a represents a hydrogen atom or a halogen atom or a group selected from: cyano-, hydroxy-, methyl-, ethyl-, trifluoromethyl-, methoxy-, ethoxy-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, -C(=O)N(R10a)R10b, -N(R10a)R10b.
In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R4a represents a hydrogen atom or a halogen atom or a group selected from: cyano-, hydroxy-, C1-C3-alkyl-, halo-C1-C3-alkyl- , C1-C3-alkoxy-, -C(=O)N(R10a)R10b, -N(R10a)R10b,
or in which R4a together with R4b represents a -C3-C5-alkylene- group. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R4a represents a hydrogen atom or a halogen atom or a group selected from: cyano-, hydroxy-, C1-C3-alkyl-, halo-C1-C3-alkyl- , C1-C3-alkoxy-, -C(=O)N(R10a)R10b, -N(R10a)R10b. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R4a represents a hydrogen atom or a group selected from: cyano-, hydroxy-, methyl-, ethyl-, trifluoromethyl-, methoxy-, ethoxy-, trifluoromethoxy-, cyclopropyl-, -N(R10a)R10b, -C(=O)N(R10a)R10b. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R4a represents a hydrogen atom or a group selected from: cyano-, hydroxy-, methyl-, ethyl-, trifluoromethyl-, methoxy-, ethoxy-, trifluoromethoxy-, -N(R10a)R10b, -C(=O)N(R10a)R10b. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R4a represents a hydrogen atom or a halogen atom or a group selected from: cyano-, hydroxy-, C1-C3-alkyl-, fluoro-C1-C3- alkyl-, C1-C3-alkoxy-, -C(=O)N(R10a)R10b, -N(R10a)R10b. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R4a represents a group selected from: C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-, -C(=O)N(R10a)R10b.
In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R4a represents a group selected from: C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-, -C(=O)N(R10a)R10b,
and in which compounds R1 represents a methyl- group, R3 represents a hydrogen atom, R4b represents a hydrogen atom and L1 represents a -CH2- group. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R4a represents a group selected from: fluoro-C1-C3-alkyl-, C1-C3-alkoxy-, -C(=O)N(R10a)R10b. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R4a represents a group selected from: fluoro-C1-C3-alkyl-, C1-C3-alkoxy-, -C(=O)N(R10a)R10b,
and in which compounds R1 represents a methyl- group, R3 represents a hydrogen atom, R4b represents a hydrogen atom and L1 represents a -CH2- group. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R4a represents a group selected from: trifluoromethyl-, methoxy-, -C(=O)NH2. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R4a represents a group selected from: trifluoromethyl-, methoxy-, -C(=O)NH2,
and in which compounds R1 represents a methyl- group, R3 represents a hydrogen atom, R4b represents a hydrogen atom and L1 represents a -CH2- group.
In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R4a represents a group selected from: trifluoromethyl-, -C(=O)NH2. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R4a represents a -C(=O)NH2 group. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R4a represents a trifluoromethyl-group. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R4b represents a hydrogen atom or group selected from: C1-C3-alkoxy-, C1-C3-alkyl-, cyano-,
or wherein R4a together with R4b represents a -C3-C5-alkylene- group. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R4b represents a hydrogen atom or a group selected from: C1-C3-alkoxy-, C1-C3-alkyl-, cyano-. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R4b represents a hydrogen atom or a C1-C3-alkyl- group. In a particularly preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R4b represents a hydrogen atom. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R5a
, R5b, R5c, R5d independently from each other represent a hydrogen atom, a halogen atom or a group selected from:
cyano, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-, phenyl-, 5- to 6-membered heteroaryl-, -C(=O)R10, -C(=O)N(H)R10, -C(=O)N(R10a)R10b, -C(=O)O-R10, -N(R10a)R10b, -N(H)C(=O)R10, -N(R10a)C(=O)R10b, said phenyl- and 5- to 6-membered heteroaryl- group being optionally substituted one or more times, identically or differently, with a group selected from: halo-, cyano-, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R5a , R5b, R5c, R5d independently from each other represent a hydrogen atom, a halogen atom or a group selected from:
cyano, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-, -C(=O)R10, -C(=O)N(H)R10, -C(=O)N(R10a)R10b, -C(=O)O-R10, -N(R10a)R10b, -N(H)C(=O)R10, -N(R10a)C(=O)R10b. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R5a , R5b, R5c, R5d independently from each other represent a hydrogen atom, a halogen atom or a group selected from:
cyano, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-, phenyl-, 5- to 6-membered heteroaryl-,
said phenyl- and 5- to 6-membered heteroaryl- group being optionally substituted one or more times, identically or differently, with a group selected from: halo-, cyano-, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R5a , R5b, R5c, R5d independently from each other represent a hydrogen atom, a halogen atom or a group selected from:
cyano, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-.
In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R5a , R5b, R5c, R5d independently from each other represent a hydrogen atom, a halogen atom or a group selected from:
cyano, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-, and in which compounds R1 represents a C1-C3-alkyl- group and R3 represents a hydrogen atom. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R5a , R5b, R5c, R5d independently from each other represent a hydrogen atom, a halogen atom or a group selected from:
C1-C3-alkyl-, C1-C3-alkoxy-. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R5a
, R5b, R5c, R5d independently from each other represent a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R5a , R5b, R5c, R5d independently from each other represent a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, and in which compounds R1 represents a methyl- group, R3 represents a hydrogen atom, R4b represents a hydrogen atom and L1 represents a -CH2- group. In another particularly preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R5a , R5c, R5d independently from each other represent hydrogen atom or a fluorine atom. In another particularly preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R5a represents a hydrogen atom or a fluorine atom.
In another particularly preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R5b represents a hydrogen atom, a chlorine atom or a bromine atom. In another particularly preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R5c represents a hydrogen atom or a fluorine atom. In another particularly preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R5d represents a hydrogen atom. In another particularly preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R5a
, R5c, R5d independently from each other represent a hydrogen atom or a fluorine atom, and in which compounds R5b represents a hydrogen atom, a chlorine atom or a bromine atom. In another particularly preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R5a , R5c, R5d independently from each other represent a hydrogen atom or a fluorine atom, and in which compounds R5b represents a hydrogen atom, a chlorine atom or a bromine atom,
and in which compounds R1 represents a methyl- group, R3 represents a hydrogen atom, R4b represents a hydrogen atom and L1 represents a -CH2- group. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R6 represents a group selected from: oxo, C1-C4-alkyl-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-,
fluoro-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, cyano-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-, -OH, -CN, halo-, -C(=O)R7, -C(=O)-O-R7, -C(=O)N(R8a)R8b, -N(R10a)R10b, -S(=O)2R7, phenyl-, 5- to 6-membered heteroaryl-. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R6 represents a group selected from: oxo, C1-C4-alkyl-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, fluoro-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, cyano-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-, -OH, -CN, halo-, -C(=O)R7, -C(=O)-O-R7, -C(=O)N(R8a)R8b, -N(R10a)R10b, -S(=O)2R7
. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R6 represents a group selected from: oxo, C1-C4-alkyl-, fluoro-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, cyano-C1-C3-alkyl-, C1-C3- alkoxy-, fluoro-C1-C3-alkoxy-, -OH, -CN, halo-, -C(=O)R7, -C(=O)-O-R7, -C(=O)N(R8a)R8b, -N(R10a)R10b, -S(=O)2R7 . In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R6 represents a group selected from: C1-C4-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-, -CN, halo-. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R6 represents a group selected from: C1-C4-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-, -CN, halo-,
and in which compounds R1 represents a methyl- group, R3 represents a hydrogen atom, R4b represents a hydrogen atom and L1 represents a -CH2- group.
In a particularly preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R6 represents a group selected from: methyl-, ethyl-, trifluoromethyl-, methoxy-, trifluoromethoxy-, -CN, fluoro-, bromo-. In another particularly preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R6 represents a group selected from: methyl-, methoxy-, trifluoromethoxy-, -CN, fluoro-. In another particularly preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R6 represents a group selected from: methyl-, methoxy-, trifluoromethoxy-, fluoro-. In another particularly preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R6 represents a group selected from: methyl-, methoxy-, trifluoromethoxy-, fluoro-,
and in which compounds R1 represents a methyl- group, R3 represents a hydrogen atom, R4b represents a hydrogen atom and L1 represents a -CH2- group. In another particularly preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R6 represents a methyl- group. In another particularly preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R6 represents a methoxy- group. In another particularly preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R6 represents a trifluoromethoxy- group.
In another particularly preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R6 represents a -CN group. In another particularly preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R6 represents a fluorine atom. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R7 represents a C1-C4-alkyl-, fluoro-C1-C3-alkyl-, cyano-C1-C3-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, C3-C7-cycloalkyl- or benzyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R7 represents a hydrogen atom or a C1-C4-alkyl-, C3-C7-cycloalkyl- or benzyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R7 represents a hydrogen atom or a C1-C6-alkyl- or benzyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R7 represents a hydrogen atom or a C1-C4-alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R7 represents a hydrogen atom. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R7 represents a C1-C4-alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R8a and R8b, independently from each other,
represent a hydrogen atom, or a C1-C4-alkyl-, C3-C7-cycloalkyl-, 4- to 7- membered heterocycloalkyl-, phenyl- or 5- to 6-membered heteroaryl- group; said C1-C4-alkyl-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, phenyl- and 5- to 6-membered heteroaryl- group being optionally substituted one or more times, identically or differently, with R9;
or R8a and R8b, together with the nitrogen atom they are attached to, represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7-membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R9. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R8a and R8b, independently from each other, represent a hydrogen atom, or a C1-C4-alkyl-, C3-C7-cycloalkyl-, 4- to 7- membered heterocycloalkyl-, phenyl- or 5- to 6-membered heteroaryl- group; said C1-C4-alkyl-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, phenyl- and 5- to 6-membered heteroaryl- group being optionally substituted one or more times, identically or differently, with R9. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R8a and R8b, together with the nitrogen atom they are attached to, represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7-membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R9. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R8a and R8b, independently from each other, represent a hydrogen atom, or a C1-C4-alkyl-, C3-C7-cycloalkyl- or 4- to 7- membered heterocycloalkyl- group;
said C1-C4-alkyl-, C3-C7-cycloalkyl- and 4- to 7-membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R9;
or R8a and R8b, together with the nitrogen atom they are attached to, represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7-membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R9. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R8a and R8b, independently from each other, represent a hydrogen atom, or a C1-C4-alkyl-, C3-C7-cycloalkyl- or 4- to 7- membered heterocycloalkyl- group;
said C1-C4-alkyl-, C3-C7-cycloalkyl- and 4- to 7-membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R9. In a particularly preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R8a and R8b, independently from each other, represent a hydrogen atom, or a C1-C2-alkyl-, cyclopropyl- or 5- to 6-membered heterocycloalkyl- group;
said C1-C2-alkyl-, cyclopropyl- and 5- to 6-membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R9;
or R8a and R8b, together with the nitrogen atom they are attached to, represent a 5- to 6-membered heterocycloalkyl- group, said 5- to 6-membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R9. In another particularly preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R8a and R8b, independently from
each other, represent a hydrogen atom, or a C1-C2-alkyl-, cyclopropyl- or 5- to 6-membered heterocycloalkyl- group;
said C1-C2-alkyl-, cyclopropyl- and 5- to 6-membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R9. In another particularly preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R8a and R8b, together with the nitrogen atom they are attached to, represent a 5- to 6-membered heterocycloalkyl- group, said 5- to 6-membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R9. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R9 represents a halogen atom or an oxo, C1-C3- alkyl-, fluoro-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, -CN, -C(=O)R10, -C(=O)N(H)R10, -C(=O)N(R10a)R10b, -C(=O)O-R10, -N(R10a)R10b, -N(H)C(=O)R10, -N(R10a)C(=O)R10b or a -OR10 group. In a particularly preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R9 represents a halogen atom or an oxo, C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, -CN, -C(=O)N(H)R10, -C(=O)N(R10a)R10b, -C(=O)O-R10 or a -OR10 group. In another particularly preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R9 represents an oxo, hydroxy-C1-C3-alkyl-, -CN, -C(=O)N(H)R10, -C(=O)N(R10a)R10b, -C(=O)O-R10 or a -OR10 group.
In another particularly preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R9 represents a halogen atom or an oxo, C1-C3-alkyl-, -C(=O)O-R10 or a -OR10 group. In another particularly preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R9 represents an oxo, -C(=O)O-R10 or a -OR10 group. In another particularly preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R9 represents an oxo, -C(=O)O-H, -C(=O)O-CH3 or a -OH group. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R10, R10a, R10b, R10c represent, independently from each other, a hydrogen atom or group selected from: C1-C3-alkyl-, fluoro-C1-C3- alkyl-, hydroxy-C1-C3-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, C3-C7-cycloalkyl;
or R10a and R10b, together with the nitrogen atom they are attached to, represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7-membered heterocycloalkyl-group being optionally substituted one or more times, identically or differently, with R12. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R10, R10a, R10b, R10c represent, independently from each other, a hydrogen atom or group selected from: C1-C3-alkyl-, fluoro-C1-C3- alkyl-, hydroxy-C1-C3-alkyl-,C1-C3-alkoxy-C1-C3-alkyl-, C3-C7-cycloalkyl. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R10a and R10b, together with the nitrogen atom they are attached to, represent a 4- to 7-membered heterocycloalkyl- group,
said 4- to 7-membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R12. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R10, R10a, R10b, R10c represent, independently from each other, a hydrogen atom or group selected from: C1-C3-alkyl-, hydroxy-C1- C3-alkyl-. In a particularly preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R10, R10a, R10b, R10c represent, independently from each other, a hydrogen atom or a C1-C3-alkyl- group. In a particularly preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R10, R10a, R10b, R10c represent, independently from each other, a hydrogen atom or a C1-C3-alkyl- group,
or R10a and R10b, together with the nitrogen atom they are attached to, represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7-membered heterocycloalkyl-group being optionally substituted one or more times, identically or differently, with R12. In another particularly preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R10, R10a, R10b, R10c represent, independently from each other, a hydrogen atom or a methyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R11 represents a hydrogen atom or a cyano-, C1- C3-alkyl-, -C(=O)R10, or -C(=O)O-R10 group.
In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R11 represents a hydrogen atom or a cyano-, -C(=O)R10, or -C(=O)O-R10 group. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R11 represents a hydrogen atom or a cyano- or -C(=O)O-R10 group. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R11 represents a -C(=O)O-R10 group. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R11 represents a cyano- group. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R11 represents a hydrogen atom. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R12 represents a halogen atom or a cyano, hydroxy, oxo, C1-C3-alkyl-, trifluoromethyl-, -C(=O)R10 or -C(=O)O-R10 group. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R12 represents a fluorine atom or a cyano, hydroxy, oxo, C1-C3-alkyl-, trifluoromethyl-, acetyl-, methoxycarbonyl- or ethoxycarbonyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein L1 represents a group selected from: -C1-C4-alkylene-, -CH2-CH=CH-, -C(phenyl)(H)-, -CH2-CH2-O-, -CH2-C(=O)-N(H)-, - CH2-C(=O)-N(R10a)-.
In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein L1 represents a group selected from: -C1-C4-alkylene-, -C(phenyl)(H)-, -CH2-CH2-O-. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein L1 represents a group selected from: -C1-C4-alkylene-, -CH2-CH2-O-. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein L1 represents a group selected from: -C1-C3-alkylene-, -CH2-CH2-O-. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein L1 represents a group selected from: -C1-C2-alkylene-, -CH2-CH2-O-. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein L1 represents a group selected from: –CH2-,–CH2–CH2-, -CH2-CH2-O-. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein L1 represents a -C1-C4-alkylene- group. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein L1 represents a -C1-C3-alkylene- group. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein L1 represents a group selected from: –CH2-,–CH2–CH2-.
In a particularly preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein L1 represents a–CH2- group. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein L2 represents a group selected from:
In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein L2 represents a–CH2- group. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein L3 represents a -C1-C4-alkylene- group. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein L3 represents a -C1-C3-alkylene- group. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein L3 represents a -C1-C2-alkylene- group. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein L3 represents a -CH2- or -CH2-CH2- group. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein p represents an integer of 0 or 1. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein p represents an integer of 1.
In a particularly preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein p represents an integer of 0. In another preferred embodiment, the invention relates to compounds of formula (I-1), supra, wherein R1 represents a methyl- group, wherein R3 represents a hydrogen atom, R4b represents a hydrogen atom, and wherein L1 represents a–CH2- group. It is to be understood that the present invention relates to any sub- combination within any embodiment of compounds of general formula (I-1), supra. Some further examples of combinations are given hereinafter. However, the invention is not limited to these combinations. In a preferred embodiment, the present invention relates to compounds of general formula (I-1) :
(I-1)
in which : R1 represents a C1-C3-alkyl- or fluoro-C1-C3-alkyl- group;
R2 represents a group selected from: phenyl-, 5- to 6-membered heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ; wherein said phenyl-, 5- to 6-membered heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L2)p-R6; and wherein two -(L2)p-R6 groups, if being present ortho to each other on a phenyl- or 5- to 6-membered heteroaryl- group optionally represent a bridge selected from: *-C3-C8-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*, *-O(CF2)O-*, *-CH2C(R10a)(R10b)O-*, *-C(=O)N(R10a)CH2-*, *-N(R10a)C(=O)CH2O-*, *-NHC(=O)NH-*; wherein each * represents the point of attachment to said phenyl- or 5- to 6-membered heteroaryl- group; R3 represents a hydrogen atom or a C1-C3-alkyl- group; R4a represents a hydrogen atom or a halogen atom or a group selected from: cyano-, hydroxy-, C1-C3-alkyl-, halo-C1-C3-alkyl-, C1-C3-alkoxy-, halo-C1-C3-alkoxy-, -C(=O)N(R10a)R10b, -N(R10a)R10b; R4b represents a hydrogen atom or a C1-C3-alkyl-group; or
R4a and together R4b represent a -C3-C5-alkylene- group;
independently from each other represent a hydrogen atom, a halogen atom or a group selected from:
cyano-, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-, phenyl-, 5- to 6-membered heteroaryl-, -C(=O)R10,
-C(=O)N(H)R10, -C(=O)N(R10a)R10b, -C(=O)O-R10, -N(R10a)R10b, -N(H)C(=O)R10, -N(R10a)C(=O)R10b,
said phenyl- and 5- to 6-membered heteroaryl- group being optionally substituted one or more times, identically or differently, with a group selected from:
halo-, cyano-, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-; R6 represents a group selected from: oxo, C1-C4-alkyl-, fluoro-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, cyano-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-, -OH, -CN, halo-, -C(=O)R7, -C(=O)-O-R7, -C(=O)N(R8a)R8b, -N(R10a)R10b, -S(=O)2R7; R7 represents a hydrogen atom or a C1-C4-alkyl-, fluoro-C1-C3-alkyl-, cyano-C1-C3-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, C3-C7-cycloalkyl- or benzyl- group; R8a, R8b
represent, independently from each other, a hydrogen atom, or a C1-C4-alkyl-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, phenyl-, 5- to 6-membered heteroaryl- group;
said C1-C4-alkyl-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, phenyl-, 5- to 6- membered heteroaryl- group being optionally substituted one or more times, identically or differently, with R9;
or
R8a and R8b, together with the nitrogen atom they are attached to,
represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7- membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R9;
R9 represents a halogen atom, or an oxo, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, -CN, -C(=O)R10, -C(=O)N(H)R10, -C(=O)N(R10a)R10b, -C(=O)O-R10, -N(R10a)R10b, -N(H)C(=O)R10, -N(R10a)C(=O)R10b, or a -OR10 group;
represent, independently from each other, a hydrogen atom or a group selected from: C1-C3-alkyl-, fluoro-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, C3-C7-cycloalkyl-;
or
R10a and R10b, together with the nitrogen atom they are attached to,
represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7- membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R12; R12 represents a fluorine atom or a cyano, hydroxy, oxo, C1-C3-alkyl-, trifluoromethyl-, acetyl-, methoxycarbonyl- or ethoxycarbonyl- group; L1 represents a group selected from: -C1-C3-alkylene-,
L2 represents a group selected from:–CH2-,–CH2–CH2-; p is an integer of 0 or 1 ; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. In another preferred embodiment, the present invention relates to compounds of general formula (I-1) :
(I-1)
in which : R1 represents a C1-C3-alkyl- or trifluoromethyl- group; R2 represents a group selected from: phenyl-, 5- to 6-membered heteroaryl-, C5-C6-cycloalkyl- and 5- to 6-membered heterocycloalkyl- ; wherein said phenyl-, 5- to 6-membered heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L2)p-R6; and wherein two -(L2)p-R6 groups, if being present ortho to each other on a phenyl- or 5- to 6-membered heteroaryl- group optionally represent a bridge selected from: *-C3-C4-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-; wherein each * represents the point of attachment to said phenyl- or 5- to 6-membered heteroaryl- group; R3 represents a hydrogen atom; R4a represents a hydrogen atom or a halogen atom or a group selected from:
C1-C3-alkyl-, halo-C1-C3-alkyl-, C1-C3-alkoxy-, halo-C1-C3-alkoxy-, -C(=O)N(R10a)R10b;
R4b represents a hydrogen atom; R5a, R5b, R5c, R5d
independently from each other represent a hydrogen atom, a halogen atom, or a group selected from:
cyano-, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-, phenyl-, 5- to 6-membered heteroaryl-,
said phenyl- and 5- to 6-membered heteroaryl- group being optionally substituted one or more times, identically or differently, with a group selected from:
halo-, cyano-, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-; R6 represents a group selected from: oxo, C1-C4-alkyl-, fluoro-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, cyano-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3- alkoxy-, -OH, -CN, halo-, -C(=O)R7, -C(=O)-O-R7, -C(=O)N(R8a)R8b, -N(R10a)R10b, -S(=O)2R7; R7 represents a hydrogen atom or a C1-C4-alkyl-, C3-C7-cycloalkyl- or benzyl- group; R8a, R8b
represent, independently from each other, a hydrogen atom, or a C1-C4-alkyl-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, phenyl-, 5- to 6-membered heteroaryl- group;
said C1-C4-alkyl-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, phenyl-, 5- to 6- membered heteroaryl- group being optionally substituted one or more times, identically or differently, with R9;
or
R8a and R8b, together with the nitrogen atom they are attached to,
represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7- membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R9; R9 represents a halogen atom, or an oxo, C1-C3-alkyl-, trifluoromethyl-, -CN, -C(=O)O-R10, -N(R10a)R10b or a -OR10 group; R10, R10a, R10b,
represent, independently from each other, a hydrogen atom or a C1-C3- alkyl-group;
or
R10a and R10b, together with the nitrogen atom they are attached to,
represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7- membered heterocycloalkyl-group being optionally substituted one or more times, identically or differently, with R12; R12 represents a fluorine atom or a cyano, hydroxy, oxo, C1-C3-alkyl-, trifluoromethyl-, acetyl-, methoxycarbonyl- or ethoxycarbonyl- group; L1 represents a group selected from: -C1-C3-alkylene-, -CH2-CH2-O-; L2 represents a group selected from:–CH2-,–CH2–CH2-; p is an integer of 0 or 1 ; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
In another preferred embodiment, the present invention relates to compounds of general formula (I-1) :
(I-1)
in which : R1 represents a C1-C3-alkyl- or trifluoromethyl- group; R2 represents a group selected from: phenyl-, 5- to 6-membered heteroaryl- and C5-C6-cycloalkyl-;
wherein said phenyl-, 5- to 6-membered heteroaryl- and C5-C6-cycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L2)p-R6; and wherein two -(L2)p-R6 groups, if being present ortho to each other on a phenyl- or 5- to 6-membered heteroaryl- group optionally represent a bridge selected from: *-C3-C4-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-; wherein each * represents the point of attachment to said phenyl- or 5- to 6-membered heteroaryl- group; R3 represents a hydrogen atom;
R4a represents a hydrogen atom or a halogen atom or a group selected from: methyl-, ethyl-, trifluoromethyl-, methoxy-, ethoxy-, trifluoromethoxy-, -C(=O)N(R10a)R10b, -N(R10a)R10b; R4b represents a hydrogen atom;
independently from each other represent a hydrogen atom, a halogen atom or a group selected from:
cyano-, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-; R6 represents a group selected from: C1-C4-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-, -CN, halo-; R10a, R10b,
represent, independently from each other, a hydrogen atom or a C1-C3- alkyl-group; L1 represents a group selected from: -C1-C3-alkylene-,
L2 represents a–CH2- group ; p is an integer of 0 or 1 ; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
In another preferred embodiment, the present invention relates to compounds of general formula (I-1) :
(I-1)
in which : R1 represents a C1-C3-alkyl- or trifluoromethyl- group; R2 represents a phenyl- group;
wherein said phenyl group is substituted once with R6; R3 represents a hydrogen atom; R4a represents a hydrogen atom or a halogen atom or a group selected from: methyl-, ethyl-, trifluoromethyl-, methoxy-, ethoxy-, trifluoromethoxy-, -C(=O)N(R10a)R10b, -N(R10a)R10b; R4b represents a hydrogen atom; R5a, R5b, R5c, R5d
independently from each other represent a hydrogen atom, a halogen atom or a group selected from:
cyano-, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-; R6 represents a group selected from: methyl-, methoxy-, trifluoromethoxy-, -CN, fluoro-; R10a, R10b,
represent, independently from each other, a hydrogen atom or a C1-C3- alkyl-group; L1 represents a -CH2- group; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. In another preferred embodiment, the present invention relates to compounds of general formula (I-1) :
(I-1)
in which : R1 represents a C1-C3-alkyl- or trifluoromethyl- group;
R2 represents a group selected from: phenyl-, 5- to 6-membered heteroaryl- and C5-C6-cycloalkyl-;
wherein said phenyl-, 5- to 6-membered heteroaryl- and C5-C6-cycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L2)p-R6; and wherein two -(L2)p-R6 groups, if being present ortho to each other on a phenyl- or 5- to 6-membered heteroaryl- group optionally represent a bridge selected from: *-C3-C4-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-; wherein each * represents the point of attachment to said phenyl- or 5- to 6-membered heteroaryl- group; R3 represents a hydrogen atom; R4a represents a group selected from: trifluoromethyl-, -C(=O)NH2; R4b represents a hydrogen atom; R5a, R5b, R5c, R5d
independently from each other represent a hydrogen atom, a halogen atom or a group selected from:
cyano-, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-; R6 represents a group selected from: C1-C4-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-, -CN, halo-; L1 represents a -CH2- group;
L2 represents a–CH2- group ; p is an integer of 0 or 1 ; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. In another preferred embodiment, the present invention relates to compounds of general formula (I-1) :
(I-1)
in which : R1 represents a C1-C3-alkyl- or trifluoromethyl- group; R2 represents a phenyl- group;
wherein said phenyl group is substituted once with R6; R3 represents a hydrogen atom; R4a represents a group selected from: trifluoromethyl-, -C(=O)NH2; R4b represents a hydrogen atom;
R5a, R5b, R5c, R5d
independently from each other represent a hydrogen atom, a halogen atom or a group selected from:
cyano-, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-; R6 represents a group selected from: methyl-, methoxy-, trifluoromethoxy-, fluoro-; L1 represents a -CH2- group; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. In another preferred embodiment, the present invention relates to compounds of general formula (I-1) :
(I-1)
in which : R1 represents a C1-C3-alkyl- group;
R2 represents a group selected from: phenyl-, 5- to 6-membered heteroaryl- and C5-C6-cycloalkyl-;
wherein said phenyl-, 5- to 6-membered heteroaryl- and C5-C6-cycloalkyl- group is optionally substituted, one or more times, identically or differently, with R6; R3 represents a hydrogen atom; R4a represents a group selected from: trifluoromethyl-, methoxy-, -C(=O)N(R10a)R10b; R4b represents a hydrogen atom; R5a, R5b, R5c, R5d
independently from each other represent a hydrogen atom or a halogen atom; R6 represents a group selected from: C1-C2-alkyl-, trifluoromethyl-, methoxy-, trifluoromethoxy-, -CN, halo-;
represent, independently from each other, a hydrogen atom or a methyl- group; L1 represents a group selected from: -C1-C2-alkylene-,
or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
In another preferred embodiment, the present invention relates to compounds of general formula (I-1) :
(I-1)
in which : R1 represents a methyl- or ethyl- group; R2 represents a group selected from: phenyl-, isoxazolyl-, oxadiazolyl- and cyclopentyl-;
wherein said phenyl-, isoxazolyl- and oxadiazolyl- group is optionally substituted, one or two times, identically or differently, with R6; R3 represents a hydrogen atom; R4a represents a group selected from: trifluoromethyl-, methoxy-, -C(=O)NH2; R4b represents a hydrogen atom; R5a, R5b, R5c, R5d
independently from each other represent a hydrogen atom, a fluorine atom, a chlorine atom or a bromine atom;
R6 represents a group selected from: C1-C2-alkyl-, trifluoromethyl-, methoxy-, trifluoromethoxy-, -CN, fluoro-, bromo-; L1 represents a group selected from: -C1-C2-alkylene-,
or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. In another preferred embodiment, the present invention relates to compounds of general formula (I-1) :
(I-1)
in which : R1 represents a methyl- or ethyl- group; R2 represents a group selected from:
*
, , , ,
,
wherein * represents the point of attachment to L1; R3 represents a hydrogen atom; R4a represents a group selected from: trifluoromethyl-, methoxy-, -C(=O)NH2; R4b represents a hydrogen atom;
independently from each other represent a hydrogen atom or a fluorine atom; R5b represents a hydrogen atom, a chlorine atom or a bromine atom; L1 represents a group selected from: -CH2-, -CH2-CH2-, -CH2-CH2-O-;
or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. In another preferred embodiment, the present invention relates to compounds of general formula (I-1) :
(I-1)
in which : R1 represents a methyl- group; R2 represents a group selected from:
,
wherein * represents the point of attachment to L1. R3 represents a hydrogen atom;
R4a represents a group selected from: trifluoromethyl-, -C(=O)NH2; R4b represents a hydrogen atom; R5a, R5c, R5d
independently from each other represent a hydrogen atom or a fluorine atom; R5b represents a hydrogen atom, a chlorine atom or a bromine atom; L1 represents a -CH2- group; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
In accordance with a second aspect, the present invention relates to compounds of general formula (I-2) :
(I-2)
in which :
R1 represents a C1-C3-alkyl-, halo-C1-C3-alkyl-, cyano-, -C(=O)O-R10 or -C(=O)N(R10a)R10b group; R2 represents a group selected from: aryl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ;
wherein said 5- to 6-membered heterocycloalkyl- group is optionally benzocondensed;
wherein said aryl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L2)p-R6; and wherein two -(L2)p-R6 groups, if being present ortho to each other on an aryl- or heteroaryl- group optionally represent a bridge selected from:
*-C3-C8-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*, *-O(CF2)O-*, *-CH2C(R10a)(R10b)O-*, *-C(=O)N(R10a)CH2-*, *-N(R10a)C(=O)CH2O-*, *-NHC(=O)NH-*; wherein each * represents the point of attachment to said aryl- or heteroaryl- group; R3 represents a hydrogen atom or group selected from: C1-C3-alkyl-,
C1-C3-alkoxy-(L2)-, hydroxy-C1-C3-alkyl-, aryl-(L2)-, heteroaryl-(L2)-; R4a represents a hydrogen atom or a halogen atom or a group selected from: cyano-, hydroxy-, C1-C3-alkyl-, halo-C1-C3-alkyl-, C1-C3-alkoxy-, halo-C1- C3-alkoxy-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, - C(=O)-OR10, -C(=O)N(R10a)R10b,
-C(=O)-N(R10a)-S(=O)2-R10, -SR10, -S(=O)-R10, -S(=NR11)-R10, -S(=O)2-R10, -S(=O)2-N(R10a)R10b, -S(=O)(=NR11)-R10, -N(R10a)R10b;
R4b represents a hydrogen atom or a group selected from: C1-C3-alkoxy-, C1-C3-alkyl-, cyano- ; or
R4a and together R4b represent a -C3-C5-alkylene- group; R5a, R5b, R5c, R5d
independently from each other represent a hydrogen atom, a halogen atom or a group selected from:
cyano-, -NO2, C1-C3-alkyl-, halo-C1-C3-alkyl-, C1-C3-alkoxy-, halo-C1-C3-alkoxy-, phenyl-, heteroaryl-, -C(=O)R10, -C(=O)N(H)R10, -C(=O)N(R10a)R10b, -C(=O)O-R10, -N(R10a)R10b, -N(H)C(=O)R10, -N(R10a)C(=O)R10b, -N(H)C(=O)N(R10a)R10b, -N(R10a)C(=O)N(R10b)R10c, -N(R10a)C(=O)C(=O)N(R10b)R10c, -N(H)C(=O)OR10, -N(R10a)C(=O)OR10b, -N(H)S(=O)2R10, -N(R10a)S(=O)2R10b, -OR10, -O(C=O)R10, -O(C=O)N(R10a)R10b, -O(C=O)OR10, -SR10, -S(=O)R10, -S(=O)2R10, -S(=O)2N(H)R10, -S(=O)2N(R10a)R10b or -S(=O)(=NR11)-R10 ,
said phenyl- and heteroaryl- group being optionally substituted one or more times, identically or differently, with a group selected from: halo-, cyano-, C1-C3-alkyl-, halo-C1-C3-alkyl-, C1-C3-alkoxy-; R6 represents a group selected from: oxo, C1-C6-alkyl-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, halo-C1-C4-alkyl-, hydroxy-C1-C4- alkyl-, cyano-C1-C4-alkyl-, C2-C4-alkenyl-, C2-C4-alkynyl-, C1-C4-alkoxy-, halo-C1-C4-alkoxy-, -OH, -CN, halo-, -C(=O)R7, -C(=O)-O-R7, -C(=O)N(R8a)R8b, -N(R10a)R10b, -S(=O)2R7, -S(=O)(=NR11)-R10, phenyl-, 5- to 6-membered heteroaryl-;
R7 represents a hydrogen atom or a C1-C6-alkyl-, halo-C1-C3-alkyl-, cyano- C1-C4-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, C3-C7-cycloalkyl-, phenyl-, 5- to 6-membered heteroaryl- or benzyl- group; R8a, R8b
represent, independently from each other, a hydrogen atom, or a C1-C10-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(L3)-, C3-C6-alkenyl-, C3-C6-alkynyl-, 4- to 10-membered heterocycloalkyl-,
(4- to 10-membered heterocycloalkyl)-(L3)-, phenyl-, heteroaryl-, phenyl-(L3)-, (phenyl)-O-(L3)-, heteroaryl-(L3)-, or
(aryl)-(4- to 10-membered heterocycloalkyl)- group; said C1-C10-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(L3)-, C3-C6-alkenyl-, C3-C6-alkynyl-, 4- to 10-membered heterocycloalkyl-, (4- to 10-membered heterocycloalkyl)-(L3)-, phenyl-, heteroaryl-, phenyl-(L3)-, (phenyl)-O-(L3)-, heteroaryl-(L3)-, and (aryl)-(4- to 10-membered heterocycloalkyl)- group being optionally substituted one or more times, identically or differently, with R9;
or
R8a and R8b, together with the nitrogen atom they are attached to,
represent a 4- to 10-membered heterocycloalkyl- group, said 4- to 10- membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R9; R9 represents a halogen atom, or an oxo, C1-C3-alkyl-, halo-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, -CN, -C(=O)R10, -C(=O)N(H)R10, -C(=O)N(R10a)R10b, -C(=O)O-R10, -N(R10a)R10b, -NO2, -N(H)C(=O)R10, -N(R10a)C(=O)R10b, -N(H)C(=O)N(R10a)R10b, -N(R10a)C(=O)N(R10b)R10c, -N(H)C(=O)OR10, -N(R10a)C(=O)OR10b, -N(H)S(=O)2R10, -N(R10a)S(=O)2R10b, -OR10, -O(C=O)R10,
-O(C=O)N(R10a)R10b, -O(C=O)OR10, -SR10, -S(=O)R10, -S(=O)2R10, -S(=O)2N(H)R10, -S(=O)2N(R10a)R10b, -S(=O)(=NR11)R10 or a tetrazolyl- group; or
two R9 groups present ortho to each other on a phenyl- or heteroaryl- ring represent a bridge selected from: *-C3-C5-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*, *-O(CF2)O-*, *-CH2C(R10a)(R10b)O-*, *-C(=O)N(R10a)CH2-*, *-N(R10a)C(=O)CH2O-*, *-NHC(=O)NH-*; wherein each * represents the point of attachment to said phenyl- or heteroaryl- ring; R10,
represent, independently from each other, a hydrogen atom or a group selected from: C1-C3-alkyl-, halo-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, C3-C7-cycloalkyl-; or
R10a and R10b, together with the nitrogen atom they are attached to,
represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7- membered heterocycloalkyl-group being optionally substituted one or more times, identically or differently, with R12; R11 represents a hydrogen atom or a cyano-, C1-C3-alkyl-, -C(=O)R10, -C(=O)N(H)R10, -C(=O)N(R10a)R10b or -C(=O)O-R10 group; R12 represents a halogen atom or a cyano, hydroxy, oxo, C1-C3-alkyl-, trifluoromethyl-, -C(=O)R10 or -C(=O)O-R10 group; R13 represents a hydrogen atom or a C1-C6-alkyl- or benzyl- group; L2 represents a group selected from:–CH2-,–CH2–CH2-, -CH2-CH2-CH2-;
L3 represents a -C1-C6-alkylene- group; L4 represents a group selected from: -C1-C4-alkylene-, -CH2-CH=CH-, -C(phenyl)(H)-, -CH2-CH2-O-, -CH2-C(=O)-N(H)-, -CH2-C(=O)-N(R10a)-, -O-, - N(R13)-; p is an integer of 0 or 1 ; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. In a preferred embodiment, the invention relates to compounds of formula (I- 2), supra, wherein R1 represents a C1-C3-alkyl-, halo-C1-C3-alkyl- or cyano- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R1 represents a C1-C3-alkyl- or halo-C1-C3-alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R1 represents a C1-C3-alkyl- or fluoro-C1-C3-alkyl- group In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R1 represents a C1-C3-alkyl- or trifluoromethyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R1 represents a C1-C3-alkyl- group.
In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R1 represents a methyl- or trifluoromethyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R1 represents a methyl- or ethyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R1 represents a methyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R1 represents an ethyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R1 represents a trifluoromethyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R2 represents a group selected from: phenyl-, 5- to 6-membered heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ;
wherein said phenyl-, 5- to 6-membered heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L2)p-R6;
and wherein two -(L2)p-R6 groups, if being present ortho to each other on a phenyl- or 5- to 6-membered heteroaryl- group optionally represent a bridge selected from: *-C3-C8-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*, *-O(CF2)O-*, *-CH2C(R10a)(R10b)O-*, *-C(=O)N(R10a)CH2-*, *-N(R10a)C(=O)CH2O-*, *-NHC(=O)NH-*; wherein each * represents the point of attachment to said phenyl- or 5- to 6-membered heteroaryl- group.
In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R2 represents a group selected from: phenyl-, 5- to 6-membered heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ;
wherein said phenyl-, 5- to 6-membered heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L2)p-R6;
and wherein two -(L2)p-R6 groups, if being present ortho to each other on a phenyl- or 5- to 6-membered heteroaryl- group optionally represent a bridge selected from: *-C3-C4-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*; wherein each * represents the point of attachment to said phenyl- or 5- to 6-membered heteroaryl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R2 represents a group selected from: phenyl-, 5- to 6-membered heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ;
wherein said phenyl-, 5- to 6-membered heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L2)p-R6;
and wherein two -(L2)p-R6 groups, if being present ortho to each other on a phenyl- or 5- to 6-membered heteroaryl- group optionally represent a bridge selected from: *-C3-C4-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*; wherein each * represents the point of attachment to said phenyl- or 5- to 6-membered heteroaryl- group,
and in which compounds R1 represents a methyl- group, R3 represents a hydrogen atom, R4b represents a hydrogen atom and L4 represents a -CH2- group.
In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R2 represents a group selected from: phenyl-, 5- to 6-membered heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ;
wherein said phenyl-, 5- to 6-membered heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with R6. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R2 represents a group selected from: phenyl-, 5- to 6-membered heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ;
wherein said phenyl-, 5- to 6-membered heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with R6,
and in which compounds R1 represents a methyl- group, R3 represents a hydrogen atom, R4b represents a hydrogen atom and L4 represents a -CH2- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R2 represents a phenyl- group;
wherein said phenyl- group is optionally substituted, one or more times, identically or differently, with–(L2)p-R6;
and wherein two -(L2)p-R6 groups, if being present ortho to each other on a phenyl- group optionally represent a bridge selected from: *-C3-C4-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*; wherein each * represents the point of attachment to said phenyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R2 represents a phenyl- group;
wherein said phenyl- group is optionally substituted, one or more times, identically or differently, with–(L2)p-R6;
and wherein two -(L2)p-R6 groups, if being present ortho to each other on a phenyl- group optionally represent a bridge selected from: *-C3-C4-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*; wherein each * represents the point of attachment to said phenyl- group,
and in which compounds R1 represents a methyl- group, R3 represents a hydrogen atom, R4b represents a hydrogen atom and L4 represents a -CH2- group. In a particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R2 represents a phenyl- group ;
wherein said phenyl- group is optionally substituted, one or more times, identically or differently, with R6. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R2 represents a phenyl- group ; wherein said phenyl- group is optionally substituted, one or more times, identically or differently, with R6,
and in which compounds R1 represents a methyl- group, R3 represents a hydrogen atom, R4b represents a hydrogen atom and L4 represents a -CH2- group. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R2 represents a phenyl- group ; wherein said phenyl- group is optionally substituted, one or two times, identically or differently, with R6. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R2 represents a phenyl- group ;
wherein said phenyl- group is optionally substituted once with R6. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R2 represents a phenyl- group ; wherein said phenyl- group is optionally substituted, one or more times, identically or differently, with a group selected from: -C(=O)N(R10a)R10b, -CN, halo-, C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R2 represents a phenyl- group ; wherein said phenyl- group is optionally substituted, one or more times, identically or differently, with a group selected from: -C(=O)N(R10a)R10b, -CN, halo-, C1-C3-alkyl-. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R2 represents a phenyl- group ; wherein said phenyl- group is optionally substituted, one or more times, identically or differently, with a group selected from: -C(=O)N(R10a)R10b, -CN, halo-, C1-C3-alkyl-,
and in which compounds R1 represents a methyl- group, R3 represents a hydrogen atom, R4b represents a hydrogen atom and L4 represents a -CH2- group. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R2 represents a phenyl- group ; wherein said phenyl- group is optionally substituted, one or more times, identically or differently, with a group selected from: -C(=O)NH2, -CN, fluoro-, methyl-.
In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R2 represents a phenyl- group ; wherein said phenyl- group is optionally substituted, one or more times, identically or differently, with a group selected from: -C(=O)NH2, -CN, fluoro-, methyl-,
and in which compounds R1 represents a methyl- group, R3 represents a hydrogen atom, R4b represents a hydrogen atom and L4 represents a -CH2- group. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R2 represents a group selected from:
* , *
wherein * represents the point of attachment to L4. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R2 represents a group selected from:
wherein * represents the point of attachment to L4.
In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R3 represents a hydrogen atom or group selected from: C1-C3-alkyl-, C1-C3-alkoxy-(L2)-, hydroxy-C1-C3-alkyl-, aryl-(L2)-, heteroaryl-(L2)-, and wherein L2 represents -CH2- or -CH2CH2-. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R3 represents a hydrogen atom or group selected from: C1-C3-alkyl-, C1-C3-alkoxy-(L2)-, hydroxy-C1-C3-alkyl-, phenyl-(L2)-, and wherein L2 represents -CH2- or -CH2CH2-. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R3 represents a hydrogen atom or group selected from: C1-C3-alkyl-, phenyl-(L2)-, and wherein L2 represents -CH2- or -CH2CH2-. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R3 represents a hydrogen atom or group selected from: C1-C3-alkyl-, phenyl-(L2)-, and wherein L2 represents -CH2-. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R3 represents a hydrogen atom or a C1-C3-alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R3 represents a C1-C3-alkyl-group. In a particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R3 represents a hydrogen atom. In a preferred embodiment, the invention relates to compounds of formula (I- 2), supra, wherein R4a represents a hydrogen atom or a halogen atom or a
group selected from: cyano-, hydroxy-, methyl-, ethyl-, -trifluoromethyl-, methoxy-, ethoxy-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, -C(=O)N(R10a)R10b, -N(R10a)R10b,
or in which R4a together with R4b represents a -C3-C5-alkylene- group. In a preferred embodiment, the invention relates to compounds of formula (I- 2), supra, wherein R4a represents a hydrogen atom or a halogen atom or a group selected from: cyano-, hydroxy-, methyl-, ethyl-, trifluoromethyl-, methoxy-, ethoxy-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, -C(=O)N(R10a)R10b, -N(R10a)R10b. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R4a represents a hydrogen atom or a halogen atom or a group selected from: cyano-, hydroxy-, C1-C3-alkyl-, halo-C1-C3-alkyl- , C3-C7-cycloalkyl-, C1-C3-alkoxy-, -C(=O)N(R10a)R10b, -N(R10a)R10b,
or in which R4a together with R4b represents a -C3-C5-alkylene- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R4a represents a hydrogen atom or a halogen atom or a group selected from: cyano-, hydroxy-, C1-C3-alkyl-, halo-C1-C3-alkyl- , C3-C7-cycloalkyl-, C1-C3-alkoxy-, -C(=O)N(R10a)R10b, -N(R10a)R10b. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R4a represents a hydrogen atom or a halogen atom or a group selected from: cyano-, hydroxy-, C1-C3-alkyl-, fluoro-C1-C3- alkyl-, C3-C7-cycloalkyl-, C1-C3-alkoxy-, -C(=O)N(R10a)R10b, -N(R10a)R10b, or in which R4a together with R4b represents a -C3-C5-alkylene- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R4a represents a hydrogen atom or a halogen
atom or a group selected from: cyano-, hydroxy-, C1-C3-alkyl-, fluoro-C1-C3- alkyl-, C3-C7-cycloalkyl-, C1-C3-alkoxy-, -C(=O)N(R10a)R10b, -N(R10a)R10b. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R4a represents a hydrogen atom or a halogen atom or a group selected from: methyl-, ethyl-, trifluoromethyl-, methoxy-, ethoxy-, trifluoromethoxy-, C3-C5-cycloalkyl-, -C(=O)N(R10a)R10b. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R4a represents a hydrogen atom or a halogen atom or a group selected from: methyl-, ethyl-, trifluoromethyl-, methoxy-, trifluoromethoxy-, cyclopropyl-, -N(R10a)R10b, -C(=O)N(R10a)R10b. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R4a represents a hydrogen atom or a halogen atom or a group selected from: cyano-, hydroxy-, C1-C3-alkyl-, fluoro-C1-C3- alkyl-, C3-C7-cycloalkyl-, C1-C3-alkoxy-, -C(=O)N(R10a)R10b, -N(R10a)R10b. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R4a represents a halogen atom or a group selected from: cyano-, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C3-C7-cycloalkyl-, C1-C3-alkoxy-, -C(=O)N(R10a)R10b. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R4a represents a halogen atom or a group selected from: C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C3-C7-cycloalkyl-, C1-C3-alkoxy-, -C(=O)N(R10a)R10b. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R4a represents a halogen atom or a group selected
from: C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C3-C7-cycloalkyl-, C1-C3-alkoxy-, -C(=O)N(R10a)R10b,
and in which compounds R1 represents a methyl- group, R3 represents a hydrogen atom, R4b represents a hydrogen atom and L4 represents a -CH2- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R4a represents a halogen atom or a group selected from: methyl-, trifluoromethyl-, methoxy-, C3-C5-cycloalkyl-, -C(=O)N(R10a)R10b. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R4a represents a chlorine atom or a group selected from: methyl-, trifluoromethyl-, cyclopropyl-, methoxy-, -C(=O)NH2. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R4a represents a chlorine atom or a group selected from: methyl-, trifluoromethyl-, cyclopropyl-, methoxy-, -C(=O)NH2, and in which compounds R1 represents a methyl- group, R3 represents a hydrogen atom, R4b represents a hydrogen atom and L4 represents a -CH2- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R4a represents a group selected from: trifluoromethyl-, cyclopropyl-, -C(=O)NH2. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R4a represents a group selected from: trifluoromethyl-, cyclopropyl-, -C(=O)NH2,
and in which compounds R1 represents a methyl- group, R3 represents a hydrogen atom, R4b represents a hydrogen atom and L4 represents a -CH2- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R4a represents a group selected from: trifluoromethyl-, -C(=O)NH2. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R4a represents a -C(=O)NH2 group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R4b represents a hydrogen atom or group selected from: C1-C3-alkoxy-, C1-C3-alkyl-, cyano-,
or wherein R4a together with R4b represents a -C3-C5-alkylene- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R4b represents a hydrogen atom or a group selected from: C1-C3-alkoxy-, C1-C3-alkyl-, cyano-. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R4b represents a hydrogen atom or a C1-C3-alkyl- group. In a particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R4b represents a hydrogen atom. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R5a , R5b, R5c, R5d independently from each other represent a hydrogen atom, a halogen atom or a group selected from:
cyano, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-, phenyl-, 5- to 6-membered heteroaryl-, -C(=O)R10, -C(=O)N(H)R10, -C(=O)N(R10a)R10b, -C(=O)O-R10, -N(R10a)R10b, -N(H)C(=O)R10, -N(R10a)C(=O)R10b, said phenyl- and 5- to 6-membered heteroaryl- group being optionally substituted one or more times, identically or differently, with a group selected from: halo-, cyano-, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R5a , R5b, R5c, R5d independently from each other represent a hydrogen atom, a halogen atom or a group selected from:
cyano, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-, -C(=O)R10, -C(=O)N(H)R10, -C(=O)N(R10a)R10b, -C(=O)O-R10, -N(R10a)R10b, -N(H)C(=O)R10, -N(R10a)C(=O)R10b. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R5a , R5b, R5c, R5d independently from each other represent a hydrogen atom, a halogen atom or a group selected from:
cyano, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-, phenyl-, 5- to 6-membered heteroaryl-,
said phenyl- and 5- to 6-membered heteroaryl- group being optionally substituted one or more times, identically or differently, with a group selected from: halo-, cyano-, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R5a , R5b, R5c, R5d independently from each other represent a hydrogen atom, a halogen atom or a group selected from:
cyano, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-.
In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R5a , R5b, R5c, R5d independently from each other represent a hydrogen atom, a halogen atom or a group selected from:
cyano, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-, and in which compounds R1 represents a C1-C3-alkyl- group and R3 represents a hydrogen atom. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R5a , R5b, R5c, R5d independently from each other represent a hydrogen atom, a halogen atom or a group selected from:
C1-C3-alkyl-, C1-C3-alkoxy-. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R5a
, R5b, R5c, R5d independently from each other represent a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, or a methyl- or methoxy- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R5a
, R5b, R5c, R5d independently from each other represent a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, or a methyl- or methoxy- group,
and in which compounds R1 represents a methyl- group, R3 represents a hydrogen atom, R4b represents a hydrogen atom and L4 represents a -CH2- group. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R5a represents a hydrogen atom.
In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R5b represents a hydrogen atom, a chlorine atom or a bromine atom, or a methyl- or methoxy- group. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R5c represents a hydrogen atom or a fluorine atom. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R5d represents a hydrogen atom. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R5a and R5d represent hydrogen, R5c represents a hydrogen atom or a fluorine atom, and in which compounds R5b represents a hydrogen atom, a chlorine atom or a bromine atom, or a methyl- or methoxy- group. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R5a and R5d represent hydrogen, R5c represents a hydrogen atom or a fluorine atom, and in which compounds R5b represents a hydrogen atom, a chlorine atom or a bromine atom, or a methyl- or methoxy- group,
and in which compounds R1 represents a methyl- group, R3 represents a hydrogen atom, R4b represents a hydrogen atom and L4 represents a -CH2- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R6 represents a group selected from: oxo, C1-C4-alkyl-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, fluoro-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, cyano-C1-C3-alkyl-, C1-C3-alkoxy-,
fluoro-C1-C3-alkoxy-, -OH, -CN, halo-, -C(=O)R7, -C(=O)-O-R7, -C(=O)N(R8a)R8b, -N(R10a)R10b, -S(=O)2R7, phenyl-, 5- to 6-membered heteroaryl-. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R6 represents a group selected from: oxo, C1-C4-alkyl-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, fluoro-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, cyano-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-, -OH, -CN, halo-, -C(=O)R7, -C(=O)-O-R7, -C(=O)N(R8a)R8b, -N(R10a)R10b, -S(=O)2R7 . In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R6 represents a group selected from: oxo, C1-C4-alkyl-, fluoro-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, cyano-C1-C3-alkyl-, C1-C3- alkoxy-, fluoro-C1-C3-alkoxy-, -OH, -CN, halo-, -C(=O)R7, -C(=O)-O-R7, -C(=O)N(R8a)R8b, -N(R10a)R10b, -S(=O)2R7
. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R6 represents a group selected from: C1-C4-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-, -CN, halo-, -C(=O)N(R8a)R8b. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R6 represents a group selected from:
C1-C4-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-, -CN, halo-, -C(=O)N(R8a)R8b,
and in which compounds R1 represents a methyl- group, R3 represents a hydrogen atom, R4b represents a hydrogen atom and L4 represents a -CH2- group.
In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R6 represents a group selected from:
C1-C4-alkyl-, -CN, halo-, -C(=O)N(R8a)R8b. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R6 represents a group selected from:
C1-C4-alkyl-, -CN, halo-, -C(=O)N(R8a)R8b,
and in which compounds R1 represents a methyl- group, R3 represents a hydrogen atom, R4b represents a hydrogen atom and L4 represents a -CH2- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R6 represents a group selected from:
C1-C2-alkyl-, -CN, halo-, -C(=O)N(R8a)R8b. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R6 represents a group selected from:
C1-C2-alkyl-, -CN, halo-, -C(=O)N(R8a)R8b,
and in which compounds R1 represents a methyl- group, R3 represents a hydrogen atom, R4b represents a hydrogen atom and L4 represents a -CH2- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R6 represents a group selected from: methyl-, -CN, fluoro-, -C(=O)NH2. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R6 represents a group selected from: methyl-, -CN, fluoro-, -C(=O)NH2,
and in which compounds R1 represents a methyl- group, R3 represents a hydrogen atom, R4b represents a hydrogen atom and L4 represents a -CH2- group. In a particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R6 represents a group selected from: methyl-, - CN, fluoro-. In a particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R6 represents a group selected from: methyl-, - CN, fluoro-,
and in which compounds R1 represents a methyl- group, R3 represents a hydrogen atom, R4b represents a hydrogen atom and L4 represents a -CH2- group. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R6 represents a methyl- group. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R6 represents a -CN group. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R6 represents a fluorine atom. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R7 represents a C1-C4-alkyl-, fluoro-C1-C3-alkyl-, cyano-C1-C3-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, C3-C7-cycloalkyl- or benzyl- group.
In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R7 represents a hydrogen atom or a C1-C4-alkyl-, C3-C7-cycloalkyl- or benzyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R7 represents a hydrogen atom or a C1-C6-alkyl- or benzyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R7 represents a hydrogen atom or a C1-C4-alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R7 represents a hydrogen atom. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R7 represents a C1-C4-alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R8a and R8b, independently from each other, represent a hydrogen atom, or a C1-C4-alkyl-, C3-C7-cycloalkyl-, 4- to 7- membered heterocycloalkyl-, phenyl- or 5- to 6-membered heteroaryl- group; said C1-C4-alkyl-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, phenyl- and 5- to 6-membered heteroaryl- group being optionally substituted one or more times, identically or differently, with R9;
or R8a and R8b, together with the nitrogen atom they are attached to, represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7-membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R9.
In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R8a and R8b, independently from each other, represent a hydrogen atom, or a C1-C4-alkyl-, C3-C7-cycloalkyl-, 4- to 7- membered heterocycloalkyl-, phenyl- or 5- to 6-membered heteroaryl- group; said C1-C4-alkyl-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, phenyl- and 5- to 6-membered heteroaryl- group being optionally substituted one or more times, identically or differently, with R9. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R8a and R8b, together with the nitrogen atom they are attached to, represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7-membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R9. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R8a and R8b, independently from each other, represent a hydrogen atom, or a C1-C4-alkyl-, C3-C7-cycloalkyl- or 4- to 7- membered heterocycloalkyl- group;
said C1-C4-alkyl-, C3-C7-cycloalkyl- and 4- to 7-membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R9;
or R8a and R8b, together with the nitrogen atom they are attached to, represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7-membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R9. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R8a and R8b, independently from each other, represent a hydrogen atom, or a C1-C4-alkyl-, C3-C7-cycloalkyl- or 4- to 7- membered heterocycloalkyl- group;
said C1-C4-alkyl-, C3-C7-cycloalkyl- and 4- to 7-membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R9. In a particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R8a and R8b, independently from each other, represent a hydrogen atom, or a C1-C2-alkyl-, cyclopropyl- or 5- to 6-membered heterocycloalkyl- group;
said C1-C2-alkyl-, cyclopropyl- and 5- to 6-membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R9;
or R8a and R8b, together with the nitrogen atom they are attached to, represent a 5- to 6-membered heterocycloalkyl- group, said 5- to 6-membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R9. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R8a and R8b, independently from each other, represent a hydrogen atom, or a C1-C2-alkyl-, cyclopropyl- or 5- to 6-membered heterocycloalkyl- group;
said C1-C2-alkyl-, cyclopropyl- and 5- to 6-membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R9. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R8a and R8b, together with the nitrogen atom they are attached to, represent a 5- to 6-membered heterocycloalkyl- group, said 5- to 6-membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R9.
In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R8a and R8b, independently from each other, represent a hydrogen atom or a C1-C2-alkyl- group. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R8a and R8b, independently from each other, represent a hydrogen atom or a methyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R9 represents a halogen atom or an oxo, C1-C3- alkyl-, fluoro-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, -CN, -C(=O)R10, -C(=O)N(H)R10, -C(=O)N(R10a)R10b, -C(=O)O-R10, -N(R10a)R10b, -N(H)C(=O)R10, -N(R10a)C(=O)R10b or a -OR10 group. In a particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R9 represents a halogen atom or an oxo, C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, -CN, -C(=O)N(H)R10, -C(=O)N(R10a)R10b, -C(=O)O-R10 or a -OR10 group. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R9 represents an oxo, hydroxy-C1-C3-alkyl-, -CN, -C(=O)N(H)R10, -C(=O)N(R10a)R10b, -C(=O)O-R10 or a -OR10 group. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R9 represents a halogen atom or an oxo, C1-C3-alkyl-, -C(=O)O-R10 or a -OR10 group.
In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R9 represents an oxo, -C(=O)O-R10 or a -OR10 group. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R9 represents an oxo, -C(=O)O-H, -C(=O)O-CH3 or a -OH group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R10, R10a, R10b, R10c represent, independently from each other, a hydrogen atom or group selected from: C1-C3-alkyl-, fluoro-C1-C3- alkyl-, hydroxy-C1-C3-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, C3-C7-cycloalkyl;
or R10a and R10b, together with the nitrogen atom they are attached to, represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7-membered heterocycloalkyl-group being optionally substituted one or more times, identically or differently, with R12. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R10, R10a, R10b, R10c represent, independently from each other, a hydrogen atom or group selected from: C1-C3-alkyl-, fluoro-C1-C3- alkyl-, hydroxy-C1-C3-alkyl-,C1-C3-alkoxy-C1-C3-alkyl-, C3-C7-cycloalkyl. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R10a and R10b, together with the nitrogen atom they are attached to, represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7-membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R12. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R10, R10a, R10b, R10c represent, independently from
each other, a hydrogen atom or group selected from: C1-C3-alkyl-, hydroxy-C1- C3-alkyl-. In a particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R10, R10a, R10b, R10c represent, independently from each other, a hydrogen atom or a C1-C3-alkyl- group. In a particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R10, R10a, R10b, R10c represent, independently from each other, a hydrogen atom or a C1-C3-alkyl- group,
or R10a and R10b, together with the nitrogen atom they are attached to, represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7-membered heterocycloalkyl-group being optionally substituted one or more times, identically or differently, with R12. In another particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R10, R10a, R10b, R10c represent, independently from each other, a hydrogen atom or a methyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R11 represents a hydrogen atom or a cyano-, C1- C3-alkyl-, -C(=O)R10, or -C(=O)O-R10 group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R11 represents a hydrogen atom or a cyano-, -C(=O)R10, or -C(=O)O-R10 group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R11 represents a hydrogen atom or a cyano- or -C(=O)O-R10 group.
In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R11 represents a -C(=O)O-R10 group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R11 represents a cyano- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R11 represents a hydrogen atom. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R12 represents a halogen atom or a cyano, hydroxy, oxo, C1-C3-alkyl-, trifluoromethyl-, -C(=O)R10 or -C(=O)O-R10 group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R12 represents a fluorine atom or a cyano, hydroxy, oxo, C1-C3-alkyl-, trifluoromethyl-, acetyl-, methoxycarbonyl- or ethoxycarbonyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R13 represents a hydrogen atom or a C1-C4-alkyl- or benzyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R13 represents a hydrogen atom or a C1-C4-alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R13 represents a hydrogen atom or a C1-C3-alkyl- group.
In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R13 represents a hydrogen atom or a C1-C2-alkyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R13 represents a hydrogen atom or a methyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R13 represents a hydrogen atom. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R13 represents a methyl- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein L4 represents a group selected from: -C1-C4-alkylene-, -C(phenyl)(H)-, -CH2-CH2-O-, -CH2-C(=O)-N(H)-, -CH2-C(=O)- N(R10a)-, -O-, -N(R13)-. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein L4 represents a group selected from: -C1-C4-alkylene-, -C(phenyl)(H)-, -CH2-CH2-O-, -O-, -N(R13)-. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein L4 represents a group selected from: -C1-C4-alkylene-, -CH2-CH2-O-, -O-, -N(R13)-.
In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein L4 represents a group selected from: -C1-C3-alkylene-, -CH2-CH2-O-, -O-, -N(R13)-. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein L4 represents a group selected from: -C1-C3-alkylene-, -O-, -N(R13)-. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein L4 represents a group selected from: -C1-C2-alkylene-, -O-, -N(R13)-. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein L4 represents a group selected from: -CH2-, -O-, -N(R13)-. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein L4 represents a group selected from:
In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein L4 represents a group selected from: –CH2-,–CH2–CH2-. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein L4 represents a -O- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein L4 represents a -N(R13)- group.
In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein L4 represents a -N(CH3)- group. In a particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein L4 represents a–CH2- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein L2 represents a group selected from:
In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein L2 represents a–CH2- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein L3 represents a -C1-C4-alkylene- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein L3 represents a -C1-C3-alkylene- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein L3 represents a -C1-C2-alkylene- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein L3 represents a -CH2- or -CH2-CH2- group. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein p represents an integer of 0 or 1. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein p represents an integer of 1.
In a particularly preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein p represents an integer of 0. In another preferred embodiment, the invention relates to compounds of formula (I-2), supra, wherein R1 represents a methyl- group, wherein R3 represents a hydrogen atom, R4b represents a hydrogen atom, and wherein L4 represents a–CH2- group. It is to be understood that the present invention relates to any sub- combination within any embodiment of compounds of general formula (I), supra. Some further examples of combinations are given hereinafter. However, the invention is not limited to these combinations. In a preferred embodiment, the present invention relates to compounds of general formula (I-2) :
(I-2)
in which :
R1 represents a C1-C3-alkyl- or fluoro-C1-C3-alkyl- group; R2 represents a group selected from: phenyl-, 5- to 6-membered heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ; wherein said phenyl-, 5- to 6-membered heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L2)p-R6; and wherein two -(L2)p-R6 groups, if being present ortho to each other on a phenyl- or 5- to 6-membered heteroaryl- group optionally represent a bridge selected from: *-C3-C8-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*, *-O(CF2)O-*, *-CH2C(R10a)(R10b)O-*, *-C(=O)N(R10a)CH2-*, *-N(R10a)C(=O)CH2O-*, *-NHC(=O)NH-*; wherein each * represents the point of attachment to said phenyl- or 5- to 6-membered heteroaryl- group; R3 represents a hydrogen atom or a C1-C3-alkyl- group; R4a represents a hydrogen atom or a halogen atom or a group selected from: cyano-, hydroxy-, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro- C1-C3-alkoxy-, C3-C7-cycloalkyl-, -C(=O)N(R10a)R10b, -N(R10a)R10b; R4b represents a hydrogen atom or a C1-C3-alkyl-group; or
R4a and together R4b represent a -C3-C5-alkylene- group; R5a, R5b, R5c, R5d
independently from each other represent a hydrogen atom, a halogen atom or a group selected from:
cyano-, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-, phenyl-, 5- to 6-membered heteroaryl-, -C(=O)R10, -C(=O)N(H)R10, -C(=O)N(R10a)R10b, -C(=O)O-R10, -N(R10a)R10b, -N(H)C(=O)R10, -N(R10a)C(=O)R10b,
said phenyl- and 5- to 6-membered heteroaryl- group being optionally substituted one or more times, identically or differently, with a group selected from:
halo-, cyano-, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-;
R6 represents a group selected from: oxo, C1-C4-alkyl-, fluoro-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, cyano-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-, -OH, -CN, halo-, -C(=O)R7, -C(=O)-O-R7, -C(=O)N(R8a)R8b, -N(R10a)R10b, -S(=O)2R7; R7 represents a hydrogen atom or a C1-C4-alkyl-, fluoro-C1-C3-alkyl-, cyano-C1-C3-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, C3-C7-cycloalkyl- or benzyl- group; R8a, R8b
represent, independently from each other, a hydrogen atom, or a C1-C4-alkyl-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, phenyl-, 5- to 6-membered heteroaryl- group;
said C1-C4-alkyl-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, phenyl-, 5- to 6- membered heteroaryl- group being optionally substituted one or more times, identically or differently, with R9;
or
R8a and R8b, together with the nitrogen atom they are attached to,
represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7- membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R9; R9 represents a halogen atom, or an oxo, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, -CN, -C(=O)R10, -C(=O)N(H)R10, -C(=O)N(R10a)R10b, -C(=O)O-R10, -N(R10a)R10b, -N(H)C(=O)R10, -N(R10a)C(=O)R10b, or a -OR10 group; R10, R10a, R10b
represent, independently from each other, a hydrogen atom or a group selected from: C1-C3-alkyl-, fluoro-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, C3-C7-cycloalkyl-;
or
R10a and R10b, together with the nitrogen atom they are attached to,
represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7- membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R12;
R12 represents a fluorine atom or a cyano, hydroxy, oxo, C1-C3-alkyl-, trifluoromethyl-, acetyl-, methoxycarbonyl- or ethoxycarbonyl- group; R13 represents a hydrogen atom or a C1-C4-alkyl- group; L4 represents a group selected from: -C1-C4-alkylene-, -CH2-CH2-O-, -O-, -N(R13)-; L2 represents a group selected from:–CH2-,–CH2–CH2-;
p is an integer of 0 or 1 ; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
In another preferred embodiment, the present invention relates to compounds of general formula (I-2) :
(I-2)
in which :
R1 represents a C1-C3-alkyl- or trifluoromethyl- group; R2 represents a group selected from: phenyl-, 5- to 6-membered heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ; wherein said phenyl-, 5- to 6-membered heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L2)p-R6; and wherein two -(L2)p-R6 groups, if being present ortho to each other on a phenyl- or 5- to 6-membered heteroaryl- group optionally represent a
bridge selected from: *-C3-C4-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-; wherein each * represents the point of attachment to said phenyl- or 5- to 6-membered heteroaryl- group; R3 represents a hydrogen atom; R4a represents a hydrogen atom or a halogen atom or a group selected from:
C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-, C3-C7-cycloalkyl-, -C(=O)N(R10a)R10b; R4b represents a hydrogen atom; R5a, R5b, R5c, R5d
independently from each other represent a hydrogen atom, a halogen atom or a group selected from:
cyano-, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-, phenyl-, 5- to 6-membered heteroaryl-,
said phenyl- and 5- to 6-membered heteroaryl- group being optionally substituted one or more times, identically or differently, with a group selected from:
halo-, cyano-, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-; R6 represents a group selected from: oxo, C1-C4-alkyl-, fluoro-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, cyano-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-, -OH, -CN, halo-, -C(=O)R7, -C(=O)-O-R7, -C(=O)N(R8a)R8b, -N(R10a)R10b, -S(=O)2R7; R7 represents a hydrogen atom or a C1-C4-alkyl-, C3-C7-cycloalkyl- or benzyl- group;
R8a, R8b
represent, independently from each other, a hydrogen atom, or a C1-C4-alkyl-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, phenyl-, 5- to 6-membered heteroaryl- group;
said C1-C4-alkyl-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, phenyl-, 5- to 6- membered heteroaryl- group being optionally substituted one or more times, identically or differently, with R9;
or
R8a and R8b, together with the nitrogen atom they are attached to,
represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7- membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R9; R9 represents a halogen atom, or an oxo, C1-C3-alkyl-, trifluoromethyl-, -CN, -C(=O)O-R10, -N(R10a)R10b or a -OR10 group; R10, R10a, R10b,
represent, independently from each other, a hydrogen atom or a C1-C3- alkyl-group;
or
R10a and R10b, together with the nitrogen atom they are attached to,
represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7- membered heterocycloalkyl-group being optionally substituted one or more times, identically or differently, with R12; R12 represents a fluorine atom or a cyano, hydroxy, oxo, C1-C3-alkyl-, trifluoromethyl-, acetyl-, methoxycarbonyl- or ethoxycarbonyl- group; R13 represents a hydrogen atom or a C1-C2-alkyl- group;
L4 represents a group selected from: -C1-C3-alkylene-, -O-, -N(R13)-; L2 represents a group selected from:–CH2-,–CH2–CH2-; p is an integer of 0 or 1 ; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
In another preferred embodiment, the present invention relates to compounds of general formula (I-2) :
(I-2)
in which :
R1 represents a C1-C3-alkyl- or trifluoromethyl- group; R2 represents a phenyl- group;
wherein said phenyl- group is optionally substituted, one or more times, identically or differently, with–(L2)p-R6;
and wherein two -(L2)p-R6 groups, if being present ortho to each other on a phenyl- group optionally represent a bridge selected from: *-C3-C4- alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-; wherein each * represents the point of attachment to said phenyl- group; R3 represents a hydrogen atom; R4a represents a hydrogen atom or a halogen atom or a group selected from: methyl-, ethyl-, trifluoromethyl-, methoxy-, ethoxy-, trifluoromethoxy-, C3-C5-cycloalkyl-, -C(=O)N(R10a)R10b; R4b represents a hydrogen atom; R5a, R5b, R5c, R5d
independently from each other represent a hydrogen atom, a halogen atom or a group selected from:
cyano-, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-; R6 represents a group selected from: C1-C4-alkyl-, fluoro-C1-C3-alkyl-, C1-C3- alkoxy-, fluoro-C1-C3-alkoxy-, -CN, halo-, -C(=O)N(R8a)R8b; R8a, R8b
represent, independently from each other, a hydrogen atom, or a C1-C2-alkyl-, cyclopropyl- or a 5- to 6-membered heterocycloalkyl- group;
said C1-C2-alkyl-, cyclopropyl- and 5- to 6-membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R9;
or
R8a and R8b, together with the nitrogen atom they are attached to,
represent a 5- to 6-membered heterocycloalkyl- group, said 5- to 6- membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R9; R9 represents an oxo, -C(=O)O-R10 or a -OR10 group; R10, R10a, R10b,
represent, independently from each other, a hydrogen atom or a C1-C3- alkyl-group; R13 represents a hydrogen atom or a C1-C2-alkyl- group; L4 represents a group selected from: -C1-C3-alkylene-, -O-, -N(R13)-; L2 represents a–CH2- group; p is an integer of 0 or 1 ; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
In another preferred embodiment, the present invention relates to compounds of general formula (I-2) :
(I-2)
in which :
R1 represents a methyl- group; R2 represents a phenyl- group;
wherein said phenyl group is substituted once with R6; R3 represents a hydrogen atom; R4a represents a hydrogen atom or a halogen atom or a group selected from: methyl-, ethyl-, trifluoromethyl-, methoxy-, ethoxy-, trifluoromethoxy-, C3-C5-cycloalkyl-, -C(=O)N(R10a)R10b; R4b represents a hydrogen atom; R5a, R5b, R5c, R5d
independently from each other represent a hydrogen atom, a halogen atom or a group selected from:
cyano-, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-;
R6 represents a group selected from: methyl-, -CN, fluoro-; R10a, R10b,
represent, independently from each other, a hydrogen atom or a C1-C3- alkyl-group; L4 represents a–CH2- group; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. In another preferred embodiment, the present invention relates to compounds of general formula (I-2) :
(I-2)
in which :
R1 represents a methyl- group; R2 represents a phenyl- group;
wherein said phenyl- group is optionally substituted, one or more times, identically or differently, with–(L2)p-R6;
and wherein two -(L2)p-R6 groups, if being present ortho to each other on a phenyl- group optionally represent a bridge selected from: *-C3-C4- alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-; wherein each * represents the point of attachment to said phenyl- group; R3 represents a hydrogen atom; R4a represents a -C(=O)NH2 group; R4b represents a hydrogen atom; R5a, R5b, R5c, R5d
independently from each other represent a hydrogen atom, a halogen atom or a group selected from:
cyano-, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-; R6 represents a group selected from: C1-C4-alkyl-, fluoro-C1-C3-alkyl-, C1-C3- alkoxy-, fluoro-C1-C3-alkoxy-, -CN, halo-, -C(=O)N(R8a)R8b; R8a, R8b
represent, independently from each other, a hydrogen atom, or a C1-C2-alkyl-, cyclopropyl- or a 5- to 6-membered heterocycloalkyl- group;
said C1-C2-alkyl-, cyclopropyl- and 5- to 6-membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R9;
or
R8a and R8b, together with the nitrogen atom they are attached to,
represent a 5- to 6-membered heterocycloalkyl- group, said 5- to 6- membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R9; R9 represents an oxo, -C(=O)O-R10 or a -OR10 group; L4 represents a–CH2- group; L2 represents a–CH2- group; p is an integer of 0 or 1 ; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. In another preferred embodiment, the present invention relates to compounds of general formula (I-2) :
wherein said phenyl group is substituted once with R6; R3 represents a hydrogen atom; R4a represents a -C(=O)NH2 group; R4b represents a hydrogen atom; R5a, R5b, R5c, R5d
independently from each other represent a hydrogen atom, a halogen atom or a group selected from:
cyano-, C1-C3-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-; R6 represents a group selected from: methyl-, -CN, fluoro-; L4 represents a–CH2- group; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. In another preferred embodiment, the present invention relates to compounds of general formula (I-2) :
(I-2)
in which :
R1 represents a methyl- or trifluoromethyl- group; R2 represents a phenyl- group;
wherein said phenyl group is substituted, one or more times, identically or differently, with R6; R3 represents a hydrogen atom; R4a represents a halogen atom or a group selected from: methyl-, trifluoromethyl-, methoxy-, C3-C5-cycloalkyl-, -C(=O)N(R10a)R10b; R4b represents a hydrogen atom; R5a, R5b, R5c, R5d
independently from each other represent a hydrogen atom, a halogen atom or a methyl- or methoxy- group; R6 represents a group selected from: C1-C2-alkyl-, -CN, halo-, -C(=O)N(R8a)R8b;
R8a, R8b
represent, independently from each other, a hydrogen atom or a methyl- group, R10a, R10b,
represent, independently from each other, a hydrogen atom or a methyl- group; R13 represents a methyl- group;
L4 represents a group selected from:–CH2-, -O-, -N(R13)-; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
In another preferred embodiment, the present invention relates to compounds of general formula (I-2) :
(I-2)
in which :
R1 represents a methyl- or trifluoromethyl- group; R2 represents a phenyl- group;
wherein said phenyl group is substituted, one or two times, identically or differently, with R6; R3 represents a hydrogen atom; R4a represents a chlorine atom or a group selected from: methyl-, trifluoromethyl-, methoxy-, cyclopropyl-, -C(=O)NH2; R4b represents a hydrogen atom; R5a, R5b, R5c, R5d
independently from each other represent a hydrogen atom, a fluorine atom, a chlorine atom or a bromine atom, or a methyl- or methoxy- group; R6 represents a group selected from: methyl-, -CN, fluoro-, -C(=O)NH2; R13 represents a methyl- group;
L4 represents a group selected from:–CH2-, -O-, -N(R13)-; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
In another preferred embodiment, the present invention relates to compounds of general formula (I-2) :
(I-2)
in which :
R1 represents a methyl- or trifluoromethyl- group; R2 represents a group selected from; * H2 , *
wherein * represents the point of attachment to L4. R3 represents a hydrogen atom; R4a represents a chlorine atom or a group selected from: methyl-, trifluoromethyl-, methoxy-, cyclopropyl-, -C(=O)NH2; R4b represents a hydrogen atom; R5a represents a hydrogen atom;
R5b a hydrogen atom, a fluorine atom, a chlorine atom or a bromine atom, or a methyl- or methoxy- group.
R5c represents a hydrogen atom or a fluorine atom; R5d represents a hydrogen atom; R13 represents a methyl- group;
L4 represents a group selected from:–CH2-, -O-, -N(R13)-; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
In another preferred embodiment, the present invention relates to compounds of general formula (I-2) :
wherein * represents the point of attachment to L4. R3 represents a hydrogen atom; R4a represents a -C(=O)NH2 group; R4b represents a hydrogen atom; R5a represents a hydrogen atom; R5b a hydrogen atom, a fluorine atom, a chlorine atom or a bromine atom, or a methyl- or methoxy- group.
R5c represents a hydrogen atom or a fluorine atom; R5d represents a hydrogen atom; L4 represents a–CH2- group; or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
In accordance with another aspect, the present invention covers methods of preparing compounds of the present invention, said methods comprising the steps as described in the Experimental Section herein.
In a preferred embodiment, the present invention relates to a method of preparing compounds of formula (I-1), in which method an intermediate compound of general formula (II-1) :
(II-1)
in which R1, R2, R3 and L1 are as defined for the compounds of general formula (I-1), supra; is allowed to react with a compound of general formula (III) :
(III) in which R4a, R4b, R5a, R5b, R5c, and R5d are as defined for the compounds of general formula (I-1), supra,
thus providing a compound of general formula (I-1) :
(I-1)
in which R1, R2, R3, R4a, R4b, R5a, R5b, R5b, R5d, and L1 are as defined for the compounds of general formula (I), supra. In accordance with a further aspect, the present invention covers intermediate compounds which are useful in the preparation of compounds of the present invention of general formula (I-1), particularly in the methods described herein. In particular, the present invention covers compounds of general formula (II-2):
(II-1) in which R1, R2, R3, and L1 are as defined for the compounds of general formula (I-1), supra.
In accordance with yet another aspect, the present invention covers the use of the intermediate compounds of general formula (II-1):
(II-1)
in which R1, R2, R3, and L1 are as defined for the compounds of general formula (I-1), supra; for the preparation of a compound of general formula (I-1) as defined supra. In another preferred embodiment, the present invention covers the use of the intermediate compounds of general formula (III):
(III) in which R4a, R4b, R5a, R5b, R5c, and R5dare as defined for the compounds of general formula (I-1), supra; for the preparation of a compound of general formula (I-1) as defined supra.
As one of ordinary skill in the art is aware of, the methods described above may comprise further steps like e.g. the introduction of a protective group and the cleavage of the protective group.
In another preferred embodiment, the present invention relates to a method of preparing compounds of formula (I-2), in which method an intermediate compound of general formula (II-2) :
in which R1, R2, R3 and L4 are as defined for the compounds of general formula (I-2), supra; is allowed to react with a compound of general formula (III) :
(III) in which R4a, R4b, R5a, R5b, R5c, and R5d are as defined for the compounds of general formula (I-2), supra,
thus providing a compound of general formula (I-2) :
(I-2) in which R1, R2, R3, R4a, R4b, R5a, R5b, R5b, R5d, and L4 are as defined for the compounds of general formula (I-2), supra.
In accordance with a further aspect, the present invention covers intermediate compounds which are useful in the preparation of compounds of the present invention of general formula (I-2), particularly in the methods described herein. In particular, the present invention covers compounds of general formula (II-2):
(II-2)
in which R1, R2, R3, and L4 are as defined for the compounds of general formula (I-2), supra.
In accordance with yet another aspect, the present invention covers the use of the intermediate compounds of general formula (II-2):
(II-2) in which R1, R2, R3, and L4 are as defined for the compounds of general formula (I-2), supra; for the preparation of a compound of general formula (I-2) as defined supra.
In another preferred embodiment, the present invention covers the use of the intermediate compounds of general formula (III):
The compounds of formula (I), supra, as described and defined herein have surprisingly been found to effectively and selectively inhibit GLUT1 and may therefore be used for the treatment and/or prophylaxis of diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, or diseases which are accompanied with uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate
cellular inflammatory responses, such as, for example, haematological tumours, solid tumours, and/or metastases thereof, e.g. leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof. In accordance with another aspect therefore, the present invention covers a compound of general formula (I), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, as described and defined herein, for use in the treatment or prophylaxis of a disease, as mentioned supra. Another particular aspect of the present invention is the use of a compound of general formula (I), described supra, or a stereoisomer, a tautomer, an N- oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, for the prophylaxis or treatment of a disease. Another particular aspect of the present invention is the use of a compound of general formula (I) described supra for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease. The compounds of the present invention can be used in particular in therapy and prevention, i.e. prophylaxis, of tumour growth and metastases, especially in solid tumours of all indications and stages with or without pre-treatment of the tumour growth.
Methods of testing for a particular pharmacological or pharmaceutical property are well known to persons skilled in the art.
The present invention relates to a method for using the compounds of the present invention and compositions thereof, to treat mammalian hyper- proliferative disorders. Compounds can be utilized to inhibit, block, reduce, decrease, etc., cell proliferation and/or cell division, and/or produce apoptosis. This method comprises administering to a mammal in need thereof, including a human, an amount of a compound of this invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof ; etc. which is effective to treat the disorder. Hyper- proliferative disorders include but are not limited, e.g., psoriasis, keloids, and other hyperplasias affecting the skin, benign prostate hyperplasia (BPH), solid tumors, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases. Those disorders also include lymphomas, sarcomas, and leukemias. Examples of breast cancer include, but are not limited to invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ. Examples of cancers of the respiratory tract include, but are not limited to small-cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma. Examples of brain cancers include, but are not limited to brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumor.
Tumors of the male reproductive organs include, but are not limited to prostate and testicular cancer. Tumors of the female reproductive organs include, but are not limited to endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus. Tumors of the digestive tract include, but are not limited to anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small- intestine, and salivary gland cancers. Tumors of the urinary tract include, but are not limited to bladder, penile, kidney, renal pelvis, ureter, urethral and human papillary renal cancers. Eye cancers include, but are not limited to intraocular melanoma and retinoblastoma. Examples of liver cancers include, but are not limited to hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma. Skin cancers include, but are not limited to squamous cell carcinoma, Kaposi’s sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer. Head-and-neck cancers include, but are not limited to laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oral cavity cancer and squamous cell. Lymphomas include, but are not limited to AIDS- related lymphoma, non-Hodgkin’s lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin’s disease, and lymphoma of the central nervous system.
Sarcomas include, but are not limited to sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma. Leukemias include, but are not limited to acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia. These disorders have been well characterized in humans, but also exist with a similar etiology in other mammals, and can be treated by administering pharmaceutical compositions of the present invention. The term“treating” or“treatment” as stated throughout this document is used conventionally, e.g., the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of, etc., of a disease or disorder, such as a carcinoma. Based upon standard laboratory techniques known to evaluate compounds useful for the treatment of hyper-proliferative disorders and angiogenic disorders, by standard toxicity tests and by standard pharmacological assays for the determination of treatment of the conditions identified above in mammals, and by comparison of these results with the results of known medicaments that are used to treat these conditions, the effective dosage of the compounds of this invention can readily be determined for treatment of each desired indication. The amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated. The total amount of the active ingredient to be administered will generally range from about 0.001 mg/kg to about 200 mg/kg body weight per day, and preferably from about 0.01 mg/kg to about 20 mg/kg body weight per day.
Clinically useful dosing schedules will range from one to three times a day dosing to once every four weeks dosing. In addition, "drug holidays" in which a patient is not dosed with a drug for a certain period of time, may be beneficial to the overall balance between pharmacological effect and tolerability. A unit dosage may contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day or less than once a day. The average daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily. The transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg. The average daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight. Of course the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like. The desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests.
General synthesis of compounds of general formula (I) of the present invention The following paragraphs outline a variety of synthetic approaches suitable to prepare compounds of the general formula (I), and intermediates useful for their synthesis.
In addition to the routes described below, also other routes may be used to synthesise the target compounds, in accordance with common general knowledge of a person skilled in the art of organic synthesis. The order of transformations exemplified in the following schemes is therefore not intended to be limiting, and suitable synthesis steps from various schemes can be combined to form additional synthesis sequences. In addition, interconversion of any of the substituents, in particular R1, R3, R4a, R4b, R5a, R5b, R5c or R5d, as well as of the R6 group attached to R2 via -(L2)p-, can be achieved before and/or after the exemplified transformations. These modifications can be such as the introduction of protective groups, cleavage of protective groups, reduction or oxidation of functional groups, halogenation, metallation, metal catalysed coupling reactions, exemplified by but not limited to Suzuki, Sonogashira and Ullmann coupling, ester saponifications, amide coupling reactions, and/or substitution or other reactions known to a person skilled in the art. These transformations include those which introduce a functionality allowing for further interconversion of substituents. Appropriate protective groups and their introduction and cleavage are well-known to a person skilled in the art (see for example T.W. Greene and P.G.M. Wuts in Protective Groups in Organic Synthesis, 4th edition, Wiley 2006).
Further, it is possible that two or more successive steps may be performed without work-up being performed between said steps, e.g. a“one-pot” reaction, as it is well-known to a person skilled in the art.
Compounds of general formula (I-1) can be assembled from 4-aminotriazole derivatives of formula (II-1), in which R1, R2, R3 and L1 are as defined for the compounds of general formula (I-1), and quinoline-4-carboxylic acid derivatives of formula (III), in which R4a, R4b, R5a, R5b, R5c and R5d are as defined for the compounds of general formula (I-1), by means of carboxamide (or peptide) coupling reaction well known to the person skilled in the art, according to Scheme 1. Said coupling reaction can be performed by reaction of compounds of the formulae (II-1) and (III) in the presence of a suitable coupling reagent, such as HATU (O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate), TBTU (O-(benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium tetrafluoroborate), PyBOP (benzotriazol-1-yl- oxytripyrrolidinophosphonium hexafluorophosphate), or EDC (1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) in combination with HOBt (1-hydroxy-1H-benzotriazole hydrate), in the presence of a base such as an aliphatic or aromatic tertiary amine, preferably a tertiary aliphatic amine of the formula N(C1-C4-alkyl)3, in an appropriate solvent. Preferred herein is the performance of said carboxamide coupling reaction using O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) as a coupling agent, in the presence of N,N- diisopropylethylamine as a base, and in dimethylsulfoxide as a solvent, within a temperature range from 0°C to 50°C. Also preferred herein is the performance of said carboxamide coupling reaction using O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) as a coupling agent, in the presence of N,N-diisopropylethylamine as a base, and in tetrahydrofuran as a solvent, within a temperature range from 0°C to 50°C.
Also preferred herein is the performance of said carboxamide coupling reaction using benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) as a coupling agent, in the presence of N,N-diisopropylethylamine as a base, and in tetrahydrofuran as a solvent, within a temperature range from 0°C to 50°C. The preparation of compounds of the general formula (I-1) from 4- aminotriazole derivatives of formula (II-1), in which R1, R2, R3 and L1 are as defined for the compounds of general formula (I), and quinoline-4-carboxylic acid derivatives of formula (III), in which R4a, R4b, R5a, R5b, R5c and R5d are as defined for the compounds of general formula (I-1), can furthermore be accomplished, as well known to the person skilled in the art, by converting carboxylic acids of the formula (III) into the corresponding acyl halides, e.g. by reacting with a halogenating agent such as thionyl chloride, oxalyl chloride, or phosphoroxy chloride, and subsequent aminolysis using said 4-aminotriazole derivatives of formula (II-1).
Scheme 1: Preparation of compounds of general formula (I-1) from 4-aminotriazole derivatives of formula (II-1) and carboxylic acids of formula (III).
4-Aminotriazole intermediates and quinazoline-4-carboxylic acid derivatives of formulae (II-1) and (III) are either commercially available in some structural variety, or they can be prepared using synthetic methods described in more detail as shown below. If aminotriazole derivatives of formula (II-1), in which R3 represents a hydrogen atom, have been employed in the carboxamide coupling reaction described supra, R3 groups different from hydrogen can also be introduced subsequently to said carboxamide coupling reaction by means of deprotonating the resulting compounds of formula (Ia-1), in which R1, R2, R4a, R4b, R5a, R5b, R5c, R5d and L1 are as defined for the compounds of general formula (I-1), with a base such as an alkali metal hydride, preferably sodium hydride, followed by reaction with a compound of the formula (IV-1), in which LG represents a leaving group, preferably chloro, bromo, or iodo, and in which R3 is as defined for the compounds of general formula (I-1) but different from hydrogen, to give compounds of formula (Ib-1), as outlined in Scheme 2.
Scheme 2: Preparation of compounds of formula (Ib-1) from compounds of formula (Ia-1).
Compounds of formula (IV-1) are well known to the person skilled in the art and are readily commercially available. As illustrated in Scheme 3a, intermediate 4-aminotriazole derivatives of formula (II-1) are available from compounds of the formula (V-1), in which R2 and L1 are as defined for the compounds of general formula (I-1), and in which LG represents a leaving group as defined herein, preferably chloro, bromo or iodo. Said compounds of formula (V-1) are reacted with an alkali azide, such as sodium azide, in the presence of a dipolar aprotic solvent, such as dimethylsulfoxide, N,N-dimethylformamide or N,N-dimethylacetamide, at a temperature between 0 °C and 50 °C, preferably at room temperature, to give organic azide compounds of formula (VI-1). Said organic azides of formula (VI- 1) can subsequently be reacted with β-ketoesters of formula (VII-1), in which R1 is as defined for the compounds of general formula (I-1), and in which RE1 represents a C1-C3-alkyl- group, preferably methyl-, in the presence of a base such as an alkali carbonate, preferably potassium carbonate, in dimethylsulfoxide as a solvent, preferably at a temperature between 20 °C and 60 °C, to give triazole derivatives of formula (VIII-1). Said triazole derivatives of formula (VIII-1) can be reacted with an alkali hydroxide, such as lithium hydroxide, sodium hydroxide, or potassium hydroxide, in a suitable solvent mixture such as aqueous methanol, aqueous ethanol or aqueous tetrahydrofuran, as well known to the person skilled in the art, to give carboxylic acids of formula (IX-1), which can be converted into the corresponding carboxamides of formula (X-1) by subsequent treatment with a halogenating agent such as thionyl chloride, oxalyl chloride, or phosphoroxy chloride, followed by aminolysis using an aqueous solution of ammonia. Carboxamides of formula (X-1) can be treated in a well-known Hofmann rearrangement reaction (Org. React. 3, p.267-306, 1946), by treatment with bromine in the presence of a strong base such as an alkali hydroxide,
preferably potassium hydroxide, in water as a solvent, at a temperature between 50 °C and 100°C, to give primary amines of formula (IIa-1).
R3 groups different from hydrogen can be either be introduced at later stage, as outlined in Scheme 2, or they may be introduced into primary amines of formula (IIa-1) by means of reductive amination reactions well known to the person skilled in the art, e.g. by reaction of said primary amines of formula (IIa-1) with suitable aldehydes or ketones, followed by reduction e.g. with sodium cyanoborohydride, to give secondary amines of formula (IIb-1). Taken together, formulae (IIa-1) and (IIb-1) constitute formula (II-1).
Compounds of formulae (V-1) and (VII-1) are well known to the person skilled in the art and can be purchased commercially in considerable structural variety.
(IIa-1): R3 = H; (IIb-1): R3 H Scheme 3a: Preparation of compounds of formula (II-1) from compounds of formula (V-1). Primary amines of formula (IIa-1) can alternatively be prepared, as outlined in Scheme 3b, from carboxylic acids of formula (IX-1), in which R1, R2 and L1 are as defined for compounds of general formula (I-1), via Curtius rearrangement, which is well known to the person skilled in the art (see e.g Synthesis 1983,
p38; Tetrahedron Lett. 1984 (25), p3515; J. Am. Chem. Soc. 1972 (94). p6203– 6205; Tetrahedron 1974 (30), p2151–2157), in which said carboxylic acid of formula (IX-1) is reacted with an azide transfer reagent, such as diphenyl phosphoryl azide, in the presence of an organic base such as an aliphatic or aromatic tertiary amine, preferably a tertiary aliphatic amine of the formula N(C1-C4-alkyl)3, in a solvent such as tetrahydrofuran. Dependent on the work-up of the reaction, i.e. whether water or an alcohol is used to stop the reaction, the amino group present in compounds of formula (IIa-1) is either generated in free form straight away, or as a carbamate which can be cleaved to release the free amine according to methods well known to the person skilled in the art, e.g. by acidic cleavage of a tert-butyl carbamate formed upon stopping the reaction by addition of tert-butanol as described in the Experimental Section (see Intermediate 2B, steps 5) and 6)).
The preparation of compounds of the general formula (I-2) from 4- aminothiazole derivatives of formula (II-2), in which R1, R2, R3 and L4 are as defined for the compounds of general formula (I-2), and quinoline-4-carboxylic acid derivatives of formula (III), in which R4a, R4b, R5a, R5b, R5c and R5d are as defined for the compounds of general formula (I-2), can furthermore be accomplished, as well known to the person skilled in the art, by converting
carboxylic acids of the formula (III) into the corresponding acyl halides, e.g. by reacting with a halogenating agent such as thionyl chloride, oxalyl chloride, or phosphoroxy chloride, and subsequent aminolysis using said 4-aminothiazole derivatives of formula (II-2).
(I-2) Scheme 4: Preparation of compounds of general formula (I-2) from 4-aminothiazole derivatives of formula (II-2) and carboxylic acids of formula (III). 4-Aminothiazole intermediates of formula (II-2) are known to the person skilled in the art and can, if not commercially available, be prepared according to Schemes 6a and 6b shown below. Quinazoline-4-carboxylic acid derivatives of formula (III) are either commercially available in some structural variety, or they can be prepared using synthetic methods described in more detail as shown below. If aminothiazole derivatives of formula (II-2), in which R3 represents a hydrogen atom, have been employed in the carboxamide coupling reaction described supra, R3 groups different from hydrogen can also be introduced subsequently to said carboxamide coupling reaction by means of deprotonating the resulting compounds of formula (Ia-2), in which R1, R2, R4a, R4b, R5a, R5b, R5c, R5d and L4
are as defined for the compounds of general formula (I-2), with a base such as an alkali metal hydride, preferably sodium hydride, followed by reaction with a compound of the formula (IV-2), in which LG represents a leaving group, preferably chloro, bromo, or iodo, and in which R3 is as defined for the compounds of general formula (I-2) but different from hydrogen, to give compounds of formula (Ib-2), as outlined in Scheme 5.
Scheme 5: Preparation of compounds of formula (Ib-2) from compounds of formula (Ia-2). Compounds of formula (IV-2) are well known to the person skilled in the art and are readily commercially available. As illustrated in Scheme 6a, intermediate 4-aminothiazole derivatives of formula (II-2) are available from carboxylic esters of the formula (V-2), in which R1, R2 and L4 are as defined for the compounds of general formula (I-2), and in which RE1 represents a C1-C3-alkyl- group, preferably methyl- or ethyl-. Said carboxylic esters of the formula (V-2) can be reacted with an alkali hydroxide, such as lithium hydroxide, sodium hydroxide, or potassium hydroxide, in a suitable solvent mixture such as aqueous methanol, aqueous
ethanol or aqueous tetrahydrofuran, as well known to the person skilled in the art, to give carboxylic acids of formula (VI-2). Said carboxylic acids of formula (VI-2) can be converted into the corresponding primary amines of formula (IIa- 2) via Curtius rearrangement, which is well known to the person skilled in the art (see e.g Synthesis 1983, p38; Tetrahedron Lett. 1984 (25), p3515; J. Am. Chem. Soc. 1972 (94). p6203–6205; Tetrahedron 1974 (30), p2151–2157), in which said carboxylic acid of formula (VI-2) is reacted with an azide transfer reagent, such as diphenyl phosphoryl azide, in the presence of an organic base such as an aliphatic or aromatic tertiary amine, preferably a tertiary aliphatic amine of the formula N(C1-C4-alkyl)3, in tert-butanol as a solvent, to give intermediate carbamates of formula (VII-2). Said carbamate of formula (VII-2) can then be cleaved to release the free amine e.g. by acidic cleavage, as well known to the person skilled in the art.
R3 groups different from hydrogen can be either be introduced at later stage, as outlined in Scheme 5, or they may be introduced into primary amines of formula (IIa-2) by means of reductive amination reactions well known to the person skilled in the art, e.g. by reaction of said primary amines of formula (IIa-2) with suitable aldehydes or ketones, followed by reduction e.g. with sodium cyanoborohydride, to give secondary amines of formula (IIb-2). Taken together, formulae (IIa-2) and (IIb-2) constitute formula (II-2).
H3
H3
(IIa-2): R 3 = H; (IIb-2): R3 H Scheme 6a: Preparation of compounds of formula (II-2) from compounds of formula (V-2). Carboxylic esters of formula (V-2) can be, if not commercially available, prepared, as exemplified in Scheme 6b, via various approaches, dependent on the nature of L4. Further approaches are known to the person skilled in the art, or can be derived from known methods. Carboxylic esters of formula (Va-2), in which R1 and R2 are as defined for the compounds of general formula (I-2), in which RE1 represents a C1-C3-alkyl- group, preferably methyl- or ethyl-, and in which L4 represents a–CH2- group, can be prepared from nitriles of formula (VIII-2), in which R2 is as defined for the compounds of general formula (I-2), and in which L4 represents a–CH2- group, by reaction with O, O’-diethyl dithiophosphate to give to thioamides of formula (IX-2). Said thioamides of formula (IX-2) can then be reacted with ketoesters of formula (X-2), in which R1 is as defined as for the compounds of general formula (I-2), in which LG represents a leaving group as defined herein, preferably chloro, and in which RE1 represents a C1-C3-alkyl- group, preferably
methyl- or ethyl-, in pyridine as a solvent, preferably at elevated temperature, to give said carboxylic esters of formula (Va-2).
In a similar fashion, said thioamides of formula (IX-2) can be replaced in the reaction with compounds of the formula (X-2) by thioureas of formula (IXa-2), in which R2 is as defined for the compounds of general formula (I-2) and in which L4 represents–N(H)-, to give carboxylic esters of formula (Vb-2), in which R1 and R2 are as defined for compounds of general formula (I-2), in which RE1 represents a C1-C3-alkyl- group, preferably methyl- or ethyl-, and in which L4 represents–N(H)-. Further modification of the–NH- group in formula (Vb-2) into a group–N(R13)- in which R13 is as defined for the compounds of general formula (I-2) but different from hydrogen can be performed by reacting said carboxylic esters of formula (Vb-2) with compounds of formula (XI-2), in which LG represents a leaving group, preferably chloro, bromo, or iodo, and in which R13 is as defined for the compounds of general formula (I-2) but different from hydrogen, in the presence of a base such as an alkali metal hydride, preferably sodium hydride, as well known to the person skilled in the art, to give carboxylic esters of formula (Vc-2).
If L4 represents an–O- group, carboxylic esters of formula (Vd-2) can be prepared from thiazole derivatives of formula (XII-2), in which R1 is as defined as for the compounds of general formula (I-2), in which LG represents a leaving group as defined herein, preferably bromo, and in which RE1 represents a C1-C3- alkyl- group, preferably methyl- or ethyl-. Said thiazole derivatives of formula (XII-2) can be reacted with compounds of formula (XIII-2), in which R2 is as defined for the compounds of general formula (I-2), in the presence of a base such as an alkali carbonate, preferably potassium carbonate, in a solvent such as N,N-dimethylformamide or N,N-dimethylacetamide, to give carboxylic esters of formula (Vd-2) in which R1 and R2 are as defined for the compounds of general formula (I-2), in which RE1 represents a C1-C3-alkyl- group, preferably methyl- or ethyl-, and in which L4 represents an–O- group.
Starting materials and reactants discussed in this paragraph, in particular compounds of formulae (VIII-2), (IXa-2), (X-2), (XI-2), (XII-2) and (XIII-2), are well known to the person skilled in the art and are widely commercially available.
(Va-2); L4 = -CH2-
(Vb-2); L4 = -NH- (Vc-2); L4 = -N(R13)- R13 H
Scheme 8: Chemoselective modification of R4a group in a subset of quinoline-4- carboxylic acid derivatives of formula (III).
Abbreviations
Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEH C18 1.7 50x2.1mm; eluent A: water + 0.1% formic acid, eluent B: acetonitril; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 mL/min; temperature: 60 °C; injection: 2 µL; DAD scan: 210-400 nm; ELSD Method 2: UPLC (ACN-NH3)
Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEH C18 1.7 50x2.1mm; eluent A: water + 0.2% ammonia, eluent B: acetonitril; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 mL/min; temperature: 60 °C; injection: 2 µL; DAD scan: 210-400 nm; ELSD Method 3: System: Waters autopurification system: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD; Column: XBrigde C18 5µm 100x30 mm;
Solvent: A = H2O + 0.1% Vol. formic acid (99%), B = acetonitrile; Gradient: 0-8 min 10-100% B, 8-10 min 100% B; Flow: 50 mL/min; temperature: room temp.; Solution: Max. 250 mg / max. 2.5 mL DMSO o. DMF; Injection: 1 x 2.5 mL; Detection: DAD scan range 210–400 nm; MS ESI+, ESI-, scan range 160-1000 m/z. Method 4: System: Waters autopurification system: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD; Column: XBrigde C18 5µm 100x30 mm;
Solvent: A = H2O + 0.1% Vol. ammonia (99%), B = acetonitrile; Gradient: 0-8 min 10- 100% B, 8-10 min 100% B; Flow: 50 mL/min; temperature: room temp.; Solution: Max. 250 mg / max. 2.5 mL DMSO o. DMF; Injection: 1 x 2.5 mL; Detection: DAD scan range 210–400 nm; MS ESI+, ESI-, scan range 160-1000 m/z.
Methode 5: (prep. HPLC) System: Labomatic, Pump: HD-5000, Fraction Collector: LABOCOL Vario-4000, UV-Detector: Knauer UVD 2.1S; Column: Chromatorex C1810µm 125x30 mm; Solvent: A = water + + 0.1% Vol. formic acid (99%), B = Acetonitril; Flow: 150 mL/min; temperature: room temperature; Solution: Max. 250 mg / 2mL DMSO; Injektion: 2 x 2mL; Detection: UV 218 nm; Software: SCPA PrepCon5.The following gradients for the preparative HPLC were used according the retention times in the analytic UPLC:
Gradient 5a: 0– 15 min 1 - 25 % B (for Rt (min): 0– 0.54)
Gradient 5b: 0– 15 min 10 - 50 % B (for Rt (min): 0.54– 0.80)
Gradient 5c: 0– 15 min 15 - 55 % B (for Rt (min): 0.80– 1.10)
Gradient 5d: 0– 15 min 30 - 70 % B (for Rt (min): 1.10– 1.35)
Gradient 5e: 0– 15 min 40 - 80 % B (for Rt (min): 1.35– 1.42)
Gradient 5f: 0– 15 min 65 - 100 % B (for Rt (min): 1.42– 2.00) Method 6: Waters autopurification system: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD; Column: XBrigde C18 5µm 100x30 mm; Solvent: A = water + 0.1% Vol. formic acid (99%), B = acetonitrile; Gradient: 0-8 min 50-90% B, 8-10 min 100% B; Flow: 50 mL/min; temperature: room temp.; Solution: Max.250 mg / max. 2.5 mL DMSO o. DMF; Injection: 4 x 0.7 mL; Detection: DAD scan range 210–400 nm; MS ESI+, ESI-, scan range 160-1000 m/z. Method 7: System: Agilent: Prep 1200, 2xPrep Pump, DLA, MWD, Prep FC; Column: Chiralpak IA 5µm 250x30 mm; Solvent: Methanol / Ethanol 50:50 (v/v); Flow: 40 mL/min; temperature: room temp.; Detection: UV 254nm Method 8: System: Sepiatec: Prep SFC100; Column: Chiralpak IC 5µm 250x20 mm; Solvent: CO2 / Ethanol +0,4%DEA 8/2; Flow: 80 mL/min; temperature: 40°C;
Detection: UV 254nm Method 9: System: Agilent: Prep 1200, 2xPrep Pump, DLA, MWD, Prep FC; Column: Chiralpak ID 5µm 250x30 mm; Solvent: Hexan / 2-Propanol 70:30 (v/v); Flow: 50 mL/min; temperature: rom temp.; Detection: UV 254nm
Method 10: System: Agilent: Prep 1200, 2xPrep Pump, DLA, MWD, Gilson: Liquid Handler 215; Column: Chiralpak IC 5µm 250x30 mm; Solvent: ACN / ethanol 90:10 (v/v); Flow: 50 mL/min; temperature: rom temp.; Detection: UV 220nm Method 11: System: Waters Acquity UPLC-MS: Binary Solvent Manager, Sample Manager/Organizer, Column Manager, PDA, ELSD, SQD 3001; Column: YMC-Triart C18, 50mm x 2.0mm, 1.9µm; Solvent: A = H2O + 0.1% Vol. formic acid (99%), B = acetonitrile; Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; Flow: 0.8 mL/min; temperature: 60°C; Detection: DAD scan range 210-400 nm -> Peak table; method: MS ESI+, ESI- Switch -> diverse scan ranges possible
Column chromatography was performed on a Biotage® Isolera™ Spektra Four Flash Purification System. NMR peak forms of selected examples are stated as they appear in the spectra, possible higher order effects have not been considered. In cases were a signal is very broad or is partially or totally hidden by a solvent peak the total number of hydrogen atoms displayed in NMR spectra can differ from the number of hydrogen atoms present in the respective molecule. When a compound described below in the synthesis intermediates and examples of the present invention is mentioned as a salt form with the corresponding base or acid, the exact stoichiometric composition of said salt form, as obtained by the respective preparation and/or purification process, is unknown in most cases. If not specified otherwise, suffixes to chemical names or structural formulas such as "hydrochloride", "trifluoroacetate", "sodium salt", or "x HCl", "x CF3COOH", "x Na+" are not to be understood as a stoichiometric specification, but solely serve the purpose to describe the components said salt form comprises.
This applies analogously to cases in which synthesis intermediates or example compounds or salts thereof have been obtained, by the preparation and/or purification processes described, as solvates such as hydrates with (if defined) unknown stoichiometric composition.
Yields in % reflect the purity of the desired product obtained if not stated otherwise; purities significantly below 90% were specified explicity if appropriate. If not stated otherwise, starting materials as mentioned in the protocols were purchased from commercial suppliers. The IUPAC names of the examples and intermediates were generated using the program ´ACD/Name batch version 12.01´ from ACD LABS, and were adapted if needed.
Intermediates
Intermediate 1A
6-bromo-2-(trifluoromethyl)quinoline-4-carboxylic acid
Intermediate 2A
2-carbamoyl-7-fluoroquinoline-4-carboxylic acid
To a mixture of 5.0 g (30.3 mmol) 6-fluoro-1H-indole-2,3-dione in 75 mL of 33% aq. potassium hydroxide solution was added 4.67 g (53.0 mmol) pyruvic acid and this mixture was heated at 40°C for 18 hours. After cooling to room temperature 10% aq. sulfuric acid was added (pH about 1). The formed solid was isolated by filtration and dried in vacuum. The solid was the desired 7-fluoroquinoline-2,4-dicarboxylic acid, which was used without further purification. Yield: 6.02 g (85%). 1H-NMR (300 MHz, DMSO d6) δ (ppm) = 7.78 (ddd, 1H), 7.99 (dd, 1H), 8.42 (s, 1H), 8.89 (dd, 1H). Step 2: dimethyl 7-fluoroquinoline-2,4-dicarboxylate
A mixture of 6.0 g (25.5 mmol) of the diacid of step 1) intermediate 2A) and 28 mL (383 mmol) thionyl chloride was heated at 80°C for 2 days. After cooling to 25°C the resulting suspension was evaporated to dryness in vacuum. This crude product was suspended in 47 mL methanol and refluxed for 3 hours. After cooling to 25°C the formed solid was isolated by filtration. Yield: 3.06 g (44%). 1H-NMR (300 MHz, DMSO d6) δ (ppm) = 3.98 (s, 3H), 4.01 (s, 3H), 7.85 (ddd, 1H), 8.07 (dd, 1H), 8.45 (s, 1H), 8.80 (dd, 1H).
Step 3: methyl 2-carbamoyl-7-fluoroquinoline-4-carboxylate
To a solution of 3.05 g (11.6 mmol) diester of step 2) intermediate 2A) in 42 mL methanol was added 41 mL of a 7M solution of ammonia in methanol and stirred for 3.5 hours at 50°C. After cooling to 25°C, the formed solid was isolated by filtration and dried. Using this methodology we obtained the desired methyl 2-carbamoyl-7- fluoroquinoline-4-carboxylate. Yield: 2.33 g (81%). 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 4.03 (s, 3H), 7.83 (ddd, 1H), 7.94 (dd, 1H), 7.97 (s, 1H), 8.39 (s, 1H), 8.52 (s, 1H), 8.83 (dd, 1H). Step 4: 2-carbamoyl-7-fluoroquinoline-4-carboxylic acid
To a solution of 3.00 g (12.1 mmol) of the compound from step 3) intermediate 2A) in 56 mL methanol and 20 ml tetrahydrofuran was added a solution of 4.35 g sodium hydroxide in 111 mL water. This mixture was stirred for 1 hour at 25°C and then concentrated in vacuum. The residue was diluted with water and 10% aq. sulfuric acid was added up to pH 5. After stirring for additional 15 minutes the formed solid was isolated by filtration and dried in vacuum. Using this methodology we obtained the desired title compound . Yield: 2.38 g (80%). 1H-NMR (300 MHz, DMSO d6) δ (ppm) = 7.76 (ddd, 1H), 7.84 - 7.96 (m, 2H), 8.35 (br. s., 1H), 8.46 (s, 1H), 8.89 (dd, 1H), 14.02 (br. s., 1H).
Intermediate 3A
2-carbamoylquinoline-4-carboxylic acid
In analogy to step 3) of intermediate 2A) 1.0 g (4.08 mmol) dimethyl quinoline-2,4- dicarboxylate of step 1) of intermediate 3A) were reacted to give 650 mg (66% yield) methyl 2-carbamoylquinoline-4-carboxylate. 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 4.01 (s, 3H), 7.85 (ddd, 1H), 7.89 (br. s., 1H), 7.95 (ddd, 1H), 8.22 (d, 1H), 8.37 (br. s., 1H), 8.53 (s, 1H), 8.71 (d, 1H). Step 3: 2-carbamoylquinoline-4-carboxylic acid
In analogy to step 4) of intermediate 2A) 650 mg (2.82 mmol) methyl 2- carbamoylquinoline-4-carboxylate of step 2) of intermediate 3A) were reacted to give 540 mg (86% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 7.82 (dt, 1H), 7.86 (br. s., 1H), 7.92 (td, 1H), 8.20 (d, 1H), 8.34 (br. s., 1H), 8.50 (s, 1H), 8.78 (d, 1H), 13.98 (br. s., 1H).
Intermediate 4A
2-carbamoyl-6-chloro-7-fluoroquinoline-4-carboxylic acid
In analogy to step 2) of intermediate 2A) 3.63 g (13.5 mmol) 6-chloro-7- fluoroquinoline-2,4-dicarboxylic acid of step 1) of intermediate 4A) were reacted to give 3.12 g (74% yield) dimethyl 6-chloro-7-fluoroquinoline-2,4-dicarboxylate. 1H-NMR (500 MHz, DMSO d6) δ (ppm) = 3.98 (s, 3H), 4.01 (s, 3H), 8.29 (d, 1H), 8.46 (s, 1H), 8.94 (d, 1H). Step 3: methyl 2-carbamoyl-6-chloro-7-fluoroquinoline-4-carboxylate
In analogy to step 3) of intermediate 2A) 3.12 g (10.5 mmol) dimethyl 6-chloro-7- fluoroquinoline-2,4-dicarboxylate of step 2) of intermediate 4A) were reacted to give 2.52 g (77% yield) methyl 2-carbamoyl-6-chloro-7-fluoroquinoline-4-carboxylate. 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 4.01 (s, 3H), 7.98 (br. s., 1H), 8.11 (d, 1H), 8.36 (br. s., 1H), 8.54 (s, 1H), 8.96 (d, 1H). Step 4: 2-carbamoyl-6-chloro-7-fluoroquinoline-4-carboxylic acid
In analogy to step 4) of intermediate 2A) 520 mg (1.84 mmol) methyl 2-carbamoyl-6- chloro-7-fluoroquinoline-4-carboxylate of step 3) of intermediate 4A) were reacted to give 390 mg (63% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 7.92 (br. s., 1H), 8.06 (d, 1H), 8.31 (br. s., 1H), 8.51 (s, 1H), 9.10 (d, 1H).
Intermediate 5A
2-carbamoyl-5-fluoroquinoline-4-carboxylic acid
In anlogy to step 1) of intermediate 2A) we got from 10.0 g (60.6 mmol) commercially available 4-fluoro-1H-indole-2,3-dione 6.63 g (46% yield) 5-fluoroquinoline-2,4- dicarboxylic acid. 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 7.67 (dd, 1H), 7.95 (ddd, 1H), 8.08 - 8.12 (m, 2H). Step 2: dimethyl 5-fluoroquinoline-2,4-dicarboxylate
In anlogy to step 2) of intermediate 2A) we got from 6.63 g (28.2 mmol) 5- fluoroquinoline-2,4-dicarboxylic acid of step 1) of intermediate 5A) 9.40 g (46% yield) dimethyl 5-fluoroquinoline-2,4-dicarboxylate. 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 3.98 (s, 3H), 3.98 (s, 3H), 7.68 - 7.76 (m, 1H), 7.98 (ddd, 2H), 8.11 - 8.18 (m, 2H), 8.27 (s, 1H). Step 3: methyl 2-carbamoyl-5-fluoroquinoline-4-carboxylate
In anlogy to step 3) of intermediate 2A) we got from 9.40 g (35.7 mmol) dimethyl 5- fluoroquinoline-2,4-dicarboxylate of step 2) of intermediate 5A) 1.84 g (21% yield) methyl 2-carbamoyl-5-fluoroquinoline-4-carboxylate. 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 3.98 (s, 3H), 7.68 (ddd, 1H), 7.93 - 8.01 (m, 2H), 8.09 (dd, 1H), 8.25 (s, 1H), 8.43 (br. s., 1H). Step 4: 2-carbamoyl-5-fluoroquinoline-4-carboxylic acid
In anlogy to step 4) of intermediate 2A) with the different to use lithium hydroxide instead sodium hydroxide we got from 1.84 g (7.41 mmol) methyl 2-carbamoyl-5-
fluoroquinoline-4-carboxylate of step 3) of intermediate 5A) 1.24 g (71% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 7.65 (ddd, 1H), 7.91 - 8.01 (m, 2H), 8.07 (dd, 1H), 8.13 (s, 1H), 8.41 (br. s., 1H), 14.06 (br. s., 1H).
Intermediate 6A
6-bromo-2-carbamoylquinoline-4-carboxylic acid
Step 1: 6-Bromoquinoline-2,4-dicarboxylic acid
To a mixture of 1.5 g (6.64 mmol) 5-bromo-1H-indole-2,3-dione in hot 15 mL of 33% aq. potassium hydroxide solution was added 1.02 g (11.6 mmol) pyruvic acid and this mixture was heated at 40°C for 16 hours. To the resulting thick paste 50 mL of 33% aq. potassium hydroxide solution was added and stirred. The solid was isolated by filtration and washed with 33% aq. potassium hydroxide solution and ethanol. The solid was then diluted in water and 10% aqueous sulfuric acid was added (pH below 7). The formed solid was isolated by filtration and dried for 8 hours in vacuum. The solid was the desired 6-bromoquinoline-2,4-dicarboxylic acid, which was used without further purification. Yield: 1.5 g (74%). 1H-NMR (300 MHz, DMSO d6) δ (ppm) = 8.06 (dd, 1H), 8.18 (d, 1H), 8.52 (s, 1H), 9.08 (d, 1H). Step 2: dimethyl 6-bromoquinoline-2,4-dicarboxylate
A mixture of 1.5 g (5.07 mmol) of the diacid of step 1) intermediate 6A) and 3.7 mL (50.7 mmol) thionyl chloride was heated at 80°C for 16 hours. After cooling to 25°C the resulting suspension was evaporated to dryness in vacuum. This crude product was suspended in 10 mL methanol and refluxed for 3 hours. After cooling to 25°C the
formed solid was isolated by filtration. To the filtrate water was added and the additionally formed solid was isolated by filtration . The combined crude products were purified via a Biotage chromatography system (25 g snap KP-Sil column, hexane / 0 – 100% ethyl acetate then ethyl acetate / 0- 10% methanol). Using this methodology we obtained the desired dimethyl 6-bromoquinoline-2,4-dicarboxylate. Yield: 180 mg (10%). 1H-NMR (300 MHz, DMSO d6) δ (ppm) = 3.98 (s, 3H), 4.02 (s, 3H), 8.10 (dd, 1H), 8.21 (d, 1H), 8.51 (s, 1H), 8.97 (d, 1H). Step 3: methyl 6-bromo-2-carbamoylquinoline-4-carboxylate
To a solution of 180 mg (0.56 mmol) diester of step 2) intermediate 6A) in 2.0 mL methanol was added 1.19 mL of a 7M solution of ammonia in methanol and stirred for 1 hour at 50°C. Then additional 15 equiv. of ammonia was added and stirring was continued for 2 hours at 50°C. After cooling to 25°C the formed solid was isolated by filtration and dried. Using this methodology we obtained the desired methyl 6- bromo-2-carbamoylquinoline-4-carboxylate. Yield: 120 mg (66%). 1H-NMR (300 MHz, DMSO d6) δ (ppm) = 4.01 (s, 3H), 7.95 (br. s., 1H), 8.04 - 8.18 (m, 2H), 8.41 (br. s., 1H), 8.57 (s, 1H), 8.97 (d, 1H). Step 4: 6-bromo-2-carbamoylquinoline-4-carboxylic acid
To a solution of 120 mg (0.39 mmol) of the compound from step 3) intermediate 6A) in 1.79 mL methanol was added a solution of 279 mg sodium hydroxide in 3.58 mL water. This mixture was stirred for 2 hours at 25°C and then concentrated in vacuum. The residue was diluted with water and 10% aq. sulfuric acid was added to adjust to pH 2. After stirring for additional 15 minutes the resulting solid was isolated by filtration and dried in vacuum. Using this methodology we obtained the desired title compound . Yield: 106 mg (74%). 1H-NMR (300 MHz, DMSO d6) δ (ppm) = 7.89 (br. s., 1H), 8.03 (dt, 1H), 8.07 - 8.18 (m, 1H), 8.36 (br. s., 1H), 8.43 - 8.55 (m, 1H), 9.10 (dd, 1H).
Intermediate 7A
2-carbamoyl-6-methoxyquinoline-4-carboxylic acid
In analogy to step 1) of intermediate 2A) we got from 5.0 g (38.2 mmol) commercially available 5-methoxy-1H-indole-2,3-dione 3.01 g (42% yield) 6-methoxyquinoline-2,4- dicarboxylic acid. 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 3.94 (s, 3H), 7.57 (dd, 1H), 8.14 (d, 1H), 8.25 (d, 1H), 8.48 (s, 1H), 13.66 (br. s., 1H). Step 2: dimethyl 6-methoxyquinoline-2,4-dicarboxylate
In analogy to step 2) of intermediate 2A) we got from 3.0 g (12.1 mmol) 6- methoxyquinoline-2,4-dicarboxylic acid of step 1) of intermediate 7A) 2.65 g (77% yield)
dimethyl 6-methoxyquinoline-2,4-dicarboxylate. 1H-NMR (300 MHz, DMSO d6) δ (ppm) = 3.95 (s, 6H), 4.00 (s, 3H), 7.60 (dd, 1H), 8.13 - 8.20 (m, 2H), 8.48 (s, 1H). Step 3: methyl 2-carbamoyl-6-methoxyquinoline-4-carboxylate
In analogy to step 3) of intermediate 2A) we got from 2.65 g (9.63 mmol) dimethyl 6- methoxyquinoline-2,4-dicarboxylate of step 2) of intermediate 7A) 1.45 g (55% yield) methyl 2-carbamoyl-6-methoxyquinoline-4-carboxylate.
1H-NMR (400 MHz, DMSO d6) δ (ppm) = 3.97 (s, 3H), 4.03 (s, 3H), 7.62 (dd, 1H), 7.82 (br. s., 1H), 8.14 (d, 1H), 8.18 (d, 1H), 8.30 (br. s., 1H), 8.56 (s, 1H). Step 4: 2-carbamoyl-6-methoxyquinoline-4-carboxylic acid
In analogy to step 4) of intermediate 2A) we got from 1.45 g (5.57 mmol) methyl 2- carbamoyl-6-methoxyquinoline-4-carboxylate of step 3) of intermediate 7A) 1.33 g (92% yield) of the desired title compound . 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 3.93 (s, 3H), 7.57 (dd, 1H), 7.79 (s, 1H), 8.09 (d, 1H), 8.25 (d, 1H), 8.27 (br. s., 1H), 8.51 (s, 1H), 13.72 (br. s., 1H), 13.79 - 13.79 (m, 1H).
Intermediate 1B
1-(4-bromobenzyl)-5-methyl-1H-1,2,3-triazol-4-amine
70.0 g p-bromo benzylbromide (280 mmol) and 27.5 g sodium azide (423 mmol) were dissolved in 550 mL dry dimethylsulfoxide. The reaction mixture was allowed to stir at room temperature for 20 h. The reaction mixture was poured into 2 L water and was extracted twice with 500 mL diethyl ether. The combined organic phase was washed with twice with 250 mL water, dried with magnesium sulfate, filtered and concentrated under reduced pressure. Yield: 56.8 g (96%). Step 2: methyl 1-(4-bromobenzyl)-5-methyl-1H-1,2,3-triazole-4-carboxylate
To a suspension of 156 g potassium carbonate (1.13 mol) in 400 mL dry dimethylsulfoxide, 58.9 g (278 mmol) azide of step 1) intermediate 1B) and 48.6 g methyl acetoacetate (419 mmol) were added and the reaction mixture was stirred at 40 °C for 72 h. The reaction mixture was poured into a mixture of 240 g ice and 1.1 L
water. The aqueous phase was extracted three times with 1L ethyl acetate. The combined organic phases were washed with 600 mL water and twice with 600 mL brine, and then dried with magnesium sulfate, filtered and concentrated under reduced pressure. Yield: 76.7 g (89%). Step 3: 1-(4-bromobenzyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid
30g (96.7 mmol) of the ester of step 2) intermediate 1B) was dissolved in 650 mL methanol. A solution of 7.74 g (193 mmol) sodium hydroxide in 64 mL water was added to the reaction mixture. The reaction mixture was stirred for 24 h at room temperature. The reaction mixture was filtered and residue was washed with 50 mL methanol. The precipitates were suspended in 500 mL water, brought to pH = 1 with 10% aqueous hydrochloric acid and stirred for 1 h at room temperature. The precipitates were filtered and washed twice with 250 mL water and dried under reduced pressure.Yield: 25.6 g (89%). Step 4: 1-(4-bromobenzyl)-5-methyl-1H-1,2,3-triazole-4-carboxamide
25g (84.4 mmol) of the carboxylic acid of step 3) intermediate 1B) was suspended in 345 mL dry chloroform. Then 51.5 mL thionyl chloride was added to the reaction mixture which was then stirred at 85 °C for 3 h. After cooling to room temperature the reaction mixture was concentrated under reduced pressure. The residue was dissolved in 86 mL dry acetonitrile. Then reaction mixture was cooled to 0 °C and 86 mL 25% ammonia solution was added dropwise to the reaction mixture during the course of 10 min. The reaction mixture was allowed to stir for 40 min at 0 °C. The reaction mixture was filtered and the residue was washed with 300 mL water. The solid was lyophilised. Yield: 23.3 g (95%). Step 5: 1-(4-bromobenzyl)-5-methyl-1H-1,2,3-triazol-4-amine
11.36 g (202 mmol) potassium hydroxide was dissolved in 52 mL water and then treated with 6.57 g (41 mmol) of bromine. To this mixture 10 g (33.8 mol) amide of step 4) intermediate 1B) was added to the reaction mixture and was stirred at 80 °C over night. The reaction mixture was stirred further at 80 °C for 24 h. The reaction mixture was allowed to cool to room temperature. The resulting precipitate was filtered, washed with 200 mL water and dried under reduced pressure. The 8.3 g
obtained solid was triturated with 40 mL diethylether with few drops of ethyl acetate. The solid was filtered and dried under reduced pressure and purified by column chromatography using silica gel (gradient, methanol: dichloromethane 0-20% as eluent) to give 2.0 g (22% yield) of the desired compound. 1H NMR (300 MHz, , DMSO d6): δ (ppm) = 2.00 (s, 3H), 4.52 (s, 2H), 5.38 (s, 2H), 7.09 (d, 2H), 7.56 (d, 2H).
Intermediate 2B
4-[(4-amino-5-methyl-1H-1,2,3-triazol-1-yl)methyl]benzonitrile
In analogy to step 1) of intermediate 1B), 70.0 g (357 mmol) p-cyano benzylbromide were reacted to give 54.0 g (96%) of the desired compound. Step 2: methyl 1-(4-cyanobenzyl)-5-methyl-1H-1,2,3-triazole-4-carboxylate
In analogy to step 2) of intermediate 1B), 55.6 g (352 mmol) of the azide from step 1) of intermediate 2B) and 61.5 g (530 mmol) methyl acetoacetate were reacted to give 74.9 g (83% yield) of the desired compound. Step 3: 1-(4-cyanobenzyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid
60g (234 mmol) of the ester of step 2) intermediate 2B) was dissolved in 550 mL tetrahydrofuran and reacted with 188.0 g (1.40 mol) lithium iodide. The reaction mixture was stirred at 70 °C overnight. Then the reaction mixture was concentrated under reduced pressure to remove tetrahydrofuran. Afterwards, the reaction mixture was diluted with 2 L water, brought to pH = 1 with 10% aqueous hydrochloric acid and extracted four times with 500 mL dichloromethane. The resulting solid was the desired compound.Yield: 48.6 g (86%)
Step 4: tert-butyl [1-(4-cyanobenzyl)-5-methyl-1H-1,2,3-triazol-4-yl]carbamate 2 g (8.2 mmol) of the acid of step 3) intermediate 2B) was dissolved in 150 mL dry THF and cooled to 0 °C. 1 g (10 mmol) dry triethylamine was added first to the reaction mixture and then 2.5 g (9.2 mmol) diphenyl phosphoryl azide was added dropwise to the reaction mixture. The mixture was brought to room temperature and and stirred for 45 min and then for 45 min stirred at reflux. Again, 0.5 mL diphenyl phosphoryl azide was added to the reaction mixture which was then stirred for further 2 h. Afterwards, 9 mL t-butanol was added to the reaction mixture and for 20 min at 65 °C stirred. Afterwards, the reaction mixture was allowed to stir at room temperature over night. Then the mixture was stirred at reflux for 24 hours, and after cooling to room temperature it was concentrated under reduced pressure. The crude product was purified by column chromatography using silica gel (gradient, ethyl acetate: c-hexane, 10-100 %) to give 643 mg (25% yield) of the desired compound. Step 5: 4-[(4-amino-5-methyl-1H-1,2,3-triazol-1-yl)methyl]benzonitrile trifluoroacetic acid salt
600 mg (1.92 mmol) the carbamate of step 4) intermediate 2B) was dissolved in 19 mL dichloromethane and then treated with 0.15 mL trifluoroacetic acid. The reaction mixture was stirred at room temperature overnight and then the mixture was concentrated under reduced pressure. The resulted solid was was purified by preparative thin layer chromatography using silica gel (chlorofom:methanol, 95:5 as eluent) to give 410 mg (100% yield) of the desired compound. 1H NMR (300 MHz, , DMSO d6): δ (ppm) = 2.09 (s, 3H), 4.33 (br. s., 3H), 5.61 (s, 2H), 7.36 (d, 2H), 7.90 (d, 2H). Step 6: 4-[(4-amino-5-methyl-1H-1,2,3-triazol-1-yl)methyl]benzonitrile
280 mg (0.86 mmol) the salt of step 5) intermediate 2B) was dissolved in 28 mL ethyl acetate and then extracted three times with 20 mL aqueous sodium bicarbonate, brine, dried over magnesium sulfate and after filtration dried under reduced
pressure. The residue (200 mg) was the desired compound, which was used in the next step without any further purification.
Intermediate 1C
2-(4-fluorobenzyl)-4-methyl-1,3-thiazol-5-amine hydrochloride
A solution of 25.2 g (186 mmol) 4-fluorophenylacetonitrile and 38.2 g (205 mmol) O,O'-diethyl dithiophosphate in a solution of 370 mL 4N hydrochloric acid in dioxane was stirred for 16 hours at room temperature. 350 mL water was added and the aqueous phase was extracted with 350 mL ethyl acetate. The combined organic phases were washed with 175 mL water, with an aqueous solution of sodium hydroxide (175 mL 0.2 N) and with 175 mL brine, dried over magnesium sulfate, filtered and concentrated.
The obtained residue was purified by successive triturations in 200 mL pentane and in 100 mL of a mixture of heptane/EtOAc 9/1. The solid was filtered, washed with heptane and dried under vacuum to give the desired product. Yield: 22 g (70%). Step 2: ethyl 2-(4-fluorobenzyl)-4-methyl-1,3-thiazole-5-carboxylate
To a suspension of 22 g (130 mmol) of the thioamide of step 1 (intermediate 1C) and 21.4 g (130 mmol) ethyl 2-chloro-3-oxobutanoate in 200 mL ethanol was added 12.7 mL pyridine. The mixture was stirred for 3 hours at room temperature. Then the suspension was stirred at 80°C over the weekend to complete the reaction. The mixture was concentrated to dryness and diethyl ether was added to the residue. The suspension was filtered and the solid was washed with diethyl ether. Then the filtrate was washed with water and brine, dried over magnesium sulfate and
concentrated to dryness to give 31.8 g (88% yield) of the desired material, which was used without any further purification. Step 3: 2-(4-fluorobenzyl)-4-methyl-1,3-thiazole-5-carboxylic acid
To a solution of 29.7 g (106 mmol) of the ester of step 2 (intermediate 1C) in 300 mL ethanol was added 117 mL of a solution of 1N sodium hydroxide. The solution was stirred for 12 hours at 50°C and for 58 hours at room temperature. 20 g Amberlite resin CG50 was added and the mixture was stirred for 30 minutes at room temperature. The suspension was filtered and the residue was washed four times with ethanol. Then the filtrate was concentrated to dryness to give 25.6 g of a crude solid of the desired compound. 22.4 g of this material was further dried under vacuum over phosphorus pentoxide to obtain 19.3 g (83% yield) of the desired compound. Step 4: tert-butyl [2-(4-fluorobenzyl)-4-methyl-1,3-thiazol-5-yl]carbamate
To a suspension of 14.2 g (56.5 mmol) of the acid of step 3 (intermediate 1C) and 11.8 mL triethylamine in 120 mL tert-butanol was stirred at 80°C, then 23.3 g ( 84.8 mmol) of diphenyl phosphoryl azide was added dropwise. The mixture was stirred for 2 hours at reflux. After cooling the mixture was partially concentrated. 150 mL water and 260 mL diethyl ether were added and after separation of the phases, the aqueous phase was extracted with 150 mL diethyl ether. The combined organic phases were washed with water and brine, dried over magnesium sulphate, filtered and concentrated to dryness.
The obtained crude product was purified by chromatography on silica gel (gradient Heptane/EtOAc) to give the desired compound.Yield: 13.6 g (74%). Step 5: 2-(4-fluorobenzyl)-4-methyl-1,3-thiazol-5-amine hydrochloride
To a solution of 13.6 g (42.2 mmol) of the carbamate of step 4 (intermediate 1C) in 100 mL ethyl acetate was added 52.8 mL of a solution of 4N hydrochloric acid in dioxane. The suspension was stirred for 2 hours at room
temperature. Then the suspension was stirred at 60°C for 8 hours and for 14 hours at room temperature. A TLC analysis indicated that some starting material was left. One additional equivalent (42 ml) of the 4N hydrochloric acid solution was added and the
suspension was stirred for additional 6 hours at 60°C to convert all the starting material. After cooling to room temperature, the suspension was filtered. The solid was washed with 400 mL of a solution of dioxane/EtOAc 5/5 and with pentane and dried under vacuum to give the desired compound. Yield: 11 g (88%). 1H NMR (400 MHz, DMSO d6): δ (ppm) = 2.22 (s, 3H), 4.35 (s, 2H), 7.14 - 7.22 (m, 2H), 7.37 - 7.46 (m, 2H).
Intermediate 2C
4-[(5-amino-4-methyl-1,3-thiazol-2-yl)methyl]benzonitrile hydrochloride
In analogy to step 1 of intermediate 1C) starting with 25.0 g (128 mmol) 4- bromophenylacetonitrile, 17.9 g (58% yield) of the desired title compound was obtained. Step 2: ethyl 2-(4-bromobenzyl)-4-methyl-1,3-thiazole-5-carboxylate
In analogy to step 2 of intermediate 1C) starting with 17.9 g (78 mmol) of the thioamide of step 1 (intermediate 2C), 23.7 g (89% yield) of the desired title compound was obtained. Step 3: 2-(4-fluorobenzyl)-4-methyl-1,3-thiazole-5-carboxylic acid
In analogy to step 3 of intermediate 1C) starting with 23.7 g (69 mmol) of the ester of step 3 (intermediate 2B), 20.2 g (94% yield) of the desired title compound was obtained. Step 4: tert-butyl [2-(4-bromobenzyl)-4-methyl-1,3-thiazol-5-yl]carbamate
In analogy to step 4 of intermediate 1C) starting with 15.0 g (48 mmol) of the acid of step 4 (intermediate 2C), 12.8 g (69% yield) of the desired title compound was obtained. Step 5: tert-butyl [2-(4-cyanobenzyl)-4-methyl-1,3-thiazol-5-yl]carbamate
To a solution 16.9 g (44 mmol) of the bromo compound of step 4 of intermediate 2B) in 205 mL N,N-dimethylformamide was added 3.1 g (26 mmol) zinc cyanide. The mixture was stirred under nitrogen atmosphere at 80°C and 5.1 g (4.4 mmol) palladiumtetrakis(triphenylphosphine) was added. After 2.5 hours the heating was stopped and after cooling 200 mL water was added. The aqueous phase was extracted twice with 300 mL ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated to dryness to give a crude material, which was purified by chromatography on silica gel (gradient Heptane/EtOAc) to give the desired compound. Yield: 14.1 g (97%). Step 6: 4-[(5-amino-4-methyl-1,3-thiazol-2-yl)methyl]benzonitrile hydrochloride In analogy to step 5 of intermediate 1C) starting with 14.4 g (43.7 mmol) of the cyano compound of step 5 (intermediate 2C) 12.0 g (91% yield) of the desired title compound was obtained. 1H NMR (400 MHz, DMSO d6): δ (ppm) = 2.22 (s, 3H), 4.43 (s, 2H), 7.53 - 7.59 (m, 2H), 7.80 - 7.86 (m, 2H).
Intermediate 3C
4-methyl-2-(4-methylbenzyl)-1,3-thiazol-5-amine hydrochloride
1H NMR (400 MHz, DMSO d6): δ (ppm) = 1.22 (t, 3H), 2.28 (s, 3H), 2.58 (s, 3H), 4.14 - 4.26 (m, 4H), 7.13 - 7.18 (m, 2H), 7.20 - 7.25 (m, 2H). Step 2: 2-(4-methylbenzyl)-4-methyl-1,3-thiazole-5-carboxylic acid
To a solution of 6.45 g (23.4 mmol) of the ester from step 2) intermediate 3C) in 50 mL ethanol was added a solution of 17.3 g sodium hydroxide in 100 mL water. This mixture was stirred for 2 hours at 25°C and then concentrated in vacuum. The residue was diluted with water and 10% aqueous sulfuric acid was added to adjust to pH 4. The formed solid was isolated by filtration and dried in vacuum. Using this methodology we obtained the desired title compound. Yield: 3.97 g (62%). 1H NMR (400 MHz, DMSO d6): δ (ppm) = 2.29 (s, 3H), 2.57 (s, 3H), 4.22 (s, 2H), 7.12 - 7.18 (m, 2H), 7.19 - 7.27 (m, 2H), 13.16 (br. s., 1H). Step 3: tert-butyl [2-(4-methylbenzyl)-4-methyl-1,3-thiazol-5-yl]carbamate
In analogy to step 4 of intermediate 1C) starting with 2.0 g (8.1 mmol) of the acid of step 2 (intermediate 3C) 2.13 g (80% yield) of the desired title compound was obtained. 1H NMR (400 MHz, DMSO d6): δ (ppm) = 1.42 (s, 9H), 2.16 (s, 3H), 2.26 (s, 3H), 4.06 (s, 2H), 7.10 - 7.18 (m, 4H), 9.49 (br. s., 1H). Step 4: 4-methyl-2-(4-methylbenzyl)-1,3-thiazol-5-amine hydrochloride
A mixture of 2.13 g (6.69 mmol) of the carbamate from step 3 of intermediate 3C) and 17.4 mL of a 4M solution of hydrogen chloride in dioxane was stirred for 2 hours at 25°C. Then the mixture was concentrated in vacuum and the obtained 1.9 g of the desired crude product was used in the next step without any further purification.
Intermediate 4C
4-{[5-amino-4-(trifluoromethyl)-1,3-thiazol-2-yl]methyl}benzonitrile
hydrochloride
In analogy to step 3 of intermediate 1C) starting with 16.7 g (42.2 mmol) of the ester of step 1 (intermediate 4C), 13.16 g (84% yield) of the desired title compound was obtained. Step 3: tert-butyl [2-(4-bromobenzyl)-4-(trifluoromethyl)-1,3-thiazol-5-yl]carbamate In analogy to step 4 of intermediate 1C) starting with 13.1 g (35.8 mmol) of the acid of step 2 (intermediate 4C), 8.0 g (51% yield) of the desired title compound was obtained. Step 4: tert-butyl [2-(4-cyanobenzyl)-4-(trifluoromethyl)-1,3-thiazol-5-yl]carbamate
In analogy to step 5 of intermediate 2C) starting with 8.0 g (18.3 mmol) of the bromo compound of step 3 (intermediate 4C), 5.34 g (76% yield) of the desired title compound was obtained. Step 5: 4-{[5-amino-4-(trifluoromethyl)-1,3-thiazol-2-yl]methyl}benzonitrile hydrochloride
In analogy to step 5 of intermediate 1C) starting with 5.3 g (13.8 mmol) of the cyano compound of step 4 (intermediate 4C), 3.06 g (62% yield) of the desired title compound was obtained. 1H NMR (400 MHz, DMSO d6): δ (ppm) = 4.18 (s, 2H), 6.35 (br. s., 4H), 7.45 - 7.51 (m, 2H), 7.77 - 7.82 (m, 2H).
Intermediate 5C
2-(4-fluorophenoxy)-4-methyl-1,3-thiazol-5-amine hydrochloride
A mixture of 1.0 g (4.0 mmol) ethyl 2-bromo-4-methyl-1,3-thiazole-5-carboxylate, 0.54 g (4.8 mmol) 4-fluorophenol and 0.72 g (5.2 mmol) potassium carbonate in 10 mL DMF was heated for 15 hours at 95°C. After cooling to room temperature the mixture was diluted with 50 mL ethylacetate and 50 mL water. After separation of the phases the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with 30 mL each of water, 2M NaOH and brine, then dried over sodium sulfate and after filtration concentrated under reduced pressure. The residue was purified via a Biotage chromatography system (25g snap KP-Sil column, hexane / 0– 100% ethyl acetate, then ethyl acetate / 0– 100% methanol) to give 1.15 g (92% yield) of the desired title compound.
1H NMR (400 MHz, DMSO d6): δ (ppm) = 1.23 (t, 3H), 4.21 (q, 2H), 7.31 - 7.38 (m, 2H), 7.45 - 7.50 (m, 2H). Step 2: 2-(4-fluorophenoxy)-4-methyl-1,3-thiazole-5-carboxylic acid
In analogy to step 2 of intermediate 3C) starting with 1.12 g (4.0 mmol) of the ester of step 1 (intermediate 5C), and using additional THF (5 mL) as co-solvent, 1.02 g (98% yield) of the desired title compound was obtained. 1H NMR (400 MHz, DMSO d6): δ (ppm) = 2.48 (s, 3H), 7.32 - 7.38 (m, 2H), 7.45 - 7.51 (m, 2H), 13.08 (br. s., 1H). Step 3: tert-butyl [2-(4-fluorophenoxy)-4-methyl-1,3-thiazol-5-yl]carbamate
In analogy to step 4 of intermediate 1C) starting with 0.25 g (1.0 mmol) of the acid from step 2 (intermediate 5C) and purification via a Biotage chromatography system (10g snap KP-Sil column, hexane / 0– 100% ethyl acetate, then ethyl acetate / 0– 80% methanol) to give 0.13 g (40% yield) of the desired not pure title compound. Step 4: 2-(4-fluorophenoxy)-4-methyl-1,3-thiazol-5-amine hydrochloride
In analogy to step 4 of intermediate 3C) starting with 0.13 g (1.0 mmol) of the carbamate of step 3 (intermediate 5C), 0.11 g of the desired not pure title compound was obtained, which used in the next step without any further purification.
Intermediate 6C
2-(3-fluorophenoxy)-4-methyl-1,3-thiazol-5-amine hydrochloride
In analogy to step 2 of intermediate 3C) starting with 1.63 g (5.8 mmol) of the ester of step 1 (intermediate 6C) , and using additional THF (5 mL) as co-solvent, 1.64 g (108% calculated yield) of the desired title compound was obtained. 1H NMR (400 MHz, DMSO d6): δ (ppm) = 2.49 (s, 3H), 7.20 - 7.30 (m, 2H), 7.42 (dt, 1H), 7.56 (td, 1H), 13.04 (br. s., 1H). Step 3: tert-butyl [2-(3-fluorophenoxy)-4-methyl-1,3-thiazol-5-yl]carbamate
In analogy to step 3 of intermediate 5C) starting with 0.60 g (2.4 mmol) of the acid from step 2 (intermediate 6C) in the first experiment and with 1.0 g (3.9 mmol) of the acid from step 2 (intermediate 6C) in a second experiment, 1.87 (91% yield) of the desired not pure title compound. Step 4: 2-(3-fluorophenoxy)-4-methyl-1,3-thiazol-5-amine hydrochloride
In analogy to step 4 of intermediate 3C) starting with 1.87 g (5.8 mmol) of the carbamate of step 3 (intermediate 6C), 1.7 g of the desired not pure title compound was obtained, which used in the next step without any further purification.
Intermediate 7C
4-[(5-amino-4-methyl-1,3-thiazol-2-yl)oxy]benzonitrile hydrochloride
In analogy to step 1 of intermediate 5C) starting with 1.5 g (6.0 mmol) ethyl 2- bromo-4-methyl-1,3-thiazole-5-carboxylate and 0.86 g (7.2 mmol) 4- hydroxybenzonitrile, 1.5 g (80% yield) of the desired title compound was obtained. 1H NMR (400 MHz, DMSO d6): δ (ppm) = 1.27 (t, 3H), 4.26 (q, 2H), 7.63 - 7.67 (m, 2H), 7.99 - 8.04 (m, 2H). Step 2: 2-(4-cyanophenoxy)-4-methyl-1,3-thiazole-5-carboxylic acid
In analogy to step 2 of intermediate 3C) starting with 1.50 g (5.2 mmol) of the ester of step 1 (intermediate 7C) , and using additional THF (2 mL) as co-solvent, 1.17 g of a 2:1 mixture of the desired title compound together with 2-(4-carbamoylphenoxy)-4- methyl-1,3-thiazole-5-carboxylic acid was obtained. This mixture was in the next step without any further purification. Step 3: tert-butyl [2-(4-cyanophenoxy)-4-methyl-1,3-thiazol-5-yl]carbamate and tert- butyl [2-(4-carbamoylphenoxy)-4-methyl-1,3-thiazol-5-yl]carbamate
In analogy to step 3 of intermediate 5C) starting with 1.17 g (about 4.5 mmol) of the mixture of the two acids from step 2 (intermediate 7C) 0.85 g (57% yield) of the not pure tert-butyl [2-(4-cyanophenoxy)-4-methyl-1,3-thiazol-5-yl]carbamate and 0.35 g (20% yield) of tert-butyl [2-(4-carbamoylphenoxy)-4-methyl-1,3-thiazol-5- yl]carbamate were obtained. tert-butyl [2-(4-cyanophenoxy)-4-methyl-1,3-thiazol-5-yl]carbamate:
1H NMR (400 MHz, DMSO d6): δ (ppm) = 1.46 (s, 9H), 2.13 (s, 3H), 7.29 - 7.33 (m, 2H), 7.92 - 7.96 (m, 2H), 9.80 (br. s., 1H). tert-butyl [2-(4-carbamoylphenoxy)-4-methyl-1,3-thiazol-5-yl]carbamate:
1H NMR (400 MHz, DMSO d6): δ (ppm) = 1.45 (s, 9H), 2.11 (s, 3H), 7.29 - 7.38 (m, 2H), 7.40 (br. s., 1H), 7.91 - 7.98 (m, 2H), 8.00 (br. s., 1H), 9.68 (br. s., 1H). Step 4: 2-(4-cyanophenoxy)-4-methyl-1,3-thiazol-5-amine hydrochloride
In analogy to step 4 of intermediate 3C) starting with 0.85 g (2.6 mmol) of tert-butyl [2-(4-cyanophenoxy)-4-methyl-1,3-thiazol-5-yl]carbamate of step 3 (intermediate 7C) 0.71 g of the desired not pure title compound was obtained, which used in the next step without any further purification.
Intermediate 8C
4-[(5-amino-4-methyl-1,3-thiazol-2-yl)oxy]benzamide hydrochloride
In analogy to step 4 of intermediate 3C) starting with 0.35 g (1.0 mmol) of tert-butyl [2-(4-carbamoylphenoxy)-4-methyl-1,3-thiazol-5-yl]carbamate of step 3 (intermediate 7C) 0.34 g of the desired not pure title compound was obtained, which used in the next step without any further purification.
Intermediate 9C
N2-(4-fluorophenyl)-N2,4-dimethyl-1,3-thiazole-2,5-diamine
To a solution of 5.0 g (29 mmol) 1-(4-fluorophenyl)thiourea (CAS-No [459-05-2], commercially available e.g. ABCR, Aldrich) and 4.8 g (29 mmol) ethyl 2-chloro-3- oxobutanoate in 100 mL ethanol was added 2.85 mL pyridine. Then this solution was heated to 80°C for 2 hours. After cooling to room temperature the mixture was concentrated under reduced pressure. To the residue was added 150 mL diethyl
ether. After filtration the filtrate was washed with 150 mL water and 50 mL brine, then dried over sodium sulfate, filtered and concentrated under reduced pressure and dried to give 2.27 g (25% yield) of the desired title compound. 1H NMR (400 MHz, DMSO d6): δ (ppm) = 1.25 (t, 3H), 2.50 (s, 3H), 4.19 (q, 2H), 7.16 - 7.21 (m, 2H), 7.58 - 7.64 (m, 2H), 10.65 (s, 1H). Step 2: ethyl 2-[(4-fluorophenyl)(methyl)amino]-4-methyl-1,3-thiazole-5-carboxylate To a suspension of 223 mg (9.3 mmol) sodium hydride (in mineral oil) in 30 mL DMF was added at 0°C 2.0 g (7.1 mmol) of the ester from step 1 of intermediate 9C). After stirring for 20 minutes at 0°C, 0.44 mL (7.1 mmol) iodomethane was added and stirring was continued at 25°C. Then the mixture was poured into ice water and extracted twice with 150 mL ethyl acetate. The combined organic phases were dried over sodium sulfate, filtrated and evaporated to dryness. The residue was purified via a Biotage chromatography system (25g snap KP-Sil column, hexane / 0– 100% ethyl acetate, then ethyl acetate / 0– 25% methanol) to give 1.11 g (48% yield) of the desired title compound. 1H NMR (500 MHz, DMSO d6): δ (ppm) = 1.18 (t, 3H), 2.46 (s, 3H), 3.44 (s, 3H), 4.12 (q, 2H), 7.30 - 7.36 (m, 2H), 7.51 - 7.57 (m, 2H). Step 3: 2-[(4-fluorophenyl)(methyl)amino]-4-methyl-1,3-thiazole-5-carboxylic acid To a solution of 1.11 g (3.77 mmol) of the ester from step 2) intermediate 9C) in 11 mL ethanol and 1 mL THF was added a solution of 2.79 g sodium hydroxide in 22 mL water. This mixture was stirred for 3 hours at 25°C and 1 hour at 40°C. After cooling to room temperate this mixture was concentrated in vacuum. The residue was diluted with water and 10% aqueous sulfuric acid was added to adjust to pH 4. The aqueous solution was then extracted twice with 125 mL ethyl acetate. The combined organic phases were dried over sodium sulfate, filtrated and evaporated to dryness. Using this methodology we obtained the desired title compound . Yield: 0.96 g (76% yield).
1H NMR (400 MHz, DMSO d6): δ (ppm) = 2.45 (s, 3H), 3.44 (s, 3H), 7.30 - 7.37 (m, 2H), 7.52 - 7.58 (m, 2H), 12.51 (br. s., 1H). Step 4: tert-butyl {2-[(4-fluorophenyl)(methyl)amino]-4-methyl-1,3-thiazol-5- yl}carbamate
In analogy to step 3 of intermediate 3C) starting with 0.96 g (2.9 mmol) of the carboxylic acid of step 3 (intermediate 9C) 0.61 g of the desired title compound was obtained. 1H NMR (400 MHz, DMSO d6): δ (ppm) = 1.39 (s, 9H), 2.00 (s, 3H), 3.32 (s, 3H), 7.22 - 7.29 (m, 2H), 7.41 - 7.47 (m, 2H), 8.94 (br. s., 1H). Step 5: N2-(4-fluorophenyl)-N2,4-dimethyl-1,3-thiazole-2,5-diamine
A mixture of 0.61 g (1.8 mmol) of the carbamate from step 4 of intermediate 9C) and 4.9 mL 4M solution of HCl in dioxane was stirred for 2 hours at 25°C. Then the mixture was concentrated under reduced pressure. The residue was dissolved in water and this solution was extracted with ethyl acetate. The organic phase was washed three times with 20 mL of saturated aqueous sodium carbonate solution, water and brine. After drying over sodium sulfate, filtration and evaporating to dryness we got 0.45 g of the desired crude product, which was used in the next step without any further purification.
Examples
Example 1-1
6-bromo-N-[1-(4-fluorobenzyl)-5-methyl-1H-1,2,3-triazol-4-yl]-2- (trifluoromethyl)quinoline-4-carboxamide
To a solution of 77 mg (0.38 mmol) 1-(4-fluorobenzyl)-5-methyl-1H-1,2,3-triazol-4- amine (commercially available e.g. Bellen Chemistry Co.) in 2.0 mL dimethylsulfoxide was added 143 mg (0.38 mmol) HATU, 82 µL (0.47 mmol) N,N- diisopropylethylamine and 100 mg (0.31 mmol) 6-bromo-2-(trifluoromethyl)quinoline- 4-carboxylic acid (intermediate 1A). The reaction mixture was stirred for 20 hours at 25°C. This mixture was directly purified via preparative HPLC (method 4) to obtain 77 mg (47% yield) of the desired title compound. 1H NMR (300 MHz, DMSO d6): δ (ppm) = 2.27 (s, 3H), 5.63 (s, 2H), 7.20 - 7.29 (m, 2H), 7.30 - 7.38 (m, 2H), 8.14 (dd, 1H), 8.23 (d, 1H), 8.34 (s, 1H), 8.49 (d, 1H), 11.07 (s, 1H).
Example 2-1
N-[1-(4-fluorobenzyl)-5-methyl-1H-1,2,3-triazol-4-yl]-2-methoxyquinoline-4- carboxamide
Example 3-1
N4-[1-(4-fluorobenzyl)-5-methyl-1H-1,2,3-triazol-4-yl]quinoline-2,4- dicarboxamide
In analogy to example 1-1, 100 mg (0.46 mmol) 2-carbamoylquinoline-4-carboxylic acid (intermediate 3A) and 114 mg (0.56 mmol) 1-(4-fluorobenzyl)-5-methyl-1H-1,2,3- triazol-4-amine (commercially available e.g. Bellen Chemistry Co.) were reacted to give after purification via preparative HPLC (method 4) 84 mg (42% yield) of the desired title compound. 1H NMR (300 MHz, DMSO d6): δ (ppm) = 2.27 (s, 3H), 5.62 (s, 2H), 7.17 - 7.29 (m, 2H), 7.30 - 7.39 (m, 2H), 7.76 - 7.85 (m, 1H), 7.87 - 7.99 (m, 2H), 8.22 (t, 2H), 8.32 (s, 1H), 8.40 (s, 1H), 10.92 (s, 1H).
Example 4-1
6-chloro-7-fluoro-N4-[1-(4-fluorobenzyl)-5-methyl-1H-1,2,3-triazol-4-yl]quinoline- 2,4-dicarboxamide
In analogy to example 1-1, 100 mg (0.46 mmol) 2-carbamoyl-6-chloro-7- fluoroquinoline-4-carboxylic acid (intermediate 4A) and 92 mg (0.48 mmol) 1-(4- fluorobenzyl)-5-methyl-1H-1,2,3-triazol-4-amine (commercially available e.g. Bellen Chemistry Co.) were reacted to give after dilution with ethyl acetate a solid which needed no further purification and was 47 mg (25% yield) of the desired title compound. 1H NMR (400 MHz, DMSO d6): δ (ppm) = 2.26 (s, 3H), 5.62 (s, 2H), 7.24 (t, 2H), 7.34 (dd, 2H), 7.97 (s, 1H), 8.12 (d, 1H), 8.37 (s, 1H), 8.42 (s, 1H), 8.50 (d, 1H), 11.04 (s, 1H).
Example 5-1
6-bromo-N-[5-methyl-1-(4-methylbenzyl)-1H-1,2,3-triazol-4-yl]-2- (trifluoromethyl)quinoline-4-carboxamide
In analogy to example 1-1, 100 mg (0.31 mmol) 6-bromo-2-(trifluoromethyl)quinoline- 4-carboxylic acid (intermediate 1A) and 76 mg (0.38 mmol) 5-methyl-1-(4- methylbenzyl)-1H-1,2,3-triazol-4-amine (commercially available e.g. Bellen Chemistry Co.) were reacted to give after purification via preparative HPLC (method 4) 121 mg (73% yield) of the desired title compound. 1H NMR (300 MHz, DMSO d6): δ (ppm) = 2.25 (s, 3H), 2.29 (s, 3H), 5.57 (s, 2H), 7.16 (d, 2H), 7.21 (d, 2H), 8.14 (dd, 1H), 8.23 (d, 1H), 8.34 (s, 1H), 8.49 (d, 1H), 11.05 (s, 1H).
Example 6-1
2-methoxy-N-[5-methyl-1-(4-methylbenzyl)-1H-1,2,3-triazol-4-yl]quinoline-4- carboxamide
Example 7-1
N4-[5-methyl-1-(4-methylbenzyl)-1H-1,2,3-triazol-4-yl]quinoline-2,4- dicarboxamide
In analogy to example 1-1, 100 mg (0.46 mmol) 2-carbamoylquinoline-4-carboxylic acid (intermediate 3A) and 112 mg (0.56 mmol) 5-methyl-1-(4-methylbenzyl)-1H- 1,2,3-triazol-4-amine (commercially available e.g. Bellen Chemistry Co.) were reacted to give after purification via preparative HPLC (method 4) 82 mg (41% yield) of the desired title compound. 1H NMR (300 MHz, DMSO d6): δ (ppm) = 2.25 (s, 3H), 2.29 (s, 3H), 5.57 (s, 2H), 7.11 - 7.25 (m, 4H), 7.72 - 7.87 (m, 1H), 7.87 - 7.99 (m, 2H), 8.22 (t, 2H), 8.32 (s, 1H), 8.39 (s, 1H), 10.91 (s, 1H).
Example 8-1
6-chloro-7-fluoro-N4-[5-methyl-1-(4-methylbenzyl)-1H-1,2,3-triazol-4- yl]quinoline-2,4-dicarboxamide
Example 9-1
6-bromo-N-[1-(4-methoxybenzyl)-5-methyl-1H-1,2,3-triazol-4-yl]-2- (trifluoromethyl)quinoline-4-carboxamide
Example 10-1
2-methoxy-N-[1-(4-methoxybenzyl)-5-methyl-1H-1,2,3-triazol-4-yl]quinoline-4- carboxamide
Example 11-1
N4-[1-(4-methoxybenzyl)-5-methyl-1H-1,2,3-triazol-4-yl]quinoline-2,4- dicarboxamide
6-chloro-7-fluoro-N4-[1-(4-methoxybenzyl)-5-methyl-1H-1,2,3-triazol-4- yl]quinoline-2,4-dicarboxamide
Example 13-1
6-bromo-N-{5-methyl-1-[4-(trifluoromethoxy)benzyl]-1H-1,2,3-triazol-4-yl}-2- (trifluoromethyl)quinoline-4-carboxamide
Example 14-1
2-methoxy-N-{5-methyl-1-[4-(trifluoromethoxy)benzyl]-1H-1,2,3-triazol-4- yl}quinoline-4-carboxamide
Example 15-1
N4-{5-methyl-1-[4-(trifluoromethoxy)benzyl]-1H-1,2,3-triazol-4-yl}quinoline-2,4- dicarboxamide
6-chloro-7-fluoro-N4-{5-methyl-1-[4-(trifluoromethoxy)benzyl]-1H-1,2,3-triazol-4- yl}quinoline-2,4-dicarboxamide
Example 17-1
7-fluoro-N4-{5-methyl-1-[4-(trifluoromethyl)benzyl]-1H-1,2,3-triazol-4- yl}quinoline-2,4-dicarboxamide
Example 18-1
N4-{5-methyl-1-[4-(trifluoromethyl)benzyl]-1H-1,2,3-triazol-4-yl}quinoline-2,4-
Example 19-1
N4-{5-ethyl-1-[2-(4-methoxyphenyl)ethyl]-1H-1,2,3-triazol-4-yl}-7- e
Example 20-1
N4-{5-ethyl-1-[2-(4-methoxyphenyl)ethyl]-1H-1,2,3-triazol-4-yl}quinoline-2,4-
Example 21-1
N4-[1-(4-bromobenzyl)-5-methyl-1H-1,2,3-triazol-4-yl]quinoline-2,4- dicarboxamide
Example 22-1
N4-[1-(4-bromobenzyl)-5-methyl-1H-1,2,3-triazol-4-yl]-7-fluoroquinoline-2,4- dicarboxamide
Example 23-1
N4-[1-(4-cyanobenzyl)-5-methyl-1H-1,2,3-triazol-4-yl]quinoline-2,4- dicarboxamide
Example 24-1
N4-[1-(4-cyanobenzyl)-5-methyl-1H-1,2,3-triazol-4-yl]-7-fluoroquinoline-2,4- dicarboxamide
7-fluoro-N4-[1-(2-fluorobenzyl)-5-methyl-1H-1,2,3-triazol-4-yl]quinoline-2,4- dicarboxamide
In analogy to example 1-1, 100 mg (0.39 mmol) 2-carbamoyl-7-fluoroquinoline-4- carboxylic acid (intermediate 2A) and 124 mg (0.51 mmol) 1-(2-fluorobenzyl)-5- methyl-1H-1,2,3-triazol-4-amine hydrochloride (commercially available e.g. VWR International or as free base at UkrOrgSynthesis Ltd.) were reacted to give after purification via preparative HPLC (method 4) 28 mg (14% yield) of the desired title compound. 1H NMR (400 MHz, DMSO d6): δ (ppm) = 2.30 (s, 3H), 5.66 (s, 2H), 7.19 - 7.33 (m, 3H), 7.37 - 7.47 (m, 1H), 7.76 (ddd, 1H), 7.87 - 7.95 (m, 2H), 8.30 - 8.40 (m, 3H), 10.96 (s, 1H).
Example 26-1
N4-[1-(2-fluorobenzyl)-5-methyl-1H-1,2,3-triazol-4-yl]quinoline-2,4- dicarboxamide
Example 27-1
N4-[1-(2,4-difluorobenzyl)-5-methyl-1H-1,2,3-triazol-4-yl]-7-fluoroquinoline-2,4- dicarboxamide
Example 28-1
N4-[1-(2,4-difluorobenzyl)-5-methyl-1H-1,2,3-triazol-4-yl]quinoline-2,4- dicarboxamide
Example 29-1
N4-[1-(4-ethylbenzyl)-5-methyl-1H-1,2,3-triazol-4-yl]-7-fluoroquinoline-2,4- dicarboxamide
Example 30-1
N4-[1-(4-ethylbenzyl)-5-methyl-1H-1,2,3-triazol-4-yl]quinoline-2,4-dicarboxamide
Example 31-1
N4-[5-ethyl-1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl]-7-fluoroquinoline-2,4- dicarboxamide
N4-[5-ethyl-1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl]quinoline-2,4-dicarboxamide
Example 33-1
7-fluoro-N4-[1-(3-fluorobenzyl)-5-methyl-1H-1,2,3-triazol-4-yl]quinoline-2,4- dicarboxamide
Example 34-1
N4-[1-(3-fluorobenzyl)-5-methyl-1H-1,2,3-triazol-4-yl]quinoline-2,4- dicarboxamide
Example 35-1
N4-[1-(cyclopentylmethyl)-5-methyl-1H-1,2,3-triazol-4-yl]-7-fluoroquinoline-2,4- dicarboxamide
N4-[1-(cyclopentylmethyl)-5-methyl-1H-1,2,3-triazol-4-yl]quinoline-2,4- dicarboxamide
Example 37-1
N4-[1-(cyclopentylmethyl)-5-methyl-1H-1,2,3-triazol-4-yl]-5-fluoroquinoline-2,4- dicarboxamide
Example 38-1
6-chloro-7-fluoro-N4-{5-methyl-1-[(3-methyl-1,2-oxazol-5-yl)methyl]-1H-1,2,3- amide
Example 39-1
5-fluoro-N4-{5-methyl-1-[(3-methyl-1,2-oxazol-5-yl)methyl]-1H-1,2,3-triazol-4- y e
7-fluoro-N4-{5-methyl-1-[(3-methyl-1,2-oxazol-5-yl)methyl]-1H-1,2,3-triazol-4-
Example 41-1
N4-{5-methyl-1-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]-1H-1,2,3-triazol-4- yl}quinoline-2,4-dicarboxamide
Example 42-1
7-fluoro-N4-{5-methyl-1-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]-1H-1,2,3-triazol- 4-yl}quinoline-2,4-dicarboxamide
Example 43-1
7-fluoro-N4-{1-[2-(4-fluorophenoxy)ethyl]-5-methyl-1H-1,2,3-triazol-4- yl}quinoline-2,4-dicarboxamide
Example 44-1
N4-{1-[2-(4-fluorophenoxy)ethyl]-5-methyl-1H-1,2,3-triazol-4-yl}quinoline-2,4- dicarboxamide
7-fluoro-N4-{5-methyl-1-[(5-methyl-1,2-oxazol-3-yl)methyl]-1H-1,2,3-triazol-4-
In analogy to example 1-1, 100 mg (0.43 mmol) 2-carbamoyl-7-fluoroquinoline-4- carboxylic acid (intermediate 2A) and 99 mg (0.51 mmol) 5-methyl-1-[(5-methyl-1,2- oxazol-3-yl)methyl]-1H-1,2,3-triazol-4-amine (commercially available e.g. UkrOrgSynthesis Ltd.) were reacted to give after purification via preparative HPLC (method 5c) 87 mg (47% yield) of the desired title compound. 1H NMR (400 MHz, DMSO d6): δ (ppm) = 2.34 (s, 3H), 2.39 - 2.45 (m, 3H), 5.72 (s, 2H), 6.23 (d, 1H), 7.79 (ddd, 1H), 7.94 (dd, 1H), 7.98 (s, 1H), 8.31 - 8.39 (m, 2H), 8.42 (d, 1H), 11.02 (s, 1H).
Example 46-1
N4-{5-methyl-1-[(5-methyl-1,2-oxazol-3-yl)methyl]-1H-1,2,3-triazol-4- e
Example 47-1
6-chloro-7-fluoro-N4-{5-methyl-1-[(5-methyl-1,2-oxazol-3-yl)methyl]-1H-1,2,3- amide
5-fluoro-N4-{5-methyl-1-[(5-methyl-1,2-oxazol-3-yl)methyl]-1H-1,2,3-triazol-4- e
Example 1-2
6-bromo-N-[2-(4-fluorobenzyl)-4-methyl-1,3-thiazol-5-yl]-2- (trifluoromethyl)quinoline-4-carboxamide
Example 2-2
N4-[2-(4-fluorobenzyl)-4-methyl-1,3-thiazol-5-yl]quinoline-2,4-dicarboxamide
Example 3-2
7-fluoro-N4-[2-(4-fluorobenzyl)-4-methyl-1,3-thiazol-5-yl]quinoline-2,4- dicarboxamide
6-bromo-N-[2-(4-cyanobenzyl)-4-methyl-1,3-thiazol-5-yl]-2- (trifluoromethyl)quinoline-4-carboxamide
Example 5-2
N4-[2-(4-cyanobenzyl)-4-methyl-1,3-thiazol-5-yl]quinoline-2,4-dicarboxamide
Example 6-2
N4-[2-(4-cyanobenzyl)-4-methyl-1,3-thiazol-5-yl]-7-fluoroquinoline-2,4- dicarboxamide
Example 7-2
6-bromo-N4-[2-(4-cyanobenzyl)-4-methyl-1,3-thiazol-5-yl]quinoline-2,4- dicarboxamide
Example 8-2
6-chloro-N4-[2-(4-cyanobenzyl)-4-methyl-1,3-thiazol-5-yl]-7-fluoroquinoline-2,4- dicarboxamide
Example 9-2
6-bromo-N-[4-methyl-2-(4-methylbenzyl)-1,3-thiazol-5-yl]-2- (trifluoromethyl)quinoline-4-carboxamide
Example 10-2
N4-[4-methyl-2-(4-methylbenzyl)-1,3-thiazol-5-yl]quinoline-2,4-dicarboxamide
Example 11-2
7-fluoro-N4-[4-methyl-2-(4-methylbenzyl)-1,3-thiazol-5-yl]quinoline-2,4- dicarboxamide
Example 12-2
6-bromo-2-cyclopropyl-N-[4-methyl-2-(4-methylbenzyl)-1,3-thiazol-5- yl]quinoline-4-carboxamide
2,6-dimethyl-N-[4-methyl-2-(4-methylbenzyl)-1,3-thiazol-5-yl]quinoline-4- carboxamide
Example 14-2
6-methoxy-N4-[4-methyl-2-(4-methylbenzyl)-1,3-thiazol-5-yl]quinoline-2,4- dicarboxamide
Example 15-2
2-chloro-N-[2-(4-cyanobenzyl)-4-(trifluoromethyl)-1,3-thiazol-5-yl]quinoline-4- carboxamide
Example 16-2
7-fluoro-N4-[2-(4-fluorophenoxy)-4-methyl-1,3-thiazol-5-yl]quinoline-2,4- dicarboxamide
Example 17-2
6-bromo-N-[2-(3-fluorophenoxy)-4-methyl-1,3-thiazol-5-yl]-2- (trifluoromethyl)quinoline-4-carboxamide
F
In analogy to example 1-2, 200 mg (0.77 mmol) 2-(3-fluorophenoxy)-4-methyl-1,3- thiazol-5-amine hydrochloride (intermediate 6C) and 123 mg (0.38 mmol) 6-bromo-2- (trifluoromethyl)quinoline-4-carboxylic acid (intermediate 1A) were reacted to give 47 mg (22% yield) of the desired title compound. 1H NMR (400 MHz, DMSO d6): δ (ppm) = 2.29 (s, 3H), 7.12 - 7.27 (m, 2H), 7.34 (dt, 1H), 7.55 (td, 1H), 8.16 (dd, 1H), 8.25 (d, 1H), 8.37 (s, 1H), 8.40 (d, 1H), 11.45 (s, 1H).
Example 18-2
N4-[2-(3-fluorophenoxy)-4-methyl-1,3-thiazol-5-yl]quinoline-2,4-dicarboxamide
F
In analogy to example 1-2, 181 mg (0.70 mmol) 2-(3-fluorophenoxy)-4-methyl-1,3- thiazol-5-amine hydrochloride (intermediate 6C) and 75 mg (0.35 mmol) 2- carbamoylquinoline-4-carboxylic acid (intermediate 3A) were reacted to give a reaction mixture which was poured into water and extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and evaporated to dryness. The resulting residue was then purified via HPLC (method 5d) to give 29 mg (19% yield) of the desired title compound. 1H NMR (400 MHz, DMSO d6): δ (ppm) = 2.28 (s, 3H), 7.13 - 7.24 (m, 2H), 7.32 (dt, 1H), 7.53 (td, 1H), 7.76 - 7.84 (m, 1H), 7.88 - 7.97 (m, 2H), 8.21 (d, 1H), 8.25 - 8.35 (m, 2H), 8.36 - 8.45 (m, 1H), 11.59 (br. s., 1H).
Example 19-2
7-fluoro-N4-[2-(3-fluorophenoxy)-4-methyl-1,3-thiazol-5-yl]quinoline-2,4- dicarboxamide
F
In analogy to example 1-2, 167 mg (0.64 mmol) 2-(3-fluorophenoxy)-4-methyl-1,3- thiazol-5-amine hydrochloride (intermediate 6C) and 75 mg (0.32 mmol) 2- carbamoyl-7-fluoroquinoline-4-carboxylic acid (intermediate 2A) were reacted to give a reaction mixture which was poured into water and extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and evaporated to dryness. The resulting residue was then purified via HPLC (method 5d) to give 29 mg (20% yield) of the desired title compound. 1H NMR (400 MHz, DMSO d6): δ (ppm) = 2.28 (s, 3H), 7.15 - 7.25 (m, 2H), 7.34 (dt, 1H), 7.54 (td, 1H), 7.77 (td, 1H), 7.94 (dd, 1H), 7.97 (d, 1H), 8.28 (dd, 1H), 8.31 (s, 1H), 8.40 (d, 1H), 11.44 (s, 1H).
Example 20-2
6-bromo-2-cyclopropyl-N-[2-(3-fluorophenoxy)-4-methyl-1,3-thiazol-5- yl]quinoline-4-carboxamide
F
N-[2-(3-fluorophenoxy)-4-methyl-1,3-thiazol-5-yl]-2-methoxyquinoline-4- carboxamide
Example 22-2
N-[2-(3-fluorophenoxy)-4-methyl-1,3-thiazol-5-yl]-2,6-dimethylquinoline-4- carboxamide
F
In analogy to example 1-2, 200 mg (0.77 mmol) 2-(3-fluorophenoxy)-4-methyl-1,3- thiazol-5-amine hydrochloride (intermediate 6C) and 77 mg (0.38 mmol) 2,6- dimethylquinoline-4-carboxylic acid (CAS-No [104175-33-9], commercially available e.g. ChemBridge Corporation or ABCR) were reacted to give 34 mg (19% yield) of the desired title compound. 1H NMR (400 MHz, DMSO d6): δ (ppm) = 2.26 (s, 3H), 2.48 (s, 3H), 2.69 (s, 3H), 7.12 - 7.24 (m, 2H), 7.31 (dt, 1H), 7.52 (td, 1H), 7.58 - 7.64 (m, 2H), 7.75 (s, 1H), 7.90 (d, 1H), 11.26 (s, 1H).
Example 23-2
N4-[2-(4-cyanophenoxy)-4-methyl-1,3-thiazol-5-yl]quinoline-2,4-dicarboxamide
Example 24-2
N4-[2-(4-cyanophenoxy)-4-methyl-1,3-thiazol-5-yl]-7-fluoroquinoline-2,4- dicarboxamide
Example 25-2
N4-[2-(4-carbamoylphenoxy)-4-methyl-1,3-thiazol-5-yl]-7-fluoroquinoline-2,4-
7-fluoro-N4-{2-[(4-fluorophenyl)(methyl)amino]-4-methyl-1,3-thiazol-5- ide
Biological Evaluation
In order that this invention may be better understood, the following examples are set forth. These examples are for the purpose of illustration only, and are not to be construed as limiting the scope of the invention in any manner. All publications mentioned herein are incorporated by reference in their entirety. Demonstration of the activity of the compounds of the present invention may be accomplished through in vitro and in vivo assays that are well known in the art. For example, to demonstrate the efficacy of a pharmaceutical agent to inhibit glucose transporter GLUT1 and/or GLUT2 the following assays may be used. Indirect measurement of GLUT1 and GLUT2 activity by quantification of intracellular ATP levels It is well known that a combination of small-molecule inhibitors of mitochondrial electron transport chain and glucose catabolism synergistically suppress ATP production and impair cellular viability (Ulanovskaya et al., 2008, 2011; Liu, et al. 2001). We therefore used DLD1 or CHO-K1 cells in combination with an oxidative phosphorylation inhibitor to identify GLUT1 and GLUT2 inhibitors. Cell lines were maintained in DMEM medium supplemented with 10% FCS and 1% Penicillin-Streptomycin solution and 2% Glutamax. The cells were treated with trypsin and seeded into 384 plates at a density of 4000 cells/well. The cells were then cultured overnight in glucose free media containing 1% FCS to reduce intracellular ATP levels. After 24h the cells were incubated at 37°C containing the respective appropriate concentrations of glucose (0.1 mM, for determining GLUT1 activity) or fructose (10 mM, for determining GLUT2
activity) with or without example compounds and 1µM Rotenone for 15 min. The CellTiter-Glo® Luminescent Cell Viability Assay from Promega was then used to measure ATP levels. Compounds able to reduce the ATP levels within 15 min of glucose/fructose application were considered to be glucose/fructose uptake inhibitors, respectively. Table 1: Measured IC50 values of compounds regarding glucose induced ATP increase (GLUT1 inhibition)
1 DLD1 cells used for ATP level measurements, all IC50 values were standardized to cytochalasin B IC50 values; Table 2: Measured IC50 values of compounds regarding fructose induced ATP increase (GLUT2 inhibition)
Cells (e.g. H460 or CHO-K1) were cultured under standard conditions. 10000 cells per well were seeded in clear 96 well tissue culture isoplate plates and cultured overnight (PerkinElmer, 1450-516) under standard conditions. Culture medium was removed and cells were washed two times with 100 µL KRP buffer and then incubated for 45 minutes at 37°C (KRP buffer: 10 mM sodium hydrogen phosphate, 130 mM sodium chloride, 5 mM potassium chloride, 1.3 mM magnesium sulfate, 1.3 mM calcium chloride (pH 7.5), 50 mM HEPES (pH 7.5), 4.7 mM potassium chloride, 1.25 mM magnesium sulfate, 1.25 mM calcium chloride) each. KRP wash buffer was removed and compound 126 (diluted in KRP buffer) was added and incubated for 30 minutes at 37°C. 200 nM radioligand (radioligand 2[1,2] 3H-Deoxy D-Glucose in KRP buffer) were added and incubated for 5 minutes at room temperature. The supernatant was removed and cells were washed with 100 µL ice-cold KRP for two times each. 25 µL of lysis buffer (1 % Triton-X, 0,5N sodium hydroxide) were added and
incubated at room temperature for 5 minutes. 75 µL scintillation solution (Microscint-20, PerkinElmer) were added and the plates were shaken for 1 minute. The plates were incubated for 3h at room temperature and the counts were determined by using a Wallace MicroBeta counter (60 seconds per well).
Biological assay: Proliferation Assay
Cultivated tumor cells (MCF7, hormone dependent human mammary carcinoma cells, ATCC HTB22; NCI-H460, human non-small cell lung carcinoma cells, ATCC HTB-177; DU 145, hormone-independent human prostate carcinoma cells, ATCC HTB-81; HeLa-MaTu, human cervical carcinoma cells, EPO-GmbH, Berlin; HeLa- MaTu-ADR, multidrug-resistant human cervical carcinoma cells, EPO-GmbH, Berlin; HeLa human cervical tumor cells, ATCC CCL-2; B16F10 mouse melanoma cells, ATCC CRL-6475) were plated at a density of 5000 cells/well (MCF7, DU145, HeLa-MaTu-ADR), 3000 cells/well (NCI-H460, HeLa-MaTu, HeLa), or 1000 cells/well (B16F10) in a 96-well multititer plate in 200 μL of their respective growth medium supplemented 10% fetal calf serum. After 24 hours, the cells of one plate (zero-point plate) were stained with crystal violet (see below), while the medium of the other plates was replaced by fresh culture medium (200 μL), to which the test substances were added in various concentrations (0 μM, as well as in the range of 0.01-30 μM; the final concentration of the solvent dimethyl sulfoxide was 0.5%). The cells were incubated for 4 days in the presence of test substances. Cell proliferation was determined by staining the cells with crystal violet: the cells were fixed by adding 20 μL/measuring point of an 11% glutaric aldehyde solution for 15 minutes at room temperature. After three washing cycles of the fixed cells with water, the plates were dried at room temperature. The cells were stained by adding 100 μL/measuring point of a 0.1% crystal violet solution (pH 3.0). After three washing cycles of the stained cells with water, the plates were dried at room temperature. The dye was dissolved by adding 100 μL/measuring point of a 10% acetic acid solution. The extinction was determined by
photometry at a wavelength of 595 nm. The change of cell number, in percent, was calculated by normalization of the measured values to the extinction values of the zero-point plate (=0%) and the extinction of the untreated (0 μm) cells (=100%). The IC50 values were determined by means of a 4 parameter fit.
Determination of metabolic stability in vitro
(including calculation of hepatic in vivo blood clearance (CL) and of maximal oral bioavailability (Fmax)) The metabolic stability of test compounds in vitro was determined by incubating them at 1 µM with a suspension liver microsomes in 100 mM phosphate buffer, pH7.4 (NaH2PO4 x H2O + Na2HPO4 x 2H2O) at a protein concentration of 0.5 mg/mL and at 37° C. The reaction was activated by adding a co-factor mix containing 1.2 mg NADP, 3 IU glucose-6-phosphate dehydrogenase, 14.6 mg glucose-6-phosphate and 4.9 mg MgCl2 in phosphate buffer, pH 7.4. Organic solvent in the incubations was limited to <0.2 % dimethylsulfoxide (DMSO) and <1% methanol. During incubation, the microsomal suspensions were continuously shaken and aliquots were taken at 2, 8, 16, 30, 45 and 60 min, to which equal volumes of cold methanol were immediately added. Samples were frozen at -20° C over night, subsequently centrifuged for 15 minutes at 3000 rpm and the supernatant was analyzed with an Agilent 1200 HPLC-system with LCMS/MS detection. The half-life of a test compound was determined from the concentration-time plot. From the half-life the intrinsic clearances were calculated. Together with the additional parameters liver blood flow, specific liver weight and microsomal protein content the hepatic in vivo blood clearance (CL) and the maximal oral bioavailability (Fmax) were calculated for the different species. The following parameter values were used: Liver blood flow– 1.3 L/h/kg
(human), 2.1 L/h/kg (dog), 4.2 L/h/kg (rat); specific liver weight– 21 g/kg (human), 39 g/kg (dog), 32 g/kg (rat); microsomal protein content– 40 mg/g. With the described assay only phase-I metabolism of microsomes is reflected, e.g. typically oxidoreductive reactions by cytochrome P450 enzymes and flavin mono-oxygenases (FMO) and hydrolytic reactions by esterases (esters and amides). Literature
Liu H, Hu YP, Savarai N, Priebe W, Lampadis T. Hypersensitization of tumor cells to glycolytic inhibitors. Biochemistry. 2001;40:5542–5547.
Ulanovskaya O, Janjic J, Matsumoto K, Schumacker PT, Kron SJ, Kozmin SA. Synthesis enables identification of the cellular target of leucascandrolide A and neopeltolide. Nat Chem Biol. 2008;4:418–424.
Ulanovskaya O, Jiayue Cui, Stephen J. Kron, and Sergey A. Kozmin. A pairwise chemical genetic screen identifies new inhibitors of glucose transport. Chem Biol. 2011 February 25; 18(2): 222–230.
Claims
CLAIMS 1. A compound of general formula (I) :
A represents a group selected from:
wherein * represents the point of attachment to the nitrogen atom; R1 represents a C1-C3-alkyl-, halo-C1-C3-alkyl-, cyano-, -C(=O)O-R10 or -C(=O)N(R10a)R10b group; R2 represents a group selected from: aryl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ;
wherein said 5- to 6-membered heterocycloalkyl- group is optionally benzocondensed;
wherein said aryl-, heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with–(L2)p-R6;
and wherein two -(L2)p-R6 groups, if being present ortho to each other on an aryl- or heteroaryl- group optionally represent a bridge selected from:
*-C3-C8-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*, *-O(CF2)O-*, *-CH2C(R10a)(R10b)O-*, *-C(=O)N(R10a)CH2-*, *-N(R10a)C(=O)CH2O-*, *-NHC(=O)NH-*; wherein each * represents the point of attachment to said aryl- or heteroaryl- group; R3 represents a hydrogen atom or group selected from: C1-C3-alkyl-,
C1-C3-alkoxy-(L2)-, hydroxy-C1-C3-alkyl-, aryl-(L2)-, heteroaryl-(L2)-; R4a represents a hydrogen atom or a halogen atom or a group selected from: cyano-, hydroxy-, C1-C3-alkyl-, halo-C1-C3-alkyl-, C1-C3-alkoxy-, halo-C1-C3-alkoxy-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, -C(=O)-OR10, -C(=O)N(R10a)R10b,
-C(=O)-N(R10a)-S(=O)2-R10, -SR10, -S(=O)-R10, -S(=NR11)-R10, -S(=O)2-R10, -S(=O)2-N(R10a)R10b, -S(=O)(=NR11)-R10, -N(R10a)R10b; R4b represents a hydrogen atom or a group selected from: C1-C3-alkoxy-, C1-C3-alkyl-, cyano- ; or
R4a and together R4b represent a -C3-C5-alkylene- group; R5a, R5b, R5c, R5d
independently from each other represent a hydrogen atom, a halogen atom or a group selected from:
cyano-, -NO2, C1-C3-alkyl-, halo-C1-C3-alkyl-, C1-C3-alkoxy-, halo-C1-C3-alkoxy-, phenyl-, heteroaryl-, -C(=O)R10, -C(=O)N(H)R10,
-C(=O)N(R10a)R10b, -C(=O)O-R10, -N(R10a)R10b, -N(H)C(=O)R10, -N(R10a)C(=O)R10b, -N(H)C(=O)N(R10a)R10b, -N(R10a)C(=O)N(R10b)R10c, -N(R10a)C(=O)C(=O)N(R10b)R10c, -N(H)C(=O)OR10, -N(R10a)C(=O)OR10b, -N(H)S(=O)2R10, -N(R10a)S(=O)2R10b, -OR10, -O(C=O)R10, -O(C=O)N(R10a)R10b, -O(C=O)OR10, -SR10, -S(=O)R10, -S(=O)2R10, -S(=O)2N(H)R10, -S(=O)2N(R10a)R10b or -S(=O)(=NR11)-R10 ,
said phenyl- and heteroaryl- group being optionally substituted one or more times, identically or differently, with a group selected from: halo-, cyano-, C1-C3-alkyl-, halo-C1-C3-alkyl-, C1-C3-alkoxy-; R6 represents a group selected from: oxo, C1-C6-alkyl-, C3-C7-cycloalkyl-, 4- to 7-membered heterocycloalkyl-, halo-C1-C4-alkyl-, hydroxy-C1-C4- alkyl-, cyano-C1-C4-alkyl-, C2-C4-alkenyl-, C2-C4-alkynyl-, C1-C4-alkoxy-, halo-C1-C4-alkoxy-, -OH, -CN, halo-, -C(=O)R7, -C(=O)-O-R7, -C(=O)N(R8a)R8b, -N(R10a)R10b, -S(=O)2R7, -S(=O)(=NR11)-R10, phenyl-, 5- to 6-membered heteroaryl-; R7 represents a hydrogen atom or a C1-C6-alkyl-, halo-C1-C3-alkyl-, cyano- C1-C4-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, C3-C7-cycloalkyl-, phenyl-, 5- to 6-membered heteroaryl- or benzyl- group; R8a, R8b
represent, independently from each other, a hydrogen atom, or a C1-C10-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(L3)-, C3-C6-alkenyl-, C3-C6-alkynyl-, 4- to 10-membered heterocycloalkyl-,
(4- to 10-membered heterocycloalkyl)-(L3)-, phenyl-, heteroaryl-, phenyl-(L3)-, (phenyl)-O-(L3)-, heteroaryl-(L3)-, or
(aryl)-(4- to 10-membered heterocycloalkyl)- group;
said C1-C10-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(L3)-, C3-C6-alkenyl-, C3-C6-alkynyl-, 4- to 10-membered heterocycloalkyl-, (4- to 10-membered heterocycloalkyl)-(L3)-, phenyl-, heteroaryl-, phenyl-(L3)-, (phenyl)-O-(L3)-, heteroaryl-(L3)-, and (aryl)-(4- to 10-membered heterocycloalkyl)- group being optionally substituted one or more times, identically or differently, with R9;
or
R8a and R8b, together with the nitrogen atom they are attached to,
represent a 4- to 10-membered heterocycloalkyl- group, said 4- to 10- membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R9; R9 represents a halogen atom, or an oxo, C1-C3-alkyl-, halo-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, -CN, -C(=O)R10, -C(=O)N(H)R10, -C(=O)N(R10a)R10b, -C(=O)O-R10, -N(R10a)R10b, -NO2, -N(H)C(=O)R10, -N(R10a)C(=O)R10b, -N(H)C(=O)N(R10a)R10b, -N(R10a)C(=O)N(R10b)R10c, -N(H)C(=O)OR10, -N(R10a)C(=O)OR10b, -N(H)S(=O)2R10, -N(R10a)S(=O)2R10b, -OR10, -O(C=O)R10, -O(C=O)N(R10a)R10b, -O(C=O)OR10, -SR10, -S(=O)R10, -S(=O)2R10, -S(=O)2N(H)R10, -S(=O)2N(R10a)R10b, -S(=O)(=NR11)R10 or a tetrazolyl- group; or
two R9 groups present ortho to each other on a phenyl- or heteroaryl- ring represent a bridge selected from: *-C3-C5-alkylene-*, *-O(CH2)2O-*, *-O(CH2)O-*, *-O(CF2)O-*, *-CH2C(R10a)(R10b)O-*, *-C(=O)N(R10a)CH2-*, *-N(R10a)C(=O)CH2O-*, *-NHC(=O)NH-*; wherein each * represents the point of attachment to said phenyl- or heteroaryl- ring; R10, R10a, R10b, R10c
represent, independently from each other, a hydrogen atom or a group selected from: C1-C3-alkyl-, halo-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, C3-C7-cycloalkyl-; or
R10a and R10b, together with the nitrogen atom they are attached to,
represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7- membered heterocycloalkyl-group being optionally substituted one or more times, identically or differently, with R12; R11 represents a hydrogen atom or a cyano-, C1-C3-alkyl-, -C(=O)R10, -C(=O)N(H)R10, -C(=O)N(R10a)R10b or -C(=O)O-R10 group; R12 represents a halogen atom or a cyano, hydroxy, oxo, C1-C3-alkyl-, trifluoromethyl-, -C(=O)R10 or -C(=O)O-R10 group; R13 represents a hydrogen atom or a C1-C6-alkyl- or benzyl- group; L1 represents a group selected from: -C1-C4-alkylene-, -CH2-CH=CH-, -C(phenyl)(H)-, -CH2-CH2-O-, -CH2-C(=O)-N(H)-, -CH2-C(=O)-N(R10a)-; L2 represents a group selected from:–CH2-,–CH2–CH2-, -CH2-CH2-CH2-; L3 represents a -C1-C6-alkylene- group; L4 represents a group selected from: -C1-C4-alkylene-, -CH2-CH=CH-, -C(phenyl)(H)-, -CH2-CH2-O-, -CH2-C(=O)-N(H)-, -CH2-C(=O)-N(R10a)-, -O-, - N(R13)-; p is an integer of 0 or 1 ;
or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
2. The compound according to claim 1
in which :
A represents:
*
wherein * represents the point of attachment to the nitrogen atom.
3. The compound according to claim 1
in which :
A represents:
*
wherein * represents the point of attachment to the nitrogen atom.
4. The compound according to claim 2, wherein
R1 represents a C1-C3-alkyl- group; R2 represents a group selected from: phenyl-, 5- to 6-membered heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ;
wherein said phenyl-, 5- to 6-membered heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with R6; R3 represents a hydrogen atom; R4a represents a group selected from: fluoro-C1-C3-alkyl-, C1-C3-alkoxy-, -C(=O)N(R10a)R10b; R4b represents a hydrogen atom; R5a, R5b, R5c, R5d
independently from each other represent a hydrogen atom, a halogen atom or a group selected from: C1-C3-alkyl-, C1-C3-alkoxy-; R6 represents a group selected from: C1-C4-alkyl-, fluoro-C1-C3-alkyl-, C1-C3-alkoxy-, fluoro-C1-C3-alkoxy-, -CN, halo-; R7 represents a hydrogen atom or a C1-C4-alkyl- group; R8a and R8b, independently from each other,
represent a hydrogen atom, or a C1-C4-alkyl-, C3-C7-cycloalkyl- or 4- to 7- membered heterocycloalkyl- group;
said C1-C4-alkyl-, C3-C7-cycloalkyl- and 4- to 7-membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R9;
or
R8a and R8b, together with the nitrogen atom they are attached to,
represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7- membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R9; R9 represents an oxo, hydroxy-C1-C3-alkyl-, -CN, -C(=O)N(H)R10, -C(=O)N(R10a)R10b, -C(=O)O-R10 or a -OR10 group; R10, R10a, R10b, R10c, independently from each other,
represent a hydrogen atom or a C1-C3-alkyl- group;
and
L1 represents a -CH2- group. 5. The compound according to claim 3, wherein R1 represents a methyl- or trifluoromethyl- group; R2 represents a group selected from: phenyl-, 5- to 6-membered heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- ; wherein said phenyl-,
5- to 6-membered heteroaryl-, C5-C6-cycloalkyl-, and 5- to 6-membered heterocycloalkyl- group is optionally substituted, one or more times, identically or differently, with R6; R3 represents a hydrogen atom; R4a represents a halogen atom or a group selected from: C1-C3-alkyl-, fluoro- C1-C3-alkyl-, C3-C7-cycloalkyl-, C1-C3-alkoxy-, -C(=O)N(R10a)R10b; R4b represents a hydrogen atom; R5a, R5b, R5c, R5d
independently from each other represent a hydrogen atom, a halogen atom or a group selected from: C1-C3-alkyl-, C1-C3-alkoxy-; R6 represents a group selected from: C1-C4-alkyl-, -CN, halo-, -C(=O)N(R8a)R8b; R7 represents a hydrogen atom or a C1-C4-alkyl- group; R8a and R8b, independently from each other,
represent a hydrogen atom, or a C1-C4-alkyl-, C3-C7-cycloalkyl- or 4- to 7- membered heterocycloalkyl- group;
said C1-C4-alkyl-, C3-C7-cycloalkyl- and 4- to 7-membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R9;
or
R8a and R8b, together with the nitrogen atom they are attached to,
represent a 4- to 7-membered heterocycloalkyl- group, said 4- to 7- membered heterocycloalkyl- group being optionally substituted one or more times, identically or differently, with R9; R9 represents an oxo, hydroxy-C1-C3-alkyl-, -CN, -C(=O)N(H)R10, -C(=O)N(R10a)R10b, -C(=O)O-R10 or a -OR10 group; R10, R10a, R10b, R10c, independently from each other,
represent a hydrogen atom or a C1-C3-alkyl- group;
and
L4 represents a group selected from: -CH2-, -O-, -N(CH3)-.
6. A compound according to claim 1, which is selected from the group consisting of:
6-bromo-N-[1-(4-fluorobenzyl)-5-methyl-1H-1,2,3-triazol-4-yl]-2- (trifluoromethyl)quinoline-4-carboxamide,
N-[1-(4-fluorobenzyl)-5-methyl-1H-1,2,3-triazol-4-yl]-2-methoxyquinoline-4- carboxamide,
N4-[1-(4-fluorobenzyl)-5-methyl-1H-1,2,3-triazol-4-yl]quinoline-2,4- dicarboxamide,
6-chloro-7-fluoro-N4-[1-(4-fluorobenzyl)-5-methyl-1H-1,2,3-triazol-4- yl]quinoline-2,4-dicarboxamide,
6-bromo-N-[5-methyl-1-(4-methylbenzyl)-1H-1,2,3-triazol-4-yl]-2- (trifluoromethyl)quinoline-4-carboxamide,
2-methoxy-N-[5-methyl-1-(4-methylbenzyl)-1H-1,2,3-triazol-4-yl]quinoline-4- carboxamide,
N4-[5-methyl-1-(4-methylbenzyl)-1H-1,2,3-triazol-4-yl]quinoline-2,4- dicarboxamide,
6-chloro-7-fluoro-N4-[5-methyl-1-(4-methylbenzyl)-1H-1,2,3-triazol-4- yl]quinoline-2,4-dicarboxamide,
6-bromo-N-[1-(4-methoxybenzyl)-5-methyl-1H-1,2,3-triazol-4-yl]-2- (trifluoromethyl)quinoline-4-carboxamide,
2-methoxy-N-[1-(4-methoxybenzyl)-5-methyl-1H-1,2,3-triazol-4-yl]quinoline-4- carboxamide,
N4-[1-(4-methoxybenzyl)-5-methyl-1H-1,2,3-triazol-4-yl]quinoline-2,4- dicarboxamide,
6-chloro-7-fluoro-N4-[1-(4-methoxybenzyl)-5-methyl-1H-1,2,3-triazol-4- yl]quinoline-2,4-dicarboxamide,
6-bromo-N-{5-methyl-1-[4-(trifluoromethoxy)benzyl]-1H-1,2,3-triazol-4-yl}-2- (trifluoromethyl)quinoline-4-carboxamide,
2-methoxy-N-{5-methyl-1-[4-(trifluoromethoxy)benzyl]-1H-1,2,3-triazol-4- yl}quinoline-4-carboxamide,
N4-{5-methyl-1-[4-(trifluoromethoxy)benzyl]-1H-1,2,3-triazol-4-yl}quinoline- 2,4-dicarboxamide,
6-chloro-7-fluoro-N4-{5-methyl-1-[4-(trifluoromethoxy)benzyl]-1H-1,2,3-triazol- 4-yl}quinoline-2,4-dicarboxamide,
7-fluoro-N4-{5-methyl-1-[4-(trifluoromethyl)benzyl]-1H-1,2,3-triazol-4- yl}quinoline-2,4-dicarboxamide,
N4-{5-methyl-1-[4-(trifluoromethyl)benzyl]-1H-1,2,3-triazol-4-yl}quinoline-2,4- dicarboxamide,
N4-{5-ethyl-1-[2-(4-methoxyphenyl)ethyl]-1H-1,2,3-triazol-4-yl}-7- fluoroquinoline-2,4-dicarboxamide,
N4-{5-ethyl-1-[2-(4-methoxyphenyl)ethyl]-1H-1,2,3-triazol-4-yl}quinoline-2,4- dicarboxamide,
N4-[1-(4-bromobenzyl)-5-methyl-1H-1,2,3-triazol-4-yl]quinoline-2,4- dicarboxamide,
N4-[1-(4-bromobenzyl)-5-methyl-1H-1,2,3-triazol-4-yl]-7-fluoroquinoline-2,4- dicarboxamide,
N4-[1-(4-cyanobenzyl)-5-methyl-1H-1,2,3-triazol-4-yl]quinoline-2,4- dicarboxamide,
N4-[1-(4-cyanobenzyl)-5-methyl-1H-1,2,3-triazol-4-yl]-7-fluoroquinoline-2,4- dicarboxamide,
7-fluoro-N4-[1-(2-fluorobenzyl)-5-methyl-1H-1,2,3-triazol-4-yl]quinoline-2,4- dicarboxamide,
N4-[1-(2-fluorobenzyl)-5-methyl-1H-1,2,3-triazol-4-yl]quinoline-2,4- dicarboxamide,
N4-[1-(2,4-difluorobenzyl)-5-methyl-1H-1,2,3-triazol-4-yl]-7-fluoroquinoline- 2,4-dicarboxamide,
N4-[1-(2,4-difluorobenzyl)-5-methyl-1H-1,2,3-triazol-4-yl]quinoline-2,4- dicarboxamide,
N4-[1-(4-ethylbenzyl)-5-methyl-1H-1,2,3-triazol-4-yl]-7-fluoroquinoline-2,4- dicarboxamide,
N4-[1-(4-ethylbenzyl)-5-methyl-1H-1,2,3-triazol-4-yl]quinoline-2,4- dicarboxamide,
N4-[5-ethyl-1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl]-7-fluoroquinoline-2,4- dicarboxamide,
N4-[5-ethyl-1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl]quinoline-2,4- dicarboxamide,
7-fluoro-N4-[1-(3-fluorobenzyl)-5-methyl-1H-1,2,3-triazol-4-yl]quinoline-2,4- dicarboxamide,
N4-[1-(3-fluorobenzyl)-5-methyl-1H-1,2,3-triazol-4-yl]quinoline-2,4- dicarboxamide,
N4-[1-(cyclopentylmethyl)-5-methyl-1H-1,2,3-triazol-4-yl]-7-fluoroquinoline- 2,4-dicarboxamide,
N4-[1-(cyclopentylmethyl)-5-methyl-1H-1,2,3-triazol-4-yl]quinoline-2,4- dicarboxamide,
N4-[1-(cyclopentylmethyl)-5-methyl-1H-1,2,3-triazol-4-yl]-5-fluoroquinoline- 2,4-dicarboxamide,
6-chloro-7-fluoro-N4-{5-methyl-1-[(3-methyl-1,2-oxazol-5-yl)methyl]-1H-1,2,3- triazol-4-yl}quinoline-2,4-dicarboxamide,
5-fluoro-N4-{5-methyl-1-[(3-methyl-1,2-oxazol-5-yl)methyl]-1H-1,2,3-triazol-4- yl}quinoline-2,4-dicarboxamide,
7-fluoro-N4-{5-methyl-1-[(3-methyl-1,2-oxazol-5-yl)methyl]-1H-1,2,3-triazol-4- yl}quinoline-2,4-dicarboxamide,
N4-{5-methyl-1-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]-1H-1,2,3-triazol-4- yl}quinoline-2,4-dicarboxamide,
7-fluoro-N4-{5-methyl-1-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]-1H-1,2,3- triazol-4-yl}quinoline-2,4-dicarboxamide,
7-fluoro-N4-{1-[2-(4-fluorophenoxy)ethyl]-5-methyl-1H-1,2,3-triazol-4- yl}quinoline-2,4-dicarboxamide,
N4-{1-[2-(4-fluorophenoxy)ethyl]-5-methyl-1H-1,2,3-triazol-4-yl}quinoline-2,4- dicarboxamide,
7-fluoro-N4-{5-methyl-1-[(5-methyl-1,2-oxazol-3-yl)methyl]-1H-1,2,3-triazol-4- yl}quinoline-2,4-dicarboxamide,
N4-{5-methyl-1-[(5-methyl-1,2-oxazol-3-yl)methyl]-1H-1,2,3-triazol-4- yl}quinoline-2,4-dicarboxamide,
6-chloro-7-fluoro-N4-{5-methyl-1-[(5-methyl-1,2-oxazol-3-yl)methyl]-1H-1,2,3- triazol-4-yl}quinoline-2,4-dicarboxamide,
5-fluoro-N4-{5-methyl-1-[(5-methyl-1,2-oxazol-3-yl)methyl]-1H-1,2,3-triazol-4- yl}quinoline-2,4-dicarboxamide,
6-bromo-N-[2-(4-fluorobenzyl)-4-methyl-1,3-thiazol-5-yl]-2- (trifluoromethyl)quinoline-4-carboxamide,
N4-[2-(4-fluorobenzyl)-4-methyl-1,3-thiazol-5-yl]quinoline-2,4-dicarboxamide, 7-fluoro-N4-[2-(4-fluorobenzyl)-4-methyl-1,3-thiazol-5-yl]quinoline-2,4- dicarboxamide,
6-bromo-N-[2-(4-cyanobenzyl)-4-methyl-1,3-thiazol-5-yl]-2- (trifluoromethyl)quinoline-4-carboxamide,
N4-[2-(4-cyanobenzyl)-4-methyl-1,3-thiazol-5-yl]quinoline-2,4-dicarboxamide, 6-bromo-N4-[2-(4-cyanobenzyl)-4-methyl-1,3-thiazol-5-yl]quinoline-2,4- dicarboxamide,
6-chloro-N4-[2-(4-cyanobenzyl)-4-methyl-1,3-thiazol-5-yl]-7-fluoroquinoline- 2,4-dicarboxamide,
6-bromo-N-[4-methyl-2-(4-methylbenzyl)-1,3-thiazol-5-yl]-2- (trifluoromethyl)quinoline-4-carboxamide,
N4-[4-methyl-2-(4-methylbenzyl)-1,3-thiazol-5-yl]quinoline-2,4-dicarboxamide, 7-fluoro-N4-[4-methyl-2-(4-methylbenzyl)-1,3-thiazol-5-yl]quinoline-2,4- dicarboxamide,
6-bromo-2-cyclopropyl-N-[4-methyl-2-(4-methylbenzyl)-1,3-thiazol-5- yl]quinoline-4-carboxamide,
2,6-dimethyl-N-[4-methyl-2-(4-methylbenzyl)-1,3-thiazol-5-yl]quinoline-4- carboxamide,
6-methoxy-N4-[4-methyl-2-(4-methylbenzyl)-1,3-thiazol-5-yl]quinoline-2,4- dicarboxamide,
2-chloro-N-[2-(4-cyanobenzyl)-4-(trifluoromethyl)-1,3-thiazol-5-yl]quinoline-4- carboxamide,
7-fluoro-N4-[2-(4-fluorophenoxy)-4-methyl-1,3-thiazol-5-yl]quinoline-2,4- dicarboxamide,
6-bromo-N-[2-(3-fluorophenoxy)-4-methyl-1,3-thiazol-5-yl]-2- (trifluoromethyl)quinoline-4-carboxamide,
N4-[2-(3-fluorophenoxy)-4-methyl-1,3-thiazol-5-yl]quinoline-2,4-dicarboxamide, 7-fluoro-N4-[2-(3-fluorophenoxy)-4-methyl-1,3-thiazol-5-yl]quinoline-2,4- dicarboxamide,
6-bromo-2-cyclopropyl-N-[2-(3-fluorophenoxy)-4-methyl-1,3-thiazol-5- yl]quinoline-4-carboxamide,
N-[2-(3-fluorophenoxy)-4-methyl-1,3-thiazol-5-yl]-2-methoxyquinoline-4- carboxamide,
N-[2-(3-fluorophenoxy)-4-methyl-1,3-thiazol-5-yl]-2,6-dimethylquinoline-4- carboxamide,
N4-[2-(4-cyanophenoxy)-4-methyl-1,3-thiazol-5-yl]quinoline-2,4-dicarboxamide, N4-[2-(4-cyanophenoxy)-4-methyl-1,3-thiazol-5-yl]-7-fluoroquinoline-2,4- dicarboxamide,
N4-[2-(4-carbamoylphenoxy)-4-methyl-1,3-thiazol-5-yl]-7-fluoroquinoline-2,4- dicarboxamide,
7-fluoro-N4-{2-[(4-fluorophenyl)(methyl)amino]-4-methyl-1,3-thiazol-5- yl}quinoline-2,4-dicarboxamide,
or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. 7. A method of preparing a compound of formula (I), in which R1, R2, R3, R4a, R4b R5a, R5b, R5c, R5d and L1 are as defined in any one of claims 1 to 6, in which method an intermediate compound of general formula (II-1) :
(II-1)
in which R1, R2, R3 and L1 are as defined in any one of claims 1 to 6; is allowed to react with a compound of general formula (III) :
thus providing a compound of general formula (I-1) :
8. A compound of formula (II-1)
(II-1) in which R1, R2, R3 and L1 are as defined in any one of claims 1 to 6.
9. Use of a compound of formula (II-1)
(II-1) in which R1, R2, R3 and L1 are as defined in any one of claims 1 to 6,
for the preparation of a compound of general formula (I) as defined in any one of claims 1 to 6.
10. A method of preparing a compound of formula (I), in which R1, R2, R3, R4a, R4b R5a, R5b, R5c, R5d and L4 are as defined in any one of claims 1 to 6, in which method an intermediate compound of general formula (II-2) :
(II-2)
in which R1, R2, R3 and L4 are as defined in any one of claims 1 to 6; is allowed to react with a compound of general formula (III) :
thus providing a compound of general formula (I-2) :
(I-2) in which R1, R2, R3, R4a, R4b R5a, R5b, R5c, R5d and L4 are as defined in any one of claims 1 to 6.
11. A compound of formula (II-2)
(II-2) in which R1, R2, R3 and L4 are as defined in any one of claims 1 to 6.
12. Use of a compound of formula (II-2)
R 2 L 4
(II-2) in which R1, R2, R3 and L4 are as defined in any one of claims 1 to 6,
for the preparation of a compound of general formula (I) as defined in any one of claims 1 to 6.
13. Use of a compound of formula (III)
for the preparation of a compound of general formula (I) as defined in any one of claims 1 to 6.
14. A compound according to any one of claims 1 to 6, or a tautomer, an N- oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically
acceptable salt thereof, or a mixture of same, for use in the treatment or prophylaxis of a disease.
15. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 6, or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, and a pharmaceutically acceptable diluent or carrier.
16. A pharmaceutical combination comprising :
- one or more compounds of formula (I) according to any one of claims 1 to 6, or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same;
and
- one or more agents selected from : a taxane, such as Docetaxel, Paclitaxel, or Taxol; an epothilone, such as Ixabepilone, Patupilone, or Sagopilone; Mitoxantrone; Predinisolone; Dexamethasone; Estramustin; Vinblastin; Vincristin; Doxorubicin; Adriamycin; Idarubicin; Daunorubicin; Bleomycin; Etoposide; Cyclophosphamide; Ifosfamide; Procarbazine; Melphalan; 5- Fluorouracil; Capecitabine; Fludarabine; Cytarabine; Ara-C; 2-Chloro-2´- deoxyadenosine; Thioguanine; an anti-androgen, such as Flutamide, Cyproterone acetate, or Bicalutamide; Bortezomib; a platinum derivative, such as Cisplatin, or Carboplatin; Chlorambucil; Methotrexate; and Rituximab.
17. Use of a compound as defined in any one of claims 1 to 6, or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, for the prophylaxis or treatment of a disease.
18. Use of a compound as defined in any one of claims 1 to 6, or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, for the preparation of a medicament for the prophylaxis or treatment of a disease.
19. Use according to claim 17 or 18, wherein said disease is a disease of uncontrolled cell growth, proliferation and/or survival, an inappropriate cellular immune response, or an inappropriate cellular inflammatory response, particularly in which the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response, or inappropriate cellular inflammatory response is mediated by GLUT1, more particularly in which the disease of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response, or inappropriate cellular inflammatory response is a haemotological tumour, a solid tumour and/or metastases thereof, e.g. leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof.
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