WO2017102091A1 - Heteroarylbenzimidazole compounds - Google Patents

Heteroarylbenzimidazole compounds Download PDF

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Publication number
WO2017102091A1
WO2017102091A1 PCT/EP2016/002126 EP2016002126W WO2017102091A1 WO 2017102091 A1 WO2017102091 A1 WO 2017102091A1 EP 2016002126 W EP2016002126 W EP 2016002126W WO 2017102091 A1 WO2017102091 A1 WO 2017102091A1
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WIPO (PCT)
Prior art keywords
methyl
amino
pyridin
benzimidazol
piperazin
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PCT/EP2016/002126
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French (fr)
Inventor
Volker Schulze
Tobias Heinrich
Florian PRINZ
Julien LEFRANC
Jens SCHRÖDER
Anne Mengel
Wilhelm Bone
Joszef BÁLINT
Antje Wengner
Knut Eis
Horst Irlbacher
Marcus Koppitz
Ulf Bömer
Benjamin Bader
Hans Briem
Philip Lienau
Clara CHRIST
Detlef STÖCKIGT
Roman Hillig
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Bayer Pharma Aktiengesellschaft
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Application filed by Bayer Pharma Aktiengesellschaft filed Critical Bayer Pharma Aktiengesellschaft
Priority to US16/063,370 priority Critical patent/US10894784B2/en
Priority to PCT/EP2016/002126 priority patent/WO2017102091A1/en
Priority to EP16829402.3A priority patent/EP3390387B1/en
Publication of WO2017102091A1 publication Critical patent/WO2017102091A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/14—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing 9-azabicyclo [3.3.1] nonane ring systems, e.g. granatane, 2-aza-adamantane; Cyclic acetals thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

Definitions

  • the present invention covers heteroarylbenzimidazole compounds of general formula (I) as described and defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds, and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of hyperproliferative and/or inflammatory disorders, as a sole agent or in combination with other active ingredients.
  • the present invention covers heteroarylbenzimidazole compounds of general formula (I) which inhibit Tank-binding kinase 1 (TBK1 ) and/or ⁇ ⁇ kinase epsilon ( ⁇ ).
  • Tank-binding kinase 1 (TBK1 ) and ⁇ ⁇ kinase epsilon ( ⁇ ) are two non-canonical ⁇ ⁇ kinases (IKKs). They play crucial roles in interferon regulatory factor (IRF) and nuclear factor kappaB (NF-KB) signaling cascades.
  • IRF interferon regulatory factor
  • NF-KB nuclear factor kappaB
  • TBK1 and ⁇ share 49% identity and 65% similarity with each other and the kinase domains are 27% identical to IKKa and ⁇ (Shen RR & Hahn WC (2011 ) Emerging roles for the non-canonical IKKs in cancer. Oncogene 30(6):631-641 ).
  • Both ⁇ and TBK1 are comprised of an N-terminal kinase domain, an ubiquitin-like domain, a C- terminal LZ and a HLH motif (Larabi A, et al. (2013) Crystal structure and mechanism of activation of TANK-binding kinase 1. Cell reports 3(3):734-746).
  • TBK1 and ⁇ exhibit differential expression patterns.
  • TBK1 like IKKa and ⁇ , is ubiquitously expressed. In contrast, ⁇ expression is restricted to particular tissue compartments, with highest levels detected in lymphoid tissues, peripheral blood lymphocytes and the pancreas.
  • TBK1 was originally identified as an IKK-related Serine/Threonine kinase which, in complex with ⁇ , induces the transcription of IFN-I genes as part of the anti-viral innate immune response.
  • TBK1 resides downstream of Toll-like receptors and has as natural substrates the transcription factors IRF3 and IRF7 which, upon phosphorylation by TBK1 , translocate to the nucleus and trigger IFN-I gene transcription (Han KJ, ei al. (2004) Mechanisms of the TRIF-induced interferon-stimulated response element and NF-kappaB activation and apoptosis pathways.
  • IRF3 and IRF7 transcription factors
  • TBK1 and ⁇ are not a part of the classical ⁇ / ⁇ / ⁇ signaling complex, these kinases were originally characterized as activators of NF- ⁇ and target multiple NF-KB members and effectors. Both IKK-related kinases phosphorylate ⁇ at one of the two-serine residues typically targeted on ⁇ (Shen RR & Hahn WC (201 1 ) Emerging roles for the non- canonical IKKs in cancer. Oncogene 30(6):631-641 ).
  • TBK1 and ⁇ have been linked to the pathophysiology of several diseases and represent promising potential targets for drug development as is demonstrated by several drug finding projects, both from academia and from the pharmaceutical industry as reviewed recently by Yu and colleagues (Yu T, et al. (2015) TBK1 inhibitors: a review of patent literature (2011 - 2014). Expert opinion on therapeutic patents: 1 -12).
  • ⁇ was found to be amplified in breast cancer lines and breast carcinomas. Subsequent experiments identified ⁇ as a breast cancer oncogene (Boehm JS, ef al. (2007) Integrative genomic approaches identify IKBKE as a breast cancer oncogene. Cell 129(6):1065-1079). Work by other groups further confirmed the role of ⁇ (and TBK1 ) in breast cancer (e.g. Barbie TU, ef al. (2014) Targeting an IKBKE cytokine network impairs triple-negative breast cancer growth.
  • TBK1 is up-regulated under hypoxic conditions and was shown to behave as a pro-angiogenic factor (Korherr C, ef al. (2006) Identification of proangiogenic genes and pathways by high- throughput functional genomics: TBK1 and the IRF3 pathway. Proceedings of the National Academy of Sciences of the United States of America 103(11 ):4240-4245). Moreover, TBK1 over-expression in HUVEC cells induces the secretion of pro-angiogenic factors via the activation of IRF3 (Korherr C, ef al. (2006) Identification of proangiogenic genes and pathways by high-throughput functional genomics: TBK1 and the IRF3 pathway.
  • TBK1 has been identified as a key factor linking innate immune signaling to tumor cell survival via the small GTPase and Ras effector RalB (Chien Y, ef al. (2006) RalB GTPase- mediated activation of the IkappaB family kinase TBK1 couples innate immune signaling to tumor cell survival. Cell 127(1 ):157-170).
  • Ras-transformed cancer cells are addicted to TBK1 -induced survival signals, and TBK1 kinase inhibition may therefore constitute a tumor cell-specific approach to cancer treatment.
  • TBK1 was shown to be essential for cell lines with activated KRas. This links RalB mediated activation of TBK1 to the generation of specific NF-KB-regulated survival signals downstream of oncogenic KRas (Barbie DA, et al. (2009) Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature 462(7269): 108-1 12).
  • TBK1 is involved in regulating rheumatoid synovitis and also acts as a key regulator in neuroinflammation, microvascular inflammation and gastritis. Additional potential indications include obesity and type 2 diabetes. TBK1 signaling has also been shown to be involved in mediating normal tension glaucoma, familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia diseases. In the field of cancer, there are an increasing number of reports demonstrating that TBK1 mediates cell apoptosis and proliferation in cancer cell lines, especially those that depend on oncogenic KRAS expression.
  • ALS familial amyotrophic lateral sclerosis
  • TBK1 plays a key role in maintaining drug resistance in prostate cancer (PCa) cells by interaction with mammalian target of rapamycin and inhibiting its function, which can induce cell-cycle arrest in PCa cells.
  • PCa prostate cancer
  • TBK1 silencing decreased the expression of epithelial markers and increased the expression of mesenchymal markers in ERa (estrogen receptor)-positive breast cancer cells.
  • TBK1 plays a significant role in radiation-induced epithelial— mesenchymal transition.
  • TBK1 -dependent mechanism for NF- ⁇ signaling pathway contributes to autophagy addiction in K-Ras-driven non-small-cell lung cancer cells (reviewed in Yu T, et al. (2015) TBK1 inhibitors: a review of patent literature (201 1 - 2014). Expert opinion on therapeutic patents: 1 -12).
  • WO 2010127754 discloses 3-([1 ,2 > 3]-triazol-4-yl-pyrrolo[2.3-b]pyridine derivatives as inhibitors of PDK1 , IKKe and TBK 1.
  • WO 201 1046970 discloses amino-pyrimidine compounds as inhibitors of TBK1 and/or ⁇ .
  • WO 2012010826 discloses pyrimidine compounds as inhibitors of TBK1 and/or ⁇ .
  • WO 2012104007 discloses 7-azaindole derivatives as inhibitors or PDK1 , ⁇ , ⁇ 1 and TGF-beta..
  • WO 2012161877 discloses pyridine and pyrazine derivatives as inhibitors of TBK1 and ⁇ .
  • WO 2012161879 discloses thiazole derivatives as inhibitors of TBK1 and ⁇ .
  • CN 103251600 discloses a 2-amino-4-(3'-cyano-4'-pyrrolidyl)phenyl pyrimidine compound inter alia as inhibitor of TBK-1.
  • WO 2013024282 discloses an inhibitor of one or both of TBK1 and ⁇ , or a down-regulator of the expression of one or both TBK1 and ⁇ , for use in a method of treating a cancer that is dependent on the PI3kinase pathway, and cites multiple further patent applications and scientific publications disclosing further inhibitors of TBK1 and ⁇ .
  • WO 2013034238 discloses benzonitrile derivatives as inhibitors of TBK1 and ⁇ .
  • WO 2013075785 discloses 3-cyanaryl-1 H-pyrazolo[2.3-b]pyridine derivatives as inhibitors of TBK1 and ⁇ .
  • WO 20 3117285 discloses furo-[3,2b] and thieno-[3.2-b]pyridine derivatives as inhibitors of TBK1 and ⁇ .
  • WO 2014004863 discloses heteroaromatic compounds as inhibitors of TBK1 and/or ⁇ .
  • US 20150344473 discloses fused heteroaromatic compounds as inhibitors of TBK1 and ⁇ .
  • US 20160289196 discloses pyrazole derivatives as inhibitors of TNIK, TBK1 and/or ⁇ .
  • US 20160297815 discloses 7-azaindole and 4,7-diazaindole derivatives as inhibitors of TBK1 and/or ⁇ .
  • WO 1998056376 discloses heteroaryl compounds for the modulation of protein tyrosine kinase related signal transduction.
  • WO 2002076438 discloses ligands of the Flt-1 receptor.
  • WO 2004058762 discloses inhibitors of Mitogen Activated Protein Kinase-activated Protein Kinase-2 (MK-2).
  • WO 2004085425 discloses fused azole derivatives as Kinase inhibitors.
  • WO 2005020921 discloses c-Kit modulators and method of use.
  • US 2005038023 discloses pyrazole compounds as Protein Kinase inhibitors.
  • WO 2006099379 discloses benzazole derivatives as beta-Secretase inhibitors.
  • WO 2007084390 discloses organic compounds as HDAC inhibitors.
  • WO 2007089512 discloses heterocyclic compounds as activators of Glucokinase.
  • WO 2007100646 discloses multicyclic compounds as modulators of various protein kinase receptor enzymes, such as Tie-2 and Aurora kinase.
  • WO 2008057280 discloses multicyclic compounds as modulators of various protein kinase receptors, such as Tie-2 and Aurora kinase.
  • WO 2010034797 discloses 1 H-benzimidazole-5-carboxamides as anti-inflammatory agents.
  • WO 20101 15736 discloses heterocyclic compounds as inhibitors of dihydroorotate dehydrogenase.
  • WO 201 1 161 159 discloses heterocyclic compounds as Kinase inhibitors.
  • WO 2012068546 discloses heterocycle amines as inhibitors of IRAK-1 and IRAK-4.
  • WO 2015031564 discloses substituted 1 H-benzo[d]imidazole series compounds as lysine specific demethylase (LSD-1 ) inhibitors.
  • LSD-1 lysine specific demethylase
  • the compounds of the present invention have surprisingly been found to effectively inhibit TBK1 and/or ⁇ and may therefore be used for the treatment or prophylaxis of hyperproliferative and/or inflammatory disorders, such as cancer, for example.
  • the present invention covers compounds of general formula (I):
  • R 1 represents a group selected from
  • pyrazolyl imidazolyl, oxadiazolyl, triazolyl, isoxazolyl, thienyl, pyridin-2-yl, pyridin-4-yl, pyrimidinyl, triazinyl and pyrazinyl, said group being optionally substituted with one R 6 group, and said group being, additionally, optionally substituted one or two times, differently or identically, with a R 7 group,
  • R 1 represents a group selected from
  • R 1 represents a group selected from pyridine-3-yl or pyridazin-3-yl, optionally substituted with one R 8 group; represents a group selected from
  • Ci-C4-alkyl represents a hydrogen atom or a halogen atom or a group selected from Ci-C4-alkyl and Ci-C6-alkoxy;
  • Ci-C4-alkyl represents a hydrogen atom or a halogen atom or a group selected from Ci-C4-alkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy and Ci-C4-haloalkoxy;
  • R 6 represents a hydrogen atom or a group selected from Ci-C4-alkyl, Ci-C4-haloalkyl and C3-Ce-cycloalkyl;
  • R 6 represents a hydrogen atom or a group selected from Ci-C6-alkyl, Ci-C6-haloalkyl, Ci- C6-hydroxyalkyl, (Ci-C 3 -alkoxy)-(Ci-C3-alkyl)-, C 3 -C 6 -cycloalkyl and (C 3 -C6-cycloalkyl)- (Ci-C 3 -alkyl)-,
  • said C 3 -C6-cycloalkyl and said (C 3 -C6-cycloalkyl)-(Ci-C3-alkyl)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or with a group selected from Ci-C 3 -alkyl and Ci- C 3 -haloalkyl;
  • R 7 represents a halogen atom or a group selected from hydroxy, Ci-C 6 -alkyl, Ci-C 6 -haloalkyl, Ci-C 6 -hydroxyalkyl, (Ci-C 3 -alkoxy)-(Ci-C 3 -alkyl)-, (Ci-C 3 -haloalkoxy)-(Ci-C 3 -alkyl)-, C2-C 6 -alkenyl, C 2 -C 3 -alkynyl, C 3 -C 8 -cycloalkyl, C 4 -C 8 - cycloalkenyl, (C 3 -C 8 -cycloalkyl)-(Ci-C 3 -alkyl)-, (phenyl)-Ci-C 3 -alkyl-, 4- to 7-membered heterocycloalkyi, 5- to 7-membered heterocycloalkenyl, heterospirocycloalkyi, phenyl
  • said C 3 -C 8 -cycloalkyl, said (C 3 -C 8 -cycloalkyl)-(Ci-C3-alkyl)- and said (C 3 -C 8 - cycloalkyl)-(Ci-C 3 -alkoxy)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or with a group selected from Ci-C 3 -alkyl and Ci-C 3 -haloalkyl,
  • said 4- to 7-membered heterocycloalkyi, said 5- to 7-membered heterocycloalkenyl and said heterospirocycloalkyi group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or with a group selected from oxo, Ci-C3-alkyl and CrC 3 - haloalkyl, and
  • heteroaryl group and said phenyl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from -CN, Ci-C 3 -alkyl, trifluoromethyl, Ci-C3-alkoxy and trifluoromethoxy;
  • R 6 and R 7 or two R 7 groups, when being attached to adjacent ring atoms of the group R 1 , together form a group selected from:
  • R 8 represents a hydrogen atom or a group selected from methyl, ethyl, methoxy, ethoxy and dimethylamino;
  • R 9 represents a hydrogen atom or a -CN or Ci-C3-alkyl group
  • said 5- to 6-membered heteroaryl group and said phenyl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from -CN, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy and Ci-
  • R 11 and R 11a independently from each other, represent a hydrogen atom or a group selected from Ci-C4-alkyl, Ci-C 4 -haloalkyl, Cs-Ce-cycloalkyl, Ci-C6-hydroxyalkyl, (Ci-C 3 -alkoxy)- (Ci-C 3 -alkyl)-, (C 3 -C 6 -cycloalkyl)-(Ci-C 3 -alkyl)- and benzyl,
  • R 12 represents a hydrogen atom or a group selected from Ci-C6-alkyl, Ci-C6-haloalkyl, Ci- Ce-hydroxyalkyl, (Ci-C 3 -alkoxy)-(Ci-C 3 -alkyl)-, C 3 -C 6 -cycloalkyl, (C 3 -C 6 -cycloalkyl)-(Ci- C 3 -alkyl)-, C2-C6-alkenyl, C2-C6-alkynyl, 4- to 7-membered heterocycloalkyi, 5- to 7- membered heterocycloalkenyl, 5- to 6-membered heteroaryl and phenyl,
  • said 5- to 6-membered heteroaryl group and said phenyl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from -CN, Ci-C3-alkyl, Ci-C 3 -haloalkyl, Ci-C3-alkoxy and Ci- C3-haloalkoxy,
  • said C 3 -C6-cycloalkyl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from -CN, Ci-
  • R 13 represents a group selected from Ci-C 4 -alkyl and benzyl
  • R 4 and R 14a independently from each other, represent a hydrogen atom or a group selected from Ci-C4-alkyl, Ci-C 4 -haloalkyl, C3-C 6 -cycloalkyl and benzyl, or
  • R 14 and R 14a together with the nitrogen atom they are attached to, represent a 4- to 7- membered heterocycloalkyl group, said group being optionally substituted one or two times, identically or differently, with a halogen atom or a group selected from hydroxyl, -CN, Ci-C 3 -alkyl, Ci-C 3 -haloalkyl, Ci-C 3 -aikoxy, Ci-C 3 -haloalkoxy and (Ci-C 3 -alkoxy)-
  • R 15 represents a group selected from Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-hydroxyalkyl, (Ci- C 3 -alkoxy)-(Ci-C 6 -alkyl)-, (Ci-C 3 -alkoxy)-(C 2 -C 3 -alkoxy)-(Ci-C 6 -alkyl)-, C 3 -C 6 -cycloalkyl, (C 3 -C6-cycloalkyl)-(Ci-C 3 -alkyl)-, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl and phenyl,
  • said 5- to 6-membered heteroaryl group and said phenyl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from -CN, Ci-C 3 -alkyl, Ci-C 3 -haloalkyl, Ci-C 3 -alkoxy and Ci-C 3 -haloalkoxy;
  • R 16 represents a hydrogen atom or a group selected from Ci-C4-alkyl and benzyl
  • R 18 represents a Ci-C3-alkyl group
  • x represents an integer selected from 1 , 2, 3 and 4,
  • substituted means that one or more hydrogen atoms on the designated atom or group are replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded. Combinations of substituents and/or variables are permissible.
  • optionally substituted means that the number of substituents can be equal to or different from zero. Unless otherwise indicated, it is possible that optionally substituted groups are substituted with as many optional substituents as can be accommodated by replacing a hydrogen atom with a non-hydrogen substituent on any available carbon or nitrogen or sulfur atom. Commonly, and if not stated otherwise, it is possible for the number of optional substituents, when present, to be 1 , 2, 3, 4 or 5, in particular 1 , 2 or 3.
  • the term "one or more”, e.g. in the definition of the substituents of the compounds of general formula (I) of the present invention means “1 , 2, 3, 4 or 5, particularly 1 , 2, 3 or 4, more particularly 1 , 2 or 3, even more particularly 1 or 2".
  • a composite substituent be composed of more than one parts, e.g. (Ci-C4-alkoxy)-(Ci-C4-alkyl)-, it is possible for the position of a given part to be at any suitable position of said composite substituent, i.e. the Ci-C4-alkoxy part can be attached to any carbon atom of the Ci-C4-alkyl part of said (Ci-C4-alkoxy)-(Ci-C 4 -alkyl)- group.
  • a hyphen at the beginning or at the end of such a composite substituent indicates the point of attachment of said composite substituent to the rest of the molecule.
  • a ring comprising carbon atoms and optionally one or more heteroatoms, such as nitrogen, oxygen or sulfur atoms for example, be substituted with a substituent
  • substituent it is possible for said substituent to be bound at any suitable position of said ring, be it bound to a suitable carbon atom and/or to a suitable heteroatom.
  • halogen atom means a fluorine, chlorine, bromine or iodine atom, particularly a fluorine, chlorine or bromine atom.
  • an oxo substituent represents an oxygen atom, which is bound to a carbon atom or to a sulfur atom via a double bond.
  • Ci-C6-alkyl means a linear or branched, saturated, monovalent hydrocarbon group having 1 , 2, 3, 4, 5 or 6 carbon atoms, e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, ferf-butyl, pentyl, isopentyl, 2-methylbutyl, 1 -methylbutyl, 1 -ethylpropyl,
  • said group has 1 , 2, 3 or 4 carbon atoms ("Ci-C4-alkyl”), e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl isobutyl, or ferf-butyl group, more particularly 1 , 2 or 3 carbon atoms (“Ci-C3-alkyl”), e.g. a methyl, ethyl, n-propyl or isopropyl group.
  • C 2 -C6-alkylene means a linear or branched, saturated, divalent hydrocarbon chain (or “tether”) having 2, 3, 4, 5 or 6 carbon atoms, e.g. -CH2-CH2- ("ethylene” or “C2-alkylene”), -CH2-CH2-CH2-, -C(H)(CH 3 )-CH 2 - or -C(CH 3 ) 2 -) ("propylene” or "C 3 -alkylene”), or, for example -CH2-C(H)(CH 3 )-CH 2 -, -CH 2 -C(CH 3 ) 2 -), -CH2-CH2-CH2-CH2- ("butylene” or "C 4 -alkylene”), "Cs-alkylene", e.g.
  • n-pentylene or "-C 6 -alkylene-", e.g. -CH2-CH2-CH2-CH2-CH2-CH2- ("n-hexylene") or -C(CH 3 ) 2 -C(CH 3 ) 2 - group.
  • alkylene is a -C(CH 3 ) 2 -C(CH 3 ) 2 - group.
  • Ci-C6-hydroxyalkyl means a linear or branched, saturated, monovalent hydrocarbon group in which the term “Ci-Ce-alkyl” is defined supra, and in which 1 , 2 or 3 hydrogen atoms are replaced with a hydroxy group, e.g.
  • a hydroxymethyl 1 -hydroxyethyl, 2-hydroxyethyl, 1 ,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropyl, 1 -hydroxypropan-2-yl, 2-hydroxypropan-2-yl, 2,3-dihydroxypropyl, 1 ,3-dihydroxypropan-2-yl, 3-hydroxy-2-methyl-propyl, 2-hydroxy-2-methyl-propyl, 1-hydroxy-2-methyl-propyl group.
  • Ci-C6-alkylsulfanyl means a linear or branched, saturated, monovalent group of formula (Ci-C6-alkyl)-S-, in which the term "Ci-C6-alkyl” is as defined supra, e.g. a methylsulfanyl, ethylsulfanyl, propylsulfanyl, isopropylsulfanyl, butylsulfanyl, sec-butylsulfanyl, isobutylsulfanyl, fert-butylsulfanyl, pentylsulfanyl, isopentylsulfanyl, hexylsulfanyl group.
  • Ci-Ce-haloalkyl means a linear or branched, saturated, monovalent hydrocarbon group in which the term "Ci-C6-alkyl” is as defined supra, and in which one or more of the hydrogen atoms are replaced, identically or differently, with a halogen atom.
  • said halogen atom is a fluorine atom, to give rise to a "Ci-C6-fluoroalkyl” group, particularly a "Ci-C 4 -fluoroalkyl” group, more particularly, a "Ci-C3-fluoroalkyl” group.
  • Said Ci-C6-haloalkyl group is, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl,
  • Ci-C6-alkoxy means a linear or branched, saturated, monovalent group of formula (Ci-C6-alkyl)-0-, in which the term "Ci-C6-alkyl” is as defined supra, e.g. a methoxy, ethoxy, / propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, ferf-butoxy, pentyloxy, isopentyloxy or n-hexyloxy group, or an isomer thereof.
  • Ci-C6-haloalkoxy means a linear or branched, saturated, monovalent Ci-C6-alkoxy group, as defined supra, in which one or more of the hydrogen atoms is replaced, identically or differently, with a halogen atom.
  • said halogen atom is a fluorine atom to give rise to a "Ci-C6-fluoroalkoxy” group, particularly a "Ci-C4-fluoroalkoxy” group, more particularly, a "Ci-C 3 -fluoroalkoxy” group.
  • Ci-C6-haloalkoxy group is, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy or pentafluoropropoxy.
  • Ci-C6-haloalkylsulfanyl means a linear or branched, saturated, monovalent C1-C6- alkylsulfanyl group, as defined supra, in which one or more of the hydrogen atoms is replaced, identically or differently, with a halogen atom.
  • said halogen atom is a fluorine atom to give rise to a "Ci-C6-fluoroalkylsulfanyl” group, particularly a "Ci-C 4 -fluoroalkylsulfanyl” group, more particularly, a "Ci-C3-fluoroalkylsulfanyl” group.
  • Ci-C6-haloalkylsulfanyl group is, for example, fluoromethylsulfanyl, difluoromethylsulfanyl, trifluoromethylsulfanyl, 2,2,2-trifluoroethylsulfanyl or pentafluoroethylsulfanyl.
  • C2-C6-alkenyl means a linear or branched, monovalent hydrocarbon group, which contains one double bond, and which has 2, 3, 4, 5 or 6 carbon atoms, particularly 2 or 3 carbon atoms (“C2-C3-alkenyl”).
  • Said alkenyl group is, for example, an ethenyl (or "vinyl"), prop-2-en-1 -yl (or “allyl”), prop-1 -en-1 -yl, but-3-enyl, but-2-enyl, but-1-enyl, pent-4-enyl, pent-3-enyl, pent-2-enyl, pent-1-enyl, hex-5-enyl, hex-4-enyl, hex-3-enyl, hex-2-enyl, hex-1 -enyl, prop-1-en-2-yl (or “isopropenyl"), 2-methylprop-2-enyl, 1-methylprop-2-enyl,
  • said group is vinyl or allyl.
  • C2-C6-alkynyl means a linear or branched, monovalent hydrocarbon group which contains one triple bond, and which contains 2, 3, 4, 5 or 6 carbon atoms, particularly 2 or 3 carbon atoms (“C2-C3-alkynyl").
  • Said C2-C6-alkynyl group is, for example, ethynyl, prop-1 -ynyl, prop-2-ynyl (or “propargyl"), 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-yny
  • Ca-Ce-cycloalkyl means a saturated, monovalent, mono- or bicyclic hydrocarbon ring which contains 3, 4, 5, 6, 7 or 8 carbon atoms ("Cs-Ce-cycloalkyl”). Particularly, said group is monocyclic and has 3, 4, 5 or 6 carbon atoms ("C3-C6-cycloalkyl”).
  • Said C3-Ce-cycloalkyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl group, or a bicyclic hydrocarbon ring, e.g. a bicyclo[4.2.0]octyl or octahydropentalenyl.
  • d-Cs-cycloalkenyl means a monovalent, mono- or bicyclic hydrocarbon ring which contains 4, 5, 6, 7 or 8 carbon atoms and one double bond. Particularly, said ring contains 4, 5 or 6 carbon atoms ("C4-C6-cycloalkenyl").
  • Said C4-Ce-cycloalkenyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl or cyclooctenyl group, or a bicyclic hydrocarbon ring, e.g. a bicyclo[2.2.1]hept-2-enyl or bicyclo[2.2.2]oct-2-enyl.
  • Cs-Ce-cycloalkoxy means a saturated, monovalent, mono- or bicyclic group of formula (C3-C8-cycloalkyl)-0-, which contains 3, 4, 5, 6, 7 or 8 carbon atoms ("C3-C8-cycloalkyloxy”), in which the term "Cs-Cs-cycloalkyl” is defined supra, e.g. a cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy or cyclooctyloxy group.
  • spirocycloalkyl means a saturated, monovalent bicyclic hydrocarbon group in which the two rings share one common ring carbon atom, and wherein said bicyclic hydrocarbon group contains 5, 6, 7, 8, 9, 10 or 1 1 carbon atoms, it being possible for said spirocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms except the spiro carbon atom.
  • Said spirocycloalkyl group is, for example, spiro[2.2]pentyl, spiro[2.3]hexyl, spiro[2.4]heptyl, spiro[2.5]octyl, spiro[2.6]nonyl, spiro[3.3]heptyl, spiro[3.4]octyl, spiro[3.5]nonyl, spiro[3.6]decyl, spiro[4.4]nonyl, spiro[4.5]decyl, spiro[4.6]undecyl or spiro[5.5]undecyl.
  • heterocycloalkyl and “4- to 6-membered heterocycloalkyl” mean a monocyclic, saturated heterocycle with 4, 5, 6 or 7 or, respectively, 4, 5 or 6 ring atoms in total, which contains one or two identical or different ring heteroatoms from the series N, O and S, 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.
  • Said heterocycloalkyl group can be a 4-membered ring, such as azetidinyl, oxetanyl or thietanyl, for example; or a 5-membered ring, such as tetrahydrofuranyl, 1 ,3-dioxolanyl, thiolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1 ,2-oxazolidinyl, 1 ,3-oxazolidinyl or 1 ,3-thiazolidinyl, for example; or a 6-membered ring, such as tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, 1 ,3-dioxanyl, 1 ,4-dioxanyl or 1 ,
  • 4- to 6-membered heterocycloalkyl means a 4- to 6-membered heterocycloalkyl as defined supra containing one ring nitrogen atom and optionally one further ring heteroatom from the series: N, O, S.
  • 5- or 6-membered heterocycloalkyl means a monocyclic, saturated heterocycle with 5 or 6 ring atoms in total, containing at least one heteroatom from the series: N, O.
  • heterocycloalkenyl means a monocyclic, unsaturated, non- aromatic heterocycle with 5, 6 or 7 ring atoms in total, which contains one or two double bonds and one or two identical or different ring heteroatoms from the series: N, O, S; it being possible for said heterocycloalkenyl group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, a nitrogen atom.
  • Said heterocycloalkenyl group is, for example, 4 -/-pyranyl, 2H-pyranyl, 2,5-dihydro-1 - -pyrrolyl, [1 ,3]dioxolyl, 4H-[1 ,3,4]thiadiazinyl, 2,5-dihydrofuranyl, 2,3-dihydrofuranyl, 2,5-dihydrothio- phenyl, 2,3-dihydrothiophenyl, 4,5-dihydrooxazolyl or 4 - -[1 ,4]thiazinyl.
  • heterospirocycloalkyl means a bicyclic, saturated heterocycle with 6, 7, 8, 9, 10 or 11 ring atoms in total, in which the two rings share one common ring carbon atom, which "heterospirocycloalkyl” contains one or two identical or different ring heteroatoms from the series: N, O, S; it being possible for said heterospirocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms, except the spiro carbon atom, 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, azaspiro[4,5]decyl, oxazaspiro [5.5]undecyl, diazaspiro[3.3]heptyl, thiazaspiro[3.3]heptyl, thiazaspiro[4.3]octyl, azaspiro[5.5]undecyl, or one of the further homologous scaffolds such as spiro[3.4]-, spiro[4.4]-, spiro[2.4]-, spiro[2.5]-,
  • fused heterocycloalkyl means a bicyclic, saturated heterocycle with 6, 7, 8, 9 or 10 ring atoms in total, in which the two rings share two adjacent ring atoms, which "fused heterocycloalkyl” contains one or two identical or different ring heteroatoms from the series: N, O, S; it being possible for said fused 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 fused heterocycloalkyl 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.
  • bridged heterocycloalkyi means a bicyclic, saturated heterocycle with 7, 8, 9 or 10 ring atoms in total, in which the two rings share two common ring atoms which are not adjacent, which "bridged heterocycloalkyi" contains one or two identical or different ring heteroatoms from the series: N, O, S; it being possible for said bridged heterocycloalkyi group to be attached to the rest of the molecule via any one of the carbon atoms, except the spiro carbon atom, or, if present, a nitrogen atom.
  • Said bridged heterocycloalkyi 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, azabi- cyclo[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, thiazabic
  • heteroaryl means a monovalent, monocyclic, bicyclic or tricyclic aromatic ring having 5, 6, 8, 9, 10, 1 1 , 12, 13 or 14 ring atoms (a "5- to 14-membered heteroaryl” group), particularly 5, 6, 9 or 10 ring atoms, which contains at least one ring heteroatom and optionally one, two or three further ring heteroatoms from the series: N, O and/or S, and which is bound via a ring carbon atom or optionally via a ring nitrogen atom (if allowed by valency).
  • Said heteroaryl group can be a 5-membered heteroaryl group, such as, for example, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl or tetrazolyl; or a 6-membered heteroaryl group, such as, for example, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl; or a tricyclic heteroaryl group, such as, for example, carbazolyl, acridinyl or phenazinyl; or a 9-membered heteroaryl group, such as, for example, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl,
  • heteroaryl or heteroarylene groups include all possible isomeric forms thereof, e.g.: tautomers and positional isomers with respect to the point of linkage to the rest of the molecule.
  • pyridinyl includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl; or the term thienyl includes thien-2-yl and thien-3-yl.
  • heteroaryl group is a 5- or 6-membered heteroaryl group.
  • heteroaryloxy means a monovalent, monocyclic, bicyclic or tricyclic aromatic group of the formula (heteroaryl)-O-, in which the term “heteroaryl” is as defined supra, e.g. thienyloxy, thiazolyloxy, pyridinyloxy, pyrimidinyloxy, benzofuranyloxy, for example.
  • phenyloxy means a group of the formula (phenyl)-O.
  • C-i-Ce as used in the present text, e.g. in the context of the definition of "Ci-Ce-alkyl”, “Ci-C 6 -haloalkyl", “Ci-C 6 -hydroxyalkyl”, “Ci-C 6 -alkoxy” or “Ci-C 6 -haloalkoxy” means 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.
  • C3-C8 as used in the present text, e.g. in the context of the definition of "Cs-Cs-cycloalkyl”, means a cycloalkyl group having a finite number of carbon atoms of 3 to 8, i.e. 3, 4, 5, 6, 7 or 8 carbon atoms.
  • Ci-Ce encompasses Ci , C2, C3, C4, C5, Ce, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6;
  • C1-C4 encompasses Ci , C 2 , C 3 , C 4 , C1-C4, C1-C3, C1-C2, C 2 -C 4 , C2-C3 and C 3 -C 4 ;
  • C1-C3 encompasses Ci , C 2 , C 3 , C1-C3, C1-C2 and C 2 -C 3 ;
  • C2-C6 encompasses C2, C3, C4, C5, Ce, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6;
  • C3-C10 encompasses C3, C 4 , C5, Ce, C7, Ce, Cg, C10, C3-C10, C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4, C4-C10, C4-C9, C4-C8, C4-C7, C4-C6, C4-C5, C5-C10, C5-C9, C5-C8, C5-C7, C5-C6, C6-C10, C6-Cg, C6-Ce, C6-C7, C7-C10, C7-C9, C7-C8, Ce-Cio, Ce-Cg and "C3-C8" encompasses C3, C 4 , C5, C6, C7, Ce, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4, C4-Ce, C4-C7, C4-C6, C4-C5,
  • C 3 -C 6 encompasses C 3 , C 4 , C 5 , C 6 , C 3 -C 6 , C3-C5, C3-C4, C 4 -C 6 , C 4 -C 5 , and C 5 -C 6 ;
  • C4-Ce encompasses C4, C5, C6, C7, Cs, C 4 -Ce, C4-C7, C4-C6, C 4 -C5, Cs-Ce, C5-C7, C5-C6, Ce-Ce, C6-C7 and C7-Ce;
  • C4-C7 encompasses C 4 , C 5 , C 6 , C 7 , C 4 -C 7 , C 4 -C 6 , C4-C5, C 5 -C 7 , C 5 -C 6 and C 6 -C 7 ;
  • C4-C6 encompasses C4, C5, C 6 , C4-C6, C4-C5 and C5-C6;
  • C5-C10 encompasses C5, C6, C7, Ce, Cg, C10, C5-C10, C5-C9, Cs-Ce, C5-C7, C5-C6, C6-C10, Ce- Cg, Ce-Ce, C6-C7, C7-C10, C7-C9, C7-C8, C8-C10, Ce-Cg and C9-C10;
  • C6-C10 encompasses C6, C7, Ce, Cg, C10, C6-C10, C6-C9, C6-Cs, C6-C7, C7-C10, C7-C9, C7-C8, Ca-Cio, Cs-Cg and Cg-Cio-
  • the term "leaving group” means an atom or a group of atoms that is displaced in a chemical reaction as stable species taking with it the bonding electrons.
  • a leaving group is selected from the group comprising: halide, in particular fluoride, chloride, bromide or iodide, (methylsulfonyl)oxy, [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)- sulfonyl]oxy, (phenylsulfonyl)oxy, [(4-methylphenyl)sulfonyl]oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2,4,6-triisopropy
  • protecting group is a protective group attached to an oxygen or nitrogen atom 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 hydroxy or amino group in order to obtain chemoselectivity in a subsequent chemical reaction. Protective groups for hydroxy and amino groups are descibed for example in T.W. Greene and P.G.M.
  • protective groups for amino 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 ierf.-butoxycarbonyl (Boc).
  • Protective groups for hydroxy groups can be selected from acyl groups such as benzoyl, acetyl, pivaloyl or tetrahydropyranoyl, or can include silicon, as in e.g. tert-butyldimethylsilyl, tert- butyldiphenylsilyl, triethylsilyl or triisopropylsilyl.
  • the invention therefore includes one or more isotopic variant(s) of the compounds of general formula (I), particularly deuterium-containing compounds of general formula (I).
  • Isotopic variant of a compound or a reagent is defined as a compound exhibiting an unnatural proportion of one or more of the isotopes that constitute such a compound.
  • Isotopic variant of the compound of general formula (I) is defined as a compound of general formula (I) exhibiting an unnatural proportion of one or more of the isotopes that constitute such a compound.
  • unnatural proportion means a proportion of such isotope which is higher than its natural abundance.
  • the natural abundances of isotopes to be applied in this context are described in "Isotopic Compositions of the Elements 1997", Pure Appl. Chem., 70(1 ), 217-235, 1998.
  • isotopes include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 11 C, 13 C, i4 C, 15 N, 17 0, 18 0, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 CI, 82 Br, 2 3 l, 124 l, 1 5 l, 129 l and 131 1, respectively.
  • stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine such as 2 H (deuterium), 3 H (tritium), 11 C, 13 C, i4 C, 15 N, 17 0, 18 0, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 CI, 82 Br, 2 3 l, 124 l, 1 5 l, 129
  • the isotopic variant(s) of the compounds of general formula (I) preferably contain deuterium ("deuterium- containing compounds of general formula (I)").
  • Isotopic variants of the compounds of general formula (I) in which one or more radioactive isotopes, such as 3 H or 4 C, are incorporated are useful e.g. in drug and/or substrate tissue distribution studies. These isotopes are particularly preferred for the ease of their incorporation and detectability.
  • Positron emitting isotopes such as 18 F or 11 C may be incorporated into a compound of general formula (I).
  • These isotopic variants of the compounds of general formula (I) are useful for in vivo imaging applications.
  • Deuterium-containing and 13 C-containing compounds of general formula (I) can be used in mass spectrometry analyses in the context of preclinical or clinical studies.
  • Isotopic variants of the compounds of general formula (I) can generally be prepared by methods known to a person skilled in the art, such as those described in the schemes and/or examples herein, by substituting a reagent for an isotopic variant of said reagent, preferably for a deuterium-containing reagent.
  • a reagent for an isotopic variant of said reagent preferably for a deuterium-containing reagent.
  • deuterium from D 2 O can be incorporated either directly into the compounds or into reagents that are useful for synthesizing such compounds.
  • Deuterium gas is also a useful reagent for incorporating deuterium into molecules. Catalytic deuteration of olefinic bonds and acetylenic bonds is a rapid route for incorporation of deuterium.
  • Metal catalysts i.e.
  • deuterated reagents and synthetic building blocks are commercially available from companies such as for example C/D/N Isotopes, Quebec, Canada; Cambridge Isotope Laboratories Inc., Andover, MA, USA; and CombiPhos Catalysts, Inc., Princeton, NJ, USA.
  • deuterium-containing compound of general formula (I) is defined as a compound of general formula (I), in which one or more hydrogen atom(s) is/are replaced by one or more deuterium atom(s) and in which the abundance of deuterium at each deuterated position of the compound of general formula (I) is higher than the natural abundance of deuterium, which is about 0.015%.
  • the abundance of deuterium at each deuterated position of the compound of general formula (I) is higher than 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80%, preferably higher than 90%, 95%, 96% or 97%, even more preferably higher than 98% or 99% at said position(s).
  • the abundance of deuterium at each deuterated position is independent of the abundance of deuterium at other deuterated position(s).
  • the selective incorporation of one or more deuterium atom(s) into a compound of general formula (I) may alter the physicochemical properties (such as for example acidity [C. L. Perrin, et al., J. Am. Chem. Soc, 2007, 129, 4490], basicity [C. L. Perrin et al., J. Am. Chem. Soc, 2005, 127, 9641], lipophilicity [B. Testa et al., Int. J.
  • deuterium substitution reduces or eliminates the formation of an undesired or toxic metabolite and enhances the formation of a desired metabolite (e.g. Nevirapine: A. M. Sharma et al., Chem. Res. Toxicol., 2013, 26, 410; Efavirenz: A. E. Mutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102).
  • the major effect of deuteration is to reduce the rate of systemic clearance. As a result, the biological half-life of the compound is increased.
  • the potential clinical benefits would include the ability to maintain similar systemic exposure with decreased peak levels and increased trough levels.
  • a compound of general formula (I) may have multiple potential sites of attack for metabolism.
  • deuterium-containing compounds of general formula (I) having a certain pattern of one or more deuterium-hydrogen exchange(s) can be selected.
  • the deuterium atom(s) of deuterium-containing compound(s) of general formula (I) is/are attached to a carbon atom and/or is/are located at those positions of the compound of general formula (I), which are sites of attack for metabolizing enzymes such as e.g. cytochrome P450.
  • cytochrome P450 e.g. cytochrome P450
  • stable compound' or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • the compounds of the present invention optionally contain one or more asymmetric centres, depending upon the location and nature of the various substituents desired. It is possible that one or more asymmetric carbon atoms are present in the (R) or (S) configuration, which can result in racemic mixtures in the case of a single asymmetric centre, and in diastereomeric mixtures in the case of multiple asymmetric centres. In certain instances, it is possible that asymmetry 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.
  • 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.
  • 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., HPLC columns using a chiral phase), with or without conventional derivatisation, optimally chosen to maximise the separation of the enantiomers.
  • Suitable HPLC columns using a chiral phase are commercially available, such as those manufactured by Daicel, e.g., Chiracel OD and Chiracel OJ, for example, among many others, which are all routinely selectable.
  • Enzymatic separations, with or without derivatisation are also useful.
  • the optically active compounds of the present invention can likewise be obtained by chiral syntheses utilizing optically active starting materials.
  • the present invention includes all possible stereoisomers of the compounds of the present invention as single stereoisomers, or as any mixture of said stereoisomers, e.g. (R)- or (S)- isomers, in any ratio.
  • Isolation of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound of the present invention is achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example.
  • any compound of the present invention can exist, as shown below, as a tautomer 1 , or tautomer 2 or tautomer 3, or even a mixture in any amount of the three tautomers, namely :
  • 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.
  • 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 covers useful forms of the compounds of the present invention, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and/or 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. It is possible for the amount of polar solvents, in particular water, to exist in a stoichiometric or non- stoichiometric ratio.
  • polar solvents in particular water
  • 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.
  • the compounds of the present invention may exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or to 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, which is customarily used in pharmacy, or which is used, for example, for isolating or purifying the compounds of the present invention.
  • pharmaceutically acceptable salt refers to an 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.
  • a suitable pharmaceutically acceptable salt of the compounds of the present invention may be, for example, an acid-addition salt of a compound of the present invention bearing a nitrogen atom, in a chain or in a ring, for example, which is sufficiently basic, such as an acid-addition salt with an inorganic acid, or "mineral acid", such as hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, bisulfuric, phosphoric, or nitric acid, for example, or with an organic acid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nico
  • an alkali metal salt for example a sodium or potassium salt
  • an alkaline earth metal salt for example a calcium, magnesium or strontium salt, or an aluminium or a zinc salt
  • acid addition salts of the claimed compounds to be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.
  • alkali and alkaline earth metal salts of acidic compounds of the present invention are prepared by reacting the compounds of the present invention with the appropriate base via a variety of known methods.
  • 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.
  • the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as single polymorph, or as a mixture of more than one polymorph, in any ratio.
  • R 1 represents a group selected from
  • pyrazolyl imidazolyl, oxadiazolyl, triazolyl, isoxazolyl, thienyl, pyridin-2-yl, pyridin-4-yl, pyrimidinyl, triazinyl and pyrazinyl, said group being optionally substituted with one R 6 group, and said group being, additionally, optionally substituted one or two times, differently or identically, with a R 7 group,
  • R 1 represents a group selected from
  • R 1 represents a group selected from pyridine-3-yl or pyridazin-3-yl, optionally substituted with one R 8 group; represents a group selected from
  • R 3 represents a hydrogen atom or a halogen atom or a group selected from Ci-C4-alkyl and Ci-C6-alkoxy;
  • R 4 represents a hydrogen atom or a halogen atom or a group selected from Ci-C4-alkyl, Ci-C4-haloalkyl, Ci-C 4 -alkoxy and
  • R 5 represents a hydrogen atom or a halogen atom or a group selected from Ci-C 4 -alkyl, Ci-C4-haloalkyl and C 3 -C 6 -cycloalkyl
  • R 6 represents a hydrogen atom or a group selected from Ci-C6-alkyl, Ci-C6-haloalkyl, Ci- Ce-hydroxyalkyl, (Ci-C 3 -alkoxy)-(Ci-C 3 -alkyl)-, C 3 -C6-cycloalkyl and (C 3 -C6-cycloalkyl)- (Ci-C 3 -alkyl)-,
  • said C 3 -C6-cycloalkyl and said (C 3 -C 6 -cycloalkyl)-(Ci-C 3 -alkyl)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or with a group selected from Ci-C 3 -alkyl and Ci- C 3 -haloalkyl;
  • R 7 represents a halogen atom or a group selected from hydroxy, Ci-C 6 -alkyl, Ci-C 6 -haloalkyl, Ci-C 6 -hydroxyalkyl, (Ci-C 3 -alkoxy)-(Ci-C 3 -alkyl)-, (Ci-C 3 -haloalkoxy)-(Ci-C 3 -alkyl)-, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 8 -cycloalkyl, C 4 -C 8 - cycloalkenyl, (C 3 -C8-cycloalkyl)-(Ci-C 3 -alkyl)-, (phenyl)-Ci-C 3 -alkyl-, 4- to 7-membered heterocycioalkyi, 5- to 7-membered heterocycloalkenyl, heterospirocycloalkyi,
  • said C 3 -C8-cycloalkyl, said (C 3 -C8-cycloalkyl)-(Ci-C 3 -alkyl)- and said (C 3 -C 8 - cycloalkyl)-(Ci-C 3 -alkoxy)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or with a group selected from Ci-C 3 -alkyl and Ci-C 3 -haloalkyl,
  • said 4- to 7-membered heterocycioalkyi, said 5- to 7-membered heterocycloalkenyl and said heterospirocycloalkyi group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or with a group selected from oxo, Ci-C 3 -alkyl and Ci-C 3 - haloalkyl, and
  • heteroaryl group and said phenyl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from -CN, Ci-C 3 -alkyl, trifluoromethyl, Ci-C3-alkoxy and trifluoromethoxy;
  • R 6 and R 7 or two R 7 groups, when being attached to adjacent ring atoms of the group R 1 , together form a group selected from: ⁇
  • R 8 represents a hydrogen atom or a group selected from methyl, ethyl, methoxy, ethoxy and dimethylamino;
  • R 9 represents a hydrogen atom or a -CN or Ci-C3-alkyl group
  • said 5- to 6-membered heteroaryl group and said phenyl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from -CN, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy and Ci- C3-haloalkoxy;
  • R 11 and R 11a independently from each other, represent a hydrogen atom or a group selected from Ci-C4-alkyl, Ci-C 4 -haloalkyl, C3-C6-cycloalkyl, Ci-C6-hydroxyalkyl, (Ci-C 3 -alkoxy)- (d-Ca-alkyl)-, (C 3 -C 6 -cycloalkyl)-(Ci-C 3 -alkyl)- and benzyl,
  • R 12 represents a hydrogen atom or a group selected from Ci-C6-alkyl, Ci-C6-haloalkyl, Ci- Ce-hydroxyalkyl, C 3 -C 6 -cycloalkyl, (C 3 -C6-cycloalkyl)-(Ci-C 3 -alkyl)-, C 2 -C 6 -alkenyl, C 2 - C6-alkynyl, 4- to 7-membered heterocycloalkyi, 5- to 7-membered heterocycloalkenyl, 5- to 6-membered heteroaryl and phenyl,
  • said 5- to 6-membered heteroaryl group and said phenyl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from -CN, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy and Ci- C 3 -haloalkoxy,
  • said C3-C6-cycloalkyl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from -CN, Ci- C3-alkyl and Ci-C3-haloalkyl;
  • R 13 represents a group selected from Ci-C4-alkyl and benzyl
  • R 14 and R 14a independently from each other, represent a hydrogen atom or a group selected from Ci-C4-alkyl, Ci-C4-haloalkyl, C3-C 6 -cycloalkyl and benzyl, or
  • R 14 and R 14a together with the nitrogen atom they are attached to, represent a 4- to 7- membered heterocycloalkyl group, said group being optionally substituted one or two times, identically or differently, with a halogen atom or a group selected from hydroxyl, -CN, Ci-C 3 -alkyl, Ci-C 3 -haloalkyl, Ci-C 3 -alkoxy, Ci-C 3 -haloalkoxy and (Ci-C 3 -alkoxy)-
  • R 15 represents a group selected from Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-hydroxyalkyl, (Ci- C 3 -alkoxy)-(Ci-C 5 -alkyl)-, (Ci-C 3 -alkoxy)-(C2-C 3 -alkoxy)-(Ci-C 6 -alkyl)-, C 3 -C 6 -cycloalkyl, (C 3 -C 6 -cycloalkyl)-(Ci-C 3 -alkyl)-, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl and phenyl,
  • said 5- to 6-membered heteroaryl group and said phenyl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from -CN, Ci-C 3 -alkyl, Ci-C 3 -haloalkyl, Ci-C 3 -alkoxy and Ci-C 3 -haloalkoxy;
  • R 16 represents a hydrogen atom or a group selected from Ci-C4-alkyl and benzyl
  • R 18 represents a Ci-C 3 -alkyl group
  • x represents an integer selected from 1 , 2, 3 and 4,
  • the present invention covers compounds of general formula (I):
  • R 1 represents a group selected from pyrazolyl, imidazolyl, oxadiazolyl, triazolyl, pyridin-2-yl, pyridin-4-yl, pyrimidinyl and pyrazinyl, said group being optionally substituted with one R 6 group, and said group being, additionally, optionally substituted one or two times, differently or identically, with a R 7 group, represents a group selected from
  • R 3 represents a hydrogen atom or a halogen atom or a group selected from d-C 4 -alkyl and Ci-C6-alkoxy;
  • R 4 represents a hydrogen atom or a halogen atom or a group selected from Ci-C4-alkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy and Ci-C4-haloalkoxy;
  • R 5 represents a hydrogen atom or a halogen atom or a group selected from Ci-C4-alkyl, Ci-C4-haloalkyl and C3-C6-cycloalkyl;
  • R 6 represents a hydrogen atom or a group selected from Ci-C6-alkyl, Ci-C6-haloalkyl, C3- Ce-cycloalkyl and (C3-C6-cycloalkyl)-(Ci-C3-alkyl)-,
  • said C3-C6-cycloalkyl and said (C3-C6-cycloalkyl)-(Ci-C3-alkyl)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or with a Ci-C3-alkyl group;
  • R 6 and R 7 or two R 7 groups, when being attached to adjacent ring atoms of the group R 1 , together form a group selected from:
  • R 8 represents a hydrogen atom or a group selected from methyl, ethyl, methoxy and ethoxy;
  • R 9 represents a hydrogen atom or a Ci-C3-alkyl group
  • said 5- to 6-membered heteroaryl group and said phenyl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from -CN, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C 3 -alkoxy and Ci- C3-haloalkoxy;
  • R 11 and R 11a independently from each other, represent a hydrogen atom or a group selected from Ci-C4-alkyl, d-d-haloalkyl, C3-C 6 -cycloalkyl and benzyl,
  • R 12 represents a group selected from Ci-C 6 -alkyl, Ci-C 6 -haloalkyl, Ci-C 6 -hydroxyalkyl, C 3 - C 6 -cycloalkyl, (C 3 -C 6 -cycloalkyl)-(Ci-C 3 -alkyl)-, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, 4- to 7- membered heterocycloalkyi, 5- to 7-membered heterocycloalkenyl, 5- to 6-membered heteroaryl and phenyl,
  • said 5- to 6-membered heteroaryl group and said phenyl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from -CN, Ci-C 3 -alkyl, Ci-C 3 -haloalkyl, Ci-C 3 -alkoxy and Ci- C 3 -haloalkoxy;
  • R 13 represents a group selected from Ci-C4-alkyl and benzyl
  • R 14 and R 14a independently from each other, represent a hydrogen atom or a group selected from Ci-C4-alkyl, Ci-C4-haloalkyl, C3-C6-cycloalkyl and benzyl,
  • R 14 and R 1 a together with the nitrogen atom they are attached to, represent a 4- to 7- membered heterocycloalkyi group, said group being optionally substituted one or two times, identically or differently, with a halogen atom or a group selected from hydroxyl, -CN, Ci-C 3 -alkyl, Ci-C 3 -haloalkyl, Ci-C 3 -alkoxy, Ci-C 3 -haloalkoxy and (Ci-C 3 -alkoxy)- (Ci-C 3 -alkyl)-;
  • R 15 represents a group selected from Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-hydroxyalkyl, (Ci- C 3 -alkoxy)-(Ci-C 6 -alkyl)-, (Ci-C 3 -alkoxy)-(C 2 -C 3 -alkoxy)-(Ci-C 6 -alkyl)-, C 3 -C 6 -cycloalkyl, (C 3 -C 6 -cycloalkyl)-(Ci-C 3 -alkyl)-, 4- to 7-membered heterocycloalkyi, 5- to 6-membered heteroaryl and phenyl,
  • said 5- to 6-membered heteroaryl group and said phenyl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from -CN, Ci-C 3 -alkyl, Ci-C 3 -haloalkyl, Ci-C 3 -alkoxy and Ci-C 3 -haloalkoxy;
  • R 16 represents a hydrogen atom or a group selected from Ci-C4-alkyl and benzyl
  • R 18 represents a Ci-C 3 -alkyl group
  • x represents an integer selected from 1 , 2, 3 and 4,
  • R represents a group selected from
  • the ring of said group being, besides R 6 , optionally substituted further one or two times, differently or identically, with a R 7 group, represents a group selected from
  • R 2 represents a group selected from
  • R 3 represents a hydrogen atom or a halogen atom or a group selected from Ci-C4-alkyl and Ci-C4-alkoxy;
  • R 4 represents a hydrogen atom or a group selected from Ci-C3-alkyl and Ci-C3-fluoroalkyl
  • R 5 represents a hydrogen atom or a bromine atom
  • R 6 represents a hydrogen atom or a group selected from Ci-C6-alkyl, Ci-C4-fluoroalkyl, Ci-C 4 -hydroxyalkyl, (Ci-C2-alkoxy)-(Ci-C3-alkyl)-, C3-C5-cycloalkyl and (C3-C5-cycloalkyl)-(methyl)-,
  • said C3-C5-cycloalkyl and said (C3-C5-cycloalkyl)-(methyl)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or with a group selected from methyl and trifluoromethyl;
  • R 7 represents a halogen atom or a group selected from hydroxy, Ci-C6-alkyl, C1-C4- fluoroalkyl, Ci-C 4 -hydroxyalkyl, (Ci-C 2 -alkoxy)-(Ci-C 3 -alkyl)-, (Ci-C 2 -fluoroalkoxy)-(Ci- C 3 -alkyl)-, C 3 -C 4 -cycloalkyl, (C 3 -C 4 -cycloalkyl)-(methyl)-, (phenyl)-(Ci-C 3 -alkyl)-, 4- to 7- membered heterocycloalkyl, heterospirocycloalkyl, 5-to 6-membered heteroaryl, -CN, -
  • said C 3 -C4-cycloalkyl, said (C3-C 4 -cycloalkyl)-(methyl)- and said (C3-C4- cycloalkyl)-(methoxy)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom or with a group selected from methyl and trifluoromethyl,
  • said 4- to 7-membered heterocycloalkyi and said heterospirocycloalkyl group being optionally substituted one, two or three times, identically or differently, with a fluorine atom or with a group selected from oxo, methyl and trifluoromethyl
  • said 5- to 6-membered heteroaryl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from methyl, trifluoromethyl and methoxy;
  • R 6 and R 7 or two R 7 groups, when being attached to adjacent ring atoms of the group R 1 , together form a group selected from:
  • R 8 represents a hydrogen atom or a group selected from methoxy and ethoxy
  • R 9 represents a hydrogen atom or a methyl or ethyl group
  • said 5- to 6-membered heteroaryl group and said phenyl group being optionally substituted one or two times, identically or differently, with a fluorine atom, chlorine atom or bromine atom, or a group selected from -CN, methyl, trifluoromethyl and methoxy;
  • R 11 and R 11a independently from each other, represent a hydrogen atom or a group selected from Ci-C4-alkyl, Ci-C4-fluoroalkyl, C3-C4-cycloalkyl, Ci-C4-hydroxyalkyl, (Ci-C 2 -alkoxy)- (Ci-C 3 -alkyl)-, (C 3 -C 4 -cycloalky!-(methyl)- and benzyl,
  • R 11 and R 11a together with the nitrogen atom they are attached to, represent a 4- to 6- membered heterocycloalkyi group, said group being optionally substituted one or two times, identically or differently, with a fluorine atom, or a group selected from hydroxy, oxo, -CN, methyl, trifluoromethyl and methoxy;
  • R 12 represents a hydrogen atom or a group selected from Ci-C4-alkyl, Ci-C 4 -fluoroalkyl, Ci-C 4 -hydroxyalkyl, (Ci-C 2 -alkoxy)-(Ci-C 3 -alkyl)-, C 3 -C 6 -cycloalkyl, (C 3 -C 6 -cycloalkyl)- (Ci-C 2 -alkyl)-, C 2 -C 4 -alkenyl, 5- to 6-membered heteroaryl and phenyl, said 5- to 6-membered heteroaryl group and said phenyl group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or a group selected from methyl, trifluormethyl and methoxy, said C3-C6-cycloalkyl group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a
  • R 13 represents a group selected from Ci-C4-alkyl and benzyl
  • R 14 and R 14a independently from each other, represent a hydrogen atom or a group selected from Ci-C3-alkyl, trifluoromethyl and cyclopropyl,
  • R 14 and R 14a together with the nitrogen atom they are attached to, represent a 4- to 7- membered heterocycloalkyi group, said group being optionally substituted one or two times, identically or differently, with a group selected from Ci-C3-alkyl, Ci-C3-fluoroalkyl, Ci-C3-alkoxy, trifluoromethoxy and (Ci-C2-alkoxy)-(Ci-C2-alkyl)-;
  • R 15 represents a group selected from Ci-C4-alkyl, Ci-C4-fluoroalkyl, (Ci-C2-alkoxy)-(Ci-C 3 - alkyl)-, (Ci-C 2 -alkoxy)-(ethoxy)-(Ci-C 3 -alkyl)-, C 3 -C 6 -cycloalkyl, (C 3 -C 6 -cycloalkyl)-(Ci- C 2 -alkyl)- and 4- to 7-membered heterocycloalkyi;
  • R 16 represents a hydrogen atom or a Ci-C 3 -alkyl group
  • x represents an integer selected from 1 and 2
  • R 1 represents a group selected from
  • the ring of said group being, besides R 6 , optionally substituted further one or two times, differently or identically, with a R 7 group, represents a group selected from
  • Ci-C4-alkyl represents a hydrogen atom or a halogen atom or a group selected from Ci-C4-alkyl and Ci-C4-alkoxy;
  • Ci-C3-alkyl represents a hydrogen atom or a group selected from Ci-C3-alkyl and Ci-C3-fluoroalkyl; represents a hydrogen atom or a bromine atom;
  • Ci-C6-alkyl represents a hydrogen atom or a group selected from Ci-C6-alkyl, Ci-C4-fluoroalkyl, Ci-C 4 -hydroxyalkyl, (Ci-C 2 -alkoxy)-(Ci-C3-alkyl)-, C3-Cs-cycloalkyl and (C3-C5-cycloalkyl)-(methyl)-,
  • said C3-C5-cycloalkyl and said (C 3 -C5-cycloalkyl)-(methyl)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or with a group selected from methyl and trifluoromethyl;
  • said C 3 -C4-cycloalkyl, said (C 3 -C 4 -cycloalkyl)-(methyl)- and said (C3-C4- cycloalkyl)-(methoxy)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom or with a group selected from methyl and trifluoromethyl,
  • said 4- to 7-membered heterocycloalkyl and said heterospirocycloalkyl group being optionally substituted one, two or three times, identically or differently, with a fluorine atom or with a group selected from oxo, methyl and trifluoromethyl
  • said 5- to 6-membered heteroaryl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from methyl, trifluoromethyl and methoxy;
  • R 6 and R 7 or two R 7 groups, when being attached to adjacent ring atoms of the group R 1 , together form a group selected from:
  • R 8 represents a hydrogen atom or a group selected from methoxy and ethoxy
  • R 9 represents a hydrogen atom or a methyl or ethyl group
  • said 5- to 6-membered heteroaryl group and said phenyl group being optionally substituted one or two times, identically or differently, with a fluorine atom, chlorine atom or bromine atom, or a group selected from -CN, methyl, trifluoromethyl and methoxy;
  • R 11 and R 11a independently from each other, represent a hydrogen atom or a group selected from Ci-C4-alkyl, Ci-C4-fluoroalkyl, C3-C4-cycloalkyl, Ci-C4-hydroxyalkyl, (Ci-C 2 -alkoxy)- (Ci-Cs-alkyl)-, (C 3 -C 4 -cycloalkyl)-(methyl)- and benzyl,
  • R 11 and R 11a together with the nitrogen atom they are attached to, represent a 4- to 6- membered heterocycloalkyl group, said group being optionally substituted one or two times, identically or differently, with a fluorine atom, or a group selected from hydroxy, oxo, -CN, methyl, trifluoromethyl and methoxy;
  • R 12 represents a hydrogen atom or a group selected from Ci-C 4 -alkyl, Ci-C4-fluoroalkyl, C3-C6-cycloalkyl, (C3-C6-cycloalkyl)-(Ci-C 2 -alkyl)-, C 2 -C4-alkenyl, 5- to 6-membered heteroaryl and phenyl, said 5- to 6-membered heteroaryl group and said phenyl group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or a group selected from methyl, trifluormethyl and methoxy, said C3-C6-cycloalkyl group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or a group selected from -CN, methyl and trifluoromethyl;
  • R 13 represents a group selected from Ci-C 4 -alkyl and benzyl
  • R 14 and R 14a independently from each other, represent a hydrogen atom or a group selected from Ci-C3-alkyl, trifluoromethyl and cyclopropyl,
  • R 14 and R 14a together with the nitrogen atom they are attached to, represent a 4- to 7- membered heterocycloalkyi group, said group being optionally substituted one or two times, identically or differently, with a group selected from Ci-C3-alkyl, Ci-C3-fluoroalkyl, Ci-C3-alkoxy, trifluoromethoxy and (Ci-C2-alkoxy)-(Ci-C2-alkyl)-;
  • R 15 represents a group selected from Ci-C4-alkyl, Ci-C4-fluoroalkyl, (Ci-C2-alkoxy)-(Ci-C3- alkyl)-, (Ci-C 2 -alkoxy)-(ethoxy)-(Ci-C 3 -alkyl)-, C 3 -C 6 -cycloalkyl, (C 3 -C 6 -cycloalkyl)-(Ci- C2-alkyl)- and 4- to 7-membered heterocycloalkyi;
  • R 16 represents a hydrogen atom or a Ci-C3-alkyl group
  • x represents an integer selected from 1 and 2
  • the present invention covers compounds of general formula (I), supra, in which:
  • R 1 represents a group selected from
  • R 1 represents a group selected from
  • R 2 represents a group selected from
  • R 3 represents a hydrogen atom or a group selected from Ci-Ct-alkyl and Ci-C4-alkoxy;
  • R 4 represents a hydrogen atom or a group selected from Ci-C3-alkyl and Ci-C3-fluoroalkyl
  • R 5 represents a hydrogen atom
  • R 6 represents a hydrogen atom or a group selected from Ci-Ce-alkyl, Ci-C4-fluoroalkyl, C3-C 4 -cycloalkyl and (C3-C4-cycloalkyl)-(methyl)-,
  • said C 3 -C 4 -cycloalkyl and said (C 3 -C 4 -cycloalkyl)-(methyl)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or with a methyl group;
  • Ci-C4-fluoroalkoxy (C3-C4-cycloalkyl)-(methoxy)- and Ci-C4-alkylsulfanyl;
  • R 6 and R 7 or two R 7 groups, when being attached to adjacent ring atoms of the group R 1 , together form a group selected from:
  • R 8 represents a hydrogen atom or a group selected from methoxy and ethoxy
  • R 9 represents a hydrogen atom or a methyl or ethyl group
  • R 11 and R 11a independently from each other, represent a hydrogen atom or a group selected from Ci-C4-alkyl and benzyl,
  • R 11 and R 11a together with the nitrogen atom they are attached to, represent a 5- to 6- membered heterocycloalkyi group, said group being optionally substituted once with a methyl group;
  • R 2 represents a group selected from Ci-C4-alkyl, Ci-C4-fluoroalkyl, C3-C6-cycloalkyl, (C3- C6-cycloalkyl)-(Ci-C2-alkyl)- and C2-C4-alkenyl;
  • R 13 represents a group selected from Ci-C4-alkyl and benzyl
  • R 14 and R 14a independently from each other, represent a hydrogen atom or a group selected from Ci-C3-alkyl, trifluoromethyl and cyclopropyl,
  • R 14 and R 14a together with the nitrogen atom they are attached to, represent a 4- to 7- membered heterocycloalkyi group, said group being optionally substituted one or two times, identically or differently, with a group selected from Ci-C 3 -alkyl, Ci-C3-fluoroalkyl, Ci-C 3 -alkoxy, trifluoromethoxy and (Ci-C2-alkoxy)-(Ci-C 2 -alkyl)-;
  • R 15 represents a group selected from Ci-C4-alkyl, Ci-C4-fluoroalkyl, (Ci-C2-alkoxy)-(Ci-C3- alkyl)-, (Ci-C 2 -alkoxy)-(ethoxy)-(Ci-C 3 -alkyl)-, C 3 -C 6 -cycloalkyl, (C 3 -C e -cycloalkyl)-(Ci- C2-alkyl)- and 4- to 7-membered heterocycloalkyi,
  • the present invention covers compounds of general formula (I), supra, in which:
  • R 1 represents a group selected from
  • R represents a group selected from
  • R 2 represents a group selected from
  • R 3 represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom or a group selected from methyl, ethoxy and iso-butoxy;
  • R 4 represents a hydrogen atom or a group selected from methyl and trifluoromethyl
  • R 5 represents a hydrogen atom
  • R 6 represents a hydrogen atom or a group selected from Ci-C6-alkyl, Ci-C4-fluoroalkyl, Ci-C4-hydroxyalkyl, (methoxy)-(Ci-C3-alkyl)-, C3-Cs-cycloalkyl and (C 3 -C 5 -cycloalkyl)-(methyl)-,
  • said C3-C5-cycloalkyl and said (C3-Cs-cycloalkyl)-(methyl)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or with a methyl group;
  • said C3-C4-cycloalkyl, said (C3-C4-cycloalkyl)-(methyl)- and said (C3-C4- cycloalkyl)-(methoxy)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom or with a group selected from methyl and trifluoromethyl, and
  • said 4- to 7-membered heterocycloalkyl and said heterospirocycloalkyl group being optionally substituted one, two or three times, identically or differently, with a fluorine atom or with a group selected from methyl and trifluoromethyl, or
  • R 8 represents a hydrogen atom or a methoxy group
  • R 9 represents a hydrogen atom or a methyl group
  • R 11 and R 11a independently from each other, represent a hydrogen atom or a group selected from Ci-C3-alkyl, Ci-C3-fluoroalkyl, C3-C4-cycloalkyl, Ci-C3-hydroxyalkyl, (Ci-C 2 -alkoxy)- (Ci-C3-alkyl)-, (C3-C4-cycloalkyl)-(methyl)- and benzyl,
  • R 11 and R 11a together with the nitrogen atom they are attached to, represent a 4- to 6- membered heterocycloalkyi group, said group being optionally substituted one or two times, identically or differently, with a fluorine atom or a group selected from methyl and trifluoromethyl;
  • R 12 represents a group selected from Ci-d-alkyl, Ci-C3-fluoroalkyl, Ci-C3-hydroxyalkyl, (methoxy)-(Ci-C3-alkyl)-, C3-C4-cycloalkyl, (cyclopropyl)-(methyl)- and allyl,
  • said C 3 -C4-cycloalkyl group being optionally substituted one, two or three times, identically or differently, with a fluorine atom or a group selected from methyl and trifluoromethyl;
  • R 3 represents a Ci-C3-alkyl group
  • R 14 and R 14a independently from each other, represent a hydrogen atom or a group selected from methyl and ethyl,
  • R 14 and R 14a together with the nitrogen atom they are attached to, represent a 5- to 6- membered heterocycloalkyi group selected from pyrrolidinyl, piperidinyl and morpholinyl, said group being optionally substituted one or two times, identically or differently, with a group selected from methyl, methoxy and (methoxy)-(methyl)-;
  • R 15 represents a group selected from ethyl, 3,3,3-trifluoropropyl, (3-methoxy)-(propyl)-, (2'- methoxy)-(2-ethoxy)-(ethyl)-, cyclopropyl, cyclohexyl and tetrahydropyranyl;
  • R 16 represents a hydrogen atom or a Ci-C2-alkyl group
  • x represents an integer 1 ,
  • the present invention covers compounds of general formula (I), supra, in which:
  • R 1 represents a group selected from
  • R 1 represents a group selected from
  • R 2 represents a group selected from
  • R 3 represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom or a group selected from methyl, ethoxy and iso-butoxy;
  • R 4 represents a hydrogen atom, or a group selected from methyl and trifluoromethyl
  • R 5 represents a hydrogen atom
  • R 6 represents a hydrogen atom or a group selected from Ci-C6-alkyl, Ci-C4-fluoroalkyl, Ci-C4-hydroxyalkyl, (methoxy)-(Ci-C3-alkyl)-, C3-Cs-cycloalkyl and (C 3 -C 5 -cycloalkyl)-(methyl)-,
  • said C3-C5-cycloalkyl and said (C3-C5-cycloalkyl)-(methyl)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or with a methyl group;
  • said C3-C4-cycloalkyl, said (C3-C4-cycloalkyl)-(methyl)- and said (C3-C4- cycloalkyl)-(methoxy)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom or with a group selected from methyl and trifluoromethyl, and
  • said 4- to 7-membered heterocycloalkyl and said heterospirocycloalkyl group being optionally substituted one, two or three times, identically or differently, with a fluorine atom or with a group selected from methyl and trifluoromethyl, or
  • R 8 represents a hydrogen atom or a methoxy group
  • R 9 represents a hydrogen atom or a methyl group
  • R 11 and R 11a independently from each other, represent a hydrogen atom or a group selected from Ci-C3-alkyl, Ci-C3-fluoroalkyl, C3-C4-cycloalkyl, Ci-C3-hydroxyalkyl, (Ci-C 2 -alkoxy)- (Ci-C3-alkyl)-, (C3-C4-cycloalkyl)-(methyl)- and benzyl,
  • R 1 and R 11a together with the nitrogen atom they are attached to, represent a 4- to 6- membered heterocycloalkyl group, said group being optionally substituted one or two times, identically or differently, with a fluorine atom or a group selected from methyl and trifluoromethyl;
  • R 12 represents a group selected from Ci-C4-alkyl, Ci-C3-fluoroalkyl, C3-C4-cycloalkyl, (cyclopropyl)-(methyl)- and allyl,
  • said C3-C4-cycloalkyl group being optionally substituted one, two or three times, identically or differently, with a fluorine atom or a group selected from methyl and trifluoromethyl;
  • R 13 represents a Ci-C3-alkyl group
  • R 14 and R 14a independently from each other, represent a hydrogen atom or a group selected from methyl and ethyl,
  • R 14 and R 14a together with the nitrogen atom they are attached to, represent a 5- to 6- membered heterocycloalkyl group selected from pyrrolidinyl, piperidinyl and morpholinyl, said group being optionally substituted one or two times, identically or differently, with a group selected from methyl, methoxy and (methoxy)-(methyl)-;
  • R 15 represents a group selected from ethyl, 3,3,3-trifluoropropyl, (3-methoxy)-(propyl)-, (2'- methoxy)-(2-ethoxy)-(ethyl)-, cyclopropyl, cyclohexyl and tetrahydropyranyl;
  • R 16 represents a hydrogen atom or a Ci-C2-alkyl group
  • x represents an integer 1 ,
  • R 1 represents a group selected from
  • R 1 represents a group selected from
  • R 3 represents a hydrogen atom or a group selected from methyl, ethoxy and iso-butoxy;
  • R 4 represents a hydrogen atom, or a group selected from methyl and trifluoromethyl;
  • R 5 represents a hydrogen atom
  • R 6 represents a group selected from Ci-C 4 -alkyl, Ci-C4-fluoroalkyl, cyclopropyl and (cyclopropyl)-(methyl)-,
  • cyclopropyl and (cyclopropyl)-(methyl)- group being optionally substituted one or two times with a fluorine atom;
  • R 8 represents a hydrogen atom or a methoxy group
  • R 9 represents a hydrogen atom or a methyl group
  • R 11 and R 11a independently from each other, represent a hydrogen atom or a group selected from methyl and ethyl;
  • R 12 represents a group selected from Ci-C4-alkyl, 0-C3-fluoroalkyl, C3-C4-cycloalkyl, (cyclopropyl)-(methyl)- and allyl;
  • R 14 and R 14a independently from each other, represent a hydrogen atom or a group selected from methyl and ethyl,
  • R 14 and R 14a together with the nitrogen atom they are attached to, represent a 5- to 6- membered heterocycloalkyl group selected from pyrrolidinyl, piperidinyl and morpholinyl, said group being optionally substituted once with a group selected from methyl, methoxy and (methoxy)-(methyl)-;
  • R 15 represents a group selected from ethyl, 3,3,3-trifluoropropyl, (3-methoxy)-(propyl)-, (2'- methoxy)-(2-ethoxy)-(ethyl)-, cyclopropyl, cyclohexyl and tetrahydropyranyl, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
  • R 1 represents a group selected from
  • the ring of said group being, besides R 6 , optionally substituted further one or two times, differently or identically, with a R 7 group;
  • R 2 represents a group
  • R 3 represents a hydrogen atom, a fluorine atom or a chlorine atom
  • R 4 represents a hydrogen atom or a methyl group
  • R 5 represents a hydrogen atom
  • R 6 represents a group selected from methyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl and (C 3 -C5-cycloalkyl)-(methyl)-,
  • said (C3-C5-cycloalkyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom, a chlorine atom or with a methyl group;
  • R 7 represents a group selected from Ci-C3-alkyl, difluoromethyl, trifluoromethyl, (methoxy)-(methyl)-, cyclopropyl, -NR 11 R 11a , Ci-C 3 -alkoxy, Ci-C 3 -fluoroalkoxy, (C 3 -C 4 - cycloalkyl)-(methoxy)- and [1 -(trifluoromethyl)cyclopropyl]-(methoxy)-; or
  • R 9 represents a hydrogen atom or a methyl group
  • R 11 and R 11a independently from each other, represent a hydrogen atom or a group selected from Ci-C 3 -alkyl, 2,2,2-trifluoroethyl, C 3 -C 4 -cycloalkyl, (Ci-C 2 -alkoxy)-(Ci-C 3 -alkyl)- and (C 3 -C 4 -cycloalkyl)-(methyl)-,
  • R 11 and R 11a together with the nitrogen atom they are attached to, represent a 4- to 6- membered heterocycloalkyl group, said group being optionally substituted one or two times with a fluorine atom or a trifluoromethyl group;
  • R 12 represents a group selected from Ci-C 2 -fluoroalkyl, C 3 -C4-cycloalkyl, 2-hydroxyprop-2- yl, (2-methoxy)-(prop-2-yl)-, (l-trifluoromethyl)-(cyclopropyl)-, 2,2-difluorocyclopropyl,
  • R 14 and R 14a independently from each other, represent a group selected from methyl and ethyl
  • R 14 and R 14a together with the nitrogen atom they are attached to, represent a 5- to 6- membered heterocycloalkyl group selected from pyrrolidinyl, piperidinyl and morpholinyl, said group being optionally substituted one or two times, identically or differently, with a group selected from methyl, methoxy and (methoxy)-(methyl)-;
  • R 15 represents a group selected from ethyl, 3,3,3-trifluoropropyl, (3-methoxy)-(propyl)-, (2'- methoxy)-(2-ethoxy)-(ethyl)-, cyclopropyl, cyclohexyl and tetrahydropyranyl;
  • R 16 represents a hydrogen atom or a methyl group
  • the present invention covers compounds of general formula (I), supra, in which:
  • R 1 represents a group selected from
  • the ring of said group being, besides R 6 , optionally substituted further one or two times, differently or identically, with a R 7 group;
  • R 2 represents a group
  • R 3 represents a hydrogen atom, a fluorine atom or a chlorine atom
  • R 4 represents a hydrogen atom or a methyl group
  • R 5 represents a hydrogen atom
  • R 6 represents a group selected from methyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyi and (C 3 -C 5 -cycloalkyl)-(methyl)-,
  • said (C3-C5-cycloalkyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom, a chlorine atom or with a methyl group;
  • R 7 represents a group selected from Ci-C3-alkyl, difluoromethyl, trifluoromethyl, (methoxy)-(methyl)-, cyclopropyl,-NR 11 R 11a , Ci-C 3 -alkoxy, Ci-C 3 -fluoroalkoxy, (C3-C4- cycloalkyl)-(methoxy)- and [1 -(trifluoromethyl)cyclopropyl]-(methoxy)-; or
  • R 9 represents a methyl group
  • R 11 and R 11a independently from each other, represent a hydrogen atom or a group selected from Ci-C 3 -alkyl, 2,2,2-trifluoroethyl, C 3 -C 4 -cycloalkyl, (Ci-C2-alkoxy)-(Ci-C 3 -alkyl)- and (C 3 -C 4 -cycloalkyl)-(methyl)-,
  • R 11 and R 11a together with the nitrogen atom they are attached to, represent a 4- to 6- membered heterocycloalkyl group, said group being optionally substituted one or two times with a fluorine atom or a trifluoromethyl group;
  • R 12 represents a group selected from 0-C2-fluoroalkyl, C 3 -C4-cycloalkyl, 2-hydroxyprop-2- yl, (2-methoxy)-(prop-2-yl)-, (l-trifluoromethyl)-(cyclopropyl)-, 2,2-difluorocyclopropyl,
  • R 14 and R 14a independently from each other, represent a group selected from methyl and ethyl
  • R 14 and R 14a together with the nitrogen atom they are attached to, represent a 5- to 6- membered heterocycloalkyl group selected from pyrrolidinyl, piperidinyl and morpholinyl, said group being optionally substituted one or two times, identically or differently, with a group selected from methyl, methoxy and (methoxy)-(methyl)-;
  • R 15 represents a group selected from ethyl, 3,3,3-trifluoropropyl, (3-methoxy)-(propyl)-, (2'- methoxy)-(2-ethoxy)-(ethyl)-, cyclopropyl, cyclohexyl and tetrahydropyranyl;
  • R 16 represents a hydrogen atom or a methyl group
  • R 1 represents a group selected from
  • R 3 represents a hydrogen atom, a fluorine atom or a chlorine atom
  • R 4 represents a hydrogen atom or a methyl group
  • R 5 represents a hydrogen atom
  • R 6 represents a group selected from methyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl and (C 3 -C 5 -cycloal kyl )-(methyl )-,
  • R 7 represents a group selected from Ci-C 3 -alkyl, difluoromethyl, trifluoromethyl, (methoxy)-(methyl)-, cyclopropyl,-NR 11 R 11a , Ci-C 3 -alkoxy, Ci-C 3 -fluoroalkoxy, (C 3 -C 4 - cycloalkyl)-(methoxy)- and [1-(trifluoromethyl)cyclopropyl]-(methoxy)-;
  • R 9 represents a hydrogen atom or a methyl group
  • R 11 and R 11a independently from each other, represent a hydrogen atom or a group selected from Ci-C 3 -alkyl, 2,2,2-trifluoroethyl, C 3 -C 4 -cycloalkyl, (Ci-C 2 -alkoxy)-(Ci-C 3 -alkyl)- and
  • R 1 and R 11a together with the nitrogen atom they are attached to, represent a 4- to 6- membered heterocycloalkyl group, said group being optionally substituted one or two times with a fluorine atom or a trifluoromethyl group;
  • R 12 represents a group selected from 0-C2-fluoroalkyl, C 3 -C4-cycloalkyl, 2-hydroxyprop-2- yl, (2-methoxy)-(prop-2-yl)-, (l -trifluoromethyl)-(cyclopropyl)-, 2,2-difluorocyclopropyl, 2,2-difluoro-1 -methylcyclopropyl and (cyclopropyl)-(methyl)-;
  • R 14 and R 14a independently from each other, represent a group selected from methyl and ethyl
  • R 14 and R 14a together with the nitrogen atom they are attached to, represent a 5- to 6- membered heterocycloalkyl group selected from pyrrolidinyl, piperidinyl and morpholinyl, said group being optionally substituted one or two times, identically or differently, with a group selected from methyl, methoxy and (methoxy)-(methyl)-;
  • R 16 represents a hydrogen atom or a methyl group
  • R 1 represents a group selected from
  • R 3 represents a hydrogen atom, a fluorine atom or a chlorine atom
  • R 4 represents a hydrogen atom or a methyl group
  • R 5 represents a hydrogen atom
  • R 6 represents a group selected from methyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl and (C 3 -C 5 -cycloalkyl)-(methyl)-,
  • R 7 represents a group selected from Ci-C 3 -alkyl, difluoromethyl, trifluoromethyl, (methoxy)-(methyl)-, cyclopropyl,-NR 11 R 11a , Ci-C 3 -alkoxy, Ci-C 3 -fluoroalkoxy, (C 3 -C 4 - cycloalkyl)-(methoxy)- and [1-(trifluoromethyl)cyclopropyl]-(methoxy)-;
  • R 9 represents a methyl group
  • R 11 and R 11a independently from each other, represent a hydrogen atom or a group selected from Ci-C 3 -alkyl, 2,2,2-trifluoroethyl, C 3 -C 4 -cycloalkyl, (Ci-C 2 -alkoxy)-(Ci-C 3 -alkyl)- and
  • R 1 and R 1 a together with the nitrogen atom they are attached to, represent a 4- to 6- membered heterocycloalkyl group, said group being optionally substituted one or two times with a fluorine atom or a trifluoromethyl group;
  • R 12 represents a group selected from Ci-C2-fluoroalkyl, C 3 -C4-cycloalkyl, 2-hydroxyprop-2- yl, (2-methoxy)-(prop-2-yl)-, ( -trifluoromethyl)-(cyclopropyl)-, 2,2-difluorocyclopropyl, 2,2-difluoro-1 -methylcyclopropyl and (cyclopropyl)-(methyl)-;
  • R 14 and R 14a independently from each other, represent a group selected from methyl and ethyl
  • R 14 and R 14a together with the nitrogen atom they are attached to, represent a 5- to 6- membered heterocycloalkyl group selected from pyrrolidinyl, piperidinyl and morpholinyl, said group being optionally substituted one or two times, identically or differently, with a group selected from methyl, methoxy and (methoxy)-(methyl)-;
  • R 16 represents a hydrogen atom or a methyl group
  • the present invention covers compounds of general formula (I), supra, in which:
  • R 1 represents a group selected from
  • R 2 represents a group
  • R 3 represents a hydrogen atom, a fluorine atom or a chlorine atom
  • R 4 represents a hydrogen atom or a methyl group
  • R 5 represents a hydrogen atom
  • R 6 represents a group selected from methyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl and (C 3 -C 5 -cycloalkyl)-(methyl)-,
  • said (C3-C5-cycloalkyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom, a chlorine atom or with a methyl group;
  • R 7 represents a group selected from Ci-C3-alkyl, difluoromethyl, trifluoromethyl, (methoxy)-(methyl)-, cyclopropyl, 2-oxa-6-azaspiro[3.3]heptyl-, -NR 11 R 11a , C1-C3- alkoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, (C3-C4-cycloalkyl)-(methoxy)- and [1 - (trifluoromethyl)cyclopropyl]-(methoxy)-;
  • R 9 represents a hydrogen atom or a methyl group
  • R 11 and R 11a independently from each other, represent a hydrogen atom or a group selected from Ci-C 3 -alkyl, 2,2,2-trifluoroethyl, C 3 -C 4 -cycloalkyl, (Ci-C 2 -alkoxy)-(Ci-C 3 -alkyl)- and (C3-C4-cycloalkyl)-(methyl)-,
  • R 11 and R 11a together with the nitrogen atom they are attached to, represent a 4- to 6- membered heterocycloalkyl group, said group being optionally substituted one or two times with a fluorine atom or a trifluoromethyl group;
  • R 12 represents a group selected from Ci-C2-fluoroalkyl, C3-C4-cycloalkyl, (1 -trifluoromethyl)- (cyclopropyl)- and (cyclopropyl)-(methyl)-;
  • R 14 and R 14a independently from each other, represent a group selected from methyl and ethyl
  • R 14 and R 14a together with the nitrogen atom they are attached to, represent a 5- to 6- membered heterocycloalkyl group selected from pyrrolidinyl, piperidinyl and morpholinyl, said group being optionally substituted one or two times, identically or differently, with a group selected from methyl, methoxy and (methoxy)-(methyl)-;
  • R 15 represents a group selected from ethyl, 3,3,3-trifluoropropyl, (3-methoxy)-(propyl)-, (2'- methoxy)-(2-ethoxy)-(ethyl)-, cyclopropyl, cyclohexyl and tetrahydropyranyl;
  • R 16 represents a hydrogen atom or a methyl group
  • R 1 represents a group selected from
  • said (C3-C5-cycloalkyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom, a chlorine atom or with a methyl group;
  • R 6 and R 7 represents a group selected from Ci-C 3 -alkyl, difluoromethyl, trifluoromethyl, (methoxy)-(methyl)-, cyclopropyl, 2-oxa-6-azaspiro[3.3]heptyl-, -NR 11 R 11a , C1-C3- alkoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, (C3-C4-cycloalkyl)-(methoxy)- and [1 - (trifluoromethyl)cyclopropyl]-(methoxy)-;
  • R 9 represents a methyl group
  • R 1 and R 11a independently from each other, represent a hydrogen atom or a group selected from Ci-Ca-alkyl, 2,2,2-trifluoroethyl, C 3 -C 4 -cycloalkyl, (Ci-C 2 -alkoxy)-(Ci-C 3 -alkyl)- and (C3-C4-cycloalkyl)-(methyl)-,
  • R 11 and R 11a together with the nitrogen atom they are attached to, represent a 4- to 6- membered heterocycloalkyl group, said group being optionally substituted one or two times with a fluorine atom or a trifluoromethyl group;
  • R 12 represents a group selected from Ci-C2-fluoroalkyl, C3-C4-cycloalkyl, (1 -trifluoromethyl)- (cyclopropyl)- and (cyclopropyl)-(methyl)-;
  • R 14 and R 14a independently from each other, represent a group selected from methyl and ethyl
  • R 14 and R 14a together with the nitrogen atom they are attached to, represent a 5- to 6- membered heterocycloalkyl group selected from pyrrolidinyl, piperidinyl and morpholinyl, said group being optionally substituted one or two times, identically or differently, with a group selected from methyl, methoxy and (methoxy)-(methyl)-;
  • R 15 represents a group selected from ethyl, 3,3,3-trifluoropropyl, (3-methoxy)-(propyl)-, (2'- methoxy)-(2-ethoxy)-(ethyl)-, cyclopropyl, cyclohexyl and tetrahydropyranyl;
  • R 16 represents a hydrogen atom or a methyl group
  • the present invention covers compounds of general formula (I), supra, in which:
  • R 1 represents a group selected from
  • R 2 represents a group
  • R 3 represents a hydrogen atom, a fluorine atom or a chlorine atom
  • R 4 represents a hydrogen atom or a methyl group
  • R 5 represents a hydrogen atom
  • R 6 represents a group selected from methyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl and (C 3 -C 5 -cycloalkyl)-(methyl)-,
  • said (C -cycloalkyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom, a chlorine atom or with a methyl group;
  • R 7 represents a group selected from Ci-C3-alkyl, difluoromethyl, trifluoromethyl, (methoxy)-(methyl)-, cyclopropyl, 2-oxa-6-azaspiro[3.3]heptyl-, -NR 11 R 1 a , C1-C3- alkoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, (C 3 -C4-cycloalkyl)-(methoxy)- and [1- (trifluoromethyl)cyclopropyl]-(methoxy)-;
  • R 9 represents a hydrogen atom or a methyl group
  • R 11 and R 11a independently from each other, represent a hydrogen atom or a group selected from Ci-C 3 -alkyl, 2,2,2-trifluoroethyl, C 3 -C 4 -cycloalkyl, (Ci-C 2 -alkoxy)-(Ci-C 3 -alkyl)- and (C 3 -C 4 -cycloalkyl)-(methyl)-,
  • R 11 and R 1a together with the nitrogen atom they are attached to, represent a 4- to 6- membered heterocycloalkyi group, said group being optionally substituted one or two times with a fluorine atom or a trifluoromethyl group;
  • R 12 represents a group selected from Ci-C2-fluoroalkyl, C 3 -C4-cycloalkyl, (1-trifluoromethyl)- (cyclopropyl)- and (cyclopropyl)-(methyl)-;
  • R 14 and R 14a independently from each other, represent a group selected from methyl and ethyl
  • R 14 and R 14a together with the nitrogen atom they are attached to, represent a 5- to 6- membered heterocycloalkyi group selected from pyrrolidinyl, piperidinyl and morpholinyl;
  • R 16 represents a hydrogen atom or a methyl group
  • the present invention covers compounds of general formula (I), supra, in which:
  • R 1 represents a group selected from
  • said (C3-C5-cycloalkyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom, a chlorine atom or with a methyl group;
  • R 6 and R 7 represents a group selected from Ci-C3-alkyl, difluoromethyl, trifluoromethyl, (methoxy)-(methyl)-, cyclopropyl, 2-oxa-6-azaspiro[3.3]heptyl-, -NR 11 R 11a , C1-C3- alkoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, (C3-C 4 -cycloalkyl)-(methoxy)- and [1 - (trifluoromethyl)cyclopropyl]-(methoxy)-;
  • R 9 represents a methyl group
  • R and R 11a independently from each other, represent a hydrogen atom or a group selected from Ci-C 3 -alkyl, 2,2,2-trifluoroethyl, C 3 -C4-cycloalkyl, (Ci-C 2 -alkoxy)-(Ci-C 3 -alkyl)- and (C3-C4-cycloalkyl)-(methyl)-,
  • R 11 and R 11a together with the nitrogen atom they are attached to, represent a 4- to 6- membered heterocycloaikyi group, said group being optionally substituted one or two times with a fluorine atom or a trifluoromethyl group;
  • R 12 represents a group selected from Ci-C2-fluoroalkyl, C3-C 4 -cycloalkyl, (1 -trifluoromethyl)- (cyclopropyl)- and (cyclopropyl)-(methyl)-;
  • R 14 and R 14a independently from each other, represent a group selected from methyl and ethyl
  • R 14 and R 14a together with the nitrogen atom they are attached to, represent a 5- to 6- membered heterocycloaikyi group selected from pyrrolidinyl, piperidinyl and morpholinyl;
  • R 16 represents a hydrogen atom or a methyl group
  • R 1 represents a group selected from
  • Ci-C3-alkyl represents a group selected from Ci-C3-alkyl, trifluoromethyl, cyclopropyl,Ci-C3-alkoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy and (cyclopropyl)-(methoxy)-;
  • R 12 represents a group selected from Ci-C 2 -fluoroalkyl, C 3 -C 4 -cycloalkyl and (cyclopropyl)- (methyl)-;
  • R 14 and R 14a independently from each other, represent a group selected from methyl and ethyl
  • R 14 and R 1 a together with the nitrogen atom they are attached to, represent a 5- to 6- membered heterocycloalkyl group selected from pyrrolidinyl, piperidinyl and morpholinyl, said group being optionally substituted once with a group selected from methyl, methoxy and (methoxy)-(methyl)-;
  • R 15 represents a group selected from ethyl, 3,3,3-trifluoropropyl, (3-methoxy)-(propyl)-, (2'- methoxy)-(2-ethoxy)-(ethyl)-, cyclopropyl, cyclohexyl and tetrahydropyranyl, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
  • R 1 represents a group selected from
  • the ring of said group being, besides R 6 , optionally substituted further one or two times, differently or identically, with a R 7 group;
  • R 3 represents a hydrogen atom, a fluorine atom or a chlorine atom,
  • R 4 represents a hydrogen atom
  • R 5 represents a hydrogen atom
  • R 6 represents a group selected from methyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, (cyclopropyl)-(methyl)-, (2,2-difluorocyclopropyl)-(methyl)-, (2,2-dichlorocyclopropyl)-
  • R 7 represents a group selected from Ci-C3-alkyl, trifluoromethyl, (methoxy)-(methyl)-, cyclopropyl,
  • R 9 represents a hydrogen atom or a methyl group
  • R 1 and R 11a independently from each other, represent a hydrogen atom or a group selected from Ci-C 3 -alkyl, 2,2,2-trifluoroethyl, C 3 -C 4 -cycloalkyl, (Ci-C 2 -alkoxy)-(Ci-C 3 -alkyl)- and
  • R 11 and R 11a together with the nitrogen atom they are attached to, represent a 4- to 6- membered heterocycloalkyi group, said group being optionally substituted one or two times with a fluorine atom or a trifluoromethyl group;
  • R 12 represents a group selected from Ci-C2-fluoroalkyl, C3-C4-cycloalkyl, 2-hydroxyprop-2- yl, (2-methoxy)-(prop-2-yl)-, (l -trifluoromethyl)-(cyclopropyl)- , 2,2-difluorocyclopropyl, 2,2-difluoro-1 -methylcyclopropyl and (cyclopropyl)-(methyl)-,
  • the present invention covers compounds of general formula (I), supra, in which:
  • R 1 represents a group selected from
  • the ring of said group being, besides R 6 , optionally substituted further one or two times, differently or identically, with a R 7 group;
  • R 3 represents a hydrogen atom, a fluorine atom or a chlorine atom,
  • R 4 represents a hydrogen atom
  • R 5 represents a hydrogen atom
  • R 6 represents a group selected from methyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, (cyclopropyl)-(methyl)-, (2,2-difluorocyclopropy!)-(methyl)-, (2,2-dichlorocyclopropyl)- (methyl)-, (2,2-dimethylcyclopropyl)-(methyl)-, (2-methylcyclopropyl)-(methyl)-, (1 - methylcyclopropyl)-(methyl)-, (l -chlorocyclopropyl)-(methyl)-, (cyclobutyl)-(methyl)-, 3,3-difluorocyclobutyl-(methyl)- and (cyclopentyl)-methyl)-; R 7 represents a group selected from Ci-C3-alkyl, trifluoromethyl, (methoxy)-(methyl)-, cyclopropyl,
  • R 9 represents a methyl group
  • R 11 and R 11a independently from each other, represent a hydrogen atom or a group selected from Ci-C 3 -alkyl, 2,2,2-trifluoroethyl, C 3 -C 4 -cycloalkyl, (Ci-C 2 -alkoxy)-(Ci-C 3 -alkyl)- and (C 3 -C 4 -cycloalkyl)-(methyl)-,
  • R 11 and R 11a together with the nitrogen atom they are attached to, represent a 4- to 6- membered heterocycloalkyl group, said group being optionally substituted one or two times with a fluorine atom or a trifluoromethyl group;
  • R 12 represents a group selected from Ci-C2-fluoroalkyl, C 3 -C4-cycloalkyl, 2-hydroxyprop-2- yl, (2-methoxy)-(prop-2-yl)-, (l-trifluoromethyl)-(cyclopropyl)- , 2,2-difluorocyclopropyl, 2,2-difluoro-1 -methylcyclopropyl and (cyclopropyl)-(methyl)-,
  • the present invention covers compounds of general formula (I), supra, in which:
  • R 1 represents a group selected from
  • the ring of said group being, besides R 6 , optionally substituted further one or two times, differently or identically, with a R 7 group;
  • R 3 represents a hydrogen atom, a fluorine atom or a chlorine atom,
  • R 4 represents a hydrogen atom
  • R 5 represents a hydrogen atom
  • R 6 represents a group selected from methyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, (cyclopropyl)-(methyl)-, (2,2-difluorocyclopropyl)-(methyl)-, (2,2-dichlorocyclopropyl)- (methyl)-, (2,2-dimethylcyclopropyl)-(methyl)-, (2-methylcyclopropyl)-(methyl)-, (1- methylcyclopropyl)-(methyl)-, (l-chlorocyclopropyl)-(methyl)-, (cyclobutyl)-(methyl)-, 3,3-difluorocyclobutyl-(methyl)- and (cyclopentyl)-methyl)-;
  • R 7 represents a group selected from Ci-C3-alkyl, trifluoromethyl, (methoxy)-(methyl)-, cyclopropyl,
  • R 9 represents a hydrogen atom or a methyl group
  • R 11 and R 11a independently from each other, represent a hydrogen atom or a group selected from Ci-C 3 -alkyl, 2,2,2-trifluoroethyl, C 3 -C 4 -cycloalkyl, (Ci-C 2 -alkoxy)-(Ci-C 3 -alkyl)- and (C 3 -C4-cycloalkyl)-(methyl)-,
  • R 11 and R 11a together with the nitrogen atom they are attached to, represent a 4- to 6- membered heterocycloalkyl group, said group being optionally substituted one or two times with a fluorine atom or a trifluoromethyl group;
  • R 12 represents a group selected from Ci-C2-fluoroalkyl, C 3 -C4-cycloalkyl, 2-hydroxyprop-2- yl, (2-methoxy)-(prop-2-yl)-, (l-trifluoromethyl)-(cyclopropyl)- , 2,2-difluorocyclopropyl, 2,2-difluoro-1 -methylcyclopropyl and (cyclopropyl)-(methyl)-,
  • the present invention covers compounds of general formula (I), supra, in which:
  • R 1 represents a group selected from in which " * " represents the point of attachment to the rest of the molecule
  • the ring of said group being, besides R 6 , optionally substituted further one or two times, differently or identically, with a R 7 group;
  • R 3 represents a hydrogen atom, a fluorine atom or a chlorine atom,
  • R 4 represents a hydrogen atom
  • R 5 represents a hydrogen atom
  • R 6 represents a group selected from methyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, (cyclopropyl)-(methyl)-, (2,2-difluorocyclopropyl)-(methyl)-, (2,2-dichlorocyclopropyl)- (methyl)-, (2,2-dimethylcyclopropyl)-(methyl)-, (2-methylcyclopropyl)-(methyl)-, (1 - methylcyclopropyl)-(methyl)-, (l-chlorocyclopropyl)-(methyl)-, (cyclobutyl)-(methyl)-, 3,3-difluorocyclobutyl-(methyl)- and (cyclopentyl)-methyl)-;
  • R 7 represents a group selected from Ci-C3-alkyl, trifluoromethyl, (methoxy)-(methyl)-, cyclopropyl,
  • R 9 represents a methyl group
  • R 11 and R 11a independently from each other, represent a hydrogen atom or a group selected from CrC 3 -alkyl, 2,2,2-trifluoroethyl, C 3 -C 4 -cycloalkyl, (Ci-C 2 -alkoxy)-(CrC 3 -alkyl)- and (C 3 -C4-cycloalkyl)-(methyl)-,
  • R 11 and R 11a together with the nitrogen atom they are attached to, represent a 4- to 6- membered heterocycloalkyi group, said group being optionally substituted one or two times with a fluorine atom or a trifluoromethyl group;
  • R 12 represents a group selected from Ci-C2-fluoroalkyl, C3-C 4 -cycloalkyl, 2-hydroxyprop-2- yl, (2-methoxy)-(prop-2-yl)-, ( -trifluoromethyl)-(cyclopropyl)- , 2,2-difluorocyclopropyl, 2,2-difluoro-1 -methylcyclopropyl and (cyclopropyl)-(methyl)-, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
  • the present invention covers compounds of general formula (I), supra, in which:
  • R 1 represents a group selected from
  • R 3 represents a hydrogen atom, a fluorine atom or a chlorine atom,
  • R 4 represents a hydrogen atom
  • R 5 represents a hydrogen atom
  • R 6 represents a group selected from methyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, (cyclopropyl)-(methyl)-, (2,2-difluorocyclopropyl)-(methyl)-, (2,2-dichlorocyclopropyl)- (methyl)-, (2,2-dimethylcyclopropyl)-(methyl)-, (2-methylcyclopropyl)-(methyl)-, (1- methylcyclopropyl)-(methyl)-, (l-chlorocyclopropyl)-(methyl)-, (cyclobutyl)-(methyl)-, 3,3-difluorocyclobutyl-(methyl)- and (cyclopentyl)-methyl)-;
  • R 7 represents a group selected from Ci-C3-alkyl, (methoxy)-(methyl)-, cyclopropyl, -NR 11 R 11a , Ci-C 3 -alkoxy and (C 3 -C 4 -cycloalkyl)-(methoxy)-;
  • R 9 represents a hydrogen atom or a methyl group
  • R 11 and R 11a independently from each other, represent a hydrogen atom or a group selected from Ci-C 3 -alkyl, 2,2,2-trifluoroethyl, Cs-C-t-cycloalkyl, (Ci-C 2 -alkoxy)-(Ci-C 3 -alkyl)- and (C 3 -C 4 -cycloalkyl )-(methyl )-,
  • R 11 and R 11a together with the nitrogen atom they are attached to, represent a 4- to 6- membered heterocycloalkyl group, said group being optionally substituted one or two times with a fluorine atom;
  • R 2 represents a group selected from Ci-C 2 -fluoroalkyl, C3-C 4 -cycloalkyl, (1 -trifluoromethyl)- (cyclopropyl)- and (cyclopropyl)-(methyl)-,
  • R 1 represents a group selected from
  • R 6 represents a hydrogen atom
  • R 6 represents a group selected from methyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, (cyclopropyl)-(methyl)-, (2,2-difluorocyclopropyl)-(methyl)-, (2,2-dichlorocyclopropyl)- (methyl)-, (2,2-dimethylcyclopropyl)-(methyl)-, (2-methylcyclopropyl)-(methyl)-, (1 - methylcyclopropyl)-(methyl)-, (l-chlorocyclopropyl)-(methyl)-, (cyclobutyl)-(methyl)-, 3,3-difluorocyclobutyl-(methyl)- and (cyc!opentyl)-methyl)-;
  • R 7 represents a group selected from Ci-C3-alkyl, (methoxy)-(methyl)-, cyclopropyl, - NR 11 R 1 a , Ci-C 3 -alkoxy and (C 3 -C 4 -cycloalkyl)-(methoxy)-;
  • R 9 represents a hydrogen atom or a methyl group
  • R 11 and R 11a independently from each other, represent a hydrogen atom or a group selected from Ci-C 3 -alkyl, 2,2,2-trifluoroethyl, C 3 -C 4 -cycloalkyl, (Ci-C 2 -alkoxy)-(Ci-C 3 -alkyl)- and (C 3 -C 4 -cycloalkyl)-(methyl)-,
  • R 11 and R 11a together with the nitrogen atom they are attached to, represent a 4- to 6- membered heterocycloalkyl group, said group being optionally substituted one or two times with a fluorine atom;
  • R 12 represents a group selected from Ci-C 2 -fluoroalkyl, C 3 -C4-cycloalkyl, (1-trifluoromethyl)- (cyclopropyl)- and (cyclopropyl)-(methyl)-,
  • the present invention covers compounds of general formula (I), supra, in which:
  • R 1 represents a group selected from
  • the ring of said group being, besides R 6 , optionally substituted further one or two times, differently or identically, with a R 7 group;
  • R 3 represents a hydrogen atom, a fluorine atom or a chlorine atom,
  • R 4 represents a hydrogen atom
  • R 5 represents a hydrogen atom
  • R 6 represents a group selected from methyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, (cyclopropyl)-(methyl)-, (2,2-difluorocyclopropyl)-(methyl)-, (2,2-dichlorocyclopropyl)- (methyl)-, (2,2-dimethylcyclopropyl)-(methyl)-, (2-methylcyclopropyl)-(methyl)-, (1- methylcyclopropyl)-(methyl)-, (l-chlorocyclopropyl)-(methyl)-, (cyclobutyl)-(methyl)-, 3,3-difluorocyclobutyl-(methyl)- and (cyclopentyl)-methyl)-;
  • R 7 represents a group selected from Ci-C3-alkyl, (methoxy)-(methyl)-, cyclopropyl, - NR 11 R 11a , Ci-C 3 -alkoxy and (C 3 -C 4 -cycloalkyl)-(methoxy)-;
  • R 9 represents a methyl group
  • R 11 and R 11a independently from each other, represent a hydrogen atom or a group selected from Ci-C 3 -alkyl, 2,2,2-trifluoroethyl, C 3 -C 4 -cycloalkyl, (Ci-C 2 -alkoxy)-(Ci-C 3 -alkyl)- and (C 3 -C 4 -cycloalkyl )-(methyl )-,
  • R 11 and R 11a together with the nitrogen atom they are attached to, represent a 4- to 6- membered heterocycloalkyi group, said group being optionally substituted one or two times with a fluorine atom;
  • R 12 represents a group selected from Ci-C 2 -fluoroalkyl, C 3 -C4-cycloalkyl, (1 -trifluoromethyl)- (cyclopropyl)- and (cyclopropyl)-(methyl)-,
  • the present invention covers compounds of general formula (I), supra, in which:
  • R 1 represents a group selected from
  • the ring of said group being, besides R 6 , optionally substituted further one or two times, differently or identically, with a R 7 group;
  • R 3 represents a hydrogen atom, a fluorine atom or a chlorine atom,
  • R 4 represents a hydrogen atom
  • R 5 represents a hydrogen atom
  • R 6 represents a group selected from methyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, (cyclopropyl)-(methyl)-, (2,2-difluorocyclopropyl)-(methyl)-, (2,2-dichlorocyclopropyl)-
  • R 7 represents a group selected from Ci-C 3 -alkyl, (methoxy)-(methyl)-, cyclopropyl, - NR 11 R 11a , Ci-C 3 -alkoxy and (C 3 -C 4 -cycloalkyl)-(methoxy)-;
  • R 9 represents a methyl group
  • R 11 and R 11a independently from each other, represent a hydrogen atom or a group selected from Ci-C 3 -alkyl, 2,2,2-trifluoroethyl, C 3 -C 4 -cycloalkyl, (Ci-C2-alkoxy)-(Ci-C 3 -alkyl)- and (C 3 -C 4 -cycloalkyl)-(methyl)-,
  • R 11 and R 1 a together with the nitrogen atom they are attached to, represent a 4- to 6- membered heterocycioalkyi group, said group being optionally substituted one or two times with a fluorine atom;
  • R 12 represents a group selected from Ci-C2-fluoroalkyl, C3-C4-cycloalkyl, (1-trifluoromethyl)- (cyclopropyl)- and (cyclopropyl)-(methyl)-,
  • the present invention covers compounds of general formula (I), supra, in which:
  • R 2 represents a group
  • R 3 represents a hydrogen atom
  • R 4 represents a hydrogen atom
  • R 5 represents a hydrogen atom
  • R 6 represents a group selected from methyl, ethyl, 2,2,2-trifluoroethyl, (cyclopropyl)- (methyl)- and (2,2-difluorocyclopropyl)-(methyl)-;
  • R 7 represents a group selected from methyl, trifluoromethyl, cyclopropyl, methoxy, ethoxy, iso-propoxy, 2,2,2-trifluoroethoxy and (cyclopropyl)-(methoxy)-;
  • R 9 represents a hydrogen atom or a methyl group
  • R 12 represents a group selected from Ci-C2-fluoroalkyl, C3-C4-cycloalkyl and (cyclopropyl)- (methyl)-;
  • the present invention covers compounds of general formula (I), supra, in which:
  • R 1 represents a group selected from
  • R 2 represents a group
  • R 3 represents a hydrogen atom
  • R 4 represents a hydrogen atom
  • R 5 represents a hydrogen atom
  • R 6 represents a group selected from methyl, ethyl, 2,2,2-trifluoroethyl, (cyclopropyl)- (methyl)- and (2,2-difluorocyclopropyl)-(methyl)-;
  • R 7 represents a group selected from methyl, trifluoromethyl, cyclopropyl, methoxy, ethoxy, iso-propoxy, 2,2,2-trifluoroethoxy and (cyclopropyl)-(methoxy)-;
  • R 9 represents a methyl group
  • R 12 represents a group selected from Ci-C 2 -fluoroalkyl, C 3 -C 4 -cycloalkyl and (cyclopropyl)- (methyl)-;
  • the present invention covers compounds of general formula (I), supra, in which:
  • R 1 represents a group selected from
  • the ring of said group being, besides R 6 , optionally substituted further one or two times, differently or identically, with a R 7 group;
  • R 3 represents a hydrogen atom
  • R 4 represents a hydrogen atom
  • R 5 represents a hydrogen atom
  • R 6 represents a group selected from methyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, (cyclopropyl)-(methyl)-, (2,2-difluorocyclopropyl)-(methyl)-, (2,2-dichlorocyclopropyl)- (methyl)-, (2,2-dimethylcyclopropyl)-(methyl)-, (2-methylcyclopropyl)-(methyl)-, (1 - methylcyclopropyl)-(methyl)-, (1 -chlorocyclopropyl)-(methyl)-, (cyclobutyl)-(methyl)-, 3,3-difluorocyclobutyl-(methyl)- and (cyclopentyl)-methyl)-;
  • R 7 represents a group selected from methyl, trifluoromethyl, (methoxy)-(methyl)-, ethylamino, isopropylamino, (cyclopropyl)-(methyl)-amino-, cyclopropylamino, cyclobutylamino, dimethylamino, azetidin-1 -yl, 3,3-difluoroazetidin-1 -yl, 3- trifluoromethylazetidin-1 -yl, pyrrolidin-1 -yl, piperidin-1-yl, morpholinyl, methoxy, ethoxy, iso-propoxy, 2,2,2-trifluoroethoxy, 2,2-difluoropropoxy and (cyclopropyl)-(methoxy)-;
  • R 9 represents a hydrogen atom or a methyl group
  • R 12 represents a group selected from 2,2,2-trifluoroethyl, cyclopropyl, (1 -trifluoromethyl)- (cyclopropyl)-, 2,2-difluorocyclopropyl and 2,2-difluoro-1-methylcyclopropyl, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
  • the present invention covers compounds of general formula (I), supra, in which:
  • R 1 represents a group selected from
  • the ring of said group being, besides R 6 , optionally substituted further one or two times, differently or identically, with a R 7 group;
  • R 3 represents a hydrogen atom
  • R 4 represents a hydrogen atom
  • R 5 represents a hydrogen atom
  • R 6 represents a group selected from methyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, (cyclopropyl)-(methyl)-, (2,2-difluorocyclopropyl)-(methyl)-, (2,2-dichlorocyclopropyl)- (methyl)-, (2,2-dimethylcyclopropyl)-(methyl)-, (2-methylcyclopropyl)-(methyl)-, (1 - methylcyclopropyl)-(methyl)-, (l-chlorocyclopropyl)-(methyl)-, (cyclobutyl)-(methyl)-, 3,3-difluorocyclobutyl-(methyl)- and (cyclopentyl)-methyl)-;
  • R 7 represents a group selected from methyl, trifluoromethyl, (methoxy)-(methyl)-, ethylamino, isopropylamino, (cyclopropyl)-(methyl)-amino-, cyclopropylamino, cyclobutylamino, dimethylamino, azetidin-1 -yl, 3,3-difluoroazetidin-1 -yl, 3- trifluoromethylazetidin-1 -yl, pyrrolidin-1 -yl, piperidin-1 -yl, morpholinyl, methoxy, ethoxy, iso-propoxy, 2,2,2-trifluoroethoxy, 2,2-difluoropropoxy and (cyclopropyl)-(methoxy)-;
  • R 9 represents a methyl group
  • R 12 represents a group selected from 2,2,2-trifluoroethyl, cyclopropyl, (1 -trifluoromethyl)- (cyclopropyl)-, 2,2-difluorocyclopropyl and 2,2-difluoro-1 -methylcyclopropyl, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
  • R 1 represents a group selected from
  • the ring of said group being, besides R 6 , optionally substituted further one or two times, differently or identically, with a R 7 group;
  • R 3 represents a hydrogen atom
  • R 4 represents a hydrogen atom
  • R 5 represents a hydrogen atom
  • R 6 represents a group selected from methyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, (cyclopropyl)-(methyl)-, (2,2-difluorocyclopropyl)-(methyl)-, (2,2-dichlorocyclopropyl)- (methyl)-, (2,2-dimethylcyclopropyl)-(methyl)-, (2-methylcyclopropyl)-(methyl)-, (1- methylcyclopropyl)-(methyl)-, (l-chlorocyclopropyl)-(methyl)-, (cyclobutyl)-(methyl)-, 3,3-difluorocyclobutyl-(methyl)- and (cyclopentyl)-methyl)-;
  • R 7 represents a group selected from methyl, trifluoromethyl, (methoxy)-(methyl)-, ethylamino, isopropylamino, (cyclopropyl)-(methyl)-amino-, cyclopropylamino, cyclobutylamino, dimethylamino, azetidin-1 -yl, 3,3-dif)uoroazetidin-1 -yl, pyrrolidin-1-yl, piperidin-1-yl, morpholinyl, methoxy, ethoxy, iso-propoxy and (cyclopropyl)-(methoxy)-;
  • R 9 represents a hydrogen atom or a methyl group
  • R 12 represents a group selected from 2,2,2-trifluoroethyl, cyclopropyl, (1 -trifluoromefhyl)- (cyclopropyl)-,
  • the present invention covers compounds of general formula (I), supra, in which:
  • R 1 represents a group selected from
  • the ring of said group being, besides R 6 , optionally substituted further one or two times, differently or identically, with a R 7 group;
  • R 7 represents a group selected from methyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, (cyclopropyl)-(methyl)-, (2,2-difluorocyclopropyl)-(methyl)-, (2,2-dichlorocyclopropyl)- (methyl)-, (2,2-dimethylcyclopropyl)-(methyl)-, (2-methylcyclopropyl)-(methyl)-, (1- methylcyclopropyl)-(methyl)-, (l-chlorocyclopropyl)-(methyl)-, (cyclobutyl)-(methyl)-, 3,3-difluorocyclobutyl-(methyl)- and (cyclopentyl)-methyl)-; R 7 represents a group selected from methyl, trifluoromethyl, (methoxy)-(methyl)-, ethylamino, isopropylamino, (cyclopropyl
  • R 12 represents a group selected from 2,2,2-trifluoroethyl, cyclopropyl, (1 -trifluoromethyl)- (cyclopropyl)-,
  • the present invention covers compounds of general formula (I), supra, in which:
  • R 1 represents a group selected from
  • R 2 represents a group
  • R 3 represents a hydrogen atom
  • R 4 represents a hydrogen atom
  • R 5 represents a hydrogen atom
  • R 6 represents a group selected from methyl, ethyl, 2,2,2-trifluoroethyl, (cyclopropyl)- (methyl)- and (2,2-difluorocyclopropyl)-(methyl)-;
  • R 7 represents a group selected from methyl, trifluoromethyl, methoxy, ethoxy, iso-propoxy and (cyclopropyl)-(methoxy)-;
  • R 9 represents a hydrogen atom or a methyl group
  • R 12 represents a group selected from 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl and (cyclopropyl)-(methyl)-;
  • R 1 represents a group selected from
  • R 2 represents a group
  • R 3 represents a hydrogen atom
  • R 4 represents a hydrogen atom
  • R 5 represents a hydrogen atom
  • R 6 represents a group selected from methyl, ethyl, 2,2,2-trifluoroethyl, (cyclopropyl )- (methyl)- and (2,2-difluorocyclopropyl)-(methyl)-;
  • R 7 represents a group selected from methyl, trifluoromethyl, methoxy, ethoxy, iso- propoxy and (cyclopropyl )-(m ethoxy)-;
  • R 9 represents a methyl group;
  • R 12 represents a group selected from 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl and (cyclopropyl)-(methyl)-;
  • R 1 represents a group
  • R 3 represents a hydrogen atom, a fluorine atom or a chlorine atom
  • R 4 represents a hydrogen atom
  • R 5 represents a hydrogen atom
  • R 6 represents a group selected from methyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, (cyclopropyl)-(methyl)-, (2,2-difluorocyclopropyl)-(methyl)-, (2,2-dichlorocyclopropyl)- (methyl)-, (2,2-dimethylcyclopropyl)-(methyl)-, (2-methylcyclopropyl)-(methyl)-, (1 - methylcyclopropyl)-(methyl)-, (l-chlorocyclopropyl)-(methyl)-, (cyclobutyl)-(methyl)-, 3,3-difluorocyclobutyl-(methyl)- and (cyclopentyl)-methyl)-;
  • R 9 represents a methyl group
  • R 12 represents a group selected from 2,2,2-trifluoroethyl, cyclopropyl, (1 -trifluoromethyl)- (cyclopropyl)-, cyclobutyl and (cyclopropyl)-(methyl)-,
  • the present invention covers compounds of general formula (I), supra, in which:
  • R 1 represents a group
  • R 3 represents a hydrogen atom, a fluorine atom or a chlorine atom
  • R 4 represents a hydrogen atom
  • R 5 represents a hydrogen atom
  • R 6 represents a group selected from methyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, (cyclopropyl)-(methyl)-, (2,2-difluorocyclopropyl)-(methyl)-, (2,2-dichlorocyclopropyl)- (methy!)-, (2,2-dimethylcyclopropyl)-(methyl)-, (2-methylcyclopropyl)-(methyl)-, (1- methylcyclopropyl)-(methyl)-, (l-chlorocyclopropyl)-(methyl)-, (cyclobutyl)-(methyl)-, 3,3-difluorocyclobutyl-(methyl)- and (cyclopentyl)-methyl)-;
  • R 9 represents a methyl group
  • R 12 represents a group selected from 2,2,2-trifluoroethyl, cyclopropyl, (1 -trifluoromethyl)- (cyclopropyl)-, cyclobutyl and (cyclopropyl)-(methyl)-,
  • the present invention covers compounds of general formula (I), supra, in which:
  • R 1 represents a group
  • R 3 represents a hydrogen atom
  • R 4 represents a hydrogen atom
  • R 5 represents a hydrogen atom
  • R 6 represents a group selected from methyl, ethyl, 2,2,2-trifluoroethyl, (cyclopropyl)- (methyl)- and (2,2-difluorocyclopropyl)-(methyl)-;
  • R 9 represents a methyl group
  • R 12 represents a group selected from 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl and (cyclopropyl)-(methyl)-;
  • the present invention covers compounds of general formula (I), supra, in which:
  • R 1 represents a group selected from in which " * " represents the point of attachment to the rest of the molecule
  • R 3 represents a hydrogen atom
  • R 4 represents a hydrogen atom
  • R 5 represents a hydrogen atom
  • R 7 represents a group selected from methyl, (methoxy)-(methyl)-, ethylamino, isopropylamino, (cyclopropyl)-(methyl)-amino-, cyclopropylamino, cyclobutylamino, dimethylamino, azetidin-1 -yl, 3,3-difluoroazetidin-1 -yl, 3-trifluoromethylazetidin-1 -yl, pyrrolidin-1 -yl, piperidin-1 -yl, morpholinyl, methoxy, ethoxy, iso-propoxy, 2,2,2- trifluoroethoxy, 2,2-difluoropropoxy and (cyclopropyl)-(methoxy)-;
  • R 9 represents a methyl group
  • R 12 represents a group selected from 2,2,2-trifluoroethyl, cyclopropyl, (1 -trifluoromethyl)- (cyclopropyl)-, 2,2-difluorocyclopropyl and 2,2-difluoro-1 -methylcyclopropyl, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
  • the present invention covers compounds of general formula (I), supra, in which:
  • R 1 represents a group selected from in which "*" represents the point of attachment to the rest of the molecule
  • R 3 represents a hydrogen atom
  • R 4 represents a hydrogen atom
  • R 5 represents a hydrogen atom
  • R 7 represents a group selected from methyl, (methoxy)-(methyl)-, ethylamino, isopropylamino, (cyclopropyl)-(methyl)-amino-, cyclopropylamino, cyclobutylamino, dimethylamino, azetidin-1-yl, 3,3-difluoroazetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholinyl, methoxy, ethoxy, iso-propoxy and (cyclopropyl)-(methoxy)-;
  • R 9 represents a methyl group

Abstract

The present invention covers heteroarylbenzimidazole compounds of general formula (I) in which R1, R2, R3, R4 and R5 are as defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of hyperproliferative and/or inflammatory disorders, as a sole agent or in combination with other active ingredients.

Description

HETEROARYLBENZIMIDAZOLE COMPOUNDS
The present invention covers heteroarylbenzimidazole compounds of general formula (I) as described and defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds, and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of hyperproliferative and/or inflammatory disorders, as a sole agent or in combination with other active ingredients.
BACKGROUND
The present invention covers heteroarylbenzimidazole compounds of general formula (I) which inhibit Tank-binding kinase 1 (TBK1 ) and/or Ι Β kinase epsilon (ΙΚΚε).
Tank-binding kinase 1 (TBK1 ) and Ι Β kinase epsilon (ΙΚΚε) are two non-canonical Ι Β kinases (IKKs). They play crucial roles in interferon regulatory factor (IRF) and nuclear factor kappaB (NF-KB) signaling cascades. TBK1 and ΙΚΚε share 49% identity and 65% similarity with each other and the kinase domains are 27% identical to IKKa and ΙΚΚβ (Shen RR & Hahn WC (2011 ) Emerging roles for the non-canonical IKKs in cancer. Oncogene 30(6):631-641 ). Both ΙΚΚε and TBK1 are comprised of an N-terminal kinase domain, an ubiquitin-like domain, a C- terminal LZ and a HLH motif (Larabi A, et al. (2013) Crystal structure and mechanism of activation of TANK-binding kinase 1. Cell reports 3(3):734-746). Despite their similarity in structure, TBK1 and ΙΚΚε exhibit differential expression patterns. TBK1 , like IKKa and ΙΚΚβ, is ubiquitously expressed. In contrast, ΙΚΚε expression is restricted to particular tissue compartments, with highest levels detected in lymphoid tissues, peripheral blood lymphocytes and the pancreas. Various epithelial-derived cell lines also exhibit ΙΚΚε expression (reviewed in Shen RR & Hahn WC (2011 ) Emerging roles for the non-canonical IKKs in cancer. Oncogene 30(6):631 -641 ).
TBK1 was originally identified as an IKK-related Serine/Threonine kinase which, in complex with ΙΚΚε, induces the transcription of IFN-I genes as part of the anti-viral innate immune response. Within this pathway, TBK1 resides downstream of Toll-like receptors and has as natural substrates the transcription factors IRF3 and IRF7 which, upon phosphorylation by TBK1 , translocate to the nucleus and trigger IFN-I gene transcription (Han KJ, ei al. (2004) Mechanisms of the TRIF-induced interferon-stimulated response element and NF-kappaB activation and apoptosis pathways. The Journal of biological chemistry 279(15): 15652-15661 ). Although TBK1 and ΙΚΚε are not a part of the classical ΙΚΚα/β/γ signaling complex, these kinases were originally characterized as activators of NF-κΒ and target multiple NF-KB members and effectors. Both IKK-related kinases phosphorylate ΙκΒα at one of the two-serine residues typically targeted on ΙκΒα (Shen RR & Hahn WC (201 1 ) Emerging roles for the non- canonical IKKs in cancer. Oncogene 30(6):631-641 ).
TBK1 and ΙΚΚε have been linked to the pathophysiology of several diseases and represent promising potential targets for drug development as is demonstrated by several drug finding projects, both from academia and from the pharmaceutical industry as reviewed recently by Yu and colleagues (Yu T, et al. (2015) TBK1 inhibitors: a review of patent literature (2011 - 2014). Expert opinion on therapeutic patents: 1 -12).
Recent literature data have provided clear and robust evidence for a role of TBK1 and ΙΚΚε in cancer biology.
ΙΚΚε was found to be amplified in breast cancer lines and breast carcinomas. Subsequent experiments identified ΙΚΚε as a breast cancer oncogene (Boehm JS, ef al. (2007) Integrative genomic approaches identify IKBKE as a breast cancer oncogene. Cell 129(6):1065-1079). Work by other groups further confirmed the role of ΙΚΚε (and TBK1 ) in breast cancer (e.g. Barbie TU, ef al. (2014) Targeting an IKBKE cytokine network impairs triple-negative breast cancer growth. The Journal of clinical investigation 124(12):54 1 -5423, Jiang Z, Liu JC, Chung PE, Egan SE, & Zacksenhaus E (2014) Targeting HER2(+) breast cancer: the TBK1/IKKepsilon axis. Oncoscience 1 (2):180-182) and demonstrated a role in glioma (Guan H, ef al. (201 1 ) IKBKE is over-expressed in glioma and contributes to resistance of glioma cells to apoptosis via activating NF-kappaB. The Journal of pathology 223(3):436-445).
TBK1 is up-regulated under hypoxic conditions and was shown to behave as a pro-angiogenic factor (Korherr C, ef al. (2006) Identification of proangiogenic genes and pathways by high- throughput functional genomics: TBK1 and the IRF3 pathway. Proceedings of the National Academy of Sciences of the United States of America 103(11 ):4240-4245). Moreover, TBK1 over-expression in HUVEC cells induces the secretion of pro-angiogenic factors via the activation of IRF3 (Korherr C, ef al. (2006) Identification of proangiogenic genes and pathways by high-throughput functional genomics: TBK1 and the IRF3 pathway. Proceedings of the National Academy of Sciences of the United States of America 103(11 ):4240-4245). In addition, TBK1 has been identified as a key factor linking innate immune signaling to tumor cell survival via the small GTPase and Ras effector RalB (Chien Y, ef al. (2006) RalB GTPase- mediated activation of the IkappaB family kinase TBK1 couples innate immune signaling to tumor cell survival. Cell 127(1 ):157-170).
Apparently, Ras-transformed cancer cells are addicted to TBK1 -induced survival signals, and TBK1 kinase inhibition may therefore constitute a tumor cell-specific approach to cancer treatment. In line with this, TBK1 was shown to be essential for cell lines with activated KRas. This links RalB mediated activation of TBK1 to the generation of specific NF-KB-regulated survival signals downstream of oncogenic KRas (Barbie DA, et al. (2009) Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature 462(7269): 108-1 12). Moreover, it was shown that an autocrine circuit between KRAs via ΤΒΚ1/ΙΚΚε to CCL5 and IL-6 secretion could be responsible for an autostimulatory growth stimulus of tumor cells. This was shown for lung adenocarcinomas, especially for non-small cell lung cancers (NSCLC) (Zhu Z, et al. (2014) Inhibition of KRAS-driven tumorigenicity by interruption of an autocrine cytokine circuit. Cancer discovery 4(4):452-465). Besides its role in cancer, TBK1 has been proposed as a target for the treatment of autoimmune diseases, inflammation and other diseases. TBK1 is involved in regulating rheumatoid synovitis and also acts as a key regulator in neuroinflammation, microvascular inflammation and gastritis. Additional potential indications include obesity and type 2 diabetes. TBK1 signaling has also been shown to be involved in mediating normal tension glaucoma, familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia diseases. In the field of cancer, there are an increasing number of reports demonstrating that TBK1 mediates cell apoptosis and proliferation in cancer cell lines, especially those that depend on oncogenic KRAS expression. Additionally, it was shown that TBK1 plays a key role in maintaining drug resistance in prostate cancer (PCa) cells by interaction with mammalian target of rapamycin and inhibiting its function, which can induce cell-cycle arrest in PCa cells. Also, several reports have suggested that TBK1 is involved in breast cancer regulation, especially in human HER2- positive breast cancer cells. TBK1 silencing decreased the expression of epithelial markers and increased the expression of mesenchymal markers in ERa (estrogen receptor)-positive breast cancer cells. Furthermore, TBK1 plays a significant role in radiation-induced epithelial— mesenchymal transition. Additionally, TBK1 -dependent mechanism for NF-κΒ signaling pathway contributes to autophagy addiction in K-Ras-driven non-small-cell lung cancer cells (reviewed in Yu T, et al. (2015) TBK1 inhibitors: a review of patent literature (201 1 - 2014). Expert opinion on therapeutic patents: 1 -12).
Prior art
Various inhibitors of TBK1 and / or ΙΚΚε derived from chemotypes different from the compounds of the present invention have been described in patent applications and scientific publications as listed below:
WO 2010127754 discloses 3-([1 ,2>3]-triazol-4-yl-pyrrolo[2.3-b]pyridine derivatives as inhibitors of PDK1 , IKKe and TBK 1.
WO 201 1046970 discloses amino-pyrimidine compounds as inhibitors of TBK1 and/or ΙΚΚε.
WO 2012010826 discloses pyrimidine compounds as inhibitors of TBK1 and/or ΙΚΚε.
WO 2012104007 discloses 7-azaindole derivatives as inhibitors or PDK1 , ΙΚΚε,ΤΒ 1 and TGF-beta..
WO 2012161877 discloses pyridine and pyrazine derivatives as inhibitors of TBK1 and ΙΚΚε.
WO 2012161879 discloses thiazole derivatives as inhibitors of TBK1 and ΙΚΚε.
E. G. Mclver et al., Bioorg. Med. Chem. Lett. 2012, 22, 7169-7173, disclose pyrimidine derivatives as inhibitors of TBK1 and ΙΚΚε.
T. Wang et al., Bioorg. Med. Chem. Lett. 2012, 22, 2063-2069, disclose azabenzimidazole derivatives as inhibitors of TBK1 and ΙΚΚε.
CN 103251600 discloses a 2-amino-4-(3'-cyano-4'-pyrrolidyl)phenyl pyrimidine compound inter alia as inhibitor of TBK-1.
WO 2013024282 discloses an inhibitor of one or both of TBK1 and ΙΚΚε, or a down-regulator of the expression of one or both TBK1 and ΙΚΚε, for use in a method of treating a cancer that is dependent on the PI3kinase pathway, and cites multiple further patent applications and scientific publications disclosing further inhibitors of TBK1 and ΙΚΚε.
WO 2013034238 discloses benzonitrile derivatives as inhibitors of TBK1 and ΙΚΚε.
WO 2013075785 discloses 3-cyanaryl-1 H-pyrazolo[2.3-b]pyridine derivatives as inhibitors of TBK1 and ΙΚΚε.
WO 20 3117285 discloses furo-[3,2b] and thieno-[3.2-b]pyridine derivatives as inhibitors of TBK1 and ΙΚΚε.
WO 2014004863 discloses heteroaromatic compounds as inhibitors of TBK1 and/or ΙΚΚε.
J. W. Johannes et al., Bioorg. Med. Chem. Lett. 2014, 24, 1138-1143, disclose 6-aryl- azabenzimidazole derivatives as inhibitors of TBK1 and ΙΚΚε.
US 20150344473 discloses fused heteroaromatic compounds as inhibitors of TBK1 and ΙΚΚε.
US 20160289196 discloses pyrazole derivatives as inhibitors of TNIK, TBK1 and/or ΙΚΚε. US 20160297815 discloses 7-azaindole and 4,7-diazaindole derivatives as inhibitors of TBK1 and/or ΙΚΚε.
The subject is also addressed by a recent review article, see T. Yu, Y. Yang, D. Q. Yin, S. Hong, Y.-J. Son, J.-H. Kim and J. Y, Cho, TBK1 inhibitors: a review of patent literature (2011- 2014), Expert Opin. Ther. Patents 2015, 25(1 1 ), 1385-1396.
A number of published patent applications disclose chemical structures showing a certain structural similarity to the compounds of the present invention which however address different mechanisms of biological activity and/or different technical fields:
WO 1998056376 discloses heteroaryl compounds for the modulation of protein tyrosine kinase related signal transduction.
WO 2002076438 discloses ligands of the Flt-1 receptor.
WO 2004058762 discloses inhibitors of Mitogen Activated Protein Kinase-activated Protein Kinase-2 (MK-2).
WO 2004085425 discloses fused azole derivatives as Kinase inhibitors.
WO 2005020921 discloses c-Kit modulators and method of use.
US 2005038023 discloses pyrazole compounds as Protein Kinase inhibitors.
WO 2006099379 discloses benzazole derivatives as beta-Secretase inhibitors.
WO 2007084390 discloses organic compounds as HDAC inhibitors.
WO 2007089512 discloses heterocyclic compounds as activators of Glucokinase.
WO 2007100646 discloses multicyclic compounds as modulators of various protein kinase receptor enzymes, such as Tie-2 and Aurora kinase.
WO 2008057280 discloses multicyclic compounds as modulators of various protein kinase receptors, such as Tie-2 and Aurora kinase.
WO 2010034797 discloses 1 H-benzimidazole-5-carboxamides as anti-inflammatory agents.
WO 20101 15736 discloses heterocyclic compounds as inhibitors of dihydroorotate dehydrogenase.
WO 201 1 161 159 discloses heterocyclic compounds as Kinase inhibitors.
WO 2012068546 discloses heterocycle amines as inhibitors of IRAK-1 and IRAK-4.
WO 2015031564 discloses substituted 1 H-benzo[d]imidazole series compounds as lysine specific demethylase (LSD-1 ) inhibitors. However, the state of the art does not describe the heteroarylbenzimidazole compounds of general formula (I) of the present invention as described and defined herein.
It has now been found, and this constitutes the basis of the present invention, that the compounds of the present invention have surprising and advantageous properties.
In particular, the compounds of the present invention have surprisingly been found to effectively inhibit TBK1 and/or ΙΚΚε and may therefore be used for the treatment or prophylaxis of hyperproliferative and/or inflammatory disorders, such as cancer, for example.
DESCRIPTION of the INVENTION
In accordance with a first aspect, the present invention covers compounds of general formula (I):
Figure imgf000008_0001
(I),
in which :
R1 represents a group selected from
pyrazolyl, imidazolyl, oxadiazolyl, triazolyl, isoxazolyl, thienyl, pyridin-2-yl, pyridin-4-yl, pyrimidinyl, triazinyl and pyrazinyl, said group being optionally substituted with one R6 group, and said group being, additionally, optionally substituted one or two times, differently or identically, with a R7 group,
or
R1 represents a group selected from
Figure imgf000008_0002
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group,
in which "*" represents the point of attachment to the rest of the molecule,
or
R1 represents a group selected from pyridine-3-yl or pyridazin-3-yl, optionally substituted with one R8 group; represents a group selected from
Figure imgf000009_0001
in which "*" represents the point of attachment to the rest of the molecule;
represents a hydrogen atom or a halogen atom or a group selected from Ci-C4-alkyl and Ci-C6-alkoxy;
represents a hydrogen atom or a halogen atom or a group selected from Ci-C4-alkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy and Ci-C4-haloalkoxy;
represents a hydrogen atom or a halogen atom or a group selected from Ci-C4-alkyl, Ci-C4-haloalkyl and C3-Ce-cycloalkyl; R6 represents a hydrogen atom or a group selected from Ci-C6-alkyl, Ci-C6-haloalkyl, Ci- C6-hydroxyalkyl, (Ci-C3-alkoxy)-(Ci-C3-alkyl)-, C3-C6-cycloalkyl and (C3-C6-cycloalkyl)- (Ci-C3-alkyl)-,
said C3-C6-cycloalkyl and said (C3-C6-cycloalkyl)-(Ci-C3-alkyl)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or with a group selected from Ci-C3-alkyl and Ci- C3-haloalkyl;
R7 represents a halogen atom or a group selected from hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-hydroxyalkyl, (Ci-C3-alkoxy)-(Ci-C3-alkyl)-, (Ci-C3-haloalkoxy)-(Ci-C3-alkyl)-, C2-C6-alkenyl, C2-C3-alkynyl, C3-C8-cycloalkyl, C4-C8- cycloalkenyl, (C3-C8-cycloalkyl)-(Ci-C3-alkyl)-, (phenyl)-Ci-C3-alkyl-, 4- to 7-membered heterocycloalkyi, 5- to 7-membered heterocycloalkenyl, heterospirocycloalkyi, phenyl, heteroaryl, -CN, -(CH2)x-N(R11)R11a, -C(=0)R13, -C(=0)-OR13, -C(=0)-N(R11 )R11a, - N(R11)R11a, -N(R>6)-C(=0)-R13, -N(R16)-S(=0)2-R13, -N(R16)-C(=0)-N(R11)R11a, -N(R16)- C(=0)-OR13, Ci-C6-alkoxy, Ci-C6-haloalkoxy, C3-C8-cycloalkoxy-, (C3-C8-cycloalkyl)- (Ci-C3-alkoxy)-, phenyloxy-, heteroaryloxy-, -0-(CH2)x-phenyl, -0-(CH2)x-heteroaryl, -O- C(=0)-R13, -0-C(=0)-N(R11)R 1a, Ci-Ce-alkylsulfanyl, Ci-C6-haloalkylsulfanyl, -S(=0)- R13, -S(=0)2-R13, -S(=0)2-N(R11)R11a and -S(=0)(=NR 7)R13,
said C3-C8-cycloalkyl, said (C3-C8-cycloalkyl)-(Ci-C3-alkyl)- and said (C3-C8- cycloalkyl)-(Ci-C3-alkoxy)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or with a group selected from Ci-C3-alkyl and Ci-C3-haloalkyl,
said 4- to 7-membered heterocycloalkyi, said 5- to 7-membered heterocycloalkenyl and said heterospirocycloalkyi group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or with a group selected from oxo, Ci-C3-alkyl and CrC3- haloalkyl, and
said heteroaryl group and said phenyl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from -CN, Ci-C3-alkyl, trifluoromethyl, Ci-C3-alkoxy and trifluoromethoxy;
or
R6 and R7, or two R7 groups, when being attached to adjacent ring atoms of the group R1 , together form a group selected from:
-(0-CH2-0)-, -(0-(CH2)2-0)-, -(0-(CH2)2)-, -(CH2-0-CH2)-, -(NR16-(CH2)2-0)-, -(NR16-(CH2)3-0)-, -(S-(CH2)2)-, -(0-(CH2)3)-, -((CH2)3)-, -((CH2)4)-, -(0-CH=CH)-, -(S-CH=CH)-; R8 represents a hydrogen atom or a group selected from methyl, ethyl, methoxy, ethoxy and dimethylamino;
R9 represents a hydrogen atom or a -CN or Ci-C3-alkyl group;
R10 represents a group selected from -C(=0)R12, -C(=0)OR13, -C(=0)N(R14)R14a, -S(=0)2R15, -S(=0)2N(R14)R14a, 5- to 6-membered heteroaryl and phenyl,
said 5- to 6-membered heteroaryl group and said phenyl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from -CN, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy and Ci-
C3-haloalkoxy;
R11 and R11a, independently from each other, represent a hydrogen atom or a group selected from Ci-C4-alkyl, Ci-C4-haloalkyl, Cs-Ce-cycloalkyl, Ci-C6-hydroxyalkyl, (Ci-C3-alkoxy)- (Ci-C3-alkyl)-, (C3-C6-cycloalkyl)-(Ci-C3-alkyl)- and benzyl,
or
R11 and R11a, together with the nitrogen atom they are attached to, represent a 4- to 7- membered heterocycloalkyi group, said group being optionally substituted one or two times, identically or differently, with a halogen atom, or a group selected from hydroxy, oxo, -CN, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy, -C(=0)R18, -C(=0)OR18 and -S(=0)2R18;
R12 represents a hydrogen atom or a group selected from Ci-C6-alkyl, Ci-C6-haloalkyl, Ci- Ce-hydroxyalkyl, (Ci-C3-alkoxy)-(Ci-C3-alkyl)-, C3-C6-cycloalkyl, (C3-C6-cycloalkyl)-(Ci- C3-alkyl)-, C2-C6-alkenyl, C2-C6-alkynyl, 4- to 7-membered heterocycloalkyi, 5- to 7- membered heterocycloalkenyl, 5- to 6-membered heteroaryl and phenyl,
said 5- to 6-membered heteroaryl group and said phenyl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from -CN, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy and Ci- C3-haloalkoxy,
said C3-C6-cycloalkyl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from -CN, Ci-
C3-alkyl and Ci-C3-haloalkyl;
R13 represents a group selected from Ci-C4-alkyl and benzyl;
R 4 and R14a, independently from each other, represent a hydrogen atom or a group selected from Ci-C4-alkyl, Ci-C4-haloalkyl, C3-C6-cycloalkyl and benzyl, or
R14 and R14a, together with the nitrogen atom they are attached to, represent a 4- to 7- membered heterocycloalkyl group, said group being optionally substituted one or two times, identically or differently, with a halogen atom or a group selected from hydroxyl, -CN, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-aikoxy, Ci-C3-haloalkoxy and (Ci-C3-alkoxy)-
(Ci-C3-alkyl)-;
R15 represents a group selected from Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-hydroxyalkyl, (Ci- C3-alkoxy)-(Ci-C6-alkyl)-, (Ci-C3-alkoxy)-(C2-C3-alkoxy)-(Ci-C6-alkyl)-, C3-C6-cycloalkyl, (C3-C6-cycloalkyl)-(Ci-C3-alkyl)-, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl and phenyl,
said 5- to 6-membered heteroaryl group and said phenyl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from -CN, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy and Ci-C3-haloalkoxy;
R16 represents a hydrogen atom or a group selected from Ci-C4-alkyl and benzyl;
R17 represents a hydrogen atom or a group selected from -CN, -C(=0)OR13, Ci-C4-alkyl and benzyl;
R18 represents a Ci-C3-alkyl group;
x represents an integer selected from 1 , 2, 3 and 4,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
DEFINITIONS
The term "substituted" means that one or more hydrogen atoms on the designated atom or group are replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded. Combinations of substituents and/or variables are permissible.
The term "optionally substituted" means that the number of substituents can be equal to or different from zero. Unless otherwise indicated, it is possible that optionally substituted groups are substituted with as many optional substituents as can be accommodated by replacing a hydrogen atom with a non-hydrogen substituent on any available carbon or nitrogen or sulfur atom. Commonly, and if not stated otherwise, it is possible for the number of optional substituents, when present, to be 1 , 2, 3, 4 or 5, in particular 1 , 2 or 3. As used herein, the term "one or more", e.g. in the definition of the substituents of the compounds of general formula (I) of the present invention, means "1 , 2, 3, 4 or 5, particularly 1 , 2, 3 or 4, more particularly 1 , 2 or 3, even more particularly 1 or 2".
Should a composite substituent be composed of more than one parts, e.g. (Ci-C4-alkoxy)-(Ci-C4-alkyl)-, it is possible for the position of a given part to be at any suitable position of said composite substituent, i.e. the Ci-C4-alkoxy part can be attached to any carbon atom of the Ci-C4-alkyl part of said (Ci-C4-alkoxy)-(Ci-C4-alkyl)- group. A hyphen at the beginning or at the end of such a composite substituent indicates the point of attachment of said composite substituent to the rest of the molecule. Should a ring, comprising carbon atoms and optionally one or more heteroatoms, such as nitrogen, oxygen or sulfur atoms for example, be substituted with a substituent, it is possible for said substituent to be bound at any suitable position of said ring, be it bound to a suitable carbon atom and/or to a suitable heteroatom.
The term "comprising" when used in the specification includes "consisting of.
If within the present text any item is referred to as "supra" within the description it is referred to any of the respective disclosures made within the specification in any of the preceding pages, or above on the same page.
If within the present text any item is referred to as "infra" within the description it is referred to any of the respective disclosures made within the specification in any of the subsequent pages, or below on the same page.
If within the present text any item is referred to as "as mentioned herein", it means that it may be mentioned anywhere in the present text.
The terms as mentioned in the present text have the following meanings:
The term "halogen atom" means a fluorine, chlorine, bromine or iodine atom, particularly a fluorine, chlorine or bromine atom.
As used herein, an oxo substituent represents an oxygen atom, which is bound to a carbon atom or to a sulfur atom via a double bond.
The term "Ci-C6-alkyl" means a linear or branched, saturated, monovalent hydrocarbon group having 1 , 2, 3, 4, 5 or 6 carbon atoms, e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, ferf-butyl, pentyl, isopentyl, 2-methylbutyl, 1 -methylbutyl, 1 -ethylpropyl,
1.2- dimethylpropyl, neo-pentyl, 1 , 1 -dimethylpropyl, hexyl, 1 -methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 1 ,1-dimethylbutyl, 2,2-dimethylbutyl,
3.3- dimethylbutyl, 2,3-dimethylbutyl, 1 ,2-dimethylbutyl or 1 ,3-dimethylbutyl group, or an isomer thereof. Particularly, said group has 1 , 2, 3 or 4 carbon atoms ("Ci-C4-alkyl"), e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl isobutyl, or ferf-butyl group, more particularly 1 , 2 or 3 carbon atoms ("Ci-C3-alkyl"), e.g. a methyl, ethyl, n-propyl or isopropyl group.
The term "C2-C6-alkylene" means a linear or branched, saturated, divalent hydrocarbon chain (or "tether") having 2, 3, 4, 5 or 6 carbon atoms, e.g. -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"), "Cs-alkylene", e.g. -CH2-CH2-CH2-CH2-CH2- ("n-pentylene"), or "-C6-alkylene-", e.g. -CH2-CH2-CH2-CH2-CH2-CH2- ("n-hexylene") or -C(CH3)2-C(CH3)2- group. Particularly, said alkylene is a -C(CH3)2-C(CH3)2- group.
The term "Ci-C6-hydroxyalkyl" means a linear or branched, saturated, monovalent hydrocarbon group in which the term "Ci-Ce-alkyl" is defined supra, and in which 1 , 2 or 3 hydrogen atoms are replaced with a hydroxy group, e.g. a hydroxymethyl, 1 -hydroxyethyl, 2-hydroxyethyl, 1 ,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropyl, 1 -hydroxypropan-2-yl, 2-hydroxypropan-2-yl, 2,3-dihydroxypropyl, 1 ,3-dihydroxypropan-2-yl, 3-hydroxy-2-methyl-propyl, 2-hydroxy-2-methyl-propyl, 1-hydroxy-2-methyl-propyl group.
The term "Ci-C6-alkylsulfanyl" means a linear or branched, saturated, monovalent group of formula (Ci-C6-alkyl)-S-, in which the term "Ci-C6-alkyl" is as defined supra, e.g. a methylsulfanyl, ethylsulfanyl, propylsulfanyl, isopropylsulfanyl, butylsulfanyl, sec-butylsulfanyl, isobutylsulfanyl, fert-butylsulfanyl, pentylsulfanyl, isopentylsulfanyl, hexylsulfanyl group.
The term "Ci-Ce-haloalkyl" means a linear or branched, saturated, monovalent hydrocarbon group in which the term "Ci-C6-alkyl" is as defined supra, and in which one or more of the hydrogen atoms are replaced, identically or differently, with a halogen atom. Particularly, said halogen atom is a fluorine atom, to give rise to a "Ci-C6-fluoroalkyl" group, particularly a "Ci-C4-fluoroalkyl" group, more particularly, a "Ci-C3-fluoroalkyl" group. Said Ci-C6-haloalkyl group is, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl,
2.2- difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl or
1.3- difluoropropan-2-yl.
The term "Ci-C6-alkoxy" means a linear or branched, saturated, monovalent group of formula (Ci-C6-alkyl)-0-, in which the term "Ci-C6-alkyl" is as defined supra, e.g. a methoxy, ethoxy, / propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, ferf-butoxy, pentyloxy, isopentyloxy or n-hexyloxy group, or an isomer thereof.
The term "Ci-C6-haloalkoxy" means a linear or branched, saturated, monovalent Ci-C6-alkoxy group, as defined supra, in which one or more of the hydrogen atoms is replaced, identically or differently, with a halogen atom. Particularly, said halogen atom is a fluorine atom to give rise to a "Ci-C6-fluoroalkoxy" group, particularly a "Ci-C4-fluoroalkoxy" group, more particularly, a "Ci-C3-fluoroalkoxy" group. Said Ci-C6-haloalkoxy group is, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy or pentafluoropropoxy.
The term "Ci-C6-haloalkylsulfanyl" means a linear or branched, saturated, monovalent C1-C6- alkylsulfanyl group, as defined supra, in which one or more of the hydrogen atoms is replaced, identically or differently, with a halogen atom. Particularly, said halogen atom is a fluorine atom to give rise to a "Ci-C6-fluoroalkylsulfanyl" group, particularly a "Ci-C4-fluoroalkylsulfanyl" group, more particularly, a "Ci-C3-fluoroalkylsulfanyl" group. Said Ci-C6-haloalkylsulfanyl group is, for example, fluoromethylsulfanyl, difluoromethylsulfanyl, trifluoromethylsulfanyl, 2,2,2-trifluoroethylsulfanyl or pentafluoroethylsulfanyl.
The term "C2-C6-alkenyl" means a linear or branched, monovalent hydrocarbon group, which contains one double bond, and which has 2, 3, 4, 5 or 6 carbon atoms, particularly 2 or 3 carbon atoms ("C2-C3-alkenyl"). Said alkenyl group is, for example, an ethenyl (or "vinyl"), prop-2-en-1 -yl (or "allyl"), prop-1 -en-1 -yl, but-3-enyl, but-2-enyl, but-1-enyl, pent-4-enyl, pent-3-enyl, pent-2-enyl, pent-1-enyl, hex-5-enyl, hex-4-enyl, hex-3-enyl, hex-2-enyl, hex-1 -enyl, prop-1-en-2-yl (or "isopropenyl"), 2-methylprop-2-enyl, 1-methylprop-2-enyl,
2- methylprop-1 -enyl, 1 -methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, 2-methylbut-2-enyl, 1-methylbut-2-enyl,
3- methylbut-1-enyl, 2-methylbut-1-enyl, 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, 3-methylpent-3-enyl,
2- methylpent-3-enyl, 1 -methylpent-3-enyl, 4-methylpent-2-enyl, 3-methylpent-2-enyl, 2-methylpent-2-enyl, 1 -methylpent-2-enyl, 4-methylpent-1 -enyl, 3-methylpent-1 -enyl, 2-methylpent-1-enyl, 1 -methylpent-1-enyl, 3-ethylbut-3-enyl, 2-ethylbut-3-enyl,
1- ethylbut-3-enyl, 3-ethylbut-2-enyl, 2-ethylbut-2-enyl, 1 -ethylbut-2-enyl, 3-ethylbut-1-enyl, 2-ethylbut-1 -enyl, 1 -ethylbut-1 -enyl, 2-propylprop-2-enyl, 1-propylprop-2-enyl,
2- isopropylprop-2-enyl, 1 -isopropylprop-2-enyl, 2-propylprop-1 -enyl, 1-propylprop-1 -enyl, 2-isopropylprop-1-enyl, 1-isopropylprop-1-enyl, 3,3-dimethylprop-1-enyl, 1 -(1 ,1-dimethylethyl)ethenyl group. Particularly, said group is vinyl or allyl.
The term "C2-C6-alkynyl" means a linear or branched, monovalent hydrocarbon group which contains one triple bond, and which contains 2, 3, 4, 5 or 6 carbon atoms, particularly 2 or 3 carbon atoms ("C2-C3-alkynyl"). Said C2-C6-alkynyl group is, for example, ethynyl, prop-1 -ynyl, prop-2-ynyl (or "propargyl"), 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 -methyl- pent-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 "Ca-Ce-cycloalkyl" means a saturated, monovalent, mono- or bicyclic hydrocarbon ring which contains 3, 4, 5, 6, 7 or 8 carbon atoms ("Cs-Ce-cycloalkyl"). Particularly, said group is monocyclic and has 3, 4, 5 or 6 carbon atoms ("C3-C6-cycloalkyl"). Said C3-Ce-cycloalkyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl group, or a bicyclic hydrocarbon ring, e.g. a bicyclo[4.2.0]octyl or octahydropentalenyl.
The term "d-Cs-cycloalkenyl" means a monovalent, mono- or bicyclic hydrocarbon ring which contains 4, 5, 6, 7 or 8 carbon atoms and one double bond. Particularly, said ring contains 4, 5 or 6 carbon atoms ("C4-C6-cycloalkenyl"). Said C4-Ce-cycloalkenyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl or cyclooctenyl group, or a bicyclic hydrocarbon ring, e.g. a bicyclo[2.2.1]hept-2-enyl or bicyclo[2.2.2]oct-2-enyl.
The term "Cs-Ce-cycloalkoxy" means a saturated, monovalent, mono- or bicyclic group of formula (C3-C8-cycloalkyl)-0-, which contains 3, 4, 5, 6, 7 or 8 carbon atoms ("C3-C8-cycloalkyloxy"), in which the term "Cs-Cs-cycloalkyl" is defined supra, e.g. a cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy or cyclooctyloxy group.
The term "spirocycloalkyl" means a saturated, monovalent bicyclic hydrocarbon group in which the two rings share one common ring carbon atom, and wherein said bicyclic hydrocarbon group contains 5, 6, 7, 8, 9, 10 or 1 1 carbon atoms, it being possible for said spirocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms except the spiro carbon atom. Said spirocycloalkyl group is, for example, spiro[2.2]pentyl, spiro[2.3]hexyl, spiro[2.4]heptyl, spiro[2.5]octyl, spiro[2.6]nonyl, spiro[3.3]heptyl, spiro[3.4]octyl, spiro[3.5]nonyl, spiro[3.6]decyl, spiro[4.4]nonyl, spiro[4.5]decyl, spiro[4.6]undecyl or spiro[5.5]undecyl.
The terms "4- to 7-membered heterocycloalkyl" and "4- to 6-membered heterocycloalkyl" mean a monocyclic, saturated heterocycle with 4, 5, 6 or 7 or, respectively, 4, 5 or 6 ring atoms in total, which contains one or two identical or different ring heteroatoms from the series N, O and S, 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.
Said heterocycloalkyl group, without being limited thereto, can be a 4-membered ring, such as azetidinyl, oxetanyl or thietanyl, for example; or a 5-membered ring, such as tetrahydrofuranyl, 1 ,3-dioxolanyl, thiolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1 ,2-oxazolidinyl, 1 ,3-oxazolidinyl or 1 ,3-thiazolidinyl, for example; or a 6-membered ring, such as tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, 1 ,3-dioxanyl, 1 ,4-dioxanyl or 1 ,2-oxazinanyl, for example, or a 7-membered ring, such as azepanyl, 1 ,4-diazepanyl or 1 ,4-oxazepanyl, for example.
Particularly, "4- to 6-membered heterocycloalkyl" means a 4- to 6-membered heterocycloalkyl as defined supra containing one ring nitrogen atom and optionally one further ring heteroatom from the series: N, O, S. More particularly, "5- or 6-membered heterocycloalkyl" means a monocyclic, saturated heterocycle with 5 or 6 ring atoms in total, containing at least one heteroatom from the series: N, O.
The term "5- to 7-membered heterocycloalkenyl" means a monocyclic, unsaturated, non- aromatic heterocycle with 5, 6 or 7 ring atoms in total, which contains one or two double bonds and one or two identical or different ring heteroatoms from the series: N, O, S; it being possible for said heterocycloalkenyl group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, a nitrogen atom.
Said heterocycloalkenyl group is, for example, 4 -/-pyranyl, 2H-pyranyl, 2,5-dihydro-1 - -pyrrolyl, [1 ,3]dioxolyl, 4H-[1 ,3,4]thiadiazinyl, 2,5-dihydrofuranyl, 2,3-dihydrofuranyl, 2,5-dihydrothio- phenyl, 2,3-dihydrothiophenyl, 4,5-dihydrooxazolyl or 4 - -[1 ,4]thiazinyl.
The term "heterospirocycloalkyl" means a bicyclic, saturated heterocycle with 6, 7, 8, 9, 10 or 11 ring atoms in total, in which the two rings share one common ring carbon atom, which "heterospirocycloalkyl" contains one or two identical or different ring heteroatoms from the series: N, O, S; it being possible for said heterospirocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms, except the spiro carbon atom, 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, azaspiro[4,5]decyl, oxazaspiro [5.5]undecyl, diazaspiro[3.3]heptyl, thiazaspiro[3.3]heptyl, thiazaspiro[4.3]octyl, azaspiro[5.5]undecyl, or one of the further homologous scaffolds such as spiro[3.4]-, spiro[4.4]-, spiro[2.4]-, spiro[2.5]-, spiro[2.6]-, spiro[3.5]-, spiro[3.6]-, spiro[4.5]- and spiro[4.6]-.
The term "fused heterocycloalkyl" means a bicyclic, saturated heterocycle with 6, 7, 8, 9 or 10 ring atoms in total, in which the two rings share two adjacent ring atoms, which "fused heterocycloalkyl" contains one or two identical or different ring heteroatoms from the series: N, O, S; it being possible for said fused 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 fused heterocycloalkyl 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 heterocycloalkyi" means a bicyclic, saturated heterocycle with 7, 8, 9 or 10 ring atoms in total, in which the two rings share two common ring atoms which are not adjacent, which "bridged heterocycloalkyi" contains one or two identical or different ring heteroatoms from the series: N, O, S; it being possible for said bridged heterocycloalkyi group to be attached to the rest of the molecule via any one of the carbon atoms, except the spiro carbon atom, or, if present, a nitrogen atom.
Said bridged heterocycloalkyi 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, azabi- cyclo[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, thiaza- bicyclo[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.
The term "heteroaryl" means a monovalent, monocyclic, bicyclic or tricyclic aromatic ring having 5, 6, 8, 9, 10, 1 1 , 12, 13 or 14 ring atoms (a "5- to 14-membered heteroaryl" group), particularly 5, 6, 9 or 10 ring atoms, which contains at least one ring heteroatom and optionally one, two or three further ring heteroatoms from the series: N, O and/or S, and which is bound via a ring carbon atom or optionally via a ring nitrogen atom (if allowed by valency).
Said heteroaryl group can be a 5-membered heteroaryl group, such as, for example, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl or tetrazolyl; or a 6-membered heteroaryl group, such as, for example, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl; or a tricyclic heteroaryl group, such as, for example, carbazolyl, acridinyl or phenazinyl; or a 9-membered heteroaryl group, such as, for example, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzothiazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, indolizinyl or purinyl; or a 10- membered heteroaryl group, such as, for example, quinolinyl, quinazolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinoxalinyl or pteridinyl.
In general, and unless otherwise mentioned, the heteroaryl or heteroarylene groups include all possible isomeric forms thereof, e.g.: tautomers and positional isomers with respect to the point of linkage to the rest of the molecule. Thus, for some illustrative non-restricting examples, the term pyridinyl includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl; or the term thienyl includes thien-2-yl and thien-3-yl.
Particularly, the heteroaryl group is a 5- or 6-membered heteroaryl group. The term "heteroaryloxy" means a monovalent, monocyclic, bicyclic or tricyclic aromatic group of the formula (heteroaryl)-O-, in which the term "heteroaryl" is as defined supra, e.g. thienyloxy, thiazolyloxy, pyridinyloxy, pyrimidinyloxy, benzofuranyloxy, for example.
The term "phenyloxy" means a group of the formula (phenyl)-O.
The term "C-i-Ce", as used in the present text, e.g. in the context of the definition of "Ci-Ce-alkyl", "Ci-C6-haloalkyl", "Ci-C6-hydroxyalkyl", "Ci-C6-alkoxy" or "Ci-C6-haloalkoxy" means 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.
Further, as used herein, the term "C3-C8", as used in the present text, e.g. in the context of the definition of "Cs-Cs-cycloalkyl", means a cycloalkyl group having a finite number of carbon atoms of 3 to 8, i.e. 3, 4, 5, 6, 7 or 8 carbon atoms.
When a range of values is given, said range encompasses each value and sub-range within said range.
For example:
"Ci-Ce" encompasses Ci , C2, C3, C4, C5, Ce, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6;
"C1-C4" encompasses Ci , C2, C3, C4, C1-C4, C1-C3, C1-C2, C2-C4, C2-C3 and C3-C4;
"C1-C3" encompasses Ci , C2, C3, C1-C3, C1-C2 and C2-C3;
"C2-C6" encompasses C2, C3, C4, C5, Ce, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6;
"C3-C10" encompasses C3, C4, C5, Ce, C7, Ce, Cg, C10, C3-C10, C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4, C4-C10, C4-C9, C4-C8, C4-C7, C4-C6, C4-C5, C5-C10, C5-C9, C5-C8, C5-C7, C5-C6, C6-C10, C6-Cg, C6-Ce, C6-C7, C7-C10, C7-C9, C7-C8, Ce-Cio, Ce-Cg and "C3-C8" encompasses C3, C4, C5, C6, C7, Ce, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4, C4-Ce, C4-C7, C4-C6, C4-C5, C5-Ce, C5-C7, C5-C6, Ce-Ce, C6-C7 and C7-C8;
"C3-C6" encompasses C3, C4, C5, C6, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6;
"C4-Ce" encompasses C4, C5, C6, C7, Cs, C4-Ce, C4-C7, C4-C6, C4-C5, Cs-Ce, C5-C7, C5-C6, Ce-Ce, C6-C7 and C7-Ce;
"C4-C7" encompasses C4, C5, C6, C7, C4-C7, C4-C6, C4-C5, C5-C7, C5-C6 and C6-C7;
"C4-C6" encompasses C4, C5, C6, C4-C6, C4-C5 and C5-C6;
"C5-C10" encompasses C5, C6, C7, Ce, Cg, C10, C5-C10, C5-C9, Cs-Ce, C5-C7, C5-C6, C6-C10, Ce- Cg, Ce-Ce, C6-C7, C7-C10, C7-C9, C7-C8, C8-C10, Ce-Cg and C9-C10; "C6-C10" encompasses C6, C7, Ce, Cg, C10, C6-C10, C6-C9, C6-Cs, C6-C7, C7-C10, C7-C9, C7-C8, Ca-Cio, Cs-Cg and Cg-Cio-
As used herein, the term "leaving group" means an atom or a group of atoms that is displaced in a chemical reaction as stable species taking with it the bonding electrons. In particular, such a leaving group is selected from the group comprising: halide, in particular fluoride, chloride, bromide or iodide, (methylsulfonyl)oxy, [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)- sulfonyl]oxy, (phenylsulfonyl)oxy, [(4-methylphenyl)sulfonyl]oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2,4,6-triisopropylphenyl)sulfonyl]oxy, [(2,4,6-trimethylphenyl)sulfonyl]oxy, [(4-ferf-butyl- phenyl)sulfonyl]oxy and [(4-methoxyphenyl)sulfonyl]oxy.
As used herein, the term "protective group" is a protective group attached to an oxygen or nitrogen atom 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 hydroxy or amino group in order to obtain chemoselectivity in a subsequent chemical reaction. Protective groups for hydroxy and amino groups are descibed for example in T.W. Greene and P.G.M. Wuts in Protective Groups in Organic Synthesis, 4th edition, Wiley 2006; more specifically, protective groups for amino 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 ierf.-butoxycarbonyl (Boc). Protective groups for hydroxy groups can be selected from acyl groups such as benzoyl, acetyl, pivaloyl or tetrahydropyranoyl, or can include silicon, as in e.g. tert-butyldimethylsilyl, tert- butyldiphenylsilyl, triethylsilyl or triisopropylsilyl.
It is possible for the compounds of general formula (I) to exist as isotopic variants. The invention therefore includes one or more isotopic variant(s) of the compounds of general formula (I), particularly deuterium-containing compounds of general formula (I).
The term "Isotopic variant" of a compound or a reagent is defined as a compound exhibiting an unnatural proportion of one or more of the isotopes that constitute such a compound.
The term "Isotopic variant of the compound of general formula (I)" is defined as a compound of general formula (I) exhibiting an unnatural proportion of one or more of the isotopes that constitute such a compound.
The expression "unnatural proportion" means a proportion of such isotope which is higher than its natural abundance. The natural abundances of isotopes to be applied in this context are described in "Isotopic Compositions of the Elements 1997", Pure Appl. Chem., 70(1 ), 217-235, 1998. Examples of such isotopes include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2H (deuterium), 3H (tritium), 11C, 13C, i4C, 15N, 170, 180, 32P, 33P, 33S, 34S, 35S, 36S, 18F, 36CI, 82Br, 23l, 124l, 1 5l, 129l and 1311, respectively.
With respect to the treatment and/or prophylaxis of the disorders specified herein the isotopic variant(s) of the compounds of general formula (I) preferably contain deuterium ("deuterium- containing compounds of general formula (I)"). Isotopic variants of the compounds of general formula (I) in which one or more radioactive isotopes, such as 3H or 4C, are incorporated are useful e.g. in drug and/or substrate tissue distribution studies. These isotopes are particularly preferred for the ease of their incorporation and detectability. Positron emitting isotopes such as 18F or 11C may be incorporated into a compound of general formula (I). These isotopic variants of the compounds of general formula (I) are useful for in vivo imaging applications. Deuterium-containing and 13C-containing compounds of general formula (I) can be used in mass spectrometry analyses in the context of preclinical or clinical studies.
Isotopic variants of the compounds of general formula (I) can generally be prepared by methods known to a person skilled in the art, such as those described in the schemes and/or examples herein, by substituting a reagent for an isotopic variant of said reagent, preferably for a deuterium-containing reagent. Depending on the desired sites of deuteration, in some cases deuterium from D2O can be incorporated either directly into the compounds or into reagents that are useful for synthesizing such compounds. Deuterium gas is also a useful reagent for incorporating deuterium into molecules. Catalytic deuteration of olefinic bonds and acetylenic bonds is a rapid route for incorporation of deuterium. Metal catalysts (i.e. Pd, Pt, and Rh) in the presence of deuterium gas can be used to directly exchange deuterium for hydrogen in functional groups containing hydrocarbons. A variety of deuterated reagents and synthetic building blocks are commercially available from companies such as for example C/D/N Isotopes, Quebec, Canada; Cambridge Isotope Laboratories Inc., Andover, MA, USA; and CombiPhos Catalysts, Inc., Princeton, NJ, USA.
The term "deuterium-containing compound of general formula (I)" is defined as a compound of general formula (I), in which one or more hydrogen atom(s) is/are replaced by one or more deuterium atom(s) and in which the abundance of deuterium at each deuterated position of the compound of general formula (I) is higher than the natural abundance of deuterium, which is about 0.015%. Particularly, in a deuterium-containing compound of general formula (I) the abundance of deuterium at each deuterated position of the compound of general formula (I) is higher than 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80%, preferably higher than 90%, 95%, 96% or 97%, even more preferably higher than 98% or 99% at said position(s). It is understood that the abundance of deuterium at each deuterated position is independent of the abundance of deuterium at other deuterated position(s). The selective incorporation of one or more deuterium atom(s) into a compound of general formula (I) may alter the physicochemical properties (such as for example acidity [C. L. Perrin, et al., J. Am. Chem. Soc, 2007, 129, 4490], basicity [C. L. Perrin et al., J. Am. Chem. Soc, 2005, 127, 9641], lipophilicity [B. Testa et al., Int. J. Pharm., 1984, 19(3), 271 ]) and/or the metabolic profile of the molecule and may result in changes in the ratio of parent compound to metabolites or in the amounts of metabolites formed. Such changes may result in certain therapeutic advantages and hence may be preferred in some circumstances. Reduced rates of metabolism and metabolic switching, where the ratio of metabolites is changed, have been reported (A. E. Mutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102). These changes in the exposure to parent drug and metabolites can have important consequences with respect to the pharmacodynamics, tolerability and efficacy of a deuterium-containing compound of general formula (I). In some cases deuterium substitution reduces or eliminates the formation of an undesired or toxic metabolite and enhances the formation of a desired metabolite (e.g. Nevirapine: A. M. Sharma et al., Chem. Res. Toxicol., 2013, 26, 410; Efavirenz: A. E. Mutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102). In other cases the major effect of deuteration is to reduce the rate of systemic clearance. As a result, the biological half-life of the compound is increased. The potential clinical benefits would include the ability to maintain similar systemic exposure with decreased peak levels and increased trough levels. This could result in lower side effects and enhanced efficacy, depending on the particular compound's pharmacokinetic/ pharmacodynamic relationship. ML-337 (C. J. Wenthur et al., J. Med. Chem., 2013, 56, 5208) and Odanacatib (K. Kassahun et al., WO2012/1 12363) are examples for this deuterium effect. Still other cases have been reported in which reduced rates of metabolism result in an increase in exposure of the drug without changing the rate of systemic clearance (e.g. Rofecoxib: F. Schneider et al., Arzneim. Forsch. / Drug. Res., 2006, 56, 295; Telaprevir: F. Maltais et al., J. Med. Chem., 2009, 52, 7993). Deuterated drugs showing this effect may have reduced dosing requirements (e.g. lower number of doses or lower dosage to achieve the desired effect) and/or may produce lower metabolite loads.
A compound of general formula (I) may have multiple potential sites of attack for metabolism. To optimize the above-described effects on physicochemical properties and metabolic profile, deuterium-containing compounds of general formula (I) having a certain pattern of one or more deuterium-hydrogen exchange(s) can be selected. Particularly, the deuterium atom(s) of deuterium-containing compound(s) of general formula (I) is/are attached to a carbon atom and/or is/are located at those positions of the compound of general formula (I), which are sites of attack for metabolizing enzymes such as e.g. cytochrome P450. 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.
By "stable compound' or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The compounds of the present invention optionally contain one or more asymmetric centres, depending upon the location and nature of the various substituents desired. It is possible that one or more asymmetric carbon atoms are present in the (R) or (S) configuration, which can result in racemic mixtures in the case of a single asymmetric centre, and in diastereomeric mixtures in the case of multiple asymmetric centres. In certain instances, it is possible that asymmetry 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.
Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of the present 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., HPLC columns using a chiral phase), with or without conventional derivatisation, optimally chosen to maximise the separation of the enantiomers. Suitable HPLC columns using a chiral phase are commercially available, such as those manufactured by Daicel, e.g., Chiracel OD and Chiracel OJ, for example, among many others, which are all routinely selectable. Enzymatic separations, with or without derivatisation, are also useful. The optically active compounds of the present invention can likewise be obtained by chiral syntheses utilizing optically active starting materials.
In order to distinguish different types of isomers from each other reference is made to lUPAC Rules Section E (Pure Appl Chem 45, 1 1-30, 1976). The present invention includes all possible stereoisomers of the compounds of the present invention as single stereoisomers, or as any mixture of said stereoisomers, e.g. (R)- or (S)- isomers, in any ratio. Isolation of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound of the present invention is achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example.
Further, it is possible for the compounds of the present invention to exist as tautomers. For example, any compound of the present invention can exist, as shown below, as a tautomer 1 , or tautomer 2 or tautomer 3, or even a mixture in any amount of the three tautomers, namely :
Figure imgf000024_0001
tautomer 1 tautomer 2 tautomer 3 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 covers useful forms of the compounds of the present invention, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and/or 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. It is possible for the amount of polar solvents, in particular water, to 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, it is possible for the compounds of the present invention to exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or to 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, which is customarily used in pharmacy, or which is used, for example, for isolating or purifying the compounds of the present invention. The term "pharmaceutically acceptable salt" refers to an 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.
A suitable pharmaceutically acceptable salt of the compounds of the present invention may be, for example, an acid-addition salt of a compound of the present invention bearing a nitrogen atom, in a chain or in a ring, for example, which is sufficiently basic, such as an acid-addition salt with an inorganic acid, or "mineral acid", such as hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, bisulfuric, phosphoric, or nitric acid, for example, or with an organic acid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nicotinic, pamoic, pectinic, 3-phenylpropionic, pivalic, 2-hydroxyethanesulfonic, itaconic, trifluoromethanesulfonic, dodecylsulfuric, ethanesulfonic, benzenesulfonic, para-toluenesulfonic, methanesulfonic, 2-naphthalenesulfonic, naphthalinedisulfonic, camphorsulfonic acid, citric, tartaric, stearic, lactic, oxalic, malonic, succinic, malic, adipic, alginic, maleic, fumaric, D-gluconic, mandelic, ascorbic, glucoheptanoic, glycerophosphoric, aspartic, sulfosalicylic, or thiocyanic acid, for example.
Further, another suitably pharmaceutically acceptable salt of a compound of the present invention which is sufficiently acidic, is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium, magnesium or strontium salt, or an aluminium or a zinc salt, or an ammonium salt derived from ammonia or from an organic primary, secondary or tertiary amine having 1 to 20 carbon atoms, such as ethylamine, diethylamine, triethy!amine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, diethylaminoethanol, tris(hydroxymethyl)aminomethane, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, 1 ,2-ethylenediamine, N-methylpiperidine, N-methyl-glucamine, N,N-dimethyl-glucamine, /V-ethyl-glucamine, 1 ,6-hexanediamine, glucosamine, sarcosine, serinol, 2-amino-1 ,3- propanediol, 3-amino-1 ,2-propanediol, 4-amino-1 ,2,3-butanetriol, or a salt with a quarternary ammonium ion having 1 to 20 carbon atoms, such as tetramethylammonium, tetraethylammonium, tetra(n-propyl)ammonium, tetra(n-butyl)ammonium, N-benzyl-N,N,N- trimethylammonium, choline or benzalkonium.
Those skilled in the art will further recognise that it is possible for acid addition salts of the claimed compounds to be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods. Alternatively, alkali and alkaline earth metal salts of acidic compounds of the present invention are prepared by reacting the compounds of the present invention with the appropriate base via a variety of known methods. 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.
In the present text, in particular in the Experimental Section, for the synthesis of compounds and of examples of the present invention, when a compound 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, in most cases, unknown.
Unless specified otherwise, suffixes to chemical names or structural formulae relating to salts, such as "hydrochloride", "trifluoroacetate", "sodium salt", or "x HCI", "x CF3COOH", "x Na+", for example, mean a salt form, the stoichiometry of which salt form not being specified.
This applies analogously to cases in which compounds or examples 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.
Furthermore, the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as single polymorph, or as a mixture of more than one polymorph, in any ratio.
In accordance with a second embodiment of the first aspect, the present invention covers compounds of general formula (I):
Figure imgf000027_0001
in which :
R1 represents a group selected from
pyrazolyl, imidazolyl, oxadiazolyl, triazolyl, isoxazolyl, thienyl, pyridin-2-yl, pyridin-4-yl, pyrimidinyl, triazinyl and pyrazinyl, said group being optionally substituted with one R6 group, and said group being, additionally, optionally substituted one or two times, differently or identically, with a R7 group,
or
R1 represents a group selected from
Figure imgf000027_0002
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group,
in which "*" represents the point of attachment to the rest of the molecule,
or
R1 represents a group selected from pyridine-3-yl or pyridazin-3-yl, optionally substituted with one R8 group; represents a group selected from
Figure imgf000028_0001
in which "*" represents the point of attachment to the rest of the molecule;
R3 represents a hydrogen atom or a halogen atom or a group selected from Ci-C4-alkyl and Ci-C6-alkoxy;
R4 represents a hydrogen atom or a halogen atom or a group selected from Ci-C4-alkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy and
Figure imgf000028_0002
R5 represents a hydrogen atom or a halogen atom or a group selected from Ci-C4-alkyl, Ci-C4-haloalkyl and C3-C6-cycloalkyl; R6 represents a hydrogen atom or a group selected from Ci-C6-alkyl, Ci-C6-haloalkyl, Ci- Ce-hydroxyalkyl, (Ci-C3-alkoxy)-(Ci-C3-alkyl)-, C3-C6-cycloalkyl and (C3-C6-cycloalkyl)- (Ci-C3-alkyl)-,
said C3-C6-cycloalkyl and said (C3-C6-cycloalkyl)-(Ci-C3-alkyl)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or with a group selected from Ci-C3-alkyl and Ci- C3-haloalkyl;
R7 represents a halogen atom or a group selected from hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-hydroxyalkyl, (Ci-C3-alkoxy)-(Ci-C3-alkyl)-, (Ci-C3-haloalkoxy)-(Ci-C3-alkyl)-, C2-C6-alkenyl, C2-C6-alkynyl, C3-C8-cycloalkyl, C4-C8- cycloalkenyl, (C3-C8-cycloalkyl)-(Ci-C3-alkyl)-, (phenyl)-Ci-C3-alkyl-, 4- to 7-membered heterocycioalkyi, 5- to 7-membered heterocycloalkenyl, heterospirocycloalkyi, phenyl, heteroaryl, -CN, -(CH2)x-N(R 1 )R11a, -C(=0)R13, -C(=0)-OR13, -C(=0)-N(R11)R11a, - N(R11 )R11a, -N(R 6)-C(=0)-R13, -N(R16)-S(=0)2-R13, -N(R16)-C(=0)-N(R11 )R 1a, -N(R16)- C(=0)-OR13, Ci-C6-alkoxy, Ci-Ce-haloalkoxy, C3-C8-cycloalkoxy-, (C3-C8-cycloalkyl)- (Ci-C3-alkoxy)-, phenyloxy-, heteroaryloxy-, -0-(CH2)x-phenyl, -0-(CH2)x-heteroaryl, -O- C(=0)-R13, -0-C(=0)-N(R 1 )R11a, Ci-C6-alkylsulfanyl, Ci-C6-haloalkylsulfanyl, -S(=0)- R13, -S(=0)2-R13, -S(=0)2-N(R11)R1 a and -S(=0)(=NR17)R13,
said C3-C8-cycloalkyl, said (C3-C8-cycloalkyl)-(Ci-C3-alkyl)- and said (C3-C8- cycloalkyl)-(Ci-C3-alkoxy)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or with a group selected from Ci-C3-alkyl and Ci-C3-haloalkyl,
said 4- to 7-membered heterocycioalkyi, said 5- to 7-membered heterocycloalkenyl and said heterospirocycloalkyi group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or with a group selected from oxo, Ci-C3-alkyl and Ci-C3- haloalkyl, and
said heteroaryl group and said phenyl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from -CN, Ci-C3-alkyl, trifluoromethyl, Ci-C3-alkoxy and trifluoromethoxy;
or
R6 and R7, or two R7 groups, when being attached to adjacent ring atoms of the group R1 , together form a group selected from: ·
-(0-CH2-0)-, -(0-(CH2)2-0)-, -(0-(CH2)2)-, -(CH2-0-CH2)-, -(NR16-(CH2)2-0)-, -(NR16-(CH2)3-0)-, -(S-(CH2)2)-, -(0-(CH2)3)-, -((CH2)3)-, -((CH2)4)-, -(0-CH=CH)-, -(S-CH=CH)-; R8 represents a hydrogen atom or a group selected from methyl, ethyl, methoxy, ethoxy and dimethylamino;
R9 represents a hydrogen atom or a -CN or Ci-C3-alkyl group;
R10 represents a group selected from -C(=0)R12, -C(=0)OR13, -C(=0)N(R 4)R14a, -S(=0)2R15, -S(=0)2N(R14)R14a, 5- to 6-membered heteroaryl and phenyl,
said 5- to 6-membered heteroaryl group and said phenyl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from -CN, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy and Ci- C3-haloalkoxy;
R11 and R11a, independently from each other, represent a hydrogen atom or a group selected from Ci-C4-alkyl, Ci-C4-haloalkyl, C3-C6-cycloalkyl, Ci-C6-hydroxyalkyl, (Ci-C3-alkoxy)- (d-Ca-alkyl)-, (C3-C6-cycloalkyl)-(Ci-C3-alkyl)- and benzyl,
or
R11 and R11a, together with the nitrogen atom they are attached to, represent a 4- to 7- membered heterocycloalkyi group, said group being optionally substituted one or two times, identically or differently, with a halogen atom, or a group selected from hydroxy, oxo, -CN, Ci-C3-alkyl, Ci-C3-haloalkyl, C C3-alkoxy, -C(=0)R18, -C(=0)OR18 and -S(=0)2R18;
R12 represents a hydrogen atom or a group selected from Ci-C6-alkyl, Ci-C6-haloalkyl, Ci- Ce-hydroxyalkyl, C3-C6-cycloalkyl, (C3-C6-cycloalkyl)-(Ci-C3-alkyl)-, C2-C6-alkenyl, C2- C6-alkynyl, 4- to 7-membered heterocycloalkyi, 5- to 7-membered heterocycloalkenyl, 5- to 6-membered heteroaryl and phenyl,
said 5- to 6-membered heteroaryl group and said phenyl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from -CN, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy and Ci- C3-haloalkoxy,
said C3-C6-cycloalkyl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from -CN, Ci- C3-alkyl and Ci-C3-haloalkyl;
R13 represents a group selected from Ci-C4-alkyl and benzyl;
R14 and R14a, independently from each other, represent a hydrogen atom or a group selected from Ci-C4-alkyl, Ci-C4-haloalkyl, C3-C6-cycloalkyl and benzyl, or
R14 and R14a, together with the nitrogen atom they are attached to, represent a 4- to 7- membered heterocycloalkyl group, said group being optionally substituted one or two times, identically or differently, with a halogen atom or a group selected from hydroxyl, -CN, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy, Ci-C3-haloalkoxy and (Ci-C3-alkoxy)-
(Ci-C3-alkyl)-;
R15 represents a group selected from Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-hydroxyalkyl, (Ci- C3-alkoxy)-(Ci-C5-alkyl)-, (Ci-C3-alkoxy)-(C2-C3-alkoxy)-(Ci-C6-alkyl)-, C3-C6-cycloalkyl, (C3-C6-cycloalkyl)-(Ci-C3-alkyl)-, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl and phenyl,
said 5- to 6-membered heteroaryl group and said phenyl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from -CN, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy and Ci-C3-haloalkoxy;
R16 represents a hydrogen atom or a group selected from Ci-C4-alkyl and benzyl;
R17 represents a hydrogen atom or a group selected from -CN, -C(=0)OR13, Ci-C-t-alkyl and benzyl;
R18 represents a Ci-C3-alkyl group;
x represents an integer selected from 1 , 2, 3 and 4,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In accordance with a third embodiment of the first aspect, the present invention covers compounds of general formula (I):
Figure imgf000031_0001
in which :
R1 represents a group selected from pyrazolyl, imidazolyl, oxadiazolyl, triazolyl, pyridin-2-yl, pyridin-4-yl, pyrimidinyl and pyrazinyl, said group being optionally substituted with one R6 group, and said group being, additionally, optionally substituted one or two times, differently or identically, with a R7 group, represents a group selected from
Figure imgf000032_0001
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group,
in which "*" represents the point of attachment to the rest of the molecule, represents a group selected from pyridine-3-yl or pyridazin-3-yl, optionally substituted with one R8 group;
represents a group selected from
Figure imgf000032_0002
Figure imgf000033_0001
in which "*" represents the point of attachment to the rest of the molecule;
R3 represents a hydrogen atom or a halogen atom or a group selected from d-C4-alkyl and Ci-C6-alkoxy;
R4 represents a hydrogen atom or a halogen atom or a group selected from Ci-C4-alkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy and Ci-C4-haloalkoxy;
R5 represents a hydrogen atom or a halogen atom or a group selected from Ci-C4-alkyl, Ci-C4-haloalkyl and C3-C6-cycloalkyl;
R6 represents a hydrogen atom or a group selected from Ci-C6-alkyl, Ci-C6-haloalkyl, C3- Ce-cycloalkyl and (C3-C6-cycloalkyl)-(Ci-C3-alkyl)-,
said C3-C6-cycloalkyl and said (C3-C6-cycloalkyl)-(Ci-C3-alkyl)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or with a Ci-C3-alkyl group;
R7 represents a halogen atom or a group selected from Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-hydroxyalkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C8-cycloalkyl, C4-Ce-cycloalkenyl, (C3-C8-cycloalkyl)-(Ci-C3-alkyl)-, (phenyl)-Ci-C3- alkyl-, 4- to 7-membered heterocycloalkyl, 5- to 7-membered heterocycloalkenyl, phenyl, heteroaryl, -CN, -C(=0)R13, -C(=0)-OR13, -C(=0)-N(R1 1)R11a, -N(R11)R 1a, -N(R16)-C(=0)-R13, -N(R16)-S(=0)2-R13, -N(R16)-C(=0)-N(R11)R11a, -N(R16)-C(=0)-OR13, Ci-C6-alkoxy, Ci-C6-haioalkoxy, Cs-Ce-cycloalkoxy-, (C3-Ce-cycloalkyl)-(Ci-C3-alkoxy)-, phenyloxy-, heteroaryloxy-, -0-(CH2)x-phenyl, -0-(CH2)x-heteroaryl, -0-C(=0)-R13 -O- C(=0)-N(R11)R11a, Ci-Ce-alkylsulfanyl, Ci-C6-haloalkylsulfanyl, -S(=0)2-R13, -S(=0)2- N(R11)R11a and -S(=0)(=NR17)R13;
or
R6 and R7, or two R7 groups, when being attached to adjacent ring atoms of the group R1, together form a group selected from:
-(O-CH2-O)-, -(0-(CH2)2-0)-, -(0-(CH2)2)-, -(S-(CH2)2)-, -(0-(CH2)3)-, -((CH2)3)-, -((CH2)4)-, -(0-CH=CH)-, -(S-CH=CH);
R8 represents a hydrogen atom or a group selected from methyl, ethyl, methoxy and ethoxy;
R9 represents a hydrogen atom or a Ci-C3-alkyl group;
R10 represents a group selected from -C(=0)R12, -C(=0)OR13, -C(=0)N(R14)R14a, -S(=0)2R15, -S(=0)2N(R14)R14a, 5- to 6-membered heteroaryl and phenyl,
said 5- to 6-membered heteroaryl group and said phenyl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from -CN, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy and Ci- C3-haloalkoxy;
R11 and R11a, independently from each other, represent a hydrogen atom or a group selected from Ci-C4-alkyl, d-d-haloalkyl, C3-C6-cycloalkyl and benzyl,
or
R11 and R a, together with the nitrogen atom they are attached to, represent a 4- to 7- membered heterocycloalkyi group, said group being optionally substituted one or two times, identically or differently, with a halogen atom, or a group selected from hydroxy, oxo, -CN, Ci-C3-alkyl, -C(=0)R18, C(=0)OR18 and S(=0)2R18;
R12 represents a group selected from Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-hydroxyalkyl, C3- C6-cycloalkyl, (C3-C6-cycloalkyl)-(Ci-C3-alkyl)-, C2-C6-alkenyl, C2-C6-alkynyl, 4- to 7- membered heterocycloalkyi, 5- to 7-membered heterocycloalkenyl, 5- to 6-membered heteroaryl and phenyl,
said 5- to 6-membered heteroaryl group and said phenyl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from -CN, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy and Ci- C3-haloalkoxy;
R13 represents a group selected from Ci-C4-alkyl and benzyl; R14 and R14a, independently from each other, represent a hydrogen atom or a group selected from Ci-C4-alkyl, Ci-C4-haloalkyl, C3-C6-cycloalkyl and benzyl,
or
R14 and R1 a, together with the nitrogen atom they are attached to, represent a 4- to 7- membered heterocycloalkyi group, said group being optionally substituted one or two times, identically or differently, with a halogen atom or a group selected from hydroxyl, -CN, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy, Ci-C3-haloalkoxy and (Ci-C3-alkoxy)- (Ci-C3-alkyl)-;
R15 represents a group selected from Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-hydroxyalkyl, (Ci- C3-alkoxy)-(Ci-C6-alkyl)-, (Ci-C3-alkoxy)-(C2-C3-alkoxy)-(Ci-C6-alkyl)-, C3-C6-cycloalkyl, (C3-C6-cycloalkyl)-(Ci-C3-alkyl)-, 4- to 7-membered heterocycloalkyi, 5- to 6-membered heteroaryl and phenyl,
said 5- to 6-membered heteroaryl group and said phenyl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from -CN, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy and Ci-C3-haloalkoxy;
R16 represents a hydrogen atom or a group selected from Ci-C4-alkyl and benzyl;
R17 represents a hydrogen atom or a group selected from -CN, -C(=0)OR13, Ci-C4-alkyl and benzyl;
R18 represents a Ci-C3-alkyl group;
x represents an integer selected from 1 , 2, 3 and 4,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In accordance with a fourth embodiment of the first aspect, the present invention compounds of general formula (I), supra, in which:
R represents a group selected from
Figure imgf000036_0001
in which "*" represents the point of attachment to the rest of the molecule;
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group, represents a group selected from
Figure imgf000036_0002
in which "*" represents the point of attachment to the rest of the molecule;
R2 represents a group selected from
Figure imgf000037_0001
in which "*" represents the point of attachment to the rest of the molecule;
R3 represents a hydrogen atom or a halogen atom or a group selected from Ci-C4-alkyl and Ci-C4-alkoxy;
R4 represents a hydrogen atom or a group selected from Ci-C3-alkyl and Ci-C3-fluoroalkyl; R5 represents a hydrogen atom or a bromine atom;
R6 represents a hydrogen atom or a group selected from Ci-C6-alkyl, Ci-C4-fluoroalkyl, Ci-C4-hydroxyalkyl, (Ci-C2-alkoxy)-(Ci-C3-alkyl)-, C3-C5-cycloalkyl and (C3-C5-cycloalkyl)-(methyl)-,
said C3-C5-cycloalkyl and said (C3-C5-cycloalkyl)-(methyl)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or with a group selected from methyl and trifluoromethyl;
R7 represents a halogen atom or a group selected from hydroxy, Ci-C6-alkyl, C1-C4- fluoroalkyl, Ci-C4-hydroxyalkyl, (Ci-C2-alkoxy)-(Ci-C3-alkyl)-, (Ci-C2-fluoroalkoxy)-(Ci- C3-alkyl)-, C3-C4-cycloalkyl, (C3-C4-cycloalkyl)-(methyl)-, (phenyl)-(Ci-C3-alkyl)-, 4- to 7- membered heterocycloalkyl, heterospirocycloalkyl, 5-to 6-membered heteroaryl, -CN, -
(CH2)x-N(R11)R11a, -C(=0)R13, -C(=0)-N(R 1)R11a, -N(R11)R11a, d-Ce-alkoxy, d-C4- fluoroalkoxy, (C3-C4-cycloalkyl)-(methoxy)-, Ci-C4-alkylsulfanyl, S(=0)-R13 and -S(=0)2- R13,
said C3-C4-cycloalkyl, said (C3-C4-cycloalkyl)-(methyl)- and said (C3-C4- cycloalkyl)-(methoxy)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom or with a group selected from methyl and trifluoromethyl,
said 4- to 7-membered heterocycloalkyi and said heterospirocycloalkyl group being optionally substituted one, two or three times, identically or differently, with a fluorine atom or with a group selected from oxo, methyl and trifluoromethyl, and said 5- to 6-membered heteroaryl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from methyl, trifluoromethyl and methoxy;
or
R6 and R7, or two R7 groups, when being attached to adjacent ring atoms of the group R1, together form a group selected from:
-(O-CH2-O)-, -(0-(CH2)2-0)-, -(0-(CH2)2)-, -(CH2-0-CH2)-, -(NR16-(CH2)2-0)-, -((CH2)3)-, -((CH2)4)-, -(0-CH=CH)-, -(S-CH=CH)-;
R8 represents a hydrogen atom or a group selected from methoxy and ethoxy;
R9 represents a hydrogen atom or a methyl or ethyl group;
R10 represents a group selected from -C(=0)R12, -C(=0)OR13, -C(=0)N(R14)R14a, -S(=0)2R15, -S(=0)2N(R14)R14a, 5- to 6-membered heteroaryl and phenyl,
said 5- to 6-membered heteroaryl group and said phenyl group being optionally substituted one or two times, identically or differently, with a fluorine atom, chlorine atom or bromine atom, or a group selected from -CN, methyl, trifluoromethyl and methoxy;
R11 and R11a, independently from each other, represent a hydrogen atom or a group selected from Ci-C4-alkyl, Ci-C4-fluoroalkyl, C3-C4-cycloalkyl, Ci-C4-hydroxyalkyl, (Ci-C2-alkoxy)- (Ci-C3-alkyl)-, (C3-C4-cycloalky!)-(methyl)- and benzyl,
or
R11 and R11a, together with the nitrogen atom they are attached to, represent a 4- to 6- membered heterocycloalkyi group, said group being optionally substituted one or two times, identically or differently, with a fluorine atom, or a group selected from hydroxy, oxo, -CN, methyl, trifluoromethyl and methoxy;
R12 represents a hydrogen atom or a group selected from Ci-C4-alkyl, Ci-C4-fluoroalkyl, Ci-C4-hydroxyalkyl, (Ci-C2-alkoxy)-(Ci-C3-alkyl)-, C3-C6-cycloalkyl, (C3-C6-cycloalkyl)- (Ci-C2-alkyl)-, C2-C4-alkenyl, 5- to 6-membered heteroaryl and phenyl, said 5- to 6-membered heteroaryl group and said phenyl group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or a group selected from methyl, trifluormethyl and methoxy, said C3-C6-cycloalkyl group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or a group selected from -CN, methyl and trifluoromethyl;
R13 represents a group selected from Ci-C4-alkyl and benzyl;
R14 and R14a, independently from each other, represent a hydrogen atom or a group selected from Ci-C3-alkyl, trifluoromethyl and cyclopropyl,
or
R14 and R14a, together with the nitrogen atom they are attached to, represent a 4- to 7- membered heterocycloalkyi group, said group being optionally substituted one or two times, identically or differently, with a group selected from Ci-C3-alkyl, Ci-C3-fluoroalkyl, Ci-C3-alkoxy, trifluoromethoxy and (Ci-C2-alkoxy)-(Ci-C2-alkyl)-;
R15 represents a group selected from Ci-C4-alkyl, Ci-C4-fluoroalkyl, (Ci-C2-alkoxy)-(Ci-C3- alkyl)-, (Ci-C2-alkoxy)-(ethoxy)-(Ci-C3-alkyl)-, C3-C6-cycloalkyl, (C3-C6-cycloalkyl)-(Ci- C2-alkyl)- and 4- to 7-membered heterocycloalkyi;
R16 represents a hydrogen atom or a Ci-C3-alkyl group;
x represents an integer selected from 1 and 2,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In accordance with a fifth embodiment of the first aspect, the present invention compounds of general formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000040_0001
in which "*" represents the point of attachment to the rest of the molecule;
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group, represents a group selected from
Figure imgf000040_0002
in which "*" represents the point of attachment to the rest of the molecule; represents a group selected from
Figure imgf000041_0001
in which "*" represents the point of attachment to the rest of the molecule;
represents a hydrogen atom or a halogen atom or a group selected from Ci-C4-alkyl and Ci-C4-alkoxy;
represents a hydrogen atom or a group selected from Ci-C3-alkyl and Ci-C3-fluoroalkyl; represents a hydrogen atom or a bromine atom;
represents a hydrogen atom or a group selected from Ci-C6-alkyl, Ci-C4-fluoroalkyl, Ci-C4-hydroxyalkyl, (Ci-C2-alkoxy)-(Ci-C3-alkyl)-, C3-Cs-cycloalkyl and (C3-C5-cycloalkyl)-(methyl)-,
said C3-C5-cycloalkyl and said (C3-C5-cycloalkyl)-(methyl)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or with a group selected from methyl and trifluoromethyl;
represents a halogen atom or a group selected from hydroxy, Ci-C6-alkyl, C1-C4- fluoroalkyl, Ci-C4-hydroxyalkyl, (Ci-C2-alkoxy)-(Ci-C3-alkyl)-, (Ci-C2-fluoroalkoxy)-(Ci- Ca-alkyl)-, C3-C4-cycloalkyl, (C3-C4-cycloalkyl)-(methyl)-, (phenyl)-(Ci-C3-alkyl)-, 4- to 7- membered heterocycloalkyl, heterospirocycloalkyl, 5-to 6-membered heteroaryl, -CN, - (CH2)x-N(R11)R1 a, -C(=0)R13, -C(=0)-N(R11)R11a, -N(R11)R11a, Ci-C6-alkoxy, C1-C4- fluoroalkoxy, (C3-C4-cycloalkyl)-(methoxy)-, Ci-C4-alkylsulfanyl, S(=0)-R13 and -S(=0)2- R13,
said C3-C4-cycloalkyl, said (C3-C4-cycloalkyl)-(methyl)- and said (C3-C4- cycloalkyl)-(methoxy)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom or with a group selected from methyl and trifluoromethyl,
said 4- to 7-membered heterocycloalkyl and said heterospirocycloalkyl group being optionally substituted one, two or three times, identically or differently, with a fluorine atom or with a group selected from oxo, methyl and trifluoromethyl, and said 5- to 6-membered heteroaryl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from methyl, trifluoromethyl and methoxy;
or
R6 and R7, or two R7 groups, when being attached to adjacent ring atoms of the group R1, together form a group selected from:
-(O-CHz-O)-, -(0-(CH2)2-0)-, -(0-(CH2)2)-, -(CH2-0-CH2)-, -(NR16-(CH2)2-0)-, -((CH2)3)-, -((CH2)4)-, -(0-CH=CH)-, -(S-CH=CH)-;
R8 represents a hydrogen atom or a group selected from methoxy and ethoxy;
R9 represents a hydrogen atom or a methyl or ethyl group;
R10 represents a group selected from -C(=0)R12, -C(=0)OR13, -C(=0)N(R 4)R14a, -S(=0)2R15, -S(=0)2N(R14)R14a, 5- to 6-membered heteroaryl and phenyl,
said 5- to 6-membered heteroaryl group and said phenyl group being optionally substituted one or two times, identically or differently, with a fluorine atom, chlorine atom or bromine atom, or a group selected from -CN, methyl, trifluoromethyl and methoxy;
R11 and R11a, independently from each other, represent a hydrogen atom or a group selected from Ci-C4-alkyl, Ci-C4-fluoroalkyl, C3-C4-cycloalkyl, Ci-C4-hydroxyalkyl, (Ci-C2-alkoxy)- (Ci-Cs-alkyl)-, (C3-C4-cycloalkyl)-(methyl)- and benzyl,
or
R11 and R11a, together with the nitrogen atom they are attached to, represent a 4- to 6- membered heterocycloalkyl group, said group being optionally substituted one or two times, identically or differently, with a fluorine atom, or a group selected from hydroxy, oxo, -CN, methyl, trifluoromethyl and methoxy;
R12 represents a hydrogen atom or a group selected from Ci-C4-alkyl, Ci-C4-fluoroalkyl, C3-C6-cycloalkyl, (C3-C6-cycloalkyl)-(Ci-C2-alkyl)-, C2-C4-alkenyl, 5- to 6-membered heteroaryl and phenyl, said 5- to 6-membered heteroaryl group and said phenyl group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or a group selected from methyl, trifluormethyl and methoxy, said C3-C6-cycloalkyl group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or a group selected from -CN, methyl and trifluoromethyl;
R13 represents a group selected from Ci-C4-alkyl and benzyl;
R14 and R14a, independently from each other, represent a hydrogen atom or a group selected from Ci-C3-alkyl, trifluoromethyl and cyclopropyl,
or
R14 and R14a, together with the nitrogen atom they are attached to, represent a 4- to 7- membered heterocycloalkyi group, said group being optionally substituted one or two times, identically or differently, with a group selected from Ci-C3-alkyl, Ci-C3-fluoroalkyl, Ci-C3-alkoxy, trifluoromethoxy and (Ci-C2-alkoxy)-(Ci-C2-alkyl)-;
R15 represents a group selected from Ci-C4-alkyl, Ci-C4-fluoroalkyl, (Ci-C2-alkoxy)-(Ci-C3- alkyl)-, (Ci-C2-alkoxy)-(ethoxy)-(Ci-C3-alkyl)-, C3-C6-cycloalkyl, (C3-C6-cycloalkyl)-(Ci- C2-alkyl)- and 4- to 7-membered heterocycloalkyi;
R16 represents a hydrogen atom or a Ci-C3-alkyl group;
x represents an integer selected from 1 and 2,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In accordance with a sixth embodiment of the first aspect, the present invention covers compounds of general formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000044_0001
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group,
or
R1 represents a group selected from
Figure imgf000044_0002
in which "*" represents the point of attachment to the rest of the molecule;
R2 represents a group selected from
Figure imgf000045_0001
in which "*" represents the point of attachment to the rest of the molecule;
R3 represents a hydrogen atom or a group selected from Ci-Ct-alkyl and Ci-C4-alkoxy;
R4 represents a hydrogen atom or a group selected from Ci-C3-alkyl and Ci-C3-fluoroalkyl; R5 represents a hydrogen atom;
R6 represents a hydrogen atom or a group selected from Ci-Ce-alkyl, Ci-C4-fluoroalkyl, C3-C4-cycloalkyl and (C3-C4-cycloalkyl)-(methyl)-,
said C3-C4-cycloalkyl and said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or with a methyl group;
R7 represents a halogen atom or a group selected from Ci-C6-alkyl, Ci-C4-fluoroalkyl, C3-C4-cycloalkyl, (C3-C4-cycloalkyl)-(methyl)-, (phenyl)- (Ci-C3-alkyl)-, -C(=0)-N(R11)R11a, Ci-Ce-alkoxy,
Ci-C4-fluoroalkoxy, (C3-C4-cycloalkyl)-(methoxy)- and Ci-C4-alkylsulfanyl;
or
R6 and R7, or two R7 groups, when being attached to adjacent ring atoms of the group R1 , together form a group selected from:
-(O-CH2-O)-, -(0-(CH2)2-0)-, -(0-(CH2)2)-, -((CH2)3)-, -((CH2)4)-;
R8 represents a hydrogen atom or a group selected from methoxy and ethoxy;
R9 represents a hydrogen atom or a methyl or ethyl group;
R10 represents a group selected from -C(=0)R12, -C(=0)OR13, -C(=0)N(R14)R14a, -S(=0)2R15, -S(=0)2N(R14)R14a and phenyl, said phenyl group being optionally substituted one or two times, identically or differently, with a fluorine atom, chlorine atom or bromine atom, or a group selected from -CN, methyl, trifluoromethyl and methoxy;
R11 and R11a, independently from each other, represent a hydrogen atom or a group selected from Ci-C4-alkyl and benzyl,
or
R11 and R11a, together with the nitrogen atom they are attached to, represent a 5- to 6- membered heterocycloalkyi group, said group being optionally substituted once with a methyl group;
R 2 represents a group selected from Ci-C4-alkyl, Ci-C4-fluoroalkyl, C3-C6-cycloalkyl, (C3- C6-cycloalkyl)-(Ci-C2-alkyl)- and C2-C4-alkenyl;
R13 represents a group selected from Ci-C4-alkyl and benzyl;
R14 and R14a, independently from each other, represent a hydrogen atom or a group selected from Ci-C3-alkyl, trifluoromethyl and cyclopropyl,
or
R14 and R14a, together with the nitrogen atom they are attached to, represent a 4- to 7- membered heterocycloalkyi group, said group being optionally substituted one or two times, identically or differently, with a group selected from Ci-C3-alkyl, Ci-C3-fluoroalkyl, Ci-C3-alkoxy, trifluoromethoxy and (Ci-C2-alkoxy)-(Ci-C2-alkyl)-;
R15 represents a group selected from Ci-C4-alkyl, Ci-C4-fluoroalkyl, (Ci-C2-alkoxy)-(Ci-C3- alkyl)-, (Ci-C2-alkoxy)-(ethoxy)-(Ci-C3-alkyl)-, C3-C6-cycloalkyl, (C3-Ce-cycloalkyl)-(Ci- C2-alkyl)- and 4- to 7-membered heterocycloalkyi,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In accordance with a seventh embodiment of the first aspect, the present invention covers compounds of general formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000047_0001
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group,
or
R represents a group selected from
Figure imgf000047_0002
in which "*" represents the point of attachment to the rest of the molecule; R2 represents a group selected from
Figure imgf000047_0003
in which "*" represents the point of attachment to the rest of the molecule; R3 represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom or a group selected from methyl, ethoxy and iso-butoxy;
R4 represents a hydrogen atom or a group selected from methyl and trifluoromethyl;
R5 represents a hydrogen atom;
R6 represents a hydrogen atom or a group selected from Ci-C6-alkyl, Ci-C4-fluoroalkyl, Ci-C4-hydroxyalkyl, (methoxy)-(Ci-C3-alkyl)-, C3-Cs-cycloalkyl and (C3-C5-cycloalkyl)-(methyl)-,
said C3-C5-cycloalkyl and said (C3-Cs-cycloalkyl)-(methyl)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or with a methyl group;
R7 represents a halogen atom or a group selected from Ci-C6-alkyl, Ci-C4-fluoroalkyl, Ci- C4-hydroxyalkyl, (Ci-C2-alkoxy)-(Ci-C3-alkyl)-, C3-C4-cycloalkyl, (C3-C4-cycloalkyl)- (methyl)-, (phenyl)-(Ci-C3-alkyl)-, 4- to 7-membered heterocycloalkyl, heterospirocycloalkyl, -CN, -(CH2)x-N(R11 )R11a, -C(=0)R13, -C(=0)-N(R11)R11a, - N(R11 )R11a, Ci-C6-alkoxy, Ci-C4-fluoroalkoxy and (C3-C4-cycloalkyl)-(methoxy)-,
said C3-C4-cycloalkyl, said (C3-C4-cycloalkyl)-(methyl)- and said (C3-C4- cycloalkyl)-(methoxy)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom or with a group selected from methyl and trifluoromethyl, and
said 4- to 7-membered heterocycloalkyl and said heterospirocycloalkyl group being optionally substituted one, two or three times, identically or differently, with a fluorine atom or with a group selected from methyl and trifluoromethyl, or
R6 and R7, or two R7 groups, when being attached to adjacent ring atoms of the group R1 , together form a group selected from -(0-CH=CH)- and -(NR16-(CH2)2-0)-;
R8 represents a hydrogen atom or a methoxy group;
R9 represents a hydrogen atom or a methyl group;
R10 represents a group selected from -C(=0)R12, -C(=0)N(R14)R14a, -S(=0)2R15 and - S(=0)2N(R14)R14a;
R11 and R11a, independently from each other, represent a hydrogen atom or a group selected from Ci-C3-alkyl, Ci-C3-fluoroalkyl, C3-C4-cycloalkyl, Ci-C3-hydroxyalkyl, (Ci-C2-alkoxy)- (Ci-C3-alkyl)-, (C3-C4-cycloalkyl)-(methyl)- and benzyl,
or R11 and R11a, together with the nitrogen atom they are attached to, represent a 4- to 6- membered heterocycloalkyi group, said group being optionally substituted one or two times, identically or differently, with a fluorine atom or a group selected from methyl and trifluoromethyl;
R12 represents a group selected from Ci-d-alkyl, Ci-C3-fluoroalkyl, Ci-C3-hydroxyalkyl, (methoxy)-(Ci-C3-alkyl)-, C3-C4-cycloalkyl, (cyclopropyl)-(methyl)- and allyl,
said C3-C4-cycloalkyl group being optionally substituted one, two or three times, identically or differently, with a fluorine atom or a group selected from methyl and trifluoromethyl;
R 3 represents a Ci-C3-alkyl group;
R14 and R14a, independently from each other, represent a hydrogen atom or a group selected from methyl and ethyl,
or
R14 and R14a, together with the nitrogen atom they are attached to, represent a 5- to 6- membered heterocycloalkyi group selected from pyrrolidinyl, piperidinyl and morpholinyl, said group being optionally substituted one or two times, identically or differently, with a group selected from methyl, methoxy and (methoxy)-(methyl)-;
R15 represents a group selected from ethyl, 3,3,3-trifluoropropyl, (3-methoxy)-(propyl)-, (2'- methoxy)-(2-ethoxy)-(ethyl)-, cyclopropyl, cyclohexyl and tetrahydropyranyl;
R16 represents a hydrogen atom or a Ci-C2-alkyl group;
x represents an integer 1 ,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In accordance with a eigth embodiment of the first aspect, the present invention covers compounds of general formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000050_0001
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group,
or
R1 represents a group selected from
Figure imgf000050_0002
in which "*" represents the point of attachment to the rest of the molecule; R2 represents a group selected from
Figure imgf000050_0003
in which "*" represents the point of attachment to the rest of the molecule; R3 represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom or a group selected from methyl, ethoxy and iso-butoxy;
R4 represents a hydrogen atom, or a group selected from methyl and trifluoromethyl;
R5 represents a hydrogen atom;
R6 represents a hydrogen atom or a group selected from Ci-C6-alkyl, Ci-C4-fluoroalkyl, Ci-C4-hydroxyalkyl, (methoxy)-(Ci-C3-alkyl)-, C3-Cs-cycloalkyl and (C3-C5-cycloalkyl)-(methyl)-,
said C3-C5-cycloalkyl and said (C3-C5-cycloalkyl)-(methyl)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or with a methyl group;
R7 represents a halogen atom or a group selected from Ci-C6-alkyl, Ci-C4-fluoroalkyl, Ci- C4-hydroxyalkyl, (Ci-C2-alkoxy)-(Ci-C3-alkyl)-, C3-C4-cycloalkyl, (C3-C4-cycloalkyl)- (methyl)-, (phenyl)-(Ci-C3-alkyl)-, 4- to 7-membered heterocycloalkyl, heterospirocycloalkyl, -CN, -(CH2)x-N(R 1)R11a, -C(=0)R13, -C(=0)-N(R11)R11a, - N(R11)R1 a, Ci-C6-alkoxy, Ci-C4-fluoroalkoxy and (C3-C4-cycloalkyl)-(methoxy)-,
said C3-C4-cycloalkyl, said (C3-C4-cycloalkyl)-(methyl)- and said (C3-C4- cycloalkyl)-(methoxy)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom or with a group selected from methyl and trifluoromethyl, and
said 4- to 7-membered heterocycloalkyl and said heterospirocycloalkyl group being optionally substituted one, two or three times, identically or differently, with a fluorine atom or with a group selected from methyl and trifluoromethyl, or
R6 and R7, or two R7 groups, when being attached to adjacent ring atoms of the group R\ together form a group selected from -(0-CH=CH)- and -(NR16-(CH2)2-0)-;
R8 represents a hydrogen atom or a methoxy group;
R9 represents a hydrogen atom or a methyl group;
R10 represents a group selected from -C(=0)R12, -C(=0)N(R 4)R14a, -S(=0)2R15 and - S(=0)2N(R14)R 4a;
R11 and R11a, independently from each other, represent a hydrogen atom or a group selected from Ci-C3-alkyl, Ci-C3-fluoroalkyl, C3-C4-cycloalkyl, Ci-C3-hydroxyalkyl, (Ci-C2-alkoxy)- (Ci-C3-alkyl)-, (C3-C4-cycloalkyl)-(methyl)- and benzyl,
or R 1 and R11a, together with the nitrogen atom they are attached to, represent a 4- to 6- membered heterocycloalkyl group, said group being optionally substituted one or two times, identically or differently, with a fluorine atom or a group selected from methyl and trifluoromethyl;
R12 represents a group selected from Ci-C4-alkyl, Ci-C3-fluoroalkyl, C3-C4-cycloalkyl, (cyclopropyl)-(methyl)- and allyl,
said C3-C4-cycloalkyl group being optionally substituted one, two or three times, identically or differently, with a fluorine atom or a group selected from methyl and trifluoromethyl;
R13 represents a Ci-C3-alkyl group;
R14 and R14a, independently from each other, represent a hydrogen atom or a group selected from methyl and ethyl,
or
R14 and R14a, together with the nitrogen atom they are attached to, represent a 5- to 6- membered heterocycloalkyl group selected from pyrrolidinyl, piperidinyl and morpholinyl, said group being optionally substituted one or two times, identically or differently, with a group selected from methyl, methoxy and (methoxy)-(methyl)-;
R15 represents a group selected from ethyl, 3,3,3-trifluoropropyl, (3-methoxy)-(propyl)-, (2'- methoxy)-(2-ethoxy)-(ethyl)-, cyclopropyl, cyclohexyl and tetrahydropyranyl;
R16 represents a hydrogen atom or a Ci-C2-alkyl group;
x represents an integer 1 ,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In accordance with a ninth embodiment of the first aspect, the present invention compounds of general formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000053_0001
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group,
or
R1 represents a group selected from
Figure imgf000053_0002
in which "*" represents the point of attachment to the rest of the molecule; represents a group selected from
Figure imgf000053_0003
in which "*" represents the point of attachment to the rest of the molecule;
R3 represents a hydrogen atom or a group selected from methyl, ethoxy and iso-butoxy; R4 represents a hydrogen atom, or a group selected from methyl and trifluoromethyl;
R5 represents a hydrogen atom; R6 represents a group selected from Ci-C4-alkyl, Ci-C4-fluoroalkyl, cyclopropyl and (cyclopropyl)-(methyl)-,
said cyclopropyl and (cyclopropyl)-(methyl)- group being optionally substituted one or two times with a fluorine atom;
R7 represents a fluorine atom or a group selected from Ci-Cs-alkyl, Ci-C2-fluoroalkyl, cyclopropyl, benzyl, -C(=0)-N(R1 )R11a, Ci-C3-alkoxy, Ci- C2-fluoroalkoxy and (cyclopropyl)-(methoxy)-;
R8 represents a hydrogen atom or a methoxy group;
R9 represents a hydrogen atom or a methyl group;
R10 represents a group selected from -C(=0)R12, -C(=0)N(R14)R14a, -S(=0)2R15, - S(=0)2N(R14)R14a and 2-chlorophenyl;
R11 and R11a, independently from each other, represent a hydrogen atom or a group selected from methyl and ethyl;
R12 represents a group selected from Ci-C4-alkyl, 0-C3-fluoroalkyl, C3-C4-cycloalkyl, (cyclopropyl)-(methyl)- and allyl;
R14 and R14a, independently from each other, represent a hydrogen atom or a group selected from methyl and ethyl,
or
R14 and R14a, together with the nitrogen atom they are attached to, represent a 5- to 6- membered heterocycloalkyl group selected from pyrrolidinyl, piperidinyl and morpholinyl, said group being optionally substituted once with a group selected from methyl, methoxy and (methoxy)-(methyl)-;
R15 represents a group selected from ethyl, 3,3,3-trifluoropropyl, (3-methoxy)-(propyl)-, (2'- methoxy)-(2-ethoxy)-(ethyl)-, cyclopropyl, cyclohexyl and tetrahydropyranyl, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In accordance with a tenth embodiment of the first aspect, the present invention compounds of general formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000055_0001
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group;
R2 represents a group
Figure imgf000055_0002
in which "*" represents the point of attachment to the rest of the molecule;
R3 represents a hydrogen atom, a fluorine atom or a chlorine atom;
R4 represents a hydrogen atom or a methyl group;
R5 represents a hydrogen atom;
R6 represents a group selected from methyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl and (C3-C5-cycloalkyl)-(methyl)-,
said (C3-C5-cycloalkyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom, a chlorine atom or with a methyl group;
R7 represents a group selected from Ci-C3-alkyl, difluoromethyl, trifluoromethyl, (methoxy)-(methyl)-, cyclopropyl, -NR11R11a, Ci-C3-alkoxy, Ci-C3-fluoroalkoxy, (C3-C4- cycloalkyl)-(methoxy)- and [1 -(trifluoromethyl)cyclopropyl]-(methoxy)-; or
R6 and R7, or two R7 groups, when being attached to adjacent ring atoms of the group R\ together form a group selected from -(0-CH=CH)- and -(NR16-(CH2)2-0)-;
R9 represents a hydrogen atom or a methyl group;
R10 represents a group selected from -C(=0)R12, -C(=0)N(R14)R14a, -S(=0)2R15 and -S(=0)2N(R14)R14a;
R11 and R11a, independently from each other, represent a hydrogen atom or a group selected from Ci-C3-alkyl, 2,2,2-trifluoroethyl, C3-C4-cycloalkyl, (Ci-C2-alkoxy)-(Ci-C3-alkyl)- and (C3-C4-cycloalkyl)-(methyl)-,
or
R11 and R11a, together with the nitrogen atom they are attached to, represent a 4- to 6- membered heterocycloalkyl group, said group being optionally substituted one or two times with a fluorine atom or a trifluoromethyl group;
R12 represents a group selected from Ci-C2-fluoroalkyl, C3-C4-cycloalkyl, 2-hydroxyprop-2- yl, (2-methoxy)-(prop-2-yl)-, (l-trifluoromethyl)-(cyclopropyl)-, 2,2-difluorocyclopropyl,
2,2-difluoro-1 -methylcyclopropyl and (cyclopropyl)-(methyl)-;
R14 and R14a, independently from each other, represent a group selected from methyl and ethyl,
or
R14 and R14a, together with the nitrogen atom they are attached to, represent a 5- to 6- membered heterocycloalkyl group selected from pyrrolidinyl, piperidinyl and morpholinyl, said group being optionally substituted one or two times, identically or differently, with a group selected from methyl, methoxy and (methoxy)-(methyl)-;
R15 represents a group selected from ethyl, 3,3,3-trifluoropropyl, (3-methoxy)-(propyl)-, (2'- methoxy)-(2-ethoxy)-(ethyl)-, cyclopropyl, cyclohexyl and tetrahydropyranyl;
R16 represents a hydrogen atom or a methyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In accordance with a eleventh embodiment of the first aspect, the present invention covers compounds of general formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000057_0001
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group;
R2 represents a group
Figure imgf000057_0002
in which "*" represents the point of attachment to the rest of the molecule;
R3 represents a hydrogen atom, a fluorine atom or a chlorine atom;
R4 represents a hydrogen atom or a methyl group;
R5 represents a hydrogen atom;
R6 represents a group selected from methyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyi and (C3-C5-cycloalkyl)-(methyl)-,
said (C3-C5-cycloalkyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom, a chlorine atom or with a methyl group;
R7 represents a group selected from Ci-C3-alkyl, difluoromethyl, trifluoromethyl, (methoxy)-(methyl)-, cyclopropyl,-NR11 R11a, Ci-C3-alkoxy, Ci-C3-fluoroalkoxy, (C3-C4- cycloalkyl)-(methoxy)- and [1 -(trifluoromethyl)cyclopropyl]-(methoxy)-; or
R6 and R7, or two R7 groups, when being attached to adjacent ring atoms of the group R1, together form a group selected from -(0-CH=CH)- and -(NR16-(CH2)2-0)-;
R9 represents a methyl group;
R10 represents a group selected from -C(=0)R12, -C(=0)N(R14)R14a, -S(=0)2R15 and -S(=0)2N(R14)R14a;
R11 and R11a, independently from each other, represent a hydrogen atom or a group selected from Ci-C3-alkyl, 2,2,2-trifluoroethyl, C3-C4-cycloalkyl, (Ci-C2-alkoxy)-(Ci-C3-alkyl)- and (C3-C4-cycloalkyl)-(methyl)-,
or
R11 and R11a, together with the nitrogen atom they are attached to, represent a 4- to 6- membered heterocycloalkyl group, said group being optionally substituted one or two times with a fluorine atom or a trifluoromethyl group;
R12 represents a group selected from 0-C2-fluoroalkyl, C3-C4-cycloalkyl, 2-hydroxyprop-2- yl, (2-methoxy)-(prop-2-yl)-, (l-trifluoromethyl)-(cyclopropyl)-, 2,2-difluorocyclopropyl,
2,2-difluoro-1-methylcyclopropyl and (cyclopropyl)-(methyl)-;
R14 and R14a, independently from each other, represent a group selected from methyl and ethyl,
or
R14 and R14a, together with the nitrogen atom they are attached to, represent a 5- to 6- membered heterocycloalkyl group selected from pyrrolidinyl, piperidinyl and morpholinyl, said group being optionally substituted one or two times, identically or differently, with a group selected from methyl, methoxy and (methoxy)-(methyl)-;
R15 represents a group selected from ethyl, 3,3,3-trifluoropropyl, (3-methoxy)-(propyl)-, (2'- methoxy)-(2-ethoxy)-(ethyl)-, cyclopropyl, cyclohexyl and tetrahydropyranyl;
R16 represents a hydrogen atom or a methyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In accordance with a twelfth embodiment of the first aspect, the present invention compounds of general formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000059_0001
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group; represents a group
Figure imgf000059_0002
in which "*" represents the point of attachment to the rest of the molecule;
R3 represents a hydrogen atom, a fluorine atom or a chlorine atom;
R4 represents a hydrogen atom or a methyl group;
R5 represents a hydrogen atom;
R6 represents a group selected from methyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl and (C3-C5-cycloal kyl )-(methyl )-,
said (C3-C5-cycloalkyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom, a chlorine atom or with a methyl group; R7 represents a group selected from Ci-C3-alkyl, difluoromethyl, trifluoromethyl, (methoxy)-(methyl)-, cyclopropyl,-NR11R11a, Ci-C3-alkoxy, Ci-C3-fluoroalkoxy, (C3-C4- cycloalkyl)-(methoxy)- and [1-(trifluoromethyl)cyclopropyl]-(methoxy)-;
or
R6 and R7, or two R7 groups, when being attached to adjacent ring atoms of the group R1, together form a group selected from -(0-CH=CH)- and -(NR16-(CH2)2-0)-;
R9 represents a hydrogen atom or a methyl group;
R10 represents a group selected from -C(=0)R12 and -C(=0)N(R14)R14a;
R11 and R11a, independently from each other, represent a hydrogen atom or a group selected from Ci-C3-alkyl, 2,2,2-trifluoroethyl, C3-C4-cycloalkyl, (Ci-C2-alkoxy)-(Ci-C3-alkyl)- and
(C3-C4-cycloalkyl)-(methyl)-,
or
R1 and R11a, together with the nitrogen atom they are attached to, represent a 4- to 6- membered heterocycloalkyl group, said group being optionally substituted one or two times with a fluorine atom or a trifluoromethyl group;
R12 represents a group selected from 0-C2-fluoroalkyl, C3-C4-cycloalkyl, 2-hydroxyprop-2- yl, (2-methoxy)-(prop-2-yl)-, (l -trifluoromethyl)-(cyclopropyl)-, 2,2-difluorocyclopropyl, 2,2-difluoro-1 -methylcyclopropyl and (cyclopropyl)-(methyl)-;
R14 and R14a, independently from each other, represent a group selected from methyl and ethyl,
or
R14 and R14a, together with the nitrogen atom they are attached to, represent a 5- to 6- membered heterocycloalkyl group selected from pyrrolidinyl, piperidinyl and morpholinyl, said group being optionally substituted one or two times, identically or differently, with a group selected from methyl, methoxy and (methoxy)-(methyl)-;
R16 represents a hydrogen atom or a methyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In accordance with a thirteenth embodiment of the first aspect, the present invention compounds of general formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000061_0001
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group; represents a group
Figure imgf000061_0002
in which "*" represents the point of attachment to the rest of the molecule;
R3 represents a hydrogen atom, a fluorine atom or a chlorine atom;
R4 represents a hydrogen atom or a methyl group;
R5 represents a hydrogen atom;
R6 represents a group selected from methyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl and (C3-C5-cycloalkyl)-(methyl)-,
said (C3-C5-cycloalkyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom, a chlorine atom or with a methyl group; R7 represents a group selected from Ci-C3-alkyl, difluoromethyl, trifluoromethyl, (methoxy)-(methyl)-, cyclopropyl,-NR11R11a, Ci-C3-alkoxy, Ci-C3-fluoroalkoxy, (C3-C4- cycloalkyl)-(methoxy)- and [1-(trifluoromethyl)cyclopropyl]-(methoxy)-;
or
R6 and R7, or two R7 groups, when being attached to adjacent ring atoms of the group R1, together form a group selected from -(0-CH=CH)- and -(NR16-(CH2)2-0)-;
R9 represents a methyl group;
R10 represents a group selected from -C(=0)R12 and -C(=0)N(R14)R14a;
R11 and R11a, independently from each other, represent a hydrogen atom or a group selected from Ci-C3-alkyl, 2,2,2-trifluoroethyl, C3-C4-cycloalkyl, (Ci-C2-alkoxy)-(Ci-C3-alkyl)- and
(C3-C4-cycloalkyl)-(methyl)-,
or
R 1 and R1 a, together with the nitrogen atom they are attached to, represent a 4- to 6- membered heterocycloalkyl group, said group being optionally substituted one or two times with a fluorine atom or a trifluoromethyl group;
R12 represents a group selected from Ci-C2-fluoroalkyl, C3-C4-cycloalkyl, 2-hydroxyprop-2- yl, (2-methoxy)-(prop-2-yl)-, ( -trifluoromethyl)-(cyclopropyl)-, 2,2-difluorocyclopropyl, 2,2-difluoro-1 -methylcyclopropyl and (cyclopropyl)-(methyl)-;
R14 and R14a, independently from each other, represent a group selected from methyl and ethyl,
or
R14 and R14a, together with the nitrogen atom they are attached to, represent a 5- to 6- membered heterocycloalkyl group selected from pyrrolidinyl, piperidinyl and morpholinyl, said group being optionally substituted one or two times, identically or differently, with a group selected from methyl, methoxy and (methoxy)-(methyl)-;
R16 represents a hydrogen atom or a methyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In accordance with a fourteenth embodiment of the first aspect, the present invention covers compounds of general formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000063_0001
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group; R2 represents a group
Figure imgf000063_0002
in which "*" represents the point of attachment to the rest of the molecule;
R3 represents a hydrogen atom, a fluorine atom or a chlorine atom;
R4 represents a hydrogen atom or a methyl group;
R5 represents a hydrogen atom;
R6 represents a group selected from methyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl and (C3-C5-cycloalkyl)-(methyl)-,
said (C3-C5-cycloalkyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom, a chlorine atom or with a methyl group;
R7 represents a group selected from Ci-C3-alkyl, difluoromethyl, trifluoromethyl, (methoxy)-(methyl)-, cyclopropyl, 2-oxa-6-azaspiro[3.3]heptyl-, -NR11R11a, C1-C3- alkoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, (C3-C4-cycloalkyl)-(methoxy)- and [1 - (trifluoromethyl)cyclopropyl]-(methoxy)-; R6 and R7, or two R7 groups, when being attached to adjacent ring atoms of the group R1, together form a group selected from -(0-CH=CH)- and -(NR16-(CH2)2-0)-;
R9 represents a hydrogen atom or a methyl group;
R 0 represents a group selected from -C(=0)R12, -C(=0)N(R14)R14a, -S(=0)2R15 and -S(=0)2N(R14)R14a;
R11 and R11a, independently from each other, represent a hydrogen atom or a group selected from Ci-C3-alkyl, 2,2,2-trifluoroethyl, C3-C4-cycloalkyl, (Ci-C2-alkoxy)-(Ci-C3-alkyl)- and (C3-C4-cycloalkyl)-(methyl)-,
or
R11 and R11a, together with the nitrogen atom they are attached to, represent a 4- to 6- membered heterocycloalkyl group, said group being optionally substituted one or two times with a fluorine atom or a trifluoromethyl group;
R12 represents a group selected from Ci-C2-fluoroalkyl, C3-C4-cycloalkyl, (1 -trifluoromethyl)- (cyclopropyl)- and (cyclopropyl)-(methyl)-;
R14 and R14a, independently from each other, represent a group selected from methyl and ethyl,
or
R14 and R14a, together with the nitrogen atom they are attached to, represent a 5- to 6- membered heterocycloalkyl group selected from pyrrolidinyl, piperidinyl and morpholinyl, said group being optionally substituted one or two times, identically or differently, with a group selected from methyl, methoxy and (methoxy)-(methyl)-;
R15 represents a group selected from ethyl, 3,3,3-trifluoropropyl, (3-methoxy)-(propyl)-, (2'- methoxy)-(2-ethoxy)-(ethyl)-, cyclopropyl, cyclohexyl and tetrahydropyranyl;
R16 represents a hydrogen atom or a methyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In accordance with a fifteenth embodiment of the first aspect, the present invention compounds of general formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000065_0001
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group; represents a group
Figure imgf000065_0002
in which "*" represents the point of attachment to the rest of the molecule;
represents a hydrogen atom, a fluorine atom or a chlorine atom;
represents a hydrogen atom or a methyl group;
represents a hydrogen atom;
represents a group selected from methyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl and (C3-C5-cycloalkyl)-(methyl)-,
said (C3-C5-cycloalkyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom, a chlorine atom or with a methyl group;
represents a group selected from Ci-C3-alkyl, difluoromethyl, trifluoromethyl, (methoxy)-(methyl)-, cyclopropyl, 2-oxa-6-azaspiro[3.3]heptyl-, -NR11R11a, C1-C3- alkoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, (C3-C4-cycloalkyl)-(methoxy)- and [1 - (trifluoromethyl)cyclopropyl]-(methoxy)-; R6 and R7, or two R7 groups, when being attached to adjacent ring atoms of the group R1, together form a group selected from -(0-CH=CH)- and -(NR16-(CH2)2-0)-;
R9 represents a methyl group;
R10 represents a group selected from -C(=0)R12, -C(=0)N(R14)R14a, -S(=0)2R15 and -S(=0)2N(R14)R14a;
R1 and R11a, independently from each other, represent a hydrogen atom or a group selected from Ci-Ca-alkyl, 2,2,2-trifluoroethyl, C3-C4-cycloalkyl, (Ci-C2-alkoxy)-(Ci-C3-alkyl)- and (C3-C4-cycloalkyl)-(methyl)-,
or
R11 and R11a, together with the nitrogen atom they are attached to, represent a 4- to 6- membered heterocycloalkyl group, said group being optionally substituted one or two times with a fluorine atom or a trifluoromethyl group;
R12 represents a group selected from Ci-C2-fluoroalkyl, C3-C4-cycloalkyl, (1 -trifluoromethyl)- (cyclopropyl)- and (cyclopropyl)-(methyl)-;
R14 and R14a, independently from each other, represent a group selected from methyl and ethyl,
or
R14 and R14a, together with the nitrogen atom they are attached to, represent a 5- to 6- membered heterocycloalkyl group selected from pyrrolidinyl, piperidinyl and morpholinyl, said group being optionally substituted one or two times, identically or differently, with a group selected from methyl, methoxy and (methoxy)-(methyl)-;
R15 represents a group selected from ethyl, 3,3,3-trifluoropropyl, (3-methoxy)-(propyl)-, (2'- methoxy)-(2-ethoxy)-(ethyl)-, cyclopropyl, cyclohexyl and tetrahydropyranyl;
R16 represents a hydrogen atom or a methyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In accordance with a sixteenth embodiment of the first aspect, the present invention covers compounds of general formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000067_0001
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group; R2 represents a group
Figure imgf000067_0002
in which "*" represents the point of attachment to the rest of the molecule;
R3 represents a hydrogen atom, a fluorine atom or a chlorine atom;
R4 represents a hydrogen atom or a methyl group;
R5 represents a hydrogen atom;
R6 represents a group selected from methyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl and (C3-C5-cycloalkyl)-(methyl)-,
said (C -cycloalkyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom, a chlorine atom or with a methyl group;
R7 represents a group selected from Ci-C3-alkyl, difluoromethyl, trifluoromethyl, (methoxy)-(methyl)-, cyclopropyl, 2-oxa-6-azaspiro[3.3]heptyl-, -NR11R1 a, C1-C3- alkoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, (C3-C4-cycloalkyl)-(methoxy)- and [1- (trifluoromethyl)cyclopropyl]-(methoxy)-; R6 and R7, or two R7 groups, when being attached to adjacent ring atoms of the group R1, together form a group selected from -(0-CH=CH)- and -(NR16-(CH2)2-0)-;
R9 represents a hydrogen atom or a methyl group;
R10 represents a group selected from -C(=0)R12 and -C(=0)N(R14)R14a;
R11 and R11a, independently from each other, represent a hydrogen atom or a group selected from Ci-C3-alkyl, 2,2,2-trifluoroethyl, C3-C4-cycloalkyl, (Ci-C2-alkoxy)-(Ci-C3-alkyl)- and (C3-C4-cycloalkyl)-(methyl)-,
or
R11 and R 1a, together with the nitrogen atom they are attached to, represent a 4- to 6- membered heterocycloalkyi group, said group being optionally substituted one or two times with a fluorine atom or a trifluoromethyl group;
R12 represents a group selected from Ci-C2-fluoroalkyl, C3-C4-cycloalkyl, (1-trifluoromethyl)- (cyclopropyl)- and (cyclopropyl)-(methyl)-;
R14 and R14a, independently from each other, represent a group selected from methyl and ethyl,
or
R14 and R14a, together with the nitrogen atom they are attached to, represent a 5- to 6- membered heterocycloalkyi group selected from pyrrolidinyl, piperidinyl and morpholinyl;
R16 represents a hydrogen atom or a methyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In accordance with a seventeenth embodiment of the first aspect, the present invention covers compounds of general formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000069_0001
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group; represents a group
Figure imgf000069_0002
in which "*" represents the point of attachment to the rest of the molecule;
represents a hydrogen atom, a fluorine atom or a chlorine atom;
represents a hydrogen atom or a methyl group;
represents a hydrogen atom;
represents a group selected from methyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl and (C3-C5-cycloalkyl)-(methyl)-,
said (C3-C5-cycloalkyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom, a chlorine atom or with a methyl group;
represents a group selected from Ci-C3-alkyl, difluoromethyl, trifluoromethyl, (methoxy)-(methyl)-, cyclopropyl, 2-oxa-6-azaspiro[3.3]heptyl-, -NR11R11a, C1-C3- alkoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, (C3-C4-cycloalkyl)-(methoxy)- and [1 - (trifluoromethyl)cyclopropyl]-(methoxy)-; R6 and R7, or two R7 groups, when being attached to adjacent ring atoms of the group R1, together form a group selected from -(0-CH=CH)- and -(NR16-(CH2)2-0)-;
R9 represents a methyl group;
R10 represents a group selected from -C(=0)R12 and -C(=0)N(R14)R14a;
R and R11a, independently from each other, represent a hydrogen atom or a group selected from Ci-C3-alkyl, 2,2,2-trifluoroethyl, C3-C4-cycloalkyl, (Ci-C2-alkoxy)-(Ci-C3-alkyl)- and (C3-C4-cycloalkyl)-(methyl)-,
or
R11 and R11a, together with the nitrogen atom they are attached to, represent a 4- to 6- membered heterocycloaikyi group, said group being optionally substituted one or two times with a fluorine atom or a trifluoromethyl group;
R12 represents a group selected from Ci-C2-fluoroalkyl, C3-C4-cycloalkyl, (1 -trifluoromethyl)- (cyclopropyl)- and (cyclopropyl)-(methyl)-;
R14 and R14a, independently from each other, represent a group selected from methyl and ethyl,
or
R14 and R14a, together with the nitrogen atom they are attached to, represent a 5- to 6- membered heterocycloaikyi group selected from pyrrolidinyl, piperidinyl and morpholinyl;
R16 represents a hydrogen atom or a methyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In accordance with a eighteenth embodiment of the first aspect, the present invention compounds of general formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000071_0001
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, besides R6, optionally substituted with one further R7 group; represents a group
Figure imgf000071_0002
in which "*" represents the point of attachment to the rest of the molecule;
represents a hydrogen atom;
represents a hydrogen atom or a methyl group;
represents a hydrogen atom;
represents a group selected from methyl, ethyl, 2,2,2-trifluoroethyl and (cyclopropyl)- (methyl)-,
said (cyclopropyl)-(methyl)- group being optionally substituted one or two times with a fluorine atom;
represents a group selected from Ci-C3-alkyl, trifluoromethyl, cyclopropyl,Ci-C3-alkoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy and (cyclopropyl)-(methoxy)-;
represents a hydrogen atom or a methyl group;
represents a group selected from -C(=0)R12, -C(=0)N(R14)R14a, -S(=0)2R15 and - S(=0)2N(R14)R14a, R12 represents a group selected from Ci-C2-fluoroalkyl, C3-C4-cycloalkyl and (cyclopropyl)- (methyl)-;
R14 and R14a, independently from each other, represent a group selected from methyl and ethyl,
or
R14 and R1 a, together with the nitrogen atom they are attached to, represent a 5- to 6- membered heterocycloalkyl group selected from pyrrolidinyl, piperidinyl and morpholinyl, said group being optionally substituted once with a group selected from methyl, methoxy and (methoxy)-(methyl)-;
R15 represents a group selected from ethyl, 3,3,3-trifluoropropyl, (3-methoxy)-(propyl)-, (2'- methoxy)-(2-ethoxy)-(ethyl)-, cyclopropyl, cyclohexyl and tetrahydropyranyl, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In accordance with a nineteenth embodiment of the first aspect, the present invention compounds of general formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000073_0001
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group;
represents a group
Figure imgf000073_0002
in which "*" represents the point of attachment to the rest of the molecule;
R3 represents a hydrogen atom, a fluorine atom or a chlorine atom,;
R4 represents a hydrogen atom;
R5 represents a hydrogen atom;
R6 represents a group selected from methyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, (cyclopropyl)-(methyl)-, (2,2-difluorocyclopropyl)-(methyl)-, (2,2-dichlorocyclopropyl)-
(methyl)-, (2,2-dimethylcyclopropyl)-(methyl)-, (2-methylcyclopropyl)-(methyl)-, (1- methylcyclopropyl)-(methyl)-, (l-chlorocyclopropyl)-(methyl)-, (cyclobutyl)-(methyl)-, 3,3-difluorocyclobutyl-(methyl)- and (cyclopentyl)-methyl)-;
R7 represents a group selected from Ci-C3-alkyl, trifluoromethyl, (methoxy)-(methyl)-, cyclopropyl,
-NR11R11a, Ci-C3-alkoxy, Ci-C3-fluoroalkoxy and (C3-C4-cycloalkyl)-(methoxy)-;
R9 represents a hydrogen atom or a methyl group;
R10 represents a -C(=0)R12 group;
R 1 and R11a, independently from each other, represent a hydrogen atom or a group selected from Ci-C3-alkyl, 2,2,2-trifluoroethyl, C3-C4-cycloalkyl, (Ci-C2-alkoxy)-(Ci-C3-alkyl)- and
(C3-C4-cycloalkyl)-(methyl)-,
or R11 and R11a, together with the nitrogen atom they are attached to, represent a 4- to 6- membered heterocycloalkyi group, said group being optionally substituted one or two times with a fluorine atom or a trifluoromethyl group;
R12 represents a group selected from Ci-C2-fluoroalkyl, C3-C4-cycloalkyl, 2-hydroxyprop-2- yl, (2-methoxy)-(prop-2-yl)-, (l -trifluoromethyl)-(cyclopropyl)- , 2,2-difluorocyclopropyl, 2,2-difluoro-1 -methylcyclopropyl and (cyclopropyl)-(methyl)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In accordance with a twentieth embodiment of the first aspect, the present invention covers compounds of general formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000074_0001
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group;
represents a group
Figure imgf000074_0002
in which "*" represents the point of attachment to the rest of the molecule;
R3 represents a hydrogen atom, a fluorine atom or a chlorine atom,;
R4 represents a hydrogen atom;
R5 represents a hydrogen atom;
R6 represents a group selected from methyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, (cyclopropyl)-(methyl)-, (2,2-difluorocyclopropy!)-(methyl)-, (2,2-dichlorocyclopropyl)- (methyl)-, (2,2-dimethylcyclopropyl)-(methyl)-, (2-methylcyclopropyl)-(methyl)-, (1 - methylcyclopropyl)-(methyl)-, (l -chlorocyclopropyl)-(methyl)-, (cyclobutyl)-(methyl)-, 3,3-difluorocyclobutyl-(methyl)- and (cyclopentyl)-methyl)-; R7 represents a group selected from Ci-C3-alkyl, trifluoromethyl, (methoxy)-(methyl)-, cyclopropyl,
-NR11R11a, Ci-C3-alkoxy, Ci-C3-fluoroalkoxy and (C3-C4-cycloalkyl)-(methoxy)-;
R9 represents a methyl group;
R 0 represents a -C(=0)R12 group;
R11 and R11a, independently from each other, represent a hydrogen atom or a group selected from Ci-C3-alkyl, 2,2,2-trifluoroethyl, C3-C4-cycloalkyl, (Ci-C2-alkoxy)-(Ci-C3-alkyl)- and (C3-C4-cycloalkyl)-(methyl)-,
or
R11 and R11a, together with the nitrogen atom they are attached to, represent a 4- to 6- membered heterocycloalkyl group, said group being optionally substituted one or two times with a fluorine atom or a trifluoromethyl group;
R12 represents a group selected from Ci-C2-fluoroalkyl, C3-C4-cycloalkyl, 2-hydroxyprop-2- yl, (2-methoxy)-(prop-2-yl)-, (l-trifluoromethyl)-(cyclopropyl)- , 2,2-difluorocyclopropyl, 2,2-difluoro-1 -methylcyclopropyl and (cyclopropyl)-(methyl)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In accordance with a twenty-first embodiment of the first aspect, the present invention covers compounds of general formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000075_0001
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group;
represents a group
Figure imgf000075_0002
in which "*" represents the point of attachment to the rest of the molecule;
R3 represents a hydrogen atom, a fluorine atom or a chlorine atom,;
R4 represents a hydrogen atom;
R5 represents a hydrogen atom;
R6 represents a group selected from methyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, (cyclopropyl)-(methyl)-, (2,2-difluorocyclopropyl)-(methyl)-, (2,2-dichlorocyclopropyl)- (methyl)-, (2,2-dimethylcyclopropyl)-(methyl)-, (2-methylcyclopropyl)-(methyl)-, (1- methylcyclopropyl)-(methyl)-, (l-chlorocyclopropyl)-(methyl)-, (cyclobutyl)-(methyl)-, 3,3-difluorocyclobutyl-(methyl)- and (cyclopentyl)-methyl)-;
R7 represents a group selected from Ci-C3-alkyl, trifluoromethyl, (methoxy)-(methyl)-, cyclopropyl,
-NR R11a, Ci-C3-alkoxy, Ci-C3-fluoroalkoxy and (C3-C4-cycloalkyl)-(metrioxy)-;
R9 represents a hydrogen atom or a methyl group;
R10 represents a -C(=0)R12 group;
R11 and R11a, independently from each other, represent a hydrogen atom or a group selected from Ci-C3-alkyl, 2,2,2-trifluoroethyl, C3-C4-cycloalkyl, (Ci-C2-alkoxy)-(Ci-C3-alkyl)- and (C3-C4-cycloalkyl)-(methyl)-,
or
R11 and R11a, together with the nitrogen atom they are attached to, represent a 4- to 6- membered heterocycloalkyl group, said group being optionally substituted one or two times with a fluorine atom or a trifluoromethyl group;
R12 represents a group selected from Ci-C2-fluoroalkyl, C3-C4-cycloalkyl, 2-hydroxyprop-2- yl, (2-methoxy)-(prop-2-yl)-, (l-trifluoromethyl)-(cyclopropyl)- , 2,2-difluorocyclopropyl, 2,2-difluoro-1 -methylcyclopropyl and (cyclopropyl)-(methyl)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In accordance with a twenty-second embodiment of the first aspect, the present invention covers compounds of general formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000076_0001
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group;
represents a group
Figure imgf000077_0001
in which "*" represents the point of attachment to the rest of the molecule;
R3 represents a hydrogen atom, a fluorine atom or a chlorine atom,;
R4 represents a hydrogen atom;
R5 represents a hydrogen atom;
R6 represents a group selected from methyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, (cyclopropyl)-(methyl)-, (2,2-difluorocyclopropyl)-(methyl)-, (2,2-dichlorocyclopropyl)- (methyl)-, (2,2-dimethylcyclopropyl)-(methyl)-, (2-methylcyclopropyl)-(methyl)-, (1 - methylcyclopropyl)-(methyl)-, (l-chlorocyclopropyl)-(methyl)-, (cyclobutyl)-(methyl)-, 3,3-difluorocyclobutyl-(methyl)- and (cyclopentyl)-methyl)-;
R7 represents a group selected from Ci-C3-alkyl, trifluoromethyl, (methoxy)-(methyl)-, cyclopropyl,
-NR11R11a, Ci-C3-alkoxy, Ci-C3-fluoroalkoxy and (C3-C4-cycloalkyl)-(methoxy)-;
R9 represents a methyl group;
R10 represents a -C(=0)R12 group;
R11 and R11a, independently from each other, represent a hydrogen atom or a group selected from CrC3-alkyl, 2,2,2-trifluoroethyl, C3-C4-cycloalkyl, (Ci-C2-alkoxy)-(CrC3-alkyl)- and (C3-C4-cycloalkyl)-(methyl)-,
or
R11 and R11a, together with the nitrogen atom they are attached to, represent a 4- to 6- membered heterocycloalkyi group, said group being optionally substituted one or two times with a fluorine atom or a trifluoromethyl group;
R12 represents a group selected from Ci-C2-fluoroalkyl, C3-C4-cycloalkyl, 2-hydroxyprop-2- yl, (2-methoxy)-(prop-2-yl)-, ( -trifluoromethyl)-(cyclopropyl)- , 2,2-difluorocyclopropyl, 2,2-difluoro-1 -methylcyclopropyl and (cyclopropyl)-(methyl)-, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In accordance with a twenty-third embodiment of the first aspect, the present invention covers compounds of general formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000078_0001
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group; represents a group
Figure imgf000078_0002
in which "*" represents the point of attachment to the rest of the molecule;
R3 represents a hydrogen atom, a fluorine atom or a chlorine atom,;
R4 represents a hydrogen atom;
R5 represents a hydrogen atom;
R6 represents a group selected from methyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, (cyclopropyl)-(methyl)-, (2,2-difluorocyclopropyl)-(methyl)-, (2,2-dichlorocyclopropyl)- (methyl)-, (2,2-dimethylcyclopropyl)-(methyl)-, (2-methylcyclopropyl)-(methyl)-, (1- methylcyclopropyl)-(methyl)-, (l-chlorocyclopropyl)-(methyl)-, (cyclobutyl)-(methyl)-, 3,3-difluorocyclobutyl-(methyl)- and (cyclopentyl)-methyl)-;
R7 represents a group selected from Ci-C3-alkyl, (methoxy)-(methyl)-, cyclopropyl, -NR11R11a, Ci-C3-alkoxy and (C3-C4-cycloalkyl)-(methoxy)-;
R9 represents a hydrogen atom or a methyl group;
R10 represents a -C(=0)R12 group; R11 and R11a, independently from each other, represent a hydrogen atom or a group selected from Ci-C3-alkyl, 2,2,2-trifluoroethyl, Cs-C-t-cycloalkyl, (Ci-C2-alkoxy)-(Ci-C3-alkyl)- and (C3-C4-cycloalkyl )-(methyl )-,
or
R11 and R11a, together with the nitrogen atom they are attached to, represent a 4- to 6- membered heterocycloalkyl group, said group being optionally substituted one or two times with a fluorine atom;
R 2 represents a group selected from Ci-C2-fluoroalkyl, C3-C4-cycloalkyl, (1 -trifluoromethyl)- (cyclopropyl)- and (cyclopropyl)-(methyl)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In accordance with a twenty-fourth embodiment of the first aspect, the present invention compounds of general formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000079_0001
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group; represents a group
Figure imgf000079_0002
in which "*" represents the point of attachment to the rest of the molecule;
represents a hydrogen atom, a fluorine atom or a chlorine atom,;
represents a hydrogen atom;
represents a hydrogen atom; R6 represents a group selected from methyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, (cyclopropyl)-(methyl)-, (2,2-difluorocyclopropyl)-(methyl)-, (2,2-dichlorocyclopropyl)- (methyl)-, (2,2-dimethylcyclopropyl)-(methyl)-, (2-methylcyclopropyl)-(methyl)-, (1 - methylcyclopropyl)-(methyl)-, (l-chlorocyclopropyl)-(methyl)-, (cyclobutyl)-(methyl)-, 3,3-difluorocyclobutyl-(methyl)- and (cyc!opentyl)-methyl)-;
R7 represents a group selected from Ci-C3-alkyl, (methoxy)-(methyl)-, cyclopropyl, - NR11R1 a, Ci-C3-alkoxy and (C3-C4-cycloalkyl)-(methoxy)-;
R9 represents a hydrogen atom or a methyl group;
R10 represents a -C(=0)R12 group;
R11 and R11a, independently from each other, represent a hydrogen atom or a group selected from Ci-C3-alkyl, 2,2,2-trifluoroethyl, C3-C4-cycloalkyl, (Ci-C2-alkoxy)-(Ci-C3-alkyl)- and (C3-C4-cycloalkyl)-(methyl)-,
or
R11 and R11a, together with the nitrogen atom they are attached to, represent a 4- to 6- membered heterocycloalkyl group, said group being optionally substituted one or two times with a fluorine atom;
R12 represents a group selected from Ci-C2-fluoroalkyl, C3-C4-cycloalkyl, (1-trifluoromethyl)- (cyclopropyl)- and (cyclopropyl)-(methyl)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In accordance with a twenty-fifth embodiment of the first aspect, the present invention covers compounds of general formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000080_0001
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group;
represents a group
Figure imgf000081_0001
in which "*" represents the point of attachment to the rest of the molecule;
R3 represents a hydrogen atom, a fluorine atom or a chlorine atom,;
R4 represents a hydrogen atom;
R5 represents a hydrogen atom;
R6 represents a group selected from methyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, (cyclopropyl)-(methyl)-, (2,2-difluorocyclopropyl)-(methyl)-, (2,2-dichlorocyclopropyl)- (methyl)-, (2,2-dimethylcyclopropyl)-(methyl)-, (2-methylcyclopropyl)-(methyl)-, (1- methylcyclopropyl)-(methyl)-, (l-chlorocyclopropyl)-(methyl)-, (cyclobutyl)-(methyl)-, 3,3-difluorocyclobutyl-(methyl)- and (cyclopentyl)-methyl)-;
R7 represents a group selected from Ci-C3-alkyl, (methoxy)-(methyl)-, cyclopropyl, - NR11R11a, Ci-C3-alkoxy and (C3-C4-cycloalkyl)-(methoxy)-;
R9 represents a methyl group;
R10 represents a -C(=0)R12 group;
R11 and R11a, independently from each other, represent a hydrogen atom or a group selected from Ci-C3-alkyl, 2,2,2-trifluoroethyl, C3-C4-cycloalkyl, (Ci-C2-alkoxy)-(Ci-C3-alkyl)- and (C3-C4-cycloalkyl )-(methyl )-,
or
R11 and R11a, together with the nitrogen atom they are attached to, represent a 4- to 6- membered heterocycloalkyi group, said group being optionally substituted one or two times with a fluorine atom;
R12 represents a group selected from Ci-C2-fluoroalkyl, C3-C4-cycloalkyl, (1 -trifluoromethyl)- (cyclopropyl)- and (cyclopropyl)-(methyl)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In accordance with a twenty-sixth embodiment of the first aspect, the present invention covers compounds of general formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000082_0001
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group;
represents a group
Figure imgf000082_0002
in which "*" represents the point of attachment to the rest of the molecule;
R3 represents a hydrogen atom, a fluorine atom or a chlorine atom,;
R4 represents a hydrogen atom;
R5 represents a hydrogen atom;
R6 represents a group selected from methyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, (cyclopropyl)-(methyl)-, (2,2-difluorocyclopropyl)-(methyl)-, (2,2-dichlorocyclopropyl)-
(methyl)-, (2,2-dimethylcyclopropyl)-(methyl)-, (2-methylcyclopropyl)-(methyl)-, (1 - methylcyclopropyl)-(methyl)-, (l-chlorocyclopropyl)-(methyl)-, (cyclobutyl)-(methyl)-, 3,3-difluorocyclobutyl-(methyl)- and (cyclopentyl)-methyl)-;
R7 represents a group selected from Ci-C3-alkyl, (methoxy)-(methyl)-, cyclopropyl, - NR11R11a, Ci-C3-alkoxy and (C3-C4-cycloalkyl)-(methoxy)-;
R9 represents a methyl group;
R10 represents a -C(=0)R12 group;
R11 and R11a, independently from each other, represent a hydrogen atom or a group selected from Ci-C3-alkyl, 2,2,2-trifluoroethyl, C3-C4-cycloalkyl, (Ci-C2-alkoxy)-(Ci-C3-alkyl)- and (C3-C4-cycloalkyl)-(methyl)-,
or R11 and R1 a, together with the nitrogen atom they are attached to, represent a 4- to 6- membered heterocycioalkyi group, said group being optionally substituted one or two times with a fluorine atom;
R12 represents a group selected from Ci-C2-fluoroalkyl, C3-C4-cycloalkyl, (1-trifluoromethyl)- (cyclopropyl)- and (cyclopropyl)-(methyl)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In accordance with a twenty-seventh embodiment of the first aspect, the present invention covers compounds of general formula (I), supra, in which:
represents a group selected from
Figure imgf000083_0001
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, besides R6, optionally substituted with one further R7 group;
R2 represents a group
Figure imgf000083_0002
in which "*" represents the point of attachment to the rest of the molecule;
R3 represents a hydrogen atom;
R4 represents a hydrogen atom;
R5 represents a hydrogen atom;
R6 represents a group selected from methyl, ethyl, 2,2,2-trifluoroethyl, (cyclopropyl)- (methyl)- and (2,2-difluorocyclopropyl)-(methyl)-;
R7 represents a group selected from methyl, trifluoromethyl, cyclopropyl, methoxy, ethoxy, iso-propoxy, 2,2,2-trifluoroethoxy and (cyclopropyl)-(methoxy)-;
R9 represents a hydrogen atom or a methyl group; R10 represents a -C(=0)R12 group;
R12 represents a group selected from Ci-C2-fluoroalkyl, C3-C4-cycloalkyl and (cyclopropyl)- (methyl)-;
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In accordance with a twenty-eigth embodiment of the first aspect, the present invention covers compounds of general formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000084_0001
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, besides R6, optionally substituted with one further R7 group;
R2 represents a group
Figure imgf000084_0002
in which "*" represents the point of attachment to the rest of the molecule;
R3 represents a hydrogen atom;
R4 represents a hydrogen atom;
R5 represents a hydrogen atom;
R6 represents a group selected from methyl, ethyl, 2,2,2-trifluoroethyl, (cyclopropyl)- (methyl)- and (2,2-difluorocyclopropyl)-(methyl)-;
R7 represents a group selected from methyl, trifluoromethyl, cyclopropyl, methoxy, ethoxy, iso-propoxy, 2,2,2-trifluoroethoxy and (cyclopropyl)-(methoxy)-;
R9 represents a methyl group;
R 0 represents a -C(=0)R12 group; R12 represents a group selected from Ci-C2-fluoroalkyl, C3-C4-cycloalkyl and (cyclopropyl)- (methyl)-;
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In accordance with a twenty-ninth embodiment of the first aspect, the present invention covers compounds of general formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000086_0001
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group;
represents a group
Figure imgf000086_0002
in which "*" represents the point of attachment to the rest of the molecule;
R3 represents a hydrogen atom;
R4 represents a hydrogen atom;
R5 represents a hydrogen atom;
R6 represents a group selected from methyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, (cyclopropyl)-(methyl)-, (2,2-difluorocyclopropyl)-(methyl)-, (2,2-dichlorocyclopropyl)- (methyl)-, (2,2-dimethylcyclopropyl)-(methyl)-, (2-methylcyclopropyl)-(methyl)-, (1 - methylcyclopropyl)-(methyl)-, (1 -chlorocyclopropyl)-(methyl)-, (cyclobutyl)-(methyl)-, 3,3-difluorocyclobutyl-(methyl)- and (cyclopentyl)-methyl)-;
R7 represents a group selected from methyl, trifluoromethyl, (methoxy)-(methyl)-, ethylamino, isopropylamino, (cyclopropyl)-(methyl)-amino-, cyclopropylamino, cyclobutylamino, dimethylamino, azetidin-1 -yl, 3,3-difluoroazetidin-1 -yl, 3- trifluoromethylazetidin-1 -yl, pyrrolidin-1 -yl, piperidin-1-yl, morpholinyl, methoxy, ethoxy, iso-propoxy, 2,2,2-trifluoroethoxy, 2,2-difluoropropoxy and (cyclopropyl)-(methoxy)-;
R9 represents a hydrogen atom or a methyl group;
R10 represents a -C(=0)R12 group;
R12 represents a group selected from 2,2,2-trifluoroethyl, cyclopropyl, (1 -trifluoromethyl)- (cyclopropyl)-, 2,2-difluorocyclopropyl and 2,2-difluoro-1-methylcyclopropyl, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In accordance with a thirtieth embodiment of the first aspect, the present invention covers compounds of general formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000087_0001
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group;
represents a group
Figure imgf000087_0002
in which "*" represents the point of attachment to the rest of the molecule;
R3 represents a hydrogen atom;
R4 represents a hydrogen atom;
R5 represents a hydrogen atom;
R6 represents a group selected from methyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, (cyclopropyl)-(methyl)-, (2,2-difluorocyclopropyl)-(methyl)-, (2,2-dichlorocyclopropyl)- (methyl)-, (2,2-dimethylcyclopropyl)-(methyl)-, (2-methylcyclopropyl)-(methyl)-, (1 - methylcyclopropyl)-(methyl)-, (l-chlorocyclopropyl)-(methyl)-, (cyclobutyl)-(methyl)-, 3,3-difluorocyclobutyl-(methyl)- and (cyclopentyl)-methyl)-;
R7 represents a group selected from methyl, trifluoromethyl, (methoxy)-(methyl)-, ethylamino, isopropylamino, (cyclopropyl)-(methyl)-amino-, cyclopropylamino, cyclobutylamino, dimethylamino, azetidin-1 -yl, 3,3-difluoroazetidin-1 -yl, 3- trifluoromethylazetidin-1 -yl, pyrrolidin-1 -yl, piperidin-1 -yl, morpholinyl, methoxy, ethoxy, iso-propoxy, 2,2,2-trifluoroethoxy, 2,2-difluoropropoxy and (cyclopropyl)-(methoxy)-;
R9 represents a methyl group; R10 represents a -C(=0)R12 group;
R12 represents a group selected from 2,2,2-trifluoroethyl, cyclopropyl, (1 -trifluoromethyl)- (cyclopropyl)-, 2,2-difluorocyclopropyl and 2,2-difluoro-1 -methylcyclopropyl, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In accordance with a thirty-first embodiment of the first aspect, the present invention compounds of general formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000088_0001
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group;
represents a group
Figure imgf000088_0002
in which "*" represents the point of attachment to the rest of the molecule;
R3 represents a hydrogen atom;
R4 represents a hydrogen atom;
R5 represents a hydrogen atom;
R6 represents a group selected from methyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, (cyclopropyl)-(methyl)-, (2,2-difluorocyclopropyl)-(methyl)-, (2,2-dichlorocyclopropyl)- (methyl)-, (2,2-dimethylcyclopropyl)-(methyl)-, (2-methylcyclopropyl)-(methyl)-, (1- methylcyclopropyl)-(methyl)-, (l-chlorocyclopropyl)-(methyl)-, (cyclobutyl)-(methyl)-, 3,3-difluorocyclobutyl-(methyl)- and (cyclopentyl)-methyl)-;
R7 represents a group selected from methyl, trifluoromethyl, (methoxy)-(methyl)-, ethylamino, isopropylamino, (cyclopropyl)-(methyl)-amino-, cyclopropylamino, cyclobutylamino, dimethylamino, azetidin-1 -yl, 3,3-dif)uoroazetidin-1 -yl, pyrrolidin-1-yl, piperidin-1-yl, morpholinyl, methoxy, ethoxy, iso-propoxy and (cyclopropyl)-(methoxy)-;
R9 represents a hydrogen atom or a methyl group;
R10 represents a -C(=0)R12 group;
R12 represents a group selected from 2,2,2-trifluoroethyl, cyclopropyl, (1 -trifluoromefhyl)- (cyclopropyl)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In accordance with a thirty-second embodiment of the first aspect, the present invention covers compounds of general formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000089_0001
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group;
represents a group
Figure imgf000089_0002
in which "*" represents the point of attachment to the rest of the molecule;
represents a hydrogen atom;
represents a hydrogen atom;
represents a hydrogen atom;
represents a group selected from methyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, (cyclopropyl)-(methyl)-, (2,2-difluorocyclopropyl)-(methyl)-, (2,2-dichlorocyclopropyl)- (methyl)-, (2,2-dimethylcyclopropyl)-(methyl)-, (2-methylcyclopropyl)-(methyl)-, (1- methylcyclopropyl)-(methyl)-, (l-chlorocyclopropyl)-(methyl)-, (cyclobutyl)-(methyl)-, 3,3-difluorocyclobutyl-(methyl)- and (cyclopentyl)-methyl)-; R7 represents a group selected from methyl, trifluoromethyl, (methoxy)-(methyl)-, ethylamino, isopropylamino, (cyclopropyl)-(methyl)-amino-, cyclopropylamino, cyclobutylamino, dimethylamino, azetidin-1-yl, 3,3-difluoroazetidin-1 -yl, pyrrolidin-1-yl, piperidin-1-yl, morpholinyl, methoxy, ethoxy, iso-propoxy and (cyclopropyl)-(methoxy)-; R9 represents a methyl group;
R10 represents a -C(=0)R12 group;
R12 represents a group selected from 2,2,2-trifluoroethyl, cyclopropyl, (1 -trifluoromethyl)- (cyclopropyl)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In accordance with a thirty-third embodiment of the first aspect, the present invention covers compounds of general formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000090_0001
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, besides R6, optionally substituted with one further R7 group;
R2 represents a group
Figure imgf000090_0002
in which "*" represents the point of attachment to the rest of the molecule;
R3 represents a hydrogen atom;
R4 represents a hydrogen atom;
R5 represents a hydrogen atom;
R6 represents a group selected from methyl, ethyl, 2,2,2-trifluoroethyl, (cyclopropyl)- (methyl)- and (2,2-difluorocyclopropyl)-(methyl)-; R7 represents a group selected from methyl, trifluoromethyl, methoxy, ethoxy, iso-propoxy and (cyclopropyl)-(methoxy)-;
R9 represents a hydrogen atom or a methyl group;
R10 represents a -C(=0)R12 group;
R12 represents a group selected from 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl and (cyclopropyl)-(methyl)-;
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In accordance with an thirty-fourth embodiment of the first aspect, the present invention compounds of general formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000091_0001
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, besides R6, optionally substituted with one further R7 group;
R2 represents a group
Figure imgf000091_0002
in which "*" represents the point of attachment to the rest of the molecule;
R3 represents a hydrogen atom;
R4 represents a hydrogen atom;
R5 represents a hydrogen atom;
R6 represents a group selected from methyl, ethyl, 2,2,2-trifluoroethyl, (cyclopropyl )- (methyl)- and (2,2-difluorocyclopropyl)-(methyl)-;
R7 represents a group selected from methyl, trifluoromethyl, methoxy, ethoxy, iso- propoxy and (cyclopropyl )-(m ethoxy)-; R9 represents a methyl group;
R 0 represents a -C(=0)R12 group;
R12 represents a group selected from 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl and (cyclopropyl)-(methyl)-;
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In accordance with a thirty-fifth embodiment of the first aspect, the present invention compounds of general formula (I), supra, in which:
R1 represents a group
Figure imgf000093_0001
in which "*" represents the point of attachment to the rest of the molecule;
represents a group
Figure imgf000093_0002
in which "*" represents the point of attachment to the rest of the molecule;
R3 represents a hydrogen atom, a fluorine atom or a chlorine atom;
R4 represents a hydrogen atom;
R5 represents a hydrogen atom;
R6 represents a group selected from methyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, (cyclopropyl)-(methyl)-, (2,2-difluorocyclopropyl)-(methyl)-, (2,2-dichlorocyclopropyl)- (methyl)-, (2,2-dimethylcyclopropyl)-(methyl)-, (2-methylcyclopropyl)-(methyl)-, (1 - methylcyclopropyl)-(methyl)-, (l-chlorocyclopropyl)-(methyl)-, (cyclobutyl)-(methyl)-, 3,3-difluorocyclobutyl-(methyl)- and (cyclopentyl)-methyl)-;
R9 represents a methyl group;
R10 represents a -C(=0)R12 group;
R12 represents a group selected from 2,2,2-trifluoroethyl, cyclopropyl, (1 -trifluoromethyl)- (cyclopropyl)-, cyclobutyl and (cyclopropyl)-(methyl)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In accordance with a thirty-sixth embodiment of the first aspect, the present invention covers compounds of general formula (I), supra, in which:
R1 represents a group
Figure imgf000094_0001
in which "*" represents the point of attachment to the rest of the molecule
represents a group
Figure imgf000094_0002
in which "*" represents the point of attachment to the rest of the molecule;
R3 represents a hydrogen atom, a fluorine atom or a chlorine atom;
R4 represents a hydrogen atom;
R5 represents a hydrogen atom;
R6 represents a group selected from methyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, (cyclopropyl)-(methyl)-, (2,2-difluorocyclopropyl)-(methyl)-, (2,2-dichlorocyclopropyl)- (methy!)-, (2,2-dimethylcyclopropyl)-(methyl)-, (2-methylcyclopropyl)-(methyl)-, (1- methylcyclopropyl)-(methyl)-, (l-chlorocyclopropyl)-(methyl)-, (cyclobutyl)-(methyl)-, 3,3-difluorocyclobutyl-(methyl)- and (cyclopentyl)-methyl)-;
R9 represents a methyl group;
R10 represents a -C(=0)R12 group;
R12 represents a group selected from 2,2,2-trifluoroethyl, cyclopropyl, (1 -trifluoromethyl)- (cyclopropyl)-, cyclobutyl and (cyclopropyl)-(methyl)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In accordance with a thirty-seventh embodiment of the first aspect, the present invention covers compounds of general formula (I), supra, in which:
R1 represents a group
Figure imgf000095_0001
in which "*" represents the point of attachment to the rest of the molecule;
represents a group
Figure imgf000095_0002
in which "*" represents the point of attachment to the rest of the molecule;
R3 represents a hydrogen atom;
R4 represents a hydrogen atom;
R5 represents a hydrogen atom;
R6 represents a group selected from methyl, ethyl, 2,2,2-trifluoroethyl, (cyclopropyl)- (methyl)- and (2,2-difluorocyclopropyl)-(methyl)-;
R9 represents a methyl group;
R10 represents a -C(=0)R12 group;
R12 represents a group selected from 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl and (cyclopropyl)-(methyl)-;
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In accordance with a thirty-eigth embodiment of the first aspect, the present invention covers compounds of general formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000096_0001
in which "*" represents the point of attachment to the rest of the molecule,
said group being optionally substituted one or two times, differently or identically, with R7 group;
represents a group
Figure imgf000096_0002
in which "*" represents the point of attachment to the rest of the molecule;
R3 represents a hydrogen atom;
R4 represents a hydrogen atom;
R5 represents a hydrogen atom;
R7 represents a group selected from methyl, (methoxy)-(methyl)-, ethylamino, isopropylamino, (cyclopropyl)-(methyl)-amino-, cyclopropylamino, cyclobutylamino, dimethylamino, azetidin-1 -yl, 3,3-difluoroazetidin-1 -yl, 3-trifluoromethylazetidin-1 -yl, pyrrolidin-1 -yl, piperidin-1 -yl, morpholinyl, methoxy, ethoxy, iso-propoxy, 2,2,2- trifluoroethoxy, 2,2-difluoropropoxy and (cyclopropyl)-(methoxy)-;
R9 represents a methyl group;
R10 represents a -C(=0)R12 group;
R12 represents a group selected from 2,2,2-trifluoroethyl, cyclopropyl, (1 -trifluoromethyl)- (cyclopropyl)-, 2,2-difluorocyclopropyl and 2,2-difluoro-1 -methylcyclopropyl, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In accordance with a thirty-ninth embodiment of the first aspect, the present invention covers compounds of general formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000097_0001
in which "*" represents the point of attachment to the rest of the molecule,
said group being optionally substituted one or two times, differently or identically, with R7 group;
represents a group
Figure imgf000097_0002
in which "*" represents the point of attachment to the rest of the molecule;
R3 represents a hydrogen atom;
R4 represents a hydrogen atom;
R5 represents a hydrogen atom;
R7 represents a group selected from methyl, (methoxy)-(methyl)-, ethylamino, isopropylamino, (cyclopropyl)-(methyl)-amino-, cyclopropylamino, cyclobutylamino, dimethylamino, azetidin-1-yl, 3,3-difluoroazetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholinyl, methoxy, ethoxy, iso-propoxy and (cyclopropyl)-(methoxy)-;
R9 represents a methyl group;
R10 represents a -C(=0)R12 group;
R12 represents a group selected from 2,2,2-trifluoroethyl, cyclopropyl, (1 -trifluoromethyl)- (cyclopropyl)-, cyclobutyl and (cyclopropyl)-(methyl)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In accordance with a forthieth embodiment of the first aspect, the present invention compounds of general formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000098_0001
in which "*" represents the point of attachment to the rest of the molecule;
said group being optionally substituted with one R7 group,
represents a group
Figure imgf000098_0002
in which "*" represents the point of attachment to the rest of the molecule;
R3 represents a hydrogen atom;
R4 represents a hydrogen atom;
R5 represents a hydrogen atom;
R7 represents a group selected from methyl, trifluoromethyl, methoxy, ethoxy, iso-propoxy and (cyclopropyl)-(methoxy)-;
R9 represents a methyl group;
R10 represents a -C(=0)R12 group;
R12 represents a group selected from 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl and (cyclopropyl)-(methyl)-;
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In accordance with an forty-first embodiment of the first aspect, the present invention compounds of general formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000099_0001
in which "*" represents the point of attachment to the rest of the molecule,
represents a group
Figure imgf000099_0002
in which "*" represents the point of attachment to the rest of the molecule;
R3 represents a hydrogen atom;
R4 represents a hydrogen atom;
R5 represents a hydrogen atom;
R6 represents a hydrogen atom or a group selected from (C3-C4-cycloalkyl)-(methyl)- and C2-C4-fluoroalkyl ,
said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one or two times with a fluorine atom or a methyl group;
R9 represents a hydrogen atom or a methyl group;
R10 represents a -C(=0)R12 group;
R12 represents a group selected from Ci-C2-fluoroalkyl, C3-C4-cycloalkyl and (cyclopropyl)- (methyl)-;
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In accordance with a forty-second embodiment of the first aspect, the present invention covers compounds of general formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000100_0001
in which "*" represents the point of attachment to the rest of the molecule;
represents a group
Figure imgf000100_0002
in which "*" represents the point of attachment to the rest of the molecule;
R3 represents a hydrogen atom;
R4 represents a hydrogen atom;
R5 represents a hydrogen atom;
R7 represents a chlorine atom or a group selected from Ci-C3-alkyl, cyclopropyl, dimethylamino, cyclopropylamino, Ci-C3-alkoxy and (cyclopropyl)-(methoxy)-;
R7a represents an additional R7 group, selected from a chlorine atom and a group selected from Ci-C3-alkoxy and (cyclopropyl)-(methoxy)- ;
R9 represents a hydrogen atom or a methyl group;
R10 represents a -C(=0)R12 group;
R12 represents a group selected from Ci-C2-fluoroalkyl, C3-C4-cycloalkyl and (cyclopropyl)- (methyl)-;
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. Further embodiments of the first aspect of the present invention
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group selected from
pyrazolyl, imidazolyl, oxadiazolyl, triazolyl, isoxazolyl, thienyl, pyridin-2-yl, pyridin-4-yl, pyrimidinyl, triazinyl and pyrazinyl, said group being optionally substituted with one R6 group, and said group being, additionally, optionally substituted one or two times, differently or identically, with a R7 group,
or
R1 represents a group selected from
Figure imgf000101_0001
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group,
in which "*" represents the point of attachment to the rest of the molecule,
or
R1 represents a group selected from pyridine-3-yl or pyridazin-3-yl, optionally substituted with one R8 group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group selected from
pyrazolyl, imidazolyl, oxadiazolyl, triazolyl, isoxazolyl, thienyl, pyridin-2-yl, pyridin-4-yl, pyrimidinyl, triazinyl and pyrazinyl, said group being optionally substituted with one R6 group, and said group being, additionally, optionally substituted one or two times, differently or identically, with a R7 group, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group selected from
pyrazolyl, imidazolyl, oxadiazolyl, triazolyl, pyridin-2-yl, pyridin-4-yl, pyrimidinyl and pyrazinyl, said group being optionally substituted with one R6 group, and said group being, additionally, optionally substituted one or two times, differently or identically, with a R7 group,
or
R1 represents a group selected from
Figure imgf000102_0001
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group,
in which "*" represents the point of attachment to the rest of the molecule,
or
R1 represents a group selected from pyridine-3-yl or pyridazin-3-yl, optionally substituted with one R8 group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group selected from
pyrazolyl, imidazolyl, oxadiazolyl, triazolyl, pyridin-2-yl, pyridin-4-yl, pyrimidinyl and pyrazinyl, said group being optionally substituted with one R6 group, and said group being, additionally, optionally substituted one or two times, differently or identically, with a R7 group, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000103_0001
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group,
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group selected from pyridine-3-yl or pyridazin-3-yl, optionally substituted with one R8 group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000104_0001
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group,
or
R1 represents a group selected from
Figure imgf000104_0002
in which "*" represents the point of attachment to the rest of the molecule, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000105_0001
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000106_0001
Figure imgf000106_0002
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group,
or
R1 represents a group selected from
Figure imgf000106_0003
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R represents a group selected from
Figure imgf000107_0001
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000107_0002
in which "*" represents the point of attachment to the rest of the molecule, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000108_0001
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group,
or
R1 represents a group selected from
Figure imgf000108_0002
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000109_0001
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000109_0002
in which "*" represents the point of attachment to the rest of the molecule, the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group, represents a group selected from
Figure imgf000110_0001
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000110_0002
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000111_0001
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000111_0002
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group, represents a group selected from
Figure imgf000112_0001
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000112_0002
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000113_0001
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000113_0002
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, besides R6, optionally substituted with one further R7 group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000114_0001
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, besides R6, optionally substituted with one further R7 group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000114_0002
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000115_0001
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, besides R6, optionally substituted with one further R7 group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000115_0002
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, besides R6, optionally substituted with one further R7 group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group
Figure imgf000115_0003
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, besides R6, optionally substituted with one further R7 group, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000116_0001
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, optionally substituted with one further R7 group, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000116_0002
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, optionally substituted with one further R7 group, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group
Figure imgf000116_0003
in which "*" represents the point of attachment to the rest of the molecule, the ring of said group being, optionally substituted with one further R7 group, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group
Figure imgf000117_0001
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, optionally substituted with one further R7 group, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group
Figure imgf000117_0002
in which "*" represents the point of attachment to the rest of the molecule;
the ring of said group being optionally substituted with one or two further R7 groups, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000118_0001
in which "*" represents the point of attachment to the rest of the molecule;
and in which R7 represents a chlorine atom or a group selected from Ci-C3-alkyl, cyclopropyl, dimethylamino, cyclopropylamino, Ci-C3-alkoxy and (cyclopropyl)- (methoxy)-,
and R7a represents an additional R7 group, selected from a chlorine atom and a group selected from Ci-C3-alkoxy and (cyclopropyl)-(methoxy)- ;
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000118_0002
in which "*" represents the point of attachment to the rest of the molecule; and in which R7 represents a chlorine atom or a group selected from Ci-C3-alkyl, C1-C3- alkoxy, and (cyclopropyl)-(methoxy)-,
and R7a represents an additional R7 group, representing a Ci-C3-alkoxy group ;
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000119_0001
in which "*" represents the point of attachment to the rest of the molecule;
and in which R7 represents a group selected from Ci-C3-alkyl, Ci-C3-alkoxy, and (cyclopropyl)-(methoxy)-,
and R7a represents an additional R7 group, representing a Ci-C3-alkoxy group ;
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000120_0001
in which "*" represents the point of attachment to the rest of the molecule;
and in which R7 represents a group selected from Ci-C3-alkyl, Ci-C3-alkoxy and (cyclopropyl)-(methoxy)-,
and R7a represents an additional R7 group, representing a methoxy group ;
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000120_0002
in which "*" represents the point of attachment to the rest of the molecule;
and in which R7 represents a chlorine atom or a group selected from Ci-C3-alkyl, C1-C3- alkoxy and (cyclopropyl)-(methoxy)-,
and R7a represents an additional R7 group selected from a chlorine atom and a group selected from Ci-C3-alkoxy and (cyclopropyl)-(methoxy)- ; and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000121_0001
in which "*" represents the point of attachment to the rest of the molecule;
and in which R7 represents a group selected from methyl, methoxy and (cyclopropyl)- (methoxy)-,
and R7a represents an additional R7 group selected from methoxy and (cyclopropyl)- (methoxy)- ;
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000121_0002
in which "*" represents the point of attachment to the rest of the molecule;
and in which R7 represents a group selected from Ci-C3-alkyl, Ci-C3-alkoxy, and (cyclopropyl)-(methoxy)-,
and R7a represents an additional R7 group, representing a Ci-C3-alkoxy group ;
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000122_0001
in which "*" represents the point of attachment to the rest of the molecule;
and in which R7 represents a group selected from Ci-C3-alkyl, Ci-C3-alkoxy and (cyclopropyl)-(methoxy)-,
and R7a represents an additional R7 group, representing a methoxy group ;
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
represents a group selected from
Figure imgf000122_0002
in which "*" represents the point of attachment to the rest of the molecule;
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000123_0001
in which "*" represents the point of attachment to the rest of the molecule;
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000123_0002
in which "*" represents the point of attachment to the rest of the molecule,
and in which R7 represents a group selected from methyl, trifluoromethyl, cyclopropyl, methoxy, ethoxy, iso-propoxy, 2,2,2-trifluoroethoxy and (cyclopropyl )-(methoxy)-, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000124_0001
in which "*" represents the point of attachment to the rest of the molecule,
and in which R7 represents a group selected from methyl, trifluoromethyl, cyclopropyl, methoxy, ethoxy, iso-propoxy and (cyclopropyl)-(methoxy)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000124_0002
in which "*" represents the point of attachment to the rest of the molecule,
and in which R7 represents an iso-propoxy group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000125_0001
in which "*" represents the point of attachment to the rest of the molecule,
and in which R7 represents a 2,2,2-trifluoroethoxy group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000125_0002
in which "*" represents the point of attachment to the rest of the molecule,
and in which R7 represents a group selected from methyl, ethylamino, isopropylamino, (cyclopropyl)-(methyl)-amino-, cyclopropylamino, cyclobutylamino, dimethylamino, azetidin-1-yl, 3,3-difluoroazetidin-1 -yl, pyrrolidin-1 -yl, piperidin-1 -yl and morpholinyl, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group
Figure imgf000126_0001
in which "*" represents the point of attachment to the rest of the molecule,
and in which R7 represents a group selected from ethylamino, isopropylamino, cyclopropylamino, cyclobutylamino, dimethylamino, azetidin-1-yl and 3,3-difluoroazetidin-1-yl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group
Figure imgf000126_0002
in which "*" represents the point of attachment to the rest of the molecule,
and in which R7 represents a group selected from isopropylamino, cyclopropylamino, cyclobutylamino, dimethylamino, azetidin-1-yl and 3,3-difluoroazetidin-1 -yl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group
Figure imgf000127_0001
in which "*" represents the point of attachment to the rest of the molecule, and in which R7 represents a group selected from (methoxy)-(methyl)- and (cyclopropyl)-(methoxy)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group
Figure imgf000127_0002
in which "*" represents the point of attachment to the rest of the molecule, and in which R7 represents a ethylamino group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group
Figure imgf000127_0003
in which "*" represents the point of attachment to the rest of the molecule, and in which R7 represents a isopropylamino group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group
Figure imgf000128_0001
in which "*" represents the point of attachment to the rest of the molecule,
and in which R7 represents a cyclopropylamino group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group
Figure imgf000128_0002
in which "*" represents the point of attachment to the rest of the molecule,
and in which R7 represents a cyclobutylamino group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group
Figure imgf000128_0003
in which "*" represents the point of attachment to the rest of the molecule,
and in which R7 represents a dimethylamino group, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group
Figure imgf000129_0001
in which "*" represents the point of attachment to the rest of the molecule,
and in which R7 represents a azetidin-1 -yl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group
Figure imgf000129_0002
in which "*" represents the point of attachment to the rest of the molecule,
and in which R7 represents a 3,3-difluoroazetidin-1 -yl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group
Figure imgf000130_0001
in which "*" represents the point of attachment to the rest of the molecule,
and in which R7 represents a (methoxy)-(methyl)- group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group
Figure imgf000130_0002
in which "*" represents the point of attachment to the rest of the molecule,
and in which R7 represents a (cyclopropyl)-(methoxy)- group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group
Figure imgf000130_0003
in which "*" represents the point of attachment to the rest of the molecule, and in which R7 represents a group selected from methyl, (cyclopropyl)-(methyl)-amino- , azetidin-1-yl, 3,3-difluoroazetidin-1 -yl and pyrrolidin-1 -yl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group
Figure imgf000131_0001
in which "*" represents the point of attachment to the rest of the molecule,
and in which R7 represents a group selected from azetidin-1 -yl, 3,3-difluoroazetidin-1 -yl and pyrrolidin-1-yl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group
H3
Figure imgf000131_0002
in which "*" represents the point of attachment to the rest of the molecule,
and in which R7 represents a methyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group
Figure imgf000132_0001
in which "*" represents the point of attachment to the rest of the molecule,
and in which R7 represents a (cyclopropyl)-(methyl)-amino- group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group
Figure imgf000132_0002
in which "*" represents the point of attachment to the rest of the molecule,
and in which R7 represents a azetidin-1 -yl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group
Figure imgf000132_0003
in which "*" represents the point of attachment to the rest of the molecule,
and in which R7 represents a 3,3-difluoroazetidin-1 -yl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group
Figure imgf000133_0001
in which "*" represents the point of attachment to the rest of the molecule,
and in which R7 represents a pyrrolidin-1 -yl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000133_0002
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000134_0002
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R represents a group selected from
Figure imgf000135_0001
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000135_0002
in which "*" represents the point of attachment to the rest of the molecule, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group
Figure imgf000136_0001
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group
Figure imgf000136_0002
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group
Figure imgf000137_0001
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group
Figure imgf000137_0002
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group
Figure imgf000138_0001
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group
Figure imgf000138_0002
in which "*" represents the point of attachment to the rest of the molecule;
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group;
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group
Figure imgf000138_0003
in which "*" represents the point of attachment to the rest of the molecule;
the ring of said group being, besides R6, optionally substituted with one or two further R7 groups,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R represents a group
Figure imgf000139_0001
in which "*" represents the point of attachment to the rest of the molecule;
the ring of said group being, besides R6, optionally substituted with one further R7 group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group
Figure imgf000139_0002
in which "*" represents the point of attachment to the rest of the molecule;
the ring of said group being, besides R6, optionally substituted with one or two further R7 groups, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group
Figure imgf000139_0003
in which "*" represents the point of attachment to the rest of the molecule;
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group
Figure imgf000140_0001
in which "*" represents the point of attachment to the rest of the molecule;
and
R6 represents a (cycloalkyl)-(methyl)-group,
said (cycloalkyl)-(methyl)- group being optionally substituted one or two times with a fluorine atom or a methyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R represents a group
Figure imgf000140_0002
in which "*" represents the point of attachment to the rest of the molecule;
and
R6 represents a hydrogen atom or a group selected from (C3-C4-cycloalkyl)-(methyl)- and C2-C4-fluoroalkyl ,
said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one or two times with a fluorine atom or a methyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group
Figure imgf000141_0001
in which "*" represents the point of attachment to the rest of the molecule;
and
R6 represents a group selected from (cyclopropyl)-(methyl)-, (cyclobutyl)-(methyl)- and 2,2,2-trifluoroethyl ,
said (cyclopropyl)-(methyl)- group being optionally substituted one or two times with a fluorine atom or a methyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group
Figure imgf000141_0002
in which "*" represents the point of attachment to the rest of the molecule;
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which: R1 represents a group
Figure imgf000142_0001
in which "*" represents the point of attachment to the rest of the molecule;
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group selected from
Figure imgf000142_0002
in which "*" represents the point of attachment to the rest of the molecule,
said group being optionally substituted one or two times, differently or identically, with a R7 group;
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a roup
Figure imgf000142_0003
in which "*" represents the point of attachment to the rest of the molecule;
said group being optionally substituted with one R7 group, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group selected from
Figure imgf000144_0001
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group selected from
Figure imgf000145_0001
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group selected from
Figure imgf000145_0002
in which "*" represents the point of attachment to the rest of the molecule, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group selected from
Figure imgf000146_0001
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group
Figure imgf000146_0002
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group
Figure imgf000147_0001
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group selected from
Figure imgf000147_0002
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group
Figure imgf000147_0003
in which "*" represents the point of attachment to the rest of the molecule, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group
Figure imgf000148_0001
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group
Figure imgf000148_0002
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group
Figure imgf000149_0001
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group
Figure imgf000149_0002
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group selected from
Figure imgf000150_0001
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group selected from
Figure imgf000151_0001
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (1), supra, in which:
R2 represents a group selected from
Figure imgf000152_0001
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group selected from
Figure imgf000153_0001
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group
Figure imgf000153_0002
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group
Figure imgf000154_0001
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group
Figure imgf000154_0002
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group
Figure imgf000154_0003
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group
Figure imgf000155_0001
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group
Figure imgf000155_0002
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group
Figure imgf000155_0003
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group
Figure imgf000156_0001
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group
Figure imgf000156_0002
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group selected from
Figure imgf000157_0001
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group selected from
Figure imgf000158_0001
in which "*" represents the point of attachment to the rest of the molecule, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group selected from
Figure imgf000159_0001
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group selected from
Figure imgf000160_0001
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group
Figure imgf000160_0002
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group
Figure imgf000161_0001
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group
Figure imgf000161_0002
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group
Figure imgf000161_0003
in which "*" represents the point of attachment to the rest of the molecule, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group
Figure imgf000162_0001
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group
Figure imgf000162_0002
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group
Figure imgf000163_0001
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group
Figure imgf000163_0002
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group
Figure imgf000163_0003
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group
Figure imgf000164_0001
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group
Figure imgf000164_0002
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group
Figure imgf000165_0001
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group
Figure imgf000165_0002
in which "*" represents the point of attachment to the rest of the molecule,
• and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group selected from
Figure imgf000166_0001
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group selected from
Figure imgf000167_0001
in which "*" represents the point of attachment to the rest of the molecule, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group selected from
Figure imgf000168_0001
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group selected from
Figure imgf000169_0001
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compound of formula (I), supra, in which:
R2 represents a group
Figure imgf000169_0002
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group
Figure imgf000170_0001
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group
Figure imgf000170_0002
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group
Figure imgf000170_0003
in which "*" represents the point of attachment to the rest of the molecule, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group
Figure imgf000171_0001
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group
Figure imgf000171_0002
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group
Figure imgf000172_0001
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group
Figure imgf000172_0002
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group
Figure imgf000172_0003
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group
Figure imgf000173_0001
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group
Figure imgf000173_0002
in which "*" represents the point of attachment to the rest of the molecule,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R3 represents a hydrogen atom or a halogen atom or a group selected from Ci-C4-alkyl and Ci-C6-alkoxy,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R3 represents a hydrogen atom or a halogen atom or a group selected from Ci-C4-alkyl and Ci-C4-alkoxy,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R3 represents a hydrogen atom or a group selected from Ci-C4-alkyl and Ci-C4-alkoxy,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R3 represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom or a group selected from methyl, ethoxy and iso-butoxy,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R3 represents a hydrogen atom or a group selected from methyl, ethoxy and iso-butoxy, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R3 represents a hydrogen atom, a fluorine atom or a chlorine atom,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R3 represents a hydrogen atom,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R3 represents a a fluorine atom,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R3 represents a chlorine atom,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R4 represents a hydrogen atom or a halogen atom or a group selected from C-i-Gt-alkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy and Ci-C4-haloalkoxy,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R4 represents a hydrogen atom or a group selected from Ci-C3-alkyl and Ci-C3-fluoroalkyl, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R4 represents a hydrogen atom, or a group selected from methyl and trifluoromethyl, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R4 represents a hydrogen atom or a methyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R4 represents a methyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R4 represents a hydrogen atom,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R5 represents a hydrogen atom or a halogen atom or a group selected from Ci-C4-alkyl, Ci-C4-haloalkyl and C3-C6-cycloalkyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R5 represents a hydrogen atom or a fluorine atom or a chlorine atom or a bromine atom or or a group selected from methyl, trifluoromethyl and cyclopropyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R5 represents a hydrogen atom or a fluorine atom or a chlorine atom or a group selected from methyl, trifluoromethyl and cyclopropyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R5 represents a hydrogen atom or a fluorine atom or a chlorine atom a group selected from methyl, trifluoromethyl and cyclopropyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R5 represents a hydrogen atom or a bromine atom, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R5 represents a hydrogen atom;
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 represents a hydrogen atom or a group selected from Ci-C6-alkyl, Ci-C6-haloalkyl, Ci- Ce-hydroxyalkyl, (Ci-C3-alkoxy)-(Ci-C3-alkyl)-, C3-C6-cycloalkyl and (C3-C6-cycloalkyl)- (Ci-C3-alkyl)-,
said C3-C6-cycloalkyl and said (C3-C6-cycloalkyl)-(Ci-C3-alkyl)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or with a group selected from Ci-C3-alkyl and Ci- C3-haloalkyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 represents a hydrogen atom or a group selected from Ci-C6-alkyl, Ci-C6-haloalkyl, C3- C6-cycloalkyl and (C3-C6-cycloalkyl)-(Ci-C3-alkyl)-,
said C3-C6-cycloalkyl and said (Cs-Ce-cycloalkylHCrCs-alkyl)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or with a Ci-C3-alkyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 represents a hydrogen atom or a group selected from Ci-C6-alkyl, Ci-C4-fluoroalkyl, CrC4-hydroxyalkyl, (Ci-C2-alkoxy)-(Ci-C3-alkyl)-, C3-C5-cycloalkyl and (C3-Cs-cycloalkyl)-(methyl)-,
said C3-C5-cycloalkyl and said (C3-C5-cycloalkyl)-(methyl)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or with a group selected from methyl and trifluoromethyl;
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 represents a hydrogen atom or a group selected from Ci-Ce-alkyl, Ci-C4-fluoroalkyl, C3-C4-cycloalkyl and (C3-C4-cycloalkyl)-(methyl)-,
said C3-C4-cycloalkyl and said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or with a methyl group;
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 represents represents a hydrogen atom or a group selected from Ci-C6-alkyl, Ci-C4-fluoroalkyl, Ci-C4-hydroxyalkyl, (methoxy)-(Ci-C3-alkyl)-, C3-Cs-cycloalkyl and (C3-C5-cycloalkyl)-(methyl)-,
said C3-C5-cycloalkyl and said (C3-Cs-cycloalkyl)-(methyl)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or with a methyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 represents a group selected from Ci-C4-alkyl, Ci-C4-fluoroalkyl, cyclopropyl and (cyclopropyl)-(methyl)-,
said cyclopropyl and (cyclopropyl)-(methyl)- group being optionally substituted one or two times with a fluorine atom,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 represents a group selected from methyl, ethyl 2,2-difluoroethyl, 2,2,2-trifluoroethyl and (C3-C5-cycloalkyl)-(methyl)-,
said (C3-C5-cycloalkyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom, a chlorine atom or with a methyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 represents a group selected from C2-C4-alkyl, C2-C4-fluoroalkyl and (C3-C4-cycloalkyl)- (methyl)-,
said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom or a chlorine atom or a methyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 represents a group selected from methyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, (cyclopropyl)-(methyl)-, (2,2-difluorocyclopropyl)-(methyl)-, (2,2-dichlorocyclopropyl)- (methyl)-, (2,2-dimethylcyclopropyl)-(methyl)-, (2-methylcyclopropyl)-(methyl)-, (1- methylcyclopropyl)-(methyl)-, (l-chlorocyclopropyl)-(methyl)-, (cyclobutyl)-(methyl)-, 3,3-difluorocyclobutyl-(methyl)- and (cyclopentyl)-methyl)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 represents a group selected from C2-C4-alkyl, C2-C4-fluoroalkyl and (cyclopropyl)- (methyl)-,
said (cyclopropyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom or a methyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 represents a group selected from C2-C4-fluoroalkyl and (C3-C4-cycloalkyl)-(methyl)-, said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom or a chlorine atom or a methyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 represents a group selected from C2-C4-fluoroalkyl and (cyclopropyl)-(methyl)-,
said (cyclopropyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom or a methyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 represents a group selected from C2-C3-fluoroalkyl and (C3-C4-cycloalkyl)-(methyl)-, said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom or a chlorine atom or a methyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 represents a group selected from C2-C3-fluoroalkyl and (cyclopropyl)-(methyl)-,
said (cyclopropyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom or a methyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 represents a group selected from C2-C4-fluoroalkyl and (C3-C4-cycloalkyl)-(methyl)-, said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom or a methyl group, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 represents a group selected from C2-C4-fluoroalkyl and (cyclopropyl)-(methyl)-,
said (cyclopropyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom or a methyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 represents a (C3-C4-cycloalkyl)-(methyl)- group,
said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom or a chlorine atom or a methyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 represents a (cyclopropyl)-(methyl)- group,
said (cyclopropyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom or a methyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 represents a (C3-C4-cycloalkyl)-(methyl)- group,
said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom or a methyl group, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 represents a (cyclopropyl)-(methyl)- group,
said (cyclopropyl)-(methyl)- group being optionally substituted one or two times, , identically or differently, with a fluorine atom or a methyl group, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 represents a group selected from methyl, ethyl 2,2,2-trifluoroethyl and (cyclopropyl)- (methyl)-,
said (cyclopropyl)-(methyl)- group being optionally substituted one or two times with a fluorine atom,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 represents a group selected from methyl, ethyl, 2,2,2-trifluoroethyl, (cyclopropyl)- (methyl)- and (2,2-difluorocyclopropyl)-(methyl)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 represents a group selected from ethyl, 2,2,2-trifluoroethyl, (cyclopropyl)-(methyl)- and (2,2-difluorocyclopropyl)-(methyl)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 represents an ethyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 represents a 2,2,2-trifluoroethyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 represents a group selected from 2,2,2-trifluoroethyl, (cyclopropyl)-(methyl)- and (2,2- difluorocyclopropyl)-(methyl)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 represents a group selected from (cyclopropyl)-(methyl)- and (2,2-difluorocyclopropyl)- (methyl)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 represents a (cyclopropyl)-(methyl)- group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 represents a (2,2-difluorocyclopropyl)-(methyl)- group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 represents a hydrogen atom or a group selected from (C3-C4-cycloalkyl)-(methyl)- and C2-C4-fluoroalkyl ,
said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one or two times with a fluorine atom or a methyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 represents a hydrogen atom or a group selected from (cyclopropyl)-(methyl)-, (cyclobutyl)-(methyl)- and 2,2,2-trifluoroethyl,
said (cyclopropyl)-(methyl)- group being optionally substituted one or two times with a fluorine atom or a methyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 representsa group selected from (cyclopropyl)-(methyl)-, (cyclobutyl)-(methyl)- and 2,2,2-trifluoroethyl,
said (cyclopropyl)-(methyl)- group being optionally substituted one or two times with a fluorine atom or a methyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 representsa group selected from (2-methylcyclopropyl)-(methyl)-, (2,2- difluorocyclopropyl)-(methyl)-, (cyclobutyl)-(methyl)- and 2,2,2-trifluoroethyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 representsa (2-methylcyclopropyl)-(methyl)- group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 representsa (cyclobutyl)-(methyl)- group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 represents a group selected from methyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, (cyclopropyl)-(methyl)-, (2,2-difluorocyclopropyl)-(methyl)-, (2,2-dichlorocyclopropyl)- (methyl)-, (2,2-dimethylcyclopropyl)-(methyl)-, (2-methylcyclopropyl)-(methyl)-, (1 - methylcyclopropyl)-(methyl)-, (l-chlorocyclopropyl)-(methyl)-, (cyclobutyl)-(methyl)-, 3,3-difluorocyclobutyl-(methyl)- and (cyclopentyl)-methyl)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 represents a group selected from methyl, ethyl, 2,2-difluoroethyl and 2,2,2-trifluoroethyl, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 represents a group selected from methyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl and (cyclopropyl)-(methyl)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 represents a group selected from (2,2-difluorocyclopropyl)-(methyl)-, (2,2- dichlorocyclopropyl)-(methyl)-, (2,2-dimethylcyclopropyl)-(methyl)-, (2- methylcyclopropyl)-(methyl)-, (1 -methylcyclopropyl)-(methyl)-, (1 -chlorocyclopropyl)- (methyl)-, (cyclobutyl)-(methyl)-, 3,3-difluorocyclobutyl-(methyl)- and (cyclopentyl)- methyl)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 represents a group selected from (2,2-difluorocyclopropyl)-(methyl)-, (2,2- dichlorocyclopropyl)-(methyl)- and (2,2-dimethylcyclopropyl)-(methyl)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 represents a group selected from (2-methylcyclopropyl)-(methyl)-, (1 - methylcyclopropyl)-(methyl)- and (l-chlorocyclopropyl)-(methyl)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 represents a group selected from (cyclopropyl)-(methyl)-, (cyclobutyl)-(methyl)-, 3,3- difluorocyclobutyl-(methyl)- and (cyclopentyl)-methyl)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 represents a group selected from (cyclobutyl)-(methyl)-, 3,3-difluorocyclobutyl-(methyl)- and (cyclopentyl)-methyl)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 represents a group selected from 2,2-difluoroethyl, (cyclopropyl)-(methyl)-, (2,2- difluorocyclopropyl)-(methyl)-, (2,2-dimethylcyclopropyl)-(methyl)-, (1 - chlorocyclopropyl)-(methyl)- and (cyclobutyl)-(methyl)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 represents a 2,2-difluoroethyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 represents a (2,2-difluorocyclopropyl)-(methyl)- group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 represents a (2,2-dimethylcyclopropyl)-(methyl)- group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 represents a (l-chlorocyclopropyl)-(methyl)- group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 represents a (cyclobutyl)-(methyl)- group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 represents a group selected from (2,2-difluorocyclopropyl)-(methyl)-, (2,2- dimethylcyclopropyl)-(methyl)- and (l -chlorocyclopropyl)-(methyl)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 represents a group selected from (2,2-difluorocyclopropyl)-(methyl)- and (2,2- dimethylcyclopropyl)-(methyl)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 represents a group selected from 2,2-difluoroethyl, (2,2-difluorocyclopropyl)-(methyl)-, (2,2-dimethylcyclopropyl)-(methyl),- (l-chlorocyclopropyl)-(methyl)- and (cyclobutyl)- (methyl)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a halogen atom or a group selected from hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-hydroxyalkyl, (Ci-C3-alkoxy)-(Ci-C3-alkyl)-, (Ci-C3-haloalkoxy)-(Ci-C3-alkyl)-, C2-C6-alkenyl, C2-C6-alkynyl, C3-C8-cycloalkyl, C4-C8- cycloalkenyl, (C3-C8-cycloalkyl)-(Ci-C3-alkyl)-, (phenyl)-Ci-C3-alkyl-, 4- to 7-membered heterocycloalkyl, 5- to 7-membered heterocycloalkenyl, heterospirocycloalkyl, phenyl, heteroaryl, -CN, -(CH2)x-N(R11)R11a, -C(=0)R13, -C(=0)-OR13, -C(=0)-N(R11)R11a, - N(R11)R11a, -N(R16)-C(=0)-R13, -N(R16)-S(=0)2-R13, -N(R16)-C(=0)-N(R11)R11a, -N(R16)- C(=0)-OR13, Ci-C6-alkoxy, Ci-C6-haloalkoxy, C3-C8-cycloalkoxy-, (C3-C8-cycloalkyl)- (Ci-C3-alkoxy)-, phenyloxy-, heteroaryloxy-, -0-(CH2)x-phenyl, -0-(CH2)x-heteroaryl, -O- C(=0)-R13, -0-C(=0)-N(R11)R11a, Ci-Ce-alkylsulfanyl, Ci-C6-haloalkylsulfanyl, -S(=0)- R13, -S(=0)2-R13, -S(=0)2-N(R 1)R11a and -S(=0)(=NR17)R13,
said C3-C8-cycloalkyl, said (C3-C8-cycloalkyl)-(Ci-C3-alkyl)- and said (C3-C8- cycloalkyl)-(Ci-C3-alkoxy)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or with a group selected from Ci-C3-alkyl and Ci-C3-haloalkyl,
said 4- to 7-membered heterocycloalkyl, said 5- to 7-membered heterocycloalkenyl and said heterospirocycloalkyl group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or with a group selected from oxo, Ci-C3-alkyl and Ci-C3- haloalkyl, and
said heteroaryl group and said phenyl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from -CN, Ci- C3-alkyl, trifluoromethyl, Ci-C3-alkoxy and trifluoromethoxy,
or
R6 and R7, or two R7 groups, when being attached to adjacent ring atoms of the group R1, together form a group selected from:
-(0-CH2-0)-, -(0-(CH2)2-0)-, -(0-(CH2)2)-, -(CH2-0-CH2)-, -(NR16-(CH2)2-0)-, -(NR16-(CH2)3-0)-, -(S-(CH2)2)-, -(0-(CH2)3)-, -((CH2)3)-, -((CH2)4)-, -(0-CH=CH)-, -(S-CH=CH)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a halogen atom or a group selected from hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-hydroxyalkyl, (Ci-C3-alkoxy)-(Ci-C3-alkyl)-, (Ci-C3-haloalkoxy)-(Ci-C3-alkyl)-, C2-C6-alkenyl, C2-C6-alkynyl, C3-C8-cycloalkyl, C4-C8- cycloalkenyl, (C3-C8-cycloalkyl)-(Ci-C3-alkyl)-, (phenyl)-Ci-C3-alkyl-, 4- to 7-membered heterocycloalkyl, 5- to 7-membered heterocycloalkenyl, heterospirocycloalkyl, phenyl, heteroaryl, -CN, -(CH2)x-N(R1 )R11a, -C(=0)R13, -C(=0)-OR13, -C(=0)-N(R11)R11a, - N(R11)R11a, -N(R16)-C(=0)-R13, -N(R16)-S(=0)2-R13, -N(R16)-C(=0)-N(R11)R11a, -N(R16)- C(=0)-OR13, Ci-Ce-alkoxy, Ci-Ce-haloalkoxy, C3-C8-cycloalkoxy-, (C3-C8-cycloalkyl)-
(Ci-C3-alkoxy)-, phenyloxy-, heteroaryloxy-, -0-(CH2)x-phenyl, -0-(CH2)x-heteroaryl, -O- C(=0)-R13, -0-C(=0)-N(R11)R 1a, Ci-C6-alkylsulfanyl, Ci-C6-haloalkylsulfanyl, -S(=0)- R13, -S(=0)2-R13, -S(=0)2-N(R1 )R11a and -S(=0)(=NR17)R13,
said C3-C8-cycloalkyl, said (C3-C8-cycloalkyl)-(Ci-C3-alkyl)- and said (C3-C8- cycloalkyl)-(Ci-C3-alkoxy)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or with a group selected from Ci-C3-alkyl and Ci-C3-haloalkyl,
said 4- to 7-membered heterocycloalkyl, said 5- to 7-membered heterocycloalkenyl and said heterospirocycloalkyl group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or with a group selected from oxo, Ci-C3-alkyl and Ci-C3- haloalkyl, and
said heteroaryl group and said phenyl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from -CN, Ci- C3-alkyl, trifluoromethyl, Ci-C3-alkoxy and trifluoromethoxy,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 and R7, or two R7 groups, when being attached to adjacent ring atoms of the group R1 , together form a group selected from:
-(0-CH2-0)-, -(0-(CH2)2-0)-, -(0-(CH2)2)-, -(CH2-0-CH2)-, -(NR 6-(CH2)2-0)-, -(NR16-(CH2)3-0)-, -(S-(CH2)2)-, -(0-(CH2)3)-, -((CH2)3)-, -((CH2)4)-, -(0-CH=CH)-, -(S-CH=CH)-, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a halogen atom or a group selected from Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-hydroxyalkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C8-cycloalkyl, C4-C8-cycloalkenyl, (C3-C8-cycloalkyl)-(Ci-C3-alkyl)-, (phenyl)-Ci-C3- alkyl-, 4- to 7-membered heterocycloalkyl, 5- to 7-membered heterocycloalkenyl, phenyl, heteroaryl, -CN, -C(=0)R13, -C(=0)-OR13, -C(=0)-N(R11)R1 a, -N(R11)R 1a, - N(R16)-C(=0)-R13, -N(R16)-S(=0)2-R13, -N(R16)-C(=0)-N(R11)R 1a, -N(R16)-C(=0)-OR13, Ci-C6-alkoxy, Ci-C6-haloalkoxy, C3-C8-cycloalkoxy-, (C3-C8-cycloalkyl)-(Ci-C3-alkoxy)-, phenyloxy-, heteroaryloxy-, -0-(CH2)x-phenyl, -0-(CH2)x-heteroaryl, -0-C(=0)-R13 -O- C(=0)-N(R 1)R11a, Ci-C6-alkylsulfanyl, Ci-C6-haloalkylsulfanyl, -S(=0)2-R13, -S(=0)2- N(R11)R1 a and -S(=0)(=NR17)R13;
or
R6 and R7, or two R7 groups, when being attached to adjacent ring atoms of the group R1, together form a group selected from:
-(0-CH2-0)-, -(0-(CH2)2-0)-, -(0-(CH2)2)-, -(S-(CH2)2)-, -(0-(CH2)3)-, -((CH2)3)-, - ((CH2)4)-, -(0-CH=CH)-, -(S-CH=CH),
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a halogen atom or a group selected from Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-hydroxyalkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C8-cycloalkyl, C4-C8-cycloalkenyl, (C3-C8-cycloalkyl)-(Ci-C3-alkyl)-, (phenyl)-Ci-C3- alkyl-, 4- to 7-membered heterocycloalkyl, 5- to 7-membered heterocycloalkenyl, phenyl, heteroaryl, -CN, -C(=0)R13, -C(=0)-OR13, -C(=0)-N(R11)R11a, -N(R11)R11a, - N(R 6)-C(=0)-R13, -N(R16)-S(=0)2-R13, -N(R16)-C(=0)-N(R, 1)R11a, -N(R16)-C(=0)-OR13, Ci-C6-alkoxy, Ci-C6-haloalkoxy, C3-C8-cycloalkoxy-, (C3-C8-cycloalkyl)-(Ci-C3-alkoxy)-, phenyloxy-, heteroaryloxy-, -0-(CH2)x-phenyl, -0-(CH2)x-heteroaryl, -0-C(=0)-R13 -O- C(=0)-N(R11)R11a, CrCe-alkylsulfanyl, Ci-C6-haloalkylsulfanyl, -S(=0)2-R13, -S(=0)2- N(R11)R11a and -S(=0)(=NR 7)R13; and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 and R7, or two R7 groups, when being attached to adjacent ring atoms of the group R1 , together form a group selected from:
-(O-CH2-O)-, -(0-(CH2)2-0)-, -(0-(CH2)2)-, -(S-(CH2)2)-, -(0-(CH2)3)-, -((CH2)3)-, - ((CH2)4)-, -(0-CH=CH)-, -(S-CH=CH);
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a halogen atom or a group selected from hydroxy, Ci-C6-alkyl, C1-C4- fluoroalkyl, Ci-C4-hydroxyalkyl, (Ci-C2-alkoxy)-(Ci-C3-alkyl)-, (Ci-C2-fluoroalkoxy)-(Ci- C3-alkyl)-, C3-C4-cycloalkyl, (C3-C4-cycloalkyl)-(methyl)-, (phenyl)-(Ci-C3-alkyl)-, 4- to 7- membered heterocycloalkyl, heterospirocycloalkyl, 5-to 6-membered heteroaryl, -CN, - (CH2)x-N(R 1)R11a, -C(=0)R13, -C(=0)-N(R11)R11a, -N(R11)R11a, Ci-C6-alkoxy, d-C4- fluoroalkoxy, (C3-C4-cycloalkyl)-(methoxy)-, Ci-C4-alkylsulfanyl, S(=0)-R13 and -S(=0)2- R13,
said C3-C4-cycloalkyl, said (C3-C4-cycloalkyl)-(methyl)- and said (C3-C4- cycloalkyl)-(methoxy)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom or with a group selected from methyl and trifluoromethyl,
said 4- to 7-membered heterocycloalkyl and said heterospirocycloalkyl group being optionally substituted one, two or three times, identically or differently, with a fluorine atom or with a group selected from oxo, methyl and trifluoromethyl, and said 5- to 6-membered heteroaryl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from methyl, trifluoromethyl and methoxy,
or R6 and R7, or two R7 groups, when being attached to adjacent ring atoms of the group R1 , together form a group selected from:
-(O-CH2-O)-, -(0-(CH2)2-0)-, -(0-(CH2)2)-, -(CH2-0-CH2)-, -(NR 6-(CH2)2-0)-, -((CH2)3)-, -((CH2)4)-, -(0-CH=CH)-, -(S-CH=CH)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a halogen atom or a group selected from hydroxy, Ci-Ce-alkyl, C1-C4- fluoroalkyl, Ci-C4-hydroxyalkyl, (Ci-C2-alkoxy)-(Ci-C3-alkyl)-, (Ci-C2-fluoroalkoxy)-(CV C3-alkyl)-, C3-C4-cycloalkyl, (C3-C4-cycloalkyl)-(methyl)-, (phenyl)-(Ci-C3-alkyl)-, 4- to 7- membered heterocycloalkyl, heterospirocycloalkyl, 5-to 6-membered heteroaryl, -CN, - (CH2)x-N(R 1 )R 1a, -C(=0)R13, -C(=0)-N(R11)R11a, -N(R11)R1 a, Ci-C6-alkoxy, C1-C4- fluoroalkoxy, (C3-C4-cycloalkyl)-(methoxy)-, Ci-C4-alkylsulfanyl, S(=0)-R13 and -S(=0)2-
R13,
said C3-C4-cycloalkyl, said (C3-C4-cycloalkyl)-(methyl)- and said (C3-C4- cycloalkyl)-(methoxy)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom or with a group selected from methyl and trifluoromethyl,
said 4- to 7-membered heterocycloalkyl and said heterospirocycloalkyl group being optionally substituted one, two or three times, identically or differently, with a fluorine atom or with a group selected from oxo, methyl and trifluoromethyl, and said 5- to 6-membered heteroaryl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from methyl, trifluoromethyl and methoxy,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 and R7, or two R7 groups, when being attached to adjacent ring atoms of the group R1 , together form a group selected from:
-(O-CH2-O)-, -(0-(CH2)2-0)-, -(0-(CH2)2)-, -(CH2-0-CH2)-, -(NR16-(CH2)2-0)-, -((CH2)3)-, -((CH2)4)-, -(0-CH=CH)-, -(S-CH=CH)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a halogen atom or a group selected from Ci-C6-alkyl, Ci-C4-fluoroalkyl, C3-C4-cycloalkyl, (C3-C4-cycloalkyl)-(methyl)-, (phenyl)- (Ci-C3-alkyl)-, -C(=0)-N(R11)R1 a, Ci-C6-alkoxy, Ci-C4-fluoroalkoxy, (C3-C -cycloalkyl)- (methoxy)- and Ci-C4-alkylsulfanyl;
or
R6 and R7, or two R7 groups, when being attached to adjacent ring atoms of the group R1 , together form a group selected from:
-(0-CH2-0)-, -(0-(CH2)2-0)-, -(0-(CH2)2)-, -((CH2)3)-, -((CH2)4)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a halogen atom or a group selected from Ci-C6-alkyl, Ci-C4-fluoroalkyl, C3-C4-cycloalkyl, (C3-C -cycloalkyl)-(methyl)-, (phenyl)- (Ci-C3-alkyl)-, -C(=0)-N(R11)R11a, Ci-C6-alkoxy, Ci-C4-fluoroalkoxy, (C3-C4-cycloalkyl)- (methoxy)- and Ci-C4-alkylsulfanyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 and R7, or two R7 groups, when being attached to adjacent ring atoms of the group R1, together form a group selected from:
-(O-CHz-O)-, -(0-(CH2)2-0)-, -(0-(CH2)2)-, -((CH2)3)-, -((CH2)4)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a halogen atom or a group selected from Ci-C6-alkyl, Ci-C4-fluoroalkyl, Ci- C4-hydroxyalkyl, (Ci-C2-alkoxy)-(Ci-C3-alkyl)-, C3-C4-cycloalkyl, (C3-C4-cycloalkyl)- (methyl)-, (phenyl)-(Ci-C3-alkyl)-, 4- to 7-membered heterocycloalkyl, heterospirocycloalkyl, -CN, -(CH2)x-N(R 1)R11a, -C(=0)R13, -C(=0)-N(R11)R 1a, - N(R11)R11a, Ci-C6-alkoxy, Ci-C4-fluoroalkoxy and (C3-C4-cycloalkyl)-(methoxy)-,
said C3-C4-cycloalkyl, said (C3-C4-cycloalkyl)-(methyl)- and said (C3-C4- cycloalkyl)-(methoxy)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom or with a group selected from methyl and trifluoromethyl, and
said 4- to 7-membered heterocycloalkyl and said heterospirocycloalkyl group being optionally substituted one, two or three times, identically or differently, with a fluorine atom or with a group selected from methyl and trifluoromethyl, or
R6 and R7, or two R7 groups, when being attached to adjacent ring atoms of the group R1, together form a group selected from:
-(0-CH=CH)- and -(NR16-(CH2)2-0)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a halogen atom or a group selected from Ci-C6-alkyl, Ci-C4-fluoroalkyl, Ci- C4-hydroxyalkyl, (Ci-C2-alkoxy)-(Ci-C3-alkyl)-, C3-C4-cycloalkyl, (C3-C4-cycloalkyl)- (methyl)-, (phenyl)-(Ci-C3-alkyl)-, 4- to 7-membered heterocycloalkyl, heterospirocycloalkyl, -CN, -(CH2)x-N(R )R1 1a, -C(=0)R13, -C(=0)-N(R1 1 )R1 1a, - N(R1 1)R11 a, Ci-C6-alkoxy, Ci-C4-fluoroalkoxy and (C3-C4-cycloalkyl)-(methoxy)-,
said C3-C4-cycloalkyl, said (C3-C4-cycloalkyl)-(methyl)- and said (C3-C4- cycloalkyl)-(methoxy)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom or with a group selected from methyl and trifluoromethyl, and
said 4- to 7-membered heterocycloalkyl and said heterospirocycloalkyl group being optionally substituted one, two or three times, identically or differently, with a fluorine atom or with a group selected from methyl and trifluoromethyl, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 and R7, or two R7 groups, when being attached to adjacent ring atoms of the group R1 , together form a group selected from:
-(0-CH=CH)- and -(NR16-(CH2)2-0)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a halogen atom or a group selected from Ci-Ce-alkyl, Ci-C4-fluoroalkyl, (C3-C4-cycloalkyl)-(methyl)-, Ci-Ce-alkoxy, C1-C4- fluoroalkoxy, (C3-C4-cycloalkyl)-(methoxy)- and Ci-C4-alkylsulfanyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a group selected from Ci-C3-alkyl, difluoromethyl, trifluoromethyl, (methoxy)-(methyl)-, cyclopropyl, -NR11R11a, Ci-C3-alkoxy, Ci-C3-fluoroalkoxy, (C3-C4- cycloalkyl)-(methoxy)- and [1-(trifluoromethyl)cyclopropyl]-(methoxy)-,
or
R6 and R7, or two R7 groups, when being attached to adjacent ring atoms of the group R , together form a group selected from:
-(0-CH=CH)- and -(NR16-(CH2)2-0)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a group selected from Ci-C3-alkyl, difluoromethyl, trifluoromethyl, (methoxy)-(methyl)-, cyclopropyl, -NR11R a, Ci-C3-alkoxy, Ci-C3-fluoroalkoxy, (C3-C4- cycloalkyl)-(methoxy)- and [1-(trifluoromethyl)cyclopropyl]-(methoxy)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a group selected from Ci-C3-alkyl, difluoromethyl, trifluoromethyl, (methoxy)-(methyl)-, cyclopropyl, 2-oxa-6-azaspiro[3.3]heptyl-, -NR 1R11a, Ci-C3- alkoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, (C3-C4-cycloalkyl)-(methoxy)- and [1 - (trifluoromethyl)cyclopropyl]-(methoxy)-,
or
R6 and R7, or two R7 groups, when being attached to adjacent ring atoms of the group R , together form a group selected from:
-(0-CH=CH)- and -(NR16-(CH2)2-0)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a group selected from Ci-C3-alkyl, difluoromethyl, trifluoromethyl, (methoxy)-(methyl)-, cyclopropyl, 2-oxa-6-azaspiro[3.3]heptyl-, -NR11R11a, C1-C3- alkoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, (C3-C4-cycloalkyl)-(methoxy)- and [1 - (trifluoromethyl)cyclopropyl]-(methoxy)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a group selected from
Ci-C6-alkyl, Ci-C4-fluoroalkyl, (C3-C4-cycloalkyl)-(methyl)-, Ci-C6-alkoxy, C1-C4- fluroalkoxy, (C3-C4-cycloalkyl)-(methoxy)- and Ci-C4-alkylsulfanyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a group selected from Ci-C3-alkyl, trifluoromethyl, (methoxy)-(methyl)-, cyclopropyl, -NR11R11a, Ci-C3-alkoxy, Ci-C3-fluoroalkoxy and (C3-C4-cycloalkyl)- (methoxy)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a group selected from Ci-C3-alkyl, (methoxy)-(methyl)-, cyclopropyl, -NR11R11a, Ci-C3-alkoxy and (C3-C4-cycloalkyl)-(methoxy)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a halogen atom or a group selected from Ci-Ce-alkyl, Ci-C4-fluoroalkyl, (C3-C4-cycloalkyl)-(methyl)-, Ci-C6-alkoxy, Ci-C - fluoroalkoxy, and (C3-C4-cycloalkyl)-(methoxy)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a group selected from
Ci-Ce-alkyl, Ci-C4-fluoroalk l, (C3-C4-cycloalkyl)-(methyl)-, Ci-C6-alkoxy, Ci-C4- fluroalkoxy, and (C3-C4-cycloalkyl)-(methoxy)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a halogen atom or a group selected from Ci-Ce-alkyl, Ci-C4-fluoroalkyl, (C3-C4-cycloalkyl)-(methyl)-, Ci-C4-alkoxy, Ci-C - fluoroalkoxy, and (C3-C4-cycloalkyl)-(methoxy)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a group selected from
Ci-Ce-alkyl, Ci-C4-fluoroalkyl, (C3-C4-cycloalkyl)-(methyl)-, Ci-C4-alkoxy, C1-C4- fluroalkoxy, and (C3-C4-cycloalkyl)-(methoxy)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a group selected from
Ci-C6-alkyl, Ci-C4-fluoroalkyl, (C3-C4-cycloalkyl)-(methyl)-, Ci-C4-alkoxy,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a group selected from
Ci-C4-alkoxy, Ci-C4-fluroalkoxy, and (C3-C4-cycloalkyl)-(methoxy)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a group selected from
Ci-C6-alkyl, Ci-C4-fluoroalkyl, (C3-C4-cycloalkyl)-(methyl)-, methoxy,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a group selected from
methoxy, Ci-C4-fluroalkoxy, and (C3-C4-cycloalkyl)-(methoxy)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a -NR11R11a group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a Ci-C4-fluroalkoxy group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a Ci-C3-fluroalkoxy group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a fluorine atom or a group selected from Ci-C5-alkyl, Ci-C2-fluoroalkyl, cyclopropyl, benzyl, -C(=0)-N(R11)R11a, Ci-C3-alkoxy, Ci- C2-fluoroalkoxy and (cyclopropyl)-(methoxy)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a group selected from Ci-C3-alkyl, trifluoromethyl, cyclopropyl, C1-C3- alkoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy and (cyclopropyl)-(methoxy)-, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a group selected from methyl, trifluoromethyl, cyclopropyl, metfioxy, ethoxy, iso-propoxy, 2,2,2-trifluoroethoxy and (cyclopropyl )-(methoxy)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a group selected from methyl, trifluoromethyl, methoxy, ethoxy, iso-propoxy and (cyclopropyl)-(methoxy)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a group selected from methyl and trifluoromethyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a group selected from methoxy, ethoxy, 2,2,2-trifluoroethoxy, 2,2- difluoropropoxy, iso-propoxy and (cyclopropyl)-(methoxy)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a group selected from methoxy, ethoxy, 2,2,2-trifluoroethoxy, iso-propoxy and (cyclopropyl)-(methoxy)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a group selected from methoxy, ethoxy, 2,2,2-trifluoroethoxy, 2,2- difluoropropoxy and iso-propoxy,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a group selected from methoxy, ethoxy, 2,2,2-trifluoroethoxy and iso- propoxy,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a group selected from methoxy, ethoxy, iso-propoxy and (cyclopropyl)- (methoxy)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a group selected from methoxy, ethoxy and iso-propoxy, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a methoxy group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a group selected from 2,2,2-trifluoroethoxy and 2,2-difluoropropoxy, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a 2,2-difluoroprooxy group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a 2,2,2-trifluoroethoxy group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents an ethoxy group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents an iso-propoxy group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a (cyclopropyl)-(methoxy)-group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a chlorine atom or a group selected from Ci-C3-alkyl, cyclopropyl, dimethylamino, cyclopropylamino, Ci-C3-alkoxy and (cyclopropyl)-(methoxy)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a chlorine atom or a group selected from Ci-C3-alkyl, Ci-C3-alkoxy and (cyclopropyl )-(methoxy)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a group selected from Ci-C3-alkyl, Ci-C3-alkoxy and (cyclopropyl)- (methoxy)-, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a chlorine atom or a group selected from Ci-C3-alkoxy and (cyclopropyl)- (methoxy)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a group selected from Ci-C3-alkoxy and (cyclopropyl)-(methoxy)-, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a chlorine atom or a group selected from methyl, methoxy and (cyclopropyl)-(methoxy)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a group selected from methyl, methoxy and (cyclopropyl)-(methoxy)-, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a chlorine atom or a group selected from methoxy and (cyclopropyl)- (methoxy)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a group selected from methoxy and (cyclopropyl)-(methoxy)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a group selected from methoxy, 2,2,2-trifluoroethoxy and (cyclopropyl)- (methoxy)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a group selected from methyl, trifluoromethyl, (methoxy)-(methyl)-, ethylamino, isopropylamino, (cyclopropyl)-(methyl)-amino-, cyclopropylamino, cyclobutylamino, dimethylamino, azetidin-1-yl, 3,3-difluoroazetidin-1-yl, 3-trifluoromethylazetidin-1-yl, pyrrolidin- 1 -yl, piperidin-1-yl, morpholinyl, methoxy, ethoxy, iso-propoxy, 2,2,2-trifluoroethoxy, 2,2-difluoropropoxy and (cyclopropyl)-(methoxy)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which: R7 represents a group selected from methyl, trifluoromethyl, (methoxy)-(methyl)-, ethylamino, isopropylamino, (cyclopropyl)-(methyl)-amino-, cyclopropylamino, cyclobutylamino, dimethylamino, azetidin-1-yl, 3,3-difluoroazetidin-1 -yl, pyrrolidin-1-yl, piperidin-1-yl, morpholinyl, methoxy, ethoxy, iso-propoxy and (cyclopropyl)-(methoxy)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a group selected from methyl, (methoxy)-(methyl)-, ethylamino, isopropylamino, (cyclopropyl)-(methyl)-amino-, cyclopropylamino, cyclobutylamino, dimethylamino, azetidin-1 -yl, 3,3-difluoroazetidin-1-yl, 3-trifluoromethylazetidin-1-yl, pyrrolidin- 1 -yl, piperidin-1 -yl, morpholinyl, methoxy, ethoxy, iso-propoxy, 2,2,2-trifluoroethoxy, 2,2-difluoropropoxy and (cyclopropyl)-(methoxy)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a group selected from methyl, (methoxy)-(methyl)-, ethylamino, isopropylamino, (cyclopropyl)-(methyl)-amino-, cyclopropylamino, cyclobutylamino, dimethylamino, azetidin-1 -yl, 3,3-difluoroazetidin-1 -yl, pyrrolidin-1 -yl, piperidin-1-yl, morpholinyl, methoxy, ethoxy, iso-propoxy and (cyclopropyl)-(methoxy)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a group selected from methyl, trifluoromethyl and (methoxy)-(methyl)-, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a group selected from methyl and (methoxy)-(methyl)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a methyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a (methoxy)-(methyl)- group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a group selected from ethylamino, isopropylamino, (cyclopropyl)-(methyl)- amino-, cyclopropylamino, cyclobutylamino, dimethylamino, azetidin-1-yl, 3,3-difluoroazetidin- 1 -yl, 3-trifluoromethylazetidin-1-yl, pyrrolidin-1 -yl, piperidin-1 -yl and morpholinyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a group selected from ethylamino, isopropylamino, (cyclopropyl)-(methyl)- amino-, cyclopropylamino, cyclobutylamino, dimethylamino, azetidin-1-yl, 3,3-difluoroazetidin- 1 -yl, pyrrolidin-1-yl, piperidin-1 -yl and morpholinyl, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a group selected from ethylamino, isopropylamino, (cyclopropyl)-(methyl)- amino-, cyclopropylamino, cyclobutylamino,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a ethylamino group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a isopropylamino group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a (cyclopropyl)-(methyl)-amino- group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a cyclopropylamino group, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a cyclobutylamino group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a group selected from dimethylamino, azetidin-1-yl, 3,3-difluoroazetidin-1 - yl, 3-trifluoromethylazetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl and morpholinyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a group selected from dimethylamino, azetidin-1-yl, 3,3-difluoroazetidin-1 - yl, pyrrolidin-1 -yl, piperidin-1 -yl and morpholinyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a dimethylamino group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a group selected from azetidin-1 -yl, 3,3-difluoroazetidin-1-yl, 3- trifluoromethylazetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl and morpholinyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a group selected from azetidin-1 -yl, 3,3-difluoroazetidin-1-yl, pyrrolidin-1 -yl, piperidin-1-yl and morpholinyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a azetidin-1 -yl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a 3,3-difluoroazetidin-1-yl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a 3-trifluoromethylazetidin-1-yl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a piperidin-1 -yl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents a morpholinyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R8 represents a hydrogen atom or a group selected from methyl, ethyl, methoxy, ethoxy and dimethylamino,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R8 represents a hydrogen atom or a group selected from methyl, ethyl, methoxy and ethoxy,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R8 represents a hydrogen atom or a group selected from methoxy and ethoxy, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R8 represents a hydrogen atom or a methoxy group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R8 represents a methoxy group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R9 represents a hydrogen atom or a -CN or Ci-C3-alkyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R9 represents a hydrogen atom or a Ci-C3-alkyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R9 represents a hydrogen atom or a methyl or an ethyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R9 represents a hydrogen atom or a methyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R9 represents a hydrogen atom,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R9 represents a methyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R10 represents a group selected from -C(=0)R12, -C(=0)OR13, -C(=0)N(R14)R 4a, -S(=0)2R15, -S(=0)2N(R14)R14a, 5- to 6-membered heteroaryl and phenyl,
said 5- to 6-membered heteroaryl group and said phenyl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from -CN, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy and Ci- C3-haloalkoxy,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R10 represents a group selected from -C(=0)R12, -C(=0)OR13, -C(=0)N(R14)R14a, -S(=0)2R15, -S(=0)2N(R14)R14a, 5- to 6-membered heteroaryl and phenyl,
said 5- to 6-membered heteroaryl group and said phenyl group being optionally substituted one or two times, identically or differently, with a fluorine atom, chlorine atom or bromine atom, or a group selected from -CN, methyl, trifluoromethyl and methoxy,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R10 represents a group selected from -C(=0)R12, -C(=0)OR13, -C(=0)N(R14)R14a, -S(=0)2R15, -S(=0)2N(R14)R14a and phenyl,
said phenyl group being optionally substituted one or two times, identically or differently, with a fluorine atom, chlorine atom or bromine atom, or a group selected from -CN, methyl, trifluoromethyl and methoxy,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R10 represents a group selected from -C(=0)R12, -C(=0)N(R14)R14a, -S(=0)2R15, - S(=0)2N(R14)R14a and 2-chlorophenyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R10 represents a group selected from -C(=0)R12, -C(=0)N(R14)R14a, -S(=0)2R15 and - S(=0)2N(R14)R14a,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R10 represents a group selected from -C(=0)R12 and -C(=0)N(R14)R1 a,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R10 represents a -C(=0)R12 group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R10 represents a , -C(=0)N(R14)R14a group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R10 represents a -S(=0)2R15 group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R10 represents a -S(=0)2N(R14)R14a group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R10 represents a -C(=0)R12 group, and in which R12 represents a group selected from 2,2,2- trifluoroethyl, cyclopropyl, cyclobutyl and (cyclopropyl)-(methyl)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R10 represents a -C(=0)R12 group, and in which R12 represents a group selected from 2,2,2- trifluoroethyl, cyclopropyl, (l -trifluoromethyl)-(cyclopropyl)-, cyclobutyl and (cyclopropyl)-(methyl)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R10 represents a -C(=0)R12 group, and in which R12 represents a group selected from 2,2,2- trifluoroethyl, cyclopropyl and (l -trifluoromethyl)-(cyclopropyl)-, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R10 represents a -C(=0)R12 group, and in which R12 represents a group selected from Ci-C2-fluoroalkyl, C3-C4-cycloalkyl, 2-hydroxyprop-2-yl, (2-methoxy)-(prop-2-yl)-, (l -trifluoromethyl)-(cyclopropyl)- , 2,2-difluorocyclopropyl, 2,2-difluoro-1 - methylcyclopropyl and (cyclopropyl)-(methyl)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R10 represents a -C(=0)R12 group, and in which R12 represents a group selected from 2- hydroxyprop-2-yl, (2-methoxy)-(prop-2-yl)-, 2,2,2-trifluoroethyl, cyclopropyl, (1 - trifluoromethyl)-(cyclopropyl)-, 2,2-difluorocyclopropyl and 2,2-difluoro-1 - methylcyclopropyl, ,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R10 represents a -C(=0)R12 group, and in which R12 represents a group selected from 2,2,2- trifluoroethyl, cyclopropyl, (l -trifluoromethyl)-(cyclopropyl)-, 2,2-difluorocyclopropyl and 2,2-difluoro-l -methylcyclopropyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R10 represents a -C(=0)R12 group, and in which R12 represents a 2,2,2-trifluoroethyl group, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R10 represents a -C(=0)R12 group, and in which R12 represents a cyclopropyl group, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R10 represents a -C(=0)R12 group, and in which R12 represents a (1 -trifluoromethyl)- (cyclopropyl)- group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R11 and R11a, independently from each other, represent a hydrogen atom or a group selected from Ci-C4-alkyl, Ci-C4-haloalkyl, C3-C6-cycloalkyl, Ci-C6-hydroxyalkyl, (Ci-C3-alkoxy)- (Ci-C3-alkyl)-, (C3-C6-cycloalkyl)-(Ci-C3-alkyl)- and benzyl,
or
R11 and R11a, together with the nitrogen atom they are attached to, represent a 4- to 7- membered heterocycloalkyl group, said group being optionally substituted one or two times, identically or differently, with a halogen atom, or a group selected from hydroxy, oxo, -CN, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy, -C(=0)R18, -C(=0)OR18 and -S(=0)2R18,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R11 and R11a, independently from each other, represent a hydrogen atom or a group selected from Ci-C4-alkyl, Ci-C4-haloalkyl, C3-C6-cycloalkyl, Ci-C6-hydroxyalkyl, (Ci-C3-alkoxy)- (Ci-C3-alkyl)-, (C3-C6-cycloalkyl)-(Ci-C3-alkyl)- and benzyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R11 and R11a, together with the nitrogen atom they are attached to, represent a 4- to 7- membered heterocycloalkyl group, said group being optionally substituted one or two times, identically or differently, with a halogen atom, or a group selected from hydroxy, oxo, -CN, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy, -C(=0)R18, -C(=0)OR18 and -S(=0)2R18,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R11 and R11a, independently from each other, represent a hydrogen atom or a group selected from Ci-C4-alkyl, Ci-C4-haloalkyl, C3-C6-cycloalkyl and benzyl,
or
R11 and R11a, together with the nitrogen atom they are attached to, represent a 4- to 7- membered heterocycloalkyl group, said group being optionally substituted one or two times, identically or differently, with a halogen atom, or a group selected from hydroxy, oxo, -CN, Ci-C3-alkyl, -C(=0)R18, C(=0)OR18 and S(=0)2R18,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R11 and R11a, independently from each other, represent a hydrogen atom or a group selected from Ci-C4-alkyl, Ci-C4-haloalkyl, Cs-Ce-cycloalkyl and benzyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R11 and R11a, together with the nitrogen atom they are attached to, represent a 4- to 7- membered heterocycloalkyl group, said group being optionally substituted one or two times, identically or differently, with a halogen atom, or a group selected from hydroxy, oxo, -CN, Ci-Ca-alkyl, -C(=0)R18, C(=0)OR18 and S(=0)2R18,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R11 and R11a, independently from each other, represent a hydrogen atom or a group selected from Ci-C4-alkyl, Ci-C4-fluoroalkyl, C3-C4-cycloalkyl, Ci-C4-hydroxyalkyl, (Ci-C2-alkoxy)- (Ci-C3-alkyl)-, (C3-C4-cycloalkyl)-(methyl)- and benzyl, or
R 1 and R1 a, together with the nitrogen atom they are attached to, represent a 4- to 6- membered heterocycloalkyl group, said group being optionally substituted one or two times, identically or differently, with a fluorine atom, or a group selected from hydroxy, oxo, -CN, methyl, trifluoromethyl and methoxy,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R11 and R11a, independently from each other, represent a hydrogen atom or a group selected from Ci-C4-alkyl, Ci-C4-fluoroalkyl, C3-C4-cycloalkyl, Ci-C4-hydroxyalkyl, (Ci-C2-alkoxy)- (Ci-C3-alkyl)-, (C3-C4-cycloalkyl)-(methyl)- and benzyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R and R11a, together with the nitrogen atom they are attached to, represent a 4- to 6- membered heterocycloalkyl group, said group being optionally substituted one or two times, identically or differently, with a fluorine atom, or a group selected from hydroxy, oxo, -CN, methyl, trifluoromethyl and methoxy,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R11 and R11a, independently from each other, represent a hydrogen atom or a group selected from Ci-C4-alkyl and benzyl,
or
R11 and R11a, together with the nitrogen atom they are attached to, represent a 5- to 6- membered heterocycloalkyl group, said group being optionally substituted once with a methyl group, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 1 and R11a, independently from each other, represent a hydrogen atom or a group selected from Ci-C4-alkyl and benzyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 and R11a, together with the nitrogen atom they are attached to, represent a 5- to 6- membered heterocycloalkyl group, said group being optionally substituted once with a methyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R 1 and R a, independently from each other, represent a hydrogen atom or a group selected from Ci-C3-alkyl, Ci-C3-fluoroalkyl, C3-C4-cycloalkyl, Ci-C3-hydroxyalkyl, (Ci-C2-alkoxy)- (Ci-C3-alkyl)-, (C3-C4-cycloalkyl)-(methyl)- and benzyl,
or
R11 and R11a, together with the nitrogen atom they are attached to, represent a 4- to 6- membered heterocycloalkyl group, said group being optionally substituted one or two times, identically or differently, with a fluorine atom or with a group selected from methyl and trifluoromethyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R11 and R 1a, independently from each other, represent a hydrogen atom or a group selected from Ci-C3-alkyl, Ci-C3-fluoroalkyl, C3-C4-cycloalkyl, Ci-C3-hydroxyalkyl, (Ci-C2-alkoxy)- (Ci-C3-alkyl)-, (C3-C4-cycloalkyl)-(methyl)- and benzyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R11 and R11a, together with the nitrogen atom they are attached to, represent a 4- to 6- membered heterocycloalkyl group, said group being optionally substituted one or two times, identically or differently, with a fluorine atom or with a group selected from methyl and trifluoromethyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R11 and R11a, independently from each other, represent a hydrogen atom or a group selected from methyl and ethyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R11 and R11a, independently from each other, represent a hydrogen atom or a group selected from Ci-C3-alkyl, 2,2,2-trifluoroethyl, C3-C4-cycloalkyl, (Ci-C2-alkoxy)-(Ci-C3-alkyl)- and (C3-C4-cycloalkyl)-(methyl)-,
or
R11 and R11a, together with the nitrogen atom they are attached to, represent a 4- to 6- membered heterocycloalkyl group, said group being optionally substituted one or two times with a fluorine atom or a trifluoromethyl group, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R11 and R11a, independently from each other, represent a hydrogen atom or a group selected from Ci-C3-alkyl, 2,2,2-trifluoroethyl, C3-C4-cycloalkyl, (Ci-C2-alkoxy)-(Ci-C3-alkyl)- and (C3-C4-cycloalkyl)-(methyl)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R11 and R1 a, together with the nitrogen atom they are attached to, represent a 4- to 6- membered heterocycloalkyl group, said group being optionally substituted one or two times with a fluorine atom or a trifluoromethyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R 1 and R11a, independently from each other, represent a hydrogen atom or a group selected from Ci-C3-alkyl, 2,2,2-trifluoroethyl, C3-C4-cycloalkyl, (Ci-C2-alkoxy)-(Ci-C3-alkyl)- and (C3-C4-cycloalkyl)-(methyl)-,
or
R11 and R11a, together with the nitrogen atom they are attached to, represent a 4- to 6- membered heterocycloalkyl group, said group being optionally substituted one or two times with a fluorine atom,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R11 and R11a, independently from each other, represent a hydrogen atom or a group selected from Ci-C3-alkyl, 2,2,2-trifluoroethyl, C3-C4-cycloalkyl, (Ci-C2-alkoxy)-(Ci-C3-alkyl)- and (C3-C4-cycloalkyl)-(methyl)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R11 and R11a, together with the nitrogen atom they are attached to, represent a 4- to 6- membered heterocycloalkyl group, said group being optionally substituted one or two times with a fluorine atom,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R11 and R11a, independently from each other, represent a hydrogen atom or a group selected from methyl, ethyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl and (cyclopropyl)-
(methyl)-,
or
R11 and R11a, together with the nitrogen atom they are attached to, represent a group selected from azetidin-1-yl, 3-fluoroazetidin-1 -yl, 3,3-difluoroazetidin-1 -yl, 3-trifluoromethylazetidin-1 -yl, pyrrolidin-1 -yl, piperidin-1 -yl, morpholinyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R11 and R11a, independently from each other, represent a hydrogen atom or a group selected from methyl, ethyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl and (cyclopropyl)- (methyl)--, or
R11 and R11a, together with the nitrogen atom they are attached to, represent a group selected from azetidin-1 -yl, 3-fluoroazetidin-1 -yl, 3,3-difluoroazetidin-1 -yl, pyrrolidin-1 -yl, piperidin-1 -yl, morpholinyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R11 and R11a, independently from each other, represent a hydrogen atom or a group selected from a hydrogen atom or a group selected from methyl, ethyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl and (cyclopropyl)-(methyl)--,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R11 and R11a, together with the nitrogen atom they are attached to, represent a group selected from azetidin-1-yl, 3-fluoroazetidin-1 -yl, 3,3-difluoroazetidin-1-yl, 3-trifluoromethylazetidin-1-yl, pyrrolidin-1 -yl, piperidin-1 -yl, morpholinyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R11 and R11a, together with the nitrogen atom they are attached to, represent a group selected from azetidin-1 -yl, 3-fluoroazetidin-1-yl, 3,3-difluoroazetidin-1 -yl, pyrrolidin-1 -yl, piperidin-1 -yl, morpholinyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R11 and R11a, independently from each other, represent a hydrogen atom or a group selected from methyl, ethyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl and (cyclopropyl)- (methyl)-,
or
R11 and R11a, together with the nitrogen atom they are attached to, represent a group selected from azetidin-1-yl, 3,3-difluoroazetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholinyl, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R11 and R11a, together with the nitrogen atom they are attached to, represent a group selected from azetidin-1-yl, 3,3-difluoroazetidin-1-yl, 3-trifluoromethylazetidin-1-yl, pyrrolidin-1-yl, piperidin-1 -yl, morpholinyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R11 and R11a, together with the nitrogen atom they are attached to, represent a group selected from azetidin-1 -yl, 3,3-difluoroazetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholinyl, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R12 represents a hydrogen atom or a group selected from Ci-C6-alkyl, Ci -C6-haloalkyl, Ci- Ce-hydroxyalkyl, (Ci -C3-alkoxy)-(Ci-C3-alkyl)-, C3-C6-cycloalkyl, (C3-C6-cycloalkyl)-(Ci- C3-alkyl)-, C2-C6-alkenyl, C2-C6-alkynyl, 4- to 7-membered heterocycloalkyl, 5- to 7- membered heterocycloalkenyl, 5- to 6-membered heteroaryl and phenyl,
said 5- to 6-membered heteroaryl group and said phenyl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from -CN, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy and Ci - C3-haloalkoxy,
said C3-C6-cycloalkyl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from -CN, Ci- C3-alkyl and Ci-C3-haloalkyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R12 represents a hydrogen atom or a group selected from C Ce-alky!, Ci-C6-haloalkyl, Ci - Ce-hydroxyalkyl, C3-C6-cycloalkyl, (C3-C6-cycloalkyl)-(Ci-C3-alkyl)-, C2-C6-alkenyl, C2-
C6-alkynyl, 4- to 7-membered heterocycloalkyl, 5- to 7-membered heterocycloalkenyl, 5- to 6-membered heteroaryl and phenyl,
said 5- to 6-membered heteroaryl group and said phenyl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from -CN, Ci -C3-aIkyl, Ci -C3-haloalkyl, Ci-C3-alkoxy and Ci-
C3-haloalkoxy,
said C3-C6-cycloalkyl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from -CN , Ci - C3-alkyl and Ci-C3-haloalkyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R12 represents a group selected from Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-hydroxyalkyl, C3- Ce-cycloalkyl, (C3-C6-cycloalkyl)-(Ci-C3-alkyl)-, C2-C6-alkenyl, C2-C6-alkynyl, 4- to 7- membered heterocycloalkyl, 5- to 7-membered heterocycloalkenyl, 5- to 6-membered heteroaryl and phenyl,
said 5- to 6-membered heteroaryl group and said phenyl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from -CN, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy and Ci- C3-haloalkoxy,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R12 represents a hydrogen atom or a group selected from Ci-C4-alkyl, Ci-C4-fluoroalkyl, Ci-C4-hydroxyalkyl, (Ci-C2-alkoxy)-(Ci-C3-alkyl)-, C3-C6-cycloalkyl, (C3-C6-cycloalkyl)- (Ci-C2-alkyl)-, C2-C4-alkenyl, 5- to 6-membered heteroaryl and phenyl,
said 5- to 6-membered heteroaryl group and said phenyl group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or a group selected from methyl, trifluormethyl and methoxy, said C3-C6-cycloalkyl group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or a group selected from -CN, methyl and trifluoromethyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R12 represents a hydrogen atom or a group selected from Ci-C4-alkyl, Ci-C4-fluoroalkyl, C3-C6-cycloalkyl, (C3-C6-cycloalkyl)-(Ci-C2-alkyl)-, C2-C4-alkenyl, 5- to 6-membered heteroaryl and phenyl,
said 5- to 6-membered heteroaryl group and said phenyl group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or a group selected from methyl, trifluormethyl and methoxy, said C3-C6-cycloalkyl group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or a group selected from -CN, methyl and trifluoromethyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R12 represents a group selected from Ci-C4-alkyl, Ci-C4-fluoroalkyl, C3-C6-cycloalkyl, (C3- C6-cycloalkyl)-(Ci-C2-alkyl)- and C2-C4-alkenyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R12 represents a group selected from Ci-C4-alkyl, Ci-C3-fluoroalkyl, Ci-C3-hydroxyalkyl, (methoxy)-(Ci-C3-alkyl)-, C3-C4-cycloalkyl, (cyclopropyl)-(methyl)- and allyl,
said C3-C4-cycloalkyl group being optionally substituted one, two or three times, identically or differently, with a fluorine atom or a group selected from methyl and trifluoromethyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further particular embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R12 represents a C3-C4-cycloalkyl group,
said C3-C4-cycloalkyl group being optionally substituted one, two or three times, identically or differently, with a fluorine atom or a group selected from methyl and trifluoromethyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further particular embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R12 represents a cyclopropyl group,
said cyclopropyl group being optionally substituted one, two or three times, identically or differently, with a fluorine atom or a group selected from methyl and trifluoromethyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further particular embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R12 represents a group selected from (l-trifluoromethyl)-(cyclopropyl)- , 2,2- difluorocyclopropyl and 2,2-difluoro-1 -methylcyclopropyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R12 represents a group selected from Ci-C4-alkyl, Ci-C3-fluoroalkyl, C3-C4-cycloalkyl, (cyclopropyl)-(methyl)- and allyl,
said C3-C4-cycloalkyl group being optionally substituted one, two or three times, identically or differently, with a fluorine atom or a group selected from methyl and trifluoromethyl, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R12 represents a group selected from Ci-Gt-alkyl, Ci-C3-fluoroalkyl, C3-C4-cycloalkyl, (cyclopropyl)-(methyl)- and allyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R12 represents a group selected from Ci-C2-fluoroalkyl, C3-C4-cycloalkyl, 2-hydroxyprop-2- yl, (2-methoxy)-(prop-2-yl)-, (l -trifluoromethyl)-(cyclopropyl)-, 2,2-difluorocyclopropyl, 2,2-difluoro-1-methylcyclopropyl and (cyclopropyl)-(methyl)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R12 represents a group selected from Ci-C2-fluoroalkyl, C3-C4-cycloalkyl, (1 -trifluoromethyl)- (cyclopropyl)- and (cyclopropyl)-(methyl)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R12 represents a group selected from Ci-C2-fluoroalkyl, C3-C4-cycloalkyl and (cyclopropyl)- (methyl)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R12 represents a Ci-C2-fluoroalkyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R12 represents a C3-C4-cycloalkyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R12 represents a (cyclopropyl)-(methyl)- group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R12 represents a group selected from 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 2- hydroxyprop-2-yl, (2-methoxy)-(prop-2-yl)-, (l -trifluoromethyl)-(cyclopropyl)- 2,2- difluorocyclopropyl, 2,2-difluoro-1 -methylcyclopropyl and (cyclopropyl)-(methyl)-, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R12 represents a group selected from 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, (1- trifluoromethyl)-(cyclopropyl)- and (cyclopropyl)-(methyl)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R12 represents a group selected from 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl and (cyclopropyl)-(methyl)-;
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R12 represents a group selected from 2,2,2-trifluoroethyl, cyclopropyl and (1- trifluoromethyl)-(cyclopropyl)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R12 represents a 2,2,2-trifluoroethyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R12 represents a cyclopropyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R12 represents a cyclobutyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R 2 represents a (l-trifluoromethyl)-(cyclopropyl)- group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R12 represents a 2,2-difluorocyclopropyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R12 represents a 2,2-difluoro-1-methylcyclopropyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R12 represents a (cyclopropyl)-(methyl)- group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R13 represents a group selected from Ci-C4-alkyl and benzyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R13 represents a group selected from methyl, ethyl, tert-butyl and benzyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R13 represents a benzyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R 3 represents a Ci-C4-alkyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R13 represents a group selected from methyl, ethyl and tert-butyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R 3 represents a tert-butyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R14 and R14a, independently from each other, represent a hydrogen atom or a group selected from Ci-C4-alkyl, Ci-C4-haloalkyl, C3-C6-cycloalkyl and benzyl,
or
R14 and R14a, together with the nitrogen atom they are attached to, represent a 4- to 7- membered heterocycloalkyl group, said group being optionally substituted one or two times, identically or differently, with a halogen atom or a group selected from hydroxyl, - CN, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy, Ci-C3-haloalkoxy and (Ci-C3-alkoxy)- (Ci-C3-alkyl)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R14 and R14a, independently from each other, represent a hydrogen atom or a group selected from Ci-C4-alkyl, Ci-C4-haloalkyl, C3-C6-cycloalkyl and benzyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R14 and R14a, together with the nitrogen atom they are attached to, represent a 4- to 7- membered heterocycloalkyl group, said group being optionally substituted one or two times, identically or differently, with a halogen atom or a group selected from hydroxyl, -
CN, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy, Ci-C3-haloalkoxy and (Ci-C3-alkoxy)- (Ci-C3-alkyl)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which: R14 and R14a, independently from each other, represent a hydrogen atom or a group selected from Ci-C3-alkyl, trifluoromethyl and cyclopropyl,
or
R14 and R14a, together with the nitrogen atom they are attached to, represent a 4- to 7- membered heterocycloalkyl group, said group being optionally substituted one or two times, identically or differently, with a group selected from Ci-C3-alkyl, Ci-C3-fluoroalkyl, Ci-C3-alkoxy, trifluoromethoxy and (Ci-C2-alkoxy)-(Ci-C2-alkyl)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R14 and R14a, independently from each other, represent a hydrogen atom or a group selected from Ci-C3-alkyl, trifluoromethyl and cyclopropyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R14 and R14a, together with the nitrogen atom they are attached to, represent a 4- to 7- membered heterocycloalkyl group, said group being optionally substituted one or two times, identically or differently, with a group selected from Ci-C3-alkyl, Ci-C3-fluoroalkyl, Ci-C3-alkoxy, trifluoromethoxy and (Ci-C2-alkoxy)-(Ci-C2-alkyl)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R14 and R14a, independently from each other, represent a hydrogen atom or a group selected from methyl and ethyl,
or
R14 and R14a, together with the nitrogen atom they are attached to, represent a 5- to 6- membered heterocycloalkyl group selected from pyrrolidinyl, piperidinyl and morpholinyl, said group being optionally substituted once with a group selected from methyl, methoxy and (methoxy)-(methyl)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R14 and R14a, independently from each other, represent a hydrogen atom or a group selected from methyl and ethyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R14 and R14a, together with the nitrogen atom they are attached to, represent a 5- to 6- membered heterocycloalkyl group selected from pyrrolidinyl, piperidinyl and morpholinyl, said group being optionally substituted once with a group selected from methyl, methoxy and (methoxy)-(methyl)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R15 represents a group selected from Ci-C6-alkyl, Ci-Ce-haloalkyl, Ci-C6-hydroxyalkyl, (Ci- C3-alkoxy)-(Ci-C6-alkyl)-, (Ci-C3-alkoxy)-(C2-C3-alkoxy)-(Ci-C6-alkyl)-, C3-C6-cycloalkyl, (C3-C6-cycloalkyl)-(Ci-C3-alkyl)-, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl and phenyl,
said 5- to 6-membered heteroaryl group and said phenyl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from -CN, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy and Ci- C3-haloalkoxy,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R 5 represents a group selected from Ci-C4-alkyl, Ci-C4-fluoroalkyl, (Ci-C2-alkoxy)-(Ci-C3- alkyl)-, (Ci-C2-alkoxy)-(ethoxy)-(Ci-C3-alkyl)-, C3-C6-cycloalkyl, (Cs-Ce-cycloalkylHd- C2-alkyl)- and 4- to 7-membered heterocycloalkyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R15 represents a group selected from ethyl, 3,3,3-trifluoropropyl, (3-methoxy)-(propyl)-, (2'- methoxy)-(2-ethoxy)-(ethyl)-, cyclopropyl, cyclohexyl and tetrahydropyranyl, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R15 represents a group selected from ethyl, 3,3,3-trifluoropropyl, (3-methoxy)-(propyl)-, (2'- methoxy)-(2-ethoxy)-(ethyl)-, cyclopropyl, cyclohexyl and tetrahydropyranyl, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R15 represents a group selected from ethyl, 3,3,3-trifluoropropyl, (3-methoxy)-(propyl)-, (2'- methoxy)-(2-ethoxy)-(ethyl)-, cyclopropyl, cyclohexyl and tetrahydropyranyl, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R16 represents a hydrogen atom or a group selected from Ci-C4-alkyl and benzyl, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R16 represents a hydrogen atom or a Ci-C3-alkyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R16 represents a hydrogen atom or a Ci-C2-alkyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R16 represents a hydrogen atom or a methyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R16 represents a hydrogen atom or a methyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
x represents an integer selected from 1 , 2, 3 and 4,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
x represents an integer selected from 1 and 2,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
x represents an integer 1 ,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group
Figure imgf000253_0001
in which "*" represents the point of attachment to the rest of the molecule;
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group;
represents a group
Figure imgf000253_0002
in which "*" represents* the point of attachment to the rest of the molecule, and
R10 represents a -C(=0)R12 group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group
Figure imgf000253_0003
in which "*" represents the point of attachment to the rest of the molecule;
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group;
represents a group
Figure imgf000254_0001
in which "*" represents the point of attachment to the rest of the molecule,
R9 represents a methyl group, and
R10 represents a -C(=0)R12 group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group
Figure imgf000254_0002
in which "*" represents the point of attachment to the rest of the molecule;
the ring of said group being, besides R6, optionally substituted with one further R7 group;
R2 represents a group
Figure imgf000254_0003
in which "*" represents the point of attachment to the rest of the molecule, and
R10 represents a -C(=0)R12 group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group
Figure imgf000255_0001
in which "*" represents the point of attachment to the rest of the molecule;
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group;
represents a group
Figure imgf000255_0002
in which "*" represents the point of attachment to the rest of the molecule,
R3 represents a hydrogen atom,
R9 represents a methyl group, and
R10 represents a -C(=0)R12 group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group
Figure imgf000255_0003
in which "*" represents the point of attachment to the rest of the molecule;
the ring of said group being, besides R6, optionally substituted with one further R7 group;
R2 represents a group
Figure imgf000256_0001
in which "*" represents the point of attachment to the rest of the molecule,
R3 represents a hydrogen atom, and
R10 represents a -C(=0)R12 group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group
Figure imgf000256_0002
in which "*" represents the point of attachment to the rest of the molecule;
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group;
R2 represents a group
Figure imgf000256_0003
in which "*" represents the point of attachment to the rest of the molecule,
R3 represents a hydrogen atom,
R4 represents a hydrogen atom,
R5 represents a hydrogen atom, and
R 0 represents a -C(=0)R12 group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R represents a group
Figure imgf000257_0001
in which "*" represents the point of attachment to the rest of the molecule;
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group;
represents a group
Figure imgf000257_0002
in which "*" represents the point of attachment to the rest of the molecule,
R3 represents a hydrogen atom,
R4 represents a hydrogen atom,
R5 represents a hydrogen atom,
R9 represents a methyl group, and
R10 represents a -C(=0)R12 group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group
Figure imgf000258_0001
in which "*" represents the point of attachment to the rest of the molecule;
the ring of said group being, besides R6, optionally substituted with one further group;
represents a group
Figure imgf000258_0002
in which "*" represents the point of attachment to the rest of the molecule,
R3 represents a hydrogen atom,
R4 represents a hydrogen atom,
R5 represents a hydrogen atom, and
R10 represents a -C(=0)R12 group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R represents a group
Figure imgf000258_0003
in which "*" represents the point of attachment to the rest of the molecule;
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group; R3 represents a hydrogen atom,
R4 represents a hydrogen atom,
R5 represents a hydrogen atom,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group
Figure imgf000259_0001
in which "*" represents the point of attachment to the rest of the molecule;
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group;
R3 represents a hydrogen atom,
R4 represents a hydrogen atom,
R5 represents a hydrogen atom, and
R9 represents a methyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group
Figure imgf000259_0002
in which "*" represents the point of attachment to the rest of the molecule;
the ring of said group being, besides R6, optionally substituted with one further R7 group; R3 represents a hydrogen atom,
R4 represents a hydrogen atom,
R5 represents a hydrogen atom, and
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents a group
Figure imgf000260_0001
in which "*" represents the point of attachment to the rest of the molecule,
R3 represents a hydrogen atom,
R4 represents a hydrogen atom,
R5 represents a hydrogen atom, and
R10 represents a -C(=0)R12 group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group
Figure imgf000260_0002
in which "*" represents the point of attachment to the rest of the molecule;
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group;
R2 represents a group
Figure imgf000261_0001
in which "*" represents the point of attachment to the rest of the molecule,
R3 represents a hydrogen atom,
R4 represents a hydrogen atom,
R5 represents a hydrogen atom, and
R10 represents a -C(=0)R12 group, in which R12 represents a group selected from 2,2,2- trifluoroethyl, cyclopropyl, cyclobutyl and (cyclopropyl)-(methyl)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents a group
Figure imgf000261_0002
in which "*" represents the point of attachment to the rest of the molecule;
the ring of said group being, besides R6, optionally substituted with one further R7 group;
R2 represents a group
Figure imgf000261_0003
in which "*" represents the point of attachment to the rest of the molecule,
R3 represents a hydrogen atom,
R4 represents a hydrogen atom,
R5 represents a hydrogen atom, and R10 represents a -C(=0)R12 group, in which R12 represents a group selected from 2,2,2- trifluoroethyl, cyclopropyl, cyclobutyl and (cyclopropyl)-(methyl)-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers combinations of two or more of the above mentioned embodiments under the heading "further embodiments of the first aspect of the present invention".
The present invention covers any sub-combination within any embodiment or aspect of the present invention of compounds of general formula (I), supra.
The present invention covers any sub-combination within any embodiment or aspect of the present invention of intermediate compounds of general formula (XL).
The present invention covers the compounds of general formula (I) which are disclosed in the Example Section of this text, infra.
General Syntheses of compounds of formula (I)
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 compounds of the general formula (I), 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, modification of any of the substituents, such as R1 , R2, R3, R4 or R5, or of substituents contained therein, such as R10 in R2, 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, alkylation, acylation, sulfonylation, metallation, metal catalysed coupling reactions, exemplified by but not limited to Suzuki, Sonogashira, Negishi and Ullmann couplings, ester saponifications, amide coupling reactions, formation and cleavage of ethers, reductive aminations, hydrogenolyses e.g. of halogen atoms bonded to aromatic rings, Mitsunobu type reactions of an alcohol with a nucleophile in the presence of an dialkyl azodicarboxylate, such as DIAD (diisopropyl azodicarboxylate) and a tertiary phosphine, such as triphenylphosphine, 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 modification 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).
Compounds of formula (I), and the intermediates used in their synthesis, may be chiral, e.g. in case of R9 being different from hydrogen, and may then be formed as mixtures of stereoisomers. Said mixtures of stereoisomers can be separated by methods well known the person skilled in the art, such as preparative chromatography, such as high pressure liquid chromatography (HPLC) or superfluid chromatography (SFC) using chiral stationary phases, which are commercially available in considerable variety. If compounds of formula (I), or intermediates used in their synthesis, are sufficiently basic or acidic, stereoisomeric mixtures, in particular mixtures of enantiomers, can be resolved using chiral, enantiomerically pure acids, such as tartaric acid and 2,3-bis(benzoyloxy)succinic acid, or chiral, enantiomerically pure amines, such as 1-phenylethylamine or strychnine, respectively, via the formation of diastereomeric salts which can be separated.
The general synthesis strategy to compounds of the general formula (I) is outlined in Scheme 1. As starting materials, diaminobenzene derivatives of formula (II), in which R3 is as defined for the compounds of general formula (I) and X represents a group selected from a boronic acid, a boronic acid ester, a -CN group, a -C(=0)-0-RE group, in which RE represents a C1-C3- alkyl group, and a R1 group which is as defined for the compounds of general formula (I), and aminopyridine derivatives of formula (III), in which R4 and R5 are as defined for the compounds of general formula (I), and in which Y represents a group selected from -CH2-O-PG1, in which PG1 represents a protective group suitable for hydroxy groups, as present e.g. in alcohols, as defined supra, such as tert-butyl dimethylsilyl, a R2 group, which is as defined for the compounds of general formula (I), and a G1 group, in which R9 is as defined for the compounds of general formula (I), and in which "#" indicates that the piperazine ring may be either unsubstituted or bridged, or substituted with one or two methyl groups, according to the definition of R2 in general formula (I), can be employed.
In a first key step, said aminopyridines of formula (III) can be reacted with di-1 H-imidazol-1- ylmethanethione or thiophosgene, in the presence of a catalytic amount of 1 H-imidazole, in a solvent such as dichloromethane, tetrahydrofuran, Ν,Ν-dimethylformamide or dioxane, followed by the addition of diaminobenzene derivatives of formula (II), to give thioureas of formulae (IV) and (IVa) as regioisomeric mixtures. Said thioureas of formulae (IV) and (IVa) can be, in a second key step, further converted into benzimidazole derivatives of formula (V) by reaction with a carbodiimide, such as N,N'-dipropan-2-ylcarbodiimide or 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide, or a salt thereof, in an aliphatic chlorinated hydrocarbon, such as dichloromethane and chloroform, as a solvent. Noteworthily, regioisomeric mixtures of thioureas of formulae (IV) and (IVa) give rise to a homogeneous benzimidazole isomer as a result of imidazole tautomery.
Figure imgf000265_0001
( V )
Scheme 1 : General synthesis strategy for the preparation of the compounds of the present invention.
Dependent of the nature of the X and Y groups, compounds of formula (V) can either already constitute compounds of the general formula (I), or various synthetic intermediates thereof. More detailed synthesis routes to compounds of general formula (I) are given below, as outlined in the Schemes 2a, 2b, 2c, 2d, 2e, 2f, 3a, 3b, 3c, 4 and 5.
Schemes 2a and 2d outline an approach to compounds of general formula (I), in which R1 can be introduced in a late step by means of the well-known Suzuki coupling, from nitroaniline derivatives of formula (VI), diaminobenzene derivatives of formula (VII), aminopyridine derivatives of formula (VIII), and piperazine derivatives of formula (IX).
Figure imgf000266_0001
Figure imgf000266_0002
Figure imgf000266_0003
Scheme 2a: Synthesis of intermediates of formulae (XI) and (XII) from starting materials of formulae (VI), (VII), (VIII) and (IX).
Nitroanilines of formula (VI), in which R3 is as defined for compounds of general formula (I), and in which LG1 represents a leaving group, preferably chloride, bromide or iodide, can be converted, using methods well known to the person skilled in the art, e.g. by reacting with a suitable boron reagent, such as 4,4,4',4',5,5,5,,5,-octamethyl-2,2'-bi-1 ,3,2-dioxaborolane, in the presence of a palladium catalyst, such as bis(diphenylphosphino)ferrocene- palladium(ll)dichloride dichloromethane adduct, to give boronic acid derivatives of formula (X). Said boronic acid derivatives of formula (X) may be a boronic acid (RB = -H) or an ester of the boronic acid, e.g. its isopropyl ester (RB = Ci-C4-alkyl, e.g. -CH(CH3)2), or an ester derived from a diol such as pinacol in which the boronic acid intermediate forms a cyclic boronic ester, such as a 4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (RB-RB = C2-C6-alkylene, e.g. -C(CH3)2- C(CH3)2-). Many boronic acids and their esters are commercially available and well-known to the person skilled in the art; see e.g. D.G. Hall, Boronic Acids, 2005 WILEY- VCH Verlag GmbH & Co. KGaA, Weinheim, ISBN 3-527-30991-8 and references cited therein. Subsequently, boronic acid derivatives of formula (X) can be reduced to the corresponding diamines of formula (XI) by methods well known to the person skilled in the art, e.g. by palladium catalysed hydrogenolysis. In an analogous fashion as described supra for the conversion of compounds of formula (VI) into boronic acid derivatives of formula (X), diaminobenzene derivatives of formula (VII), in which R3 is as defined for the compounds of general formula (I), and in which LG1 represents a leaving group, preferably chloride, bromide or iodide, can be converted into compounds of formula (XI) in one step. Preferably, dichloropalladium - tricyclohexylphosphane (1 :2) is used as a catalyst in this Suzuki coupling reaction.
Further, aminopyridines of formula (VIII), in which R4, R5 and R9 are as defined for compounds of general formula (I), and in which LG2 represents a leaving group, preferably chloride or bromide, can be reacted with piperazine derivatives of formula (IX), in which R10 is as defined for compounds of general formula (I), and in which "#" indicates that the piperazine ring may be either unsubstituted or bridged, or substituted with one or two methyl groups, according to the definition of R2 in general formula (I), to give intermediates of formula (XII). The aminopyridines of formula (VIII) may be employed as free bases or as salts; furthermore, their amino group can optionally be protected by a protective group which is removed on later stage. Suitable groups for protection of amines, e.g. the phthalimido group, and methods for their introduction and removal, are well known to the person skilled in the art, see e.g. T.W. Greene and P.G.M. Wuts in Protective Groups in Organic Synthesis, 4th edition, Wiley 2006.
The reader is further referred to the fact that the definition of R10 for compounds of general formula (I) includes some protective groups, such as ie -butoxycarbonyl, which may be cleaved off and replaced by another R10 group at a later stage.
Starting materials of formulae (VI), (VII) (VIII) and (IX) are well known to the person skilled in the art and are commercially available in considerable variety, or can be prepared by well- known synthesis methods. Special reference is being made to protected aminopyridine derivatives of formula (XV), which are useful in particular for the preparation of compounds of general formula (I) and advanced intermediates thereof, in which R9 is different from a hydrogen atom. They can be prepared according to Scheme 2b from aminopyridines of formula (XIII), in which R4, R5 and R9 are as described for the compounds of general formula (I) with the proviso that R9 is different from a hydrogen atom, by reaction with benzene-1 ,2- dicarbonyl dichloride (also known as phthaloyl chloride) in the presence of a base, e.g. an aliphatic tertiary amine such as triethylamine, in an aliphatic halogenated hydrocarbon, such as dichloromethane, as a solvent, to give phthalimide derivatives of formula (XIV). Said phthalimide derivatives can subsequently be reacted with reagents suitable for the introduction of LG2, such as /V-halo succinimides, e.g. /V-bromo succinimide, and a radical starter, such as 2,2'-(£)-diazene-1 ,2-diylbis(2-methylpropanenitrile) (also known as AIBN), to give compounds of formula (XV), in which R4, R5 and R9 are as described for the compounds of general formula (I) with the proviso that R9 is different from hydrogen, and in which LG2 represents a leaving group, preferably chloride or bromide.
Figure imgf000268_0001
Scheme 2b: Synthesis of protected aminopyridine intermediates of formula (XV).
Diamines of formula (Xla), in which R3 represents a Ci-C4-alkoxy group, thus constituting a sub-compartment of formula (XI), can be advantageously approached using the modified approach shown below in Scheme 2c. Commercially available 2-bromo-5-nitrophenol (XVI) can be reacted with 1 , 1 ,1 -tri-(Ci-C3-alkyl)methylhydrazinium salts such as 1 , 1 , 1- trimethylhydrazinium iodide in the presence of a suitable base, such as an alkali alkoxide, such as sodium 2-methylbutan-2-olate, to give 2-amino-6-bromo-3-nitrophenol (XVII), which in turn can be reacted with a compound of formula RA-LG3, in which RA represents a Ci-C4-alkyl group, and LG3 represents a leaving group, preferably bromide or iodide, in the presence of a base such as sodium carbonate in a solvent such as acetonitrile or Ν,Ν-dimethylformamide, to yield a phenyl ether compound of formula (XVIII). Said aryl ether compounds of formula (XVIII) can be converted into the corresponding boronic acid derivatives of formula (XIX), which may be a boronic acid (RB = -H) or an ester of the boronic acid, e.g. its isopropyl ester (RB = Ci-C4- alkyl, e.g. -CH(CH3)2), or an ester derived from a diol such as pinacol in which the boronic acid intermediate forms a cyclic boronic ester, such as a 4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (RB-RB = C2-C6-alkylene, e.g. -C(CH3)2-C(CH3)2-), in an analogous fashion as described supra for the conversion of compounds of formula (VI) into boronic acid derivatives of formula (X). Subsequently, boronic acid derivatives of formula (XIX) can be reduced to the corresponding diamines of formula (Xla), in which R3 represents -ORA, i.e. Ci-C4-alkoxy, by methods well known to the person skilled in the art, e.g. by palladium catalysed hydrogenolysis.
Figure imgf000269_0001
Figure imgf000269_0002
( XIX ) ( Xla ) R3 = -ORA
Scheme 2c: Synthesis of intermediates of formula (Xla) from 2-bromo-5-nitrophenol (XVI).
As outlined in Scheme 2d, infra, compounds of formula (Xlla), formula (Xlla) being equivalent to formula (XII) in Scheme 2a, can be reacted with di-1 H-imidazol-1 -ylmethanethione or thiophosgene, in the presence of a catalytic amount of 1 H-imidazole, in a solvent such as dichloromethane, tetrahydrofuran, Ν,Ν-dimethylformamide or dioxane, preferably dichloromethane, followed by the addition of diaminobenzene derivatives of formula (XI), to give thioureas of formulae (XX) and (XXa) as regioisomeric mixtures. Said thiourea derivatives can be further converted into benzimidazole derivatives of formula (XXI) by reaction with a carbodiimide of formula RD1-N=C=N-RD2 (or a salt thereof), in which RD1 and RD2 represent, independently from each other, a Ci-Gralkyl group optionally substituted with one N,N- dimethylamino group, preferably RD1 being ethyl and RD2 being 3-N,N-dimethylaminopropyl, or both RD1 and RD2 being isopropyl, in a halogenated aliphatic hydrocarbon comprising 1 , 2 or 3 carbon atoms and 1 , 2, 3, 4, 5 or 6 halogen atoms, preferably chlorine atoms, as a solvent, particularly preferred solvents being dichloromethane and chloroform. As mentioned supra, regioisomeric mixtures of thioureas of formulae (XX) and (XXa) give rise to a homogeneous benzimidazole isomer as a result of imidazole tautomery. In a final step, the resulting benzimidazole derivatives of formula (XXI) can be reacted with compounds of formula (XXII), in which R1 is as defined for compounds of general formula (I), and in which LG4 represents a leaving group, preferably chloride, bromide or iodide, in a Suzuki coupling to give compounds of general formula (I). Specific examples are described in the Experimental Section.
Figure imgf000270_0001
Figure imgf000270_0002
Scheme 2d: Conversion of intermediates of formulae (XI) and (Xlla) into compounds of general formula (I).
Said Suzuki coupling reaction is catalysed by palladium catalysts, e.g. by Pd(0) catalysts such as tetrakis(triphenylphosphine)palladium(0) [Pd(PPh3)4], tris(dibenzylideneacetone)di- palladium(O) [Pd2(dba)3], or by Pd(ll) catalysts such as dichlorobis(triphenylphosphine)- palladium(ll) [Pd(PPh3)2CI2], dichloropalladium - tricyclohexylphosphane (1 :2) and palladium(ll) acetate in combination with triphenylphosphine or by [1 , 1 - bis(diphenylphosphino)ferrocene]palladium dichloride, in free form [Pd(dppf)C ] or as dichloromethane adduct [Pd(dppf)Cl2 x CH2CI2]. Preferred is the use of dichlorobis(triphenylphosphine)-palladium(ll) [Pd(PPh3)2Cl2] in combination with triphenylphosphine or the use of [1 ,1 '-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane adduct [Pd(dppf)Cl2 x CH2CI2] as a catalyst. The reaction is preferably carried out in a mixture of a solvent such as 1 ,2-dimethoxyethane, dioxane, DMF, THF, or n-propanol with water and in the presence of a base such as aqueous potassium carbonate, aqueous sodium bicarbonate or potassium phosphate.
The reaction is performed at temperatures ranging from room temperature (i.e. 20X) to the boiling point of the solvent. Further on, the reaction can be performed at temperatures above the boiling point using pressure tubes and a microwave oven, (review: D.G. Hall, Boronic Acids, 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim, ISBN 3-527-30991-8 and references cited therein).
The reaction is preferably completed after 1 to 36 hours of reaction time.
Compounds of formula (XXII) are well known to the person skilled in the art and are commercially available in considerable variety, or can be prepared by well-known synthesis methods. For the preparation of less common compounds of formula (XXII), the reader is also referred to the methods described in the Experimental section, see e.g. the protocols describing the syntheses of Compounds 07.04. and 08.06.
In a somewhat related approach, certain R1 groups such as 1 ,2,4-oxadiazol-5-yl and 1 ,2,4- triazol-5-yl can be formed from acyclic precursor groups.
As shown in Scheme 2e, aminopyridine derivatives of formula (XXIV), in which R4, R5 and R9 are as defined for compounds of general formula (I), and in which PG1 represents a protective group suitable for hydroxy groups, as present e.g. in alcohols, as defined supra, such as tert- butyl dimethylsilyl, are reacted with di-1 H-imidazol-1 -ylmethanethione or thiophosgene, in the presence of a catalytic amount of 1 H-imidazole, in dichloromethane as a solvent, followed by the addition of esters of 3,4-diaminobenzoic acid of formula (XXIII), in which R3 is as defined for compounds of general formula (I), and in which RE represents a Ci-C3-alkyl group, to give thiourea derivatives of formulae (XXV) and (XXVa) as regioisomeric mixtures. Said thiourea derivatives can be further converted into benzimidazole derivatives of formula (XXVI) by reaction with a carbodiimide, such as N,N'-dipropan-2-ylcarbodiimide or 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide, or a salt thereof, in an aliphatic chlorinated hydrocarbon such as dichloromethane or chloroform as a solvent. As mentioned supra, regioisomeric mixtures of thioureas of formulae (XXV) and (XXVa) give rise to a homogeneous benzimidazole isomer as a result of imidazole tautomery.
Figure imgf000272_0001
Figure imgf000272_0002
Scheme 2e: Synthesis of intermediates of formulae (XXVIII) from starting materials of formulae (XXIII) and (XXIV).
The moiety -OPG1 present in formula (XXVI) is then converted into a group LG5, which is a leaving group as defined supra, preferably chloride, giving rise to compounds of formula (XXVII), by first cleaving off said protective group PG1 by a method known to the person skilled in the art, e.g. by treatment with tetra-n-butylammonium fluoride in case said PG1 is tert-butyl dimethylsilyl, followed by treatment e.g. with a halogenating agent such as thionyl chloride (SOCI2), phosphoroxychloride (POCI3), or phosphorus trichloride (PCI3), or with a sulfonyl chloride such as methylsulfonyl chloride. In a similar fashion as discussed in context of Scheme 2a, supra, said compounds of formula (XXVII) can be reacted with piperazine derivatives of formula (IX), in which R10 is as defined for compounds of general formula (I), and in which "#" indicates that the piperazine ring may be either unsubstituted or bridged, or substituted with one or two methyl groups, according to the definition of R2 in general formula (I), to give intermediates of formula (XXVIII).
Starting materials of formulae (XXIII) and (XXIV) are well known to the person skilled in the art and can be purchased commercially in many cases, or can be prepared by known methods.
As shown in Scheme 2f, the further elaboration of compounds of formula (XXVIIIa), which is equivalent to formula (XXVIII) in Scheme 2e, commences with the hydrolytic cleavage of the carboxylic ester moiety present in formulae (XXVIII) and (XXVIIIa), using methodology well known to the person skilled in the art, such as by treatment with an aqueous alkali hydroxide, such as lithium hydroxide, sodium hydroxide or potassium hydroxide, in a solvent such as methanol, ethanol or tetrahydrofuran, or a mixture thereof, at elevated temperature, preferably between 40Ό and 80 "C, to give carboxylic acids of formula (XXIX). Said carboxylic acids of formula (XXIX) can be subsequently reacted with compounds of formula (XXX), in which R7 is as defined for compounds of general formula (I), and in which Q represents -O- or -N(R6)-, in which, in turn, R6 is as defined for compounds of general formula (I), in the presence of a suitable coupling agent, such as benzotriazol-1 -yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), and a base, such as N.N'-diisopropyethylamine, to give intermediates of formula (XXXI). Cyclisation to compounds of formula (la), constituting a sub- compartment of general formula (I), can be accomplished by heating said compounds of formula (XXXI) in a mixture of an aliphatic alcohol of the formula Ci-Gt-alkyl-OH, such as n- propanol, and water, in the presence of an alkali acetate, such as sodium acetate or potassium acetate. Optionally, a carboxamide based solvent such as Ν,Ν-dimethylformamide, N,N- dimethylacetamide or N-methylpyrrolidin-2-one can be added as a co-solvent to enhance solubility of the reactants. Specific examples are described in the Experimental Section.
Compounds of formula (XXX) are well known to the person skilled in the art, and can be prepared using known methods, the reader is further referred to the protocols e.g. for the preparation of Compounds 18.01 , 19.01 , 20.01 , and 42.02 in the Experimental Section.
In a similar fashion, R1 = 1 ,2,4-oxadiazol-3-yl can be elaborated from a cyano group, see Examples 22.01 and 22.02 and the corresponding precursors, e.g. Compounds 22.06 and 22.07, in the Experimental Section.
In a similar fashion, R1 = 1 ,3,4-oxadiazol-2-yl can be elaborated from a carboxy group, see e.g. Compounds 126.01 , 126.02 and 126.03, in the Experimental Section.
Figure imgf000274_0001
Figure imgf000274_0002
Figure imgf000274_0003
Scheme 2f: Conversion of intermediates of formula (XVIa) into compounds of formula (la).
In an alternative approach, the benzimidazole core in formula (I) is constructed on late stage. This synthesis route proceeds via diamines of formula (XXXIV), the synthesis of which is outlined in Scheme 3a, and which can be prepared from nitroaniline derivatives of formula (XXXIII) by methods well known to the person skilled in the art, such as catalytic hydrogenolysis, e.g. by reacting an ethanolic solution of compounds of formula (XXXIII) with an atmosphere of hydrogen in the presence of palladium on carbon. Alternatively, diamines of formula (XXXIV) can be prepared by a Suzuki coupling, as discussed supra, from compounds of formula (VII) in which R3 is as defined for the compounds of general formula (I), and in which LG1 represents a leaving group, preferably chloride, bromide or iodide (see Scheme 2a). Said nitroaniline derivatives of formula (XXXIII) can also be prepared by a Suzuki coupling as discussed supra, either employing boronic acid derivatives of formula (XXXII) and nitroaniline derivatives of formula (VI), cf. protocols of Compounds 39.01 , 39.02 and 39.03. in the Experimental section, or employing boronic acid derivatives of formula (X) and compounds of formula (XXII). In said compounds of formulae (VI), (X), (XXII) and (XXXII), R1 and R3 are as defined for compounds of general formula (I), LG1 and LG4 represent, independently from each other, a leaving group, preferably chloride, bromide or iodide, and RB represents hydrogen, a Ci-C-t-alkyl group such as isopropyl, or RB-RB together form a C2-C6-alkylene group, such as a -C(CH3)2-C(CH3)2- group, giving rise e.g. to a 4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane. The availability of compounds of formulae (VI), (VII), (X) and (XXII) is described supra; boronic acid derivatives of formula (XXXII) are well known to the person skilled in the art and are commercially available in considerable variety.
Diaminobenzene derivatives of formula (XXXIVa), constituting a sub-compartment of formula (XXXIV), can be prepared in one step from diaminobenzoate derivatives of formula (XXIII), in which R3 is as defined for the compounds of general formula (I), and in which RE represents Ci-C3-alkyl, by reaction with a compound of formula (XXX) (see also Scheme 2f) in a solvent such as dioxane in the presence of a base such as cesium carbonate. Diaminobenzoate derivatives of formula (XXIII) are known to the person skilled in the art, and can be prepared by known methods and can be purchased commercially in certain cases.
Figure imgf000275_0001
Scheme 3a: Synthesis of intermediates of formulae (XXXIV) and (XXXIVa). Within said synthesis routes to diamines of formula (XXXIV), R groups such as R6 or R7 groups, which constitute substituents of heteroaromatic R1 groups, can be modified as outlined in the initial paragraphs of this chapter. Instructive examples of such modifications can be readily found in the Experimental section, see e.g. the protocols of Compounds 36.01., 36.02., 36.03. and 36.04., for diamines of formula (XXXIV) in which R1 is a substituted pyrimidine, and e.g. the protocols of Compounds 39.01., 67.01., 68.01., 69.02., and 78.01., for diamines of formula (XXXIV) in which R1 is a pyrazole.
As shown below in Scheme 3b, diamines of formula (XXXIVb), in which R is as defined for the compounds of general formula (I), and in which R3 represents a Ci-C4-alkoxy group, said diamines constituting a further sub-compartment of formula (XXXIV), can be prepared advantageously in certain cases from aryl ether derivatives of formula (XVIII), in which RA represents a Ci-C4-alkyl group (see Scheme 2c), by means of Suzuki coupling as discussed supra, by reacting with boronic acid derivatives of formula (XXXII) resulting in intermediates of formula (XXXV) followed by reduction of the nitro group, e.g. by palladium catalysed hydrogenol sis, to give diamines of formula (XXXIVb).
Figure imgf000276_0001
( XVIII ) ( XXXV ) ( XXXIVb ) R3 = -OR*
Scheme 3b: Synthesis of intermediates of formula (XXIIb)
The further transformation of said diamine intermediates of formula (XXXIV) can be, as outlined in Scheme 3c, accomplished by reacting aminopyridines of formula (Xlla) (see Scheme 2d), in which R2, R4 and R5 are as defined for compounds of general formula (I), with di-1 H-imidazol-1 -ylmethanethione or thiophosgene, in the presence of a catalytic amount of 1 H-imidazole, in a solvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide or dioxane, followed by the addition of diaminobenzene derivatives of formula (XXXIV), to give thioureas of formulae (XXXVI) and (XXXVIa) as regioisomeric mixture. Said thiourea derivatives can be further converted into compounds of general formula (I) by reaction with a carbodiimide of formula RD1-N=C=N-RD2 (or a salt thereof), in which RD1 and RD2 represent, independently from each other, a Ci-C4-alkyl group optionally substituted with one N,N- dimethylamino group, preferably RD1 being ethyl and RD2 being 3-N,N-dimethylaminopropyl, or both RD1 and RD2 being isopropyl, in a halogenated aliphatic hydrocarbon comprising 1 , 2 or 3 carbon atoms and 1 , 2, 3, 4, 5 or 6 halogen atoms, preferably chlorine atoms, as a solvent, particularly preferred solvents being dichloromethane and chloroform. As mentioned supra, regioisomeric mixtures of thioureas of formulae (XXXVI) and (XXXVIa) give rise to a homogeneous benzimidazole isomer as a result of imidazole tautomery. Specific examples are described in the Experimental Section.
Figure imgf000277_0001
( XXXVI ) ( XXXVIa )
Figure imgf000277_0002
Scheme 3c: Synthesis of compounds of general formula (I) from diamine intermediates of formula (XXXIV).
A third approach proceeds via late-stage elaboration of the R2 moiety by attaching its piperazine pharmacophore, using nucleophilic substitution. As shown in Scheme 4, aminopyridine derivatives of formula (XXIV) (see also Scheme 2e), in which R4, R5 and R9 are as defined for compounds of general formula (I), and in which PG1 represents a protective group suitable for hydroxy groups, as present e.g. in alcohols, as defined supra, such as tert- butyl dimethylsilyl, can be reacted with with di-1 H-imidazol-1 -ylmethanethione or thiophosgene, in the presence of a catalytic amount of 1 H-imidazole, a solvent such as dichloromethane, tetrahydrofuran, Ν,Ν-dimethylformamide or dioxane, followed by the addition of diamine intermediates of formula (XXXIV) (see also Scheme 3a), in which R1 and R3 are as defined for compounds of general formula (I), to give thiourea derivatives of formulae (XXXVII) and (XXXVIIa) as regioisomeric mixtures. Said thiourea derivatives can be further converted into benzimidazole derivatives of formula (XXXVIII) by reaction with a carbodiimide, such as N,N'-dipropan-2-ylcarbodiimide or 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide, or a salt thereof, in an aliphatic chlorinated hydrocarbon such as dichloromethane or chloroform as a solvent. As mentioned supra, regioisomeric mixtures of thioureas of formulae (XXXVII) and (XXXVIIa) give rise to a homogeneous benzimidazole isomer as a result of imidazole tautomery. The moiety -OPG1 present in formula (XXXVIII) is then converted into a group LG6, which is a leaving group as defined supra, preferably chloride or (methylsulfonyl)oxy, giving rise to compounds of formula (XXXIX), by first cleaving off said protective group PG1 by a method known to the person skilled in the art, e.g. by treatment with tetra-n-butylammonium fluoride in case said PG1 is tert-butyl dimethylsilyl, followed by treatment e.g. with a halogenating agent such as thionyl chloride (SOCfe), phosphoroxychloride (POCb), or phosphorus trichloride (PC ), or with a sulfonyl chloride such as methylsulfonyl chloride. In a similar fashion as discussed in context of Schemes 2a and 2e, supra, said compounds of formula (XXXIX) can be reacted with piperazine derivatives of formula (IX), in which R10 is as defined for compounds of general formula (I), and in which "#" indicates that the piperazine ring may be either unsubstituted or bridged, or substituted with one or two methyl groups, according to the definition of R2 in general formula (I), to give compounds of formula (lb), which is equivalent to general formula (I). Specific examples are described in the Experimental Section.
Figure imgf000279_0001
Figure imgf000279_0002
Scheme 4: Synthesis of compounds of general formula (I) from diamine intermediates of formula (XXXIV) and aminopyridine derivatives of formula (XXIV). The reader is referred to the fact that the definition of R10 for compounds of general formula (I) includes some protective groups, such as tert-butoxycarbonyl, which may be cleaved off and replaced by another R10 group at a later stage, thus particularly qualifying this synthesis route for late-stage diversification of R10, by e.g. acidic cleavage of said tert-butoxycarbonyl group, followed by reaction of the resulting free NH group with reagents (RG) suitable for the introduction of R10 groups, such as R12-C(=0)OH, R12-C(=0)-LG7, R130-C(=0)-LG7, R1 a(R 4)N-C(=0)-LG7, R14a(R14)N-S(=0)2-LG7 and R15-S(=0)2-LG7, in which R12, R 3, R14, R14a and R15 are as defined for the compounds of general formula (I), and in which LG7 represents a leaving group as defined supra, preferably chloride, using methods well known to the person skilled in the art and as broadly exemplified in the Experimental Section.
This sequence is also outlined in Scheme 5, according to which tert-butoxycarbonyl derivatives of formula (lc), in which R1, R3, R4, R5 and R9 are as defined for the compounds of general formula (I), and in which "#" indicates that the piperazine ring may be either unsubstituted or bridged, or substituted with one or two methyl groups, according to the definition of R2 in general formula (I), rendering formula (lc) yet another sub-set of general formula (I), can be converted into the corresponding monosubstituted piperazines of formula (XL), by treatment with a strong acid, preferably hydrochloric acid or trifluoroacetic acid. Said monosubstituted piperazines of formula (XL) can be formed as free bases or as salts, and can be reacted with one reagent selected from the group (RG) consisting of R12-C(=0)OH, R12-C(=0)-LG7, R130- C(=0)-LG7, R14a(R14)N-C(=0)-LG7, R14a(R14)N-S(=0)2-LG7 and R15-S(=0)2-LG7, in which R12, R13, R14, R14a and R15 are as defined for the compounds of general formula (I), and in which LG7 represents a leaving group as defined supra, preferably chloride, as described in the preceding paragraph. Said reagents are ail well known to the person skilled in the art and are commercially available in considerable variety.
Figure imgf000281_0001
Figure imgf000281_0002
Scheme 5: Synthesis of compounds of general formula (I) from compounds of formula (Ic) via monosubstituted piperazine derivatives of formula (XL). Particularly, said free NH group can be subjected to a peptide coupling by reaction with a carboxylic acid of formula R12-C(=0)OH, in which R12 is as defined for compounds of general formula (I), in the presence of a peptide coupling reagent, selected from HATU (0-(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 T3P (2,4,6-tripropyl-1 ,3,5,2,4,6- trioxatriphosphinane 2,4,6-trioxide), all of them being well known to the person skilled in the art and all of them being commercially available, in the presence of a base such as a tertiary aliphatic amine of the formula N(Ci-C4-alkyl)3, or sodium bicarbonate, in an appropriate solvent such as N,N-dimethylformamide, Ν,Ν-dimethylacetamide, dimethylsulfoxide or N-methyl pyrrolidin-2-one. Specific examples are described in the Experimental Section. In accordance with a second aspect, the present invention covers methods of preparing compounds of general formula (I) as defined supra.
In one embodiment of the invention, said methods comprise the step of allowing an intermediate compound of general formula (XXI) :
Figure imgf000282_0001
(XXI) ,
in which R2, R3, R4 and R5 are as defined for the compound of general formula (I) as defined supra, and in which RB, which can be different or identical, represent a hydrogen atom or a Ci- C4-alkyl group, or both RB groups together form a C2-C6-alkylene group,
to react with a compound of general formula (XXII) :
R1— LG4
(XXII) ,
in which R1 is as defined for the compound of general formula (I) as defined supra, and in which LG4 represents a leaving group,
in the presence of a palladium catalyst,
thereby giving a compound of general formula (I) :
Figure imgf000282_0002
(I),
in which R1, R2, R3, R4 and R5 are as defined for the compound of general formula (I) as defined supra. In another embodiment of the invention, said methods comprise the steps of
I. allowing an intermediate compound of general formula (Xlla) :
Figure imgf000283_0001
(Xlla),
in which R2, R4 and R5 are as defined for the compound of general formula (I) as defined supra,
to react with a reagent selected from thiophosgene and di-1 H-imidazol-1- ylmethanethione, in the presence of a catalytic amount of 1 H-imidazole, followed by the addition of an intermediate compound of general formula (XXXIV) :
Figure imgf000283_0002
(XXXIV),
in which R1 and R3 are as defined for the compound of general formula (I) as defined supra,
thereby giving a regioisomeric mixture of intermediates of formulae (XXXVI) and (XXXVIa) :
Figure imgf000283_0003
(XXXVI) (XXXVIa),
in which R\ R2, R3, R4 and R5 are as defined for the compound of general formula (I) as defined supra, followed by ii. allowing said regioisomeric mixture of intermediates of formulae (XXXVI) and (XXXVIa):
Figure imgf000284_0001
(XXXVI) (XXXVIa), in which R1, R2, R3, R4 and R5 are as defined for the compound of general formula (I) as defined supra,
to react with a carbodiimide of formula RD1-N=C=N-RD2, in which RD1 and RD2 represent, independently from each other, a Ci-C4-alkyl group optionally substituted with one N,N- dimethylamino group,
thereby giving a compound of general formula (I) :
Figure imgf000284_0002
(I),
in which R1, R2, R3, R4 and R5 are as defined for the compound of general formula (I) as defined supra. In another embodiment of the invention, said methods comprise the steps of
i. allowing an intermediate compound of general formula (Xlla) :
Figure imgf000284_0003
in which R2, R4 and R5 are as defined for the compound of general formula (I) as defined supra,
to react with a reagent selected from thiophosgene and di-1 H-imidazol-1 - ylmethanethione, in the presence of a catalytic amount of 1 H-imidazole, followed by the addition of an intermediate compound of general formula (XXXIV) :
Figure imgf000285_0001
(XXXIV),
in which R1 and R3 are as defined for the compound of general formula (I) as defined supra,
thereby giving a regioisomeric mixture of intermediates of formulae (XXXVI) and
(XXXVIa) :
Figure imgf000285_0002
(XXXVI) (XXXVIa),
in which R1, R2, R3, R4 and R5 are as defined for the compound of general formula (I) as defined supra, followed by ii. allowing said regioisomeric mixture of intermediates of formulae (XXXVI) and (XXXVIa):
Figure imgf000285_0003
(XXXVI) (XXXVIa), in which R1, R2, R3, R4 and R5 are as defined for the compound of general formula (I) as defined supra,
to react with a carbodiimide of formula RD1-N=C=N-RD2 or a salt thereof, in which RD1 and RD2 represent, independently from each other, a d-Ct-alkyl group optionally substituted with one Ν,Ν-dimethylamino group,
thereby giving a compound of general formula (I) :
Figure imgf000286_0001
(I).
in which R1 , R2, R3, R4 and R5 are as defined for the compound of general formula (I) defined supra.
In another embodiment of the invention, said methods comprise the step of allowing intermediate compound of general formula (XL) or a salt thereof:
Figure imgf000286_0002
in which R1, R3, R4, R5 and R9 are as defined for the compound of general formula (I) as defined supra, and in which "#" indicates that the piperazine ring can be either unsubstituted or bridged, or substituted with one or two methyl groups, according to the definition of R2 in general formula (I) as defined supra,
to react with one reagent selected from the group (RG) consisting of R1 -C(=0)OH, R12-C(=0)- LG7, R130-C(=0)-LG7, R14a(R14)N-C(=0)-LG7, R14a(R14)N-S(=0)2-LG7 and R15-S(=0)2-LG7, in which R12, R13, R14, R14a and R15 are as defined for the compounds of general formula (I) as defined supra, and in which LG7 represents a leaving group,
thereby giving a compound of general formula (I) :
Figure imgf000286_0003
0.
in which R1 , R2, R3, R4 and R5 are as defined for the compound of general formula (I) as defined supra. In accordance with a third aspect, the present invention covers further methods of preparing compounds of general formula (I) as defined supra.
In one embodiment of the invention, said methods comprise the step of allowing an intermediate compound of general formula (XXI) :
Figure imgf000287_0001
(XXI),
in which R2, R3, R4 and R5 are as defined for the compound of general formula (I) as defined supra, and in which RB, which can be different or identical, represent a hydrogen atom or a Ci- C4-alkyl group, or both RB groups together form a C2-C6-alkylene group,
to react with a compound of general formula (XXII) :
R1— LG4
(XXII),
in which R1 is as defined for the compound of general formula (I) as defined supra, and in which LG4 represents a leaving group,
in the presence of a palladium catalyst,
thereby giving a compound of general formula (I) :
Figure imgf000287_0002
(I),
in which R1, R2, R3, R4 and R5 are as defined for the compound of general formula (I) as defined supra,
then optionally converting said compound into solvates, salts and/or solvates of such salts using the corresponding (i) solvents and/or (ii) bases or acids. In another embodiment of the invention, said methods comprise the steps of
I. allowing an intermediate compound of general formula (XI la) :
Figure imgf000288_0001
(Xlla),
in which R2, R4 and R5 are as defined for the compound of general formula (I) as defined supra,
to react with a reagent selected from thiophosgene and di-1 H-imidazol-1 - ylmethanethione, in the presence of a catalytic amount of 1 H-imidazole, followed by the addition of an intermediate compound of general formula (XXXIV) :
Figure imgf000288_0002
(XXXIV),
in which R1 and R3 are as defined for the compound of general formula (I) as defined supra,
thereby giving a regioisomeric mixture of intermediates of formulae (XXXVI) and (XXXVIa) :
Figure imgf000288_0003
(XXXVI) (XXXVIa),
in which R1, R2, R3, R4 and R5 are as defined for the compound of general formula (I) as defined supra, followed by ii. allowing said regioisomeric mixture of intermediates of formulae (XXXVI) and (XXXVIa):
Figure imgf000289_0001
(XXXVI) (XXXVIa), in which R1, R2, R3, R4 and R5 are as defined for the compound of general formula (I) as defined supra,
to react with a carbodiimide of formula RD1-N=C=N-RD2, in which RD1 and RD2 represent, independently from each other, a Ci-Gt-alkyl group optionally substituted with one N,N- dimethylamino group,
thereby giving a compound of general formula (I) :
Figure imgf000289_0002
(I),
in which R1 , R2, R3, R4 and R5 are as defined for the compound of general formula (I) as defined supra,
then optionally converting said compound into solvates, salts and/or solvates of such salts using the corresponding (i) solvents and/or (ii) bases or acids.
In another embodiment of the invention, said methods comprise the steps of
i. allowing an intermediate compound of general formula (XI la) :
Figure imgf000289_0003
(XI la),
in which R2, R4 and R5 are as defined for the compound of general formula (I) as defined supra, to react with a reagent selected from thiophosgene and di-1 H-imidazol-1 - ylmethanethione, in the presence of a catalytic amount of 1 H-imidazole, followed by the addition of an intermediate compound of general formula (XXXIV) :
Figure imgf000290_0001
(XXXIV),
in which R1 and R3 are as defined for the compound of general formula (I) as defined supra,
thereby giving a regioisomeric mixture of intermediates of formulae (XXXVI) and (XXXVIa) :
Figure imgf000290_0002
(XXXVI) (XXXVIa),
in which R\ R2, R3, R4 and R5 are as defined for the compound of general formula (I) as defined supra, followed by allowing said regioisomeric mixture of intermediates of formulae (XXXVI) and (XXXVIa)
Figure imgf000290_0003
(XXXVI) (XXXVIa), in which R1 , R2, R3, R4 and R5 are as defined for the compound of general formula (I) as defined supra,
to react with a carbodiimide of formula RD1-N=C=N-RD2 or a salt thereof, in which RD1 and RD2 represent, independently from each other, a Ci-C4-alkyl group optionally substituted with one N,N-dimethylamino group,
thereby giving a compound of general formula (I) :
Figure imgf000291_0001
(I).
in which R1, R2, R3, R4 and R5 are as defined for the compound of general formula (I) as defined supra,
then optionally converting said compound into solvates, salts and/or solvates of such salts using the corresponding (i) solvents and/or (ii) bases or acids.
In another embodiment of the invention, said methods comprise the step of allowing intermediate compound of general formula (XL) or a salt thereof:
Figure imgf000291_0002
(XL),
in which R1, R3, R4, R5 and R9 are as defined for the compound of general formula (I) as defined supra, and in which "#" indicates that the piperazine ring can be either unsubstituted or bridged, or substituted with one or two methyl groups, according to the definition of R2 in general formula (I) as defined supra,
to react with one reagent selected from the group (RG) consisting of R12-C(=0)OH, R12-C(=0)- LG7, R130-C(=0)-LG7, R14a(R14)N-C(=0)-LG7, R14a(R14)N-S(=0)2-LG7 and R15-S(=0)2-LG7, in which R12, R13, R14, R14a and R15 are as defined for the compounds of general formula (I) as defined supra, and in which LG7 represents a leaving group,
thereby giving a compound of general formula (I) :
Figure imgf000291_0003
(I), in which R1 , R2, R3, R4 and R5 are as defined for the compound of general formula (I) as defined supra,
then optionally converting said compound into solvates, salts and/or solvates of such salts using the corresponding (i) solvents and/or (ii) bases or acids.
The present invention covers methods of preparing compounds of the present invention of general formula (I), said methods comprising the steps as described in the Experimental Section herein.
In accordance with a fourth aspect, the present invention covers intermediate compounds which are useful for the preparation of the compounds of general formula (I), supra.
In one embodiment, the invention covers the intermediate compounds of general formula (XXI):
Figure imgf000293_0001
(XXI),
in which R2, R3, R4 and R5 are as defined for the compound of general formula (I) as defined supra, and in which RB, which can be different or identical, represent a hydrogen atom or a Ci- C4-alkyl group, or both RB groups together form a C2-C6-alkylene group.
In another embodiment, the invention covers the intermediate compounds of general formula (XI la):
Figure imgf000293_0002
in which R2, R4 and R5 are as defined for the compound of general formula (I) as defined supra.
In another embodiment, the invention covers the intermediate compounds of general formula (XXXIV):
Figure imgf000293_0003
(XXXIV),
which R1 and R3 are as defined for the compound of general formula (I) as defined supra. In another embodiment, the invention covers the intermediate compounds of general formula (XL):
Figure imgf000294_0001
(XL),
in which R1, R3, R4, R5 and R9 are as defined for the compound of general formula (I) as defined supra, and in which "#" indicates that the piperazine ring can be either unsubstituted or bridged, or substituted with one or two methyl groups, according to the definition of R2 in general formula (I) as defined supra.
In accordance with a fifth aspect, the present invention covers the use of said intermediate compounds for the preparation of a compound of general formula (I) as defined supra.
In one embodiment, the invention covers the use of intermediate compounds of general formula (XXI):
Figure imgf000295_0001
(XXI),
in which R2, R3, R4 and R5 are as defined for the compound of general formula (I) as defined supra, and in which RB, which can be different or identical, represent a hydrogen atom or a Ci- C4-alkyl group, or both RB groups together form a C2-C6-alkylene group, for the preparation of a compound of general formula (I) as defined supra.
In another embodiment, the invention covers the use of intermediate compounds of general formula (Xlla):
Figure imgf000295_0002
(Xlla),
in which R2, R4 and R5 are as defined for the compound of general formula (I) as defined supra, for the preparation of a compound of general formula (I) as defined supra.
In another embodiment, the invention covers the use of intermediate compounds of general formula (XXXIV):
Figure imgf000295_0003
(XXXIV), in which R and R3 are as defined for the compound of general formula (I) as defined supra, for the preparation of a compound of general formula (I) as defined supra.
In another embodiment, the invention covers the use of intermediate compounds of general formula (XL):
Figure imgf000296_0001
(XL),
in which R1, R3, R4, R5 and R9 are as defined for the compound of general formula (I) as defined supra, and in which "#" indicates that the piperazine ring can be either unsubstituted or bridged, or substituted with one or two methyl groups, according to the definition of R2 in general formula (I) as defined supra, for the preparation of a compound of general formula (I) as defined supra.
The present invention covers the intermediate compounds which are disclosed in the Example Section of this text, infra.
The present invention covers any sub-combination within any embodiment or aspect of the present invention of intermediate compounds of general formula (XL), supra.
The compounds of general formula (I) of the present invention can be converted to any salt, preferably pharmaceutically acceptable salts, as described herein, by any method which is known to the person skilled in the art. Similarly, any salt of a compound of general formula (I) of the present invention can be converted into the free compound, by any method which is known to the person skilled in the art.
Compounds of general formula (I) of the present invention demonstrate a valuable pharmacological spectrum of action which could not have been predicted. Compounds of the present invention have surprisingly been found to effectively inhibit TBK1 kinase and/or ΙΚΚε kinase and it is possible therefore that said compounds be used for the treatment or prophylaxis of diseases, preferably hyperproliferative and/or inflammatory disorders in humans and animals.
Compounds of the present invention can be utilized to inhibit the activity of TBK1 and/or ΙΚΚε kinases. This method comprises administering to a mammal in need thereof, including a human, an amount of a compound of general formula (I) of the present invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof, which is effective to treat hyperproliferative and/or inflammatory disorders.
Hyperproliferative disorders include, but are not limited to, for example : psoriasis, keloids, and other hyperplasias affecting the skin, benign prostate hyperplasia (BPH), solid tumours, 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 leukaemias.
Examples of breast cancers 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 tumour.
Tumours of the male reproductive organs include, but are not limited to, prostate and testicular cancer.
Tumours 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.
Tumours of the digestive tract include, but are not limited to, anal, colon, colorectal, oesophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.
Tumours 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.
The present invention also provides methods of treating angiogenic disorders including diseases associated with excessive and/or abnormal angiogenesis.
Inappropriate and ectopic expression of angiogenesis can be deleterious to an organism. A number of pathological conditions are associated with the growth of extraneous blood vessels. These include, for example, diabetic retinopathy, ischemic retinal-vein occlusion, and retinopathy of prematurity [Aiello et al., New Engl. J. Med., 1994, 331 , 1480 ; Peer et al., Lab. Invest., 1995, 72, 638], age-related macular degeneration (AMD) [Lopez et al., Invest. Opththalmol. Vis. Sci., 1996, 37, 855], neovascular glaucoma, psoriasis, retrolental fibroplasias, angiofibroma, inflammation, rheumatoid arthritis ( A), restenosis, in-stent restenosis, vascular graft restenosis, etc. In addition, the increased blood supply associated with cancerous and neoplastic tissue, encourages growth, leading to rapid tumour enlargement and metastasis. Moreover, the growth of new blood and lymph vessels in a tumour provides an escape route for renegade cells, encouraging metastasis and the consequence spread of the cancer. Thus, compounds of general formula (I) of the present invention can be utilized to treat and/or prevent any of the aforementioned angiogenesis disorders, for example by inhibiting and/or reducing blood vessel formation; by inhibiting, blocking, reducing, decreasing, etc. endothelial cell proliferation, or other types involved in angiogenesis, as well as causing cell death or apoptosis of such cell types.
In yet another aspect, the present invention provides methods of treating or preventing a disease or condition associated with inflammation, a metabolic disorder, infection or an immune disease or condition by administering to a subject having such a condition or disease, a therapeutically effective amount of a compound or composition of the invention. In one group of embodiments, diseases or conditions, including chronic diseases, of humans or other species can be treated or prevented by inhibition of IRF-3 phosphorylation through inhibition of TBK1 kinase and/or ΙΚΚε kinase. These diseases or conditions include (1 ) inflammatory or allergic diseases such as systemic anaphylaxis and hypersensitivity responses, drug allergies, insect sting allergies and food allergies, (2) inflammatory bowel diseases, such as Crohn's disease, ulcerative colitis, ileitis and enteritis, (3) vaginitis, (4) psoriasis and inflammatory dermatoses such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis and urticaria, (5) vasculitis, (6) spondyloarthropathies, (7) scleroderma, (8) asthma and respiratory allergic diseases such as allergic asthma, allergic rhinitis, allergic conjunctivitis, hypersensitivity lung diseases and the like, and (9) autoimmune diseases, such as arthritis (including rheumatoid and psoriatic), systemic lupus erythematosus, type I diabetes, glomerulonephritis and the like, (10) graft rejection (including allograft rejection and graft-v-host disease), (11 ) other diseases in which undesired inflammatory responses are to be inhibited, e.g., atherosclerosis, myositis, neurological disorders such as stroke, ischemic reperfusion injury, traumatic brain injury and closed-head injuries, neurodegenerative diseases (e.g., Parkinson's disease), multiple sclerosis, Alzheimer's disease, encephalitis, meningitis, osteoporosis, gout, hepatitis, nephritis, gall bladder disease, sepsis, sarcoidosis, conjunctivitis, otitis, chronic obstructive pulmonary disease, sinusitis and Behcet's syndrome; (12) metabolic disorders that are sensitive to inhibition of TNF or IL-1 signaling, such as obesity, type II diabetes, Syndrome X, insulin resistance, hyperglycemia, hyperuricemia, hyperinsulinemia, cachexia, hypercholesterolemia, hyperhpidemia, dyslipidemia, mixed dyslipidemia and hypertriglyceridemia, eating disorders, such as anorexia nervosa and bulimia, (13) infectious diseases, e.g., bacteremia and septic shock; (14) cardiovascular disorders, such as acute heart failure, hypotension, hypertension, angina pectoris, myocardial infarction, cardiomyopathy, congestive heart failure, atherosclerosis, coronary artery disease, restenosis and vascular stenosis; and (15) immune diseases or conditions.
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, for example the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of a disease or disorder, such as a carcinoma. 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. Generally, the use of chemotherapeutic agents and/or anti-cancer agents in combination with a compound or pharmaceutical composition of the present invention will serve to:
yield better efficacy in reducing the growth of a tumour or even eliminate the tumour as compared to administration of either agent alone,
provide for the administration of lesser amounts of the administered chemotherapeutic agents, provide for a chemotherapeutic treatment that is well tolerated in the patient with fewer deleterious pharmacological complications than observed with single agent chemotherapies and certain other combined therapies,
provide for treating a broader spectrum of different cancer types in mammals, especially humans,
provide for a higher response rate among treated patients,
provide for a longer survival time among treated patients compared to standard chemotherapy treatments,
provide a longer time for tumour progression, and/or
yield efficacy and tolerability results at least as good as those of the agents used alone, compared to known instances where other cancer agent combinations produce antagonistic effects.
In addition, the compounds of general formula (I) of the present invention can also be used in combination with radiotherapy and/or surgical intervention.
In a further embodiment of the present invention, the compounds of general formula (I) of the present invention may be used to sensitize a cell to radiation, i.e. treatment of a cell with a compound of the present invention prior to radiation treatment of the cell renders the cell more susceptible to DNA damage and cell death than the cell would be in the absence of any treatment with a compound of the present invention. In one aspect, the cell is treated with at least one compound of general formula (I) of the present invention.
Thus, the present invention also provides a method of killing a cell, wherein a cell is administered one or more compounds of the present invention in combination with conventional radiation therapy.
The present invention also provides a method of rendering a cell more susceptible to cell death, wherein the cell is treated with one or more compounds of general formula (I) of the present invention prior to the treatment of the cell to cause or induce cell death. In one aspect, after the cell is treated with one or more compounds of general formula (I) of the present invention, the cell is treated with at least one compound, or at least one method, or a combination thereof, in order to cause DNA damage for the purpose of inhibiting the function of the normal cell or killing the cell.
In other embodiments of the present invention, a cell is killed by treating the cell with at least one DNA damaging agent, i.e. after treating a cell with one or more compounds of general formula (I) of the present invention to sensitize the cell to cell death, the cell is treated with at least one DNA damaging agent to kill the cell. DNA damaging agents useful in the present invention include, but are not limited to, chemotherapeutic agents (e.g. cis platin), ionizing radiation (X-rays, ultraviolet radiation), carcinogenic agents, and mutagenic agents.
In other embodiments, a cell is killed by treating the cell with at least one method to cause or induce DNA damage. Such methods include, but are not limited to, activation of a cell signalling pathway that results in DNA damage when the pathway is activated, inhibiting of a cell signalling pathway that results in DNA damage when the pathway is inhibited, and inducing a biochemical change in a cell, wherein the change results in DNA damage. By way of a non-limiting example, a DNA repair pathway in a cell can be inhibited, thereby preventing the repair of DNA damage and resulting in an abnormal accumulation of DNA damage in a cell.
In one aspect of the invention, a compound of general formula (I) of the present invention is administered to a cell prior to the radiation or other induction of DNA damage in the cell. In another aspect of the invention, a compound of general formula (I) of the present invention is administered to a cell concomitantly with the radiation or other induction of DNA damage in the cell. In yet another aspect of the invention, a compound of general formula (I) of the present invention is administered to a cell immediately after radiation or other induction of DNA damage in the cell has begun.
In another aspect, the cell is in vitro. In another embodiment, the cell is in vivo.
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 used in the present text is used conventionally, e.g., the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of a disease or disorder, such as a carcinoma.
The compounds of the present invention can be used in particular in therapy and prevention, i.e. prophylaxis, of hyperproliferative and/or inflammatory disorders.
In accordance with a further aspect, the present invention covers compounds of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for use in the treatment or prophylaxis of diseases, in particular hyperproliferative and/or inflammatory disorders.
The pharmaceutical activity of the compounds according to the invention can be explained by their activity as inhibitors of TBK1 and/or ΙΚΚε kinase.
In accordance with a further aspect, the present invention covers the use of compounds of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for the treatment or prophylaxis of diseases, in particular hyperproliferative and/or inflammatory disorders, particularly cancer.
In accordance with a further aspect, the present invention covers the use of compounds of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, in a method of treatment or prophylaxis of diseases, in particular hyperproliferative and/or inflammatory disorders, particularly cancer.
In accordance with a further aspect, the present invention covers use of a compound of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for the preparation of a pharmaceutical composition, preferably a medicament, for the prophylaxis or treatment of diseases, in particular hyperproliferative and/or inflammatory disorders, particularly cancer.
In accordance with a further aspect, the present invention covers a method of treatment or prophylaxis of diseases, in particular hyperproliferative and/or inflammatory disorders, particularly cancer, using an effective amount of a compound of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same.
In accordance with a further aspect, the present invention covers a compound inhibiting TBK1 kinase and/or ΙΚΚε kinase, for the treatment of a hyperproliferative and/or inflammatory disease, such as cancer.
In accordance with a further aspect, the present invention covers a method for controlling the activity of TBK1 kinase and/or ΙΚΚε kinase in humans and animals by administering an effective amount of at least one compound of the general formula (I), as defined supra, or of a medicament comprising the same. In accordance with a further aspect, the present invention covers a method for controlling the activity of IRF-3 phosphorylation in humans and animals by administering an effective amount of at least one compound of the general formula (I), as defined supra, or of a medicament comprising the same.
In accordance with a further aspect, the present invention covers a method for controlling a hyperproliferative and/or inflammatory disease, such as cancer, in humans and animals by administering an effective amount of at least one compound of the general formula (I), as defined supra, or of a medicament comprising the same.
In accordance with a further aspect, the present invention covers pharmaceutical compositions, in particular a medicament, comprising a compound of general formula (I), as described supra, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, a salt thereof, particularly a pharmaceutically acceptable salt, or a mixture of same, and one or more excipients), in particular one or more pharmaceutically acceptable excipient(s). Conventional procedures for preparing such pharmaceutical compositions in appropriate dosage forms can be utilized.
The present invention furthermore covers pharmaceutical compositions, in particular medicaments, which comprise at least one compound according to the invention, conventionally together with one or more pharmaceutically suitable excipients, and to their use for the above mentioned purposes.
It is possible for the compounds according to the invention to have systemic and/or local activity. For this purpose, they can be administered in a suitable manner, such as, for example, via the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, otic route or as an implant or stent.
For these administration routes, it is possible for the compounds according to the invention to be administered in suitable administration forms.
For oral administration, it is possible to formulate the compounds according to the invention to dosage forms known in the art that deliver the compounds of the invention rapidly and/or in a modified manner, such as, for example, tablets (uncoated or coated tablets, for example with enteric or controlled release coatings that dissolve with a delay or are insoluble), orally- disintegrating tablets, films/wafers, films/lyophylisates, capsules (for example hard or soft gelatine capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions. It is possible to incorporate the compounds according to the invention in crystalline and/or amorphised and/or dissolved form into said dosage forms.
Parenteral administration can be effected with avoidance of an absorption step (for example intravenous, intraarterial, intracardial, intraspinal or intralumbal) or with inclusion of absorption (for example intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal). Administration forms which are suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophylisates or sterile powders.
Examples which are suitable for other administration routes are pharmaceutical forms for inhalation [inter alia powder inhalers, nebulizers], nasal drops, nasal solutions, nasal sprays; tablets/films/wafers/capsules for lingual, sublingual or buccal administration; suppositories; eye drops, eye ointments, eye baths, ocular inserts, ear drops, ear sprays, ear powders, ear- rinses, ear tampons; vaginal capsules, aqueous suspensions (lotions, mixturae agitandae), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (such as, for example, patches), milk, pastes, foams, dusting powders, implants or stents.
The compounds according to the invention can be incorporated into the stated administration forms. This can be effected in a manner known per se by mixing with pharmaceutically suitable excipients. Pharmaceutically suitable excipients include, inter alia,
• fillers and carriers (for example cellulose, microcrystalline cellulose (such as, for example, Avicel®), lactose, mannitol, starch, calcium phosphate (such as, for example,
Di-Cafos®)),
• ointment bases (for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols),
• bases for suppositories (for example polyethylene glycols, cacao butter, hard fat), · solvents (for example water, ethanol, isopropanol, glycerol, propylene glycol, medium chain-length triglycerides fatty oils, liquid polyethylene glycols, paraffins),
• surfactants, emulsifiers, dispersants or wetters (for example sodium dodecyl sulfate), lecithin, phospholipids, fatty alcohols (such as, for example, Lanette®), sorbitan fatty acid esters (such as, for example, Span®), polyoxyethylene sorbitan fatty acid esters (such as, for example, Tween®), polyoxyethylene fatty acid glycerides (such as, for example, Cremophor®), polyoxethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamers (such as, for example, Pluronic®), buffers, acids and bases (for example phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine),
isotonicity agents (for example glucose, sodium chloride),
adsorbents (for example highly-disperse silicas),
viscosity-increasing agents, gel formers, thickeners and/or binders (for example polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropyl- cellulose, carboxymethylcellu!ose-sodium, starch, carbomers, polyacrylic acids (such as, for example, Carbopol®); alginates, gelatine),
disintegrants (for example modified starch, carboxymethylcellulose-sodium, sodium starch glycolate (such as, for example, Explotab®), cross- linked polyvinylpyrrolidone, croscarmellose-sodium (such as, for example, AcDiSol®)),
flow regulators, lubricants, glidants arid mould release agents (for example magnesium stearate, stearic acid, talc, highly-disperse silicas (such as, for example, Aerosil®)), coating materials (for example sugar, shellac) and film formers for films or diffusion membranes which dissolve rapidly or in a modified manner (for example polyvinylpyrrolidones (such as, for example, Kollidon®), polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates such as, for example, Eudragit®)),
capsule materials (for example gelatine, hydroxypropylmethylcellulose),
synthetic polymers (for example polylactides, polyglycolides, polyacrylates, polymethacrylates (such as, for example, Eudragit®), polyvinylpyrrolidones (such as, for example, Kollidon®), polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols and their copolymers and blockcopolymers),
plasticizers (for example polyethylene glycols, propylene glycol, glycerol, triacetine, triacetyl citrate, dibutyl phthalate),
penetration enhancers,
stabilisers (for example antioxidants such as, for example, ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate), preservatives (for example parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate), • colourants (for example inorganic pigments such as, for example, iron oxides, titanium dioxide),
• flavourings, sweeteners, flavour- and/or odour-masking agents.
The present invention furthermore relates to a pharmaceutical composition which comprise at least one compound according to the invention, conventionally together with one or more pharmaceutically suitable excipient(s), and to their use according to the present invention.
In accordance with another aspect, the present invention covers pharmaceutical combinations, in particular medicaments, comprising at least one compound of general formula (I) of the present invention and at least one or more further active ingredients, in particular for the treatment and/or prophylaxis of a hyperproliferative disorder, particularly cancer.
Particularly, the present invention covers a pharmaceutical combination, which comprises:
• one or more first active ingredients, in particular compounds of general formula (I) as defined supra, and
• one or more further active ingredients, in particular for the treatment and/or prophylaxis of a hyperproliferative disorder, more particularly cancer..
The term "combination" in the present invention is used as known to persons skilled in the art, it being possible for said combination to be a fixed combination, a non-fixed combination or a kit-of-parts.
A "fixed combination" in the present invention is used as known to persons skilled in the art and is defined as a combination wherein, for example, a first active ingredient, such as one or more compounds of general formula (I) of the present invention, and a further active ingredient are present together in one unit dosage or in one single entity. One example of a "fixed combination" is a pharmaceutical composition wherein a first active ingredient and a further active ingredient are present in admixture for simultaneous administration, such as in a formulation. Another example of a "fixed combination" is a pharmaceutical combination wherein a first active ingredient and a further active ingredient are present in one unit without being in admixture.
A non-fixed combination or "kit-of-parts" in the present invention is used as known to persons skilled in the art and is defined as a combination wherein a first active ingredient and a further active ingredient are present in more than one unit. One example of a non-fixed combination or kit-of-parts is a combination wherein the first active ingredient and the further active ingredient are present separately. It is possible for the components of the non-fixed combination or kit-of- parts to be administered separately, sequentially, simultaneously, concurrently or chronologically staggered. The compounds of the present invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutically active ingredients where the combination causes no unacceptable adverse effects. The present invention also covers such pharmaceutical combinations. For example, the compounds of the present invention can be combined with known agents for the treatment and/or prophylaxis of cancer.
Examples of agents for the treatment and/or prophylaxis of cancer include:
1311-chTNT, abarelix, abiraterone, aclarubicin, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alemtuzumab, Alendronic acid, alitretinoin, altretamine, amifostine, aminoglutethimide, Hexyl aminolevulinate.amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, angiotensin II, antithrombin I II, aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase, axitinib, azacitidine, basiliximab, belotecan, bendamustine, belinostat, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, bortezomib, buserelin, bosutinib, brentuximab vedotin, busulfan, cabazitaxel, cabozantinib, calcium folinate, calcium levofolinate, capecitabine, capromab, carboplatin, carfilzomib, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, ceritinib, cetuximab, chlorambucil, chlormadinone, chlormethine, cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid, clofarabine, copanlisib , crisantaspase, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, darbepoetin alfa, dabrafenib, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, depreotide, deslorelin, dexrazoxane, dibrospidium chloride, dianhydrogalactitol, diclofenac, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin + estrone, dronabinol, eculizumab, edrecolomab, elliptinium acetate, eltrombopag, endostatin, enocitabine, enzalutamide, epirubicin, epitiostanol, epoetin alfa, epoetin beta, epoetin zeta, eptaplatin, eribulin, erlotinib, esomeprazole, estradiol, estramustine, etoposide, everolimus, exemestane, fadrozoie, fentanyl, filgrastim, fluoxymesterone, floxuridine, fludarabine, fluorouracil, flutamide, folinic acid, formestane, fosaprepitant, fotemustine, fulvestrant, gadobutrol, gadoteridol, gadoteric acid meglumine, gadoversetamide, gadoxetic acid, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, Glucarpidase, glutoxim, GM-CSF, goserelin, granisetron, granulocyte colony stimulating factor, histamine dihydrochloride, histrelin, hydroxycarbamide, I- 125 seeds, lansoprazole, ibandronic acid, ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, indisetron, incadronic acid, ingenol mebutate, interferon alfa, interferon beta, interferon gamma, iobitridol, iobenguane (1231), iomeprol, ipilimumab, irinotecan, Itraconazole, ixabepilone, lanreotide, lapatinib, lasocholine, lenalidomide, lenograstim, lentinan, letrozole, leuprorelin, levamisole, levonorgestrel, levothyroxine sodium, lisuride, lobaplatin, lomustine, lonidamine, masoprocol, medroxyprogesterone, megestrol, melarsoprol, melphalan, mepitiostane, mercaptopurine, mesna, methadone, methotrexate, methoxsalen, methylaminolevulinate, methylprednisolone, methyltestosterone, metirosine, mifamurtide, miltefosine, miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, mogamulizumab, molgramostim, mopidamol, morphine hydrochloride, morphine sulfate, nabilone, nabiximols, nafarelin, naloxone + pentazocine, naltrexone, nartograstim, nedaplatin, nelarabine, neridronic acid, nivolumabpentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustine, nitracrine, nivolumab, obinutuzumab, octreotide, ofatumumab, omacetaxine mepesuccinate, omeprazole, ondansetron, oprelvekin, orgotein, orilotimod, oxaliplatin, oxycodone, oxymetholone, ozogamicine, p53 gene therapy, paclitaxel, palifermin, palladium-103 seed, palonosetron, pamidronic acid, panitumumab, pantoprazole, pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin beta), pembrolizumab, pegfilgrastim, peginterferon alfa-2b, pemetrexed, pentazocine, pentostatin, peplomycin, Perflubutane, perfosfamide, Pertuzumab, picibanil, pilocarpine, pirarubicin, pixantrone, plerixafor, plicamycin, poliglusam, polyestradiol phosphate, polyvinylpyrrolidone + sodium hyaluronate, polysaccharide-K, pomalidomide, ponatinib, porfimer sodium, pralatrexate, prednimustine, prednisone, procarbazine, procodazole, propranolol, quinagolide, rabeprazole, racotumomab, radium-223 chloride, radotinib, raloxifene, raltitrexed, ramosetron, ramucirumab, ranimustine, rasburicase, razoxane, refametinib , regorafenib, risedronic acid, rhenium- 86 etidronate, rituximab, romidepsin, romiplostim, romurtide, roniciclib , samarium (153Sm) lexidronam, sargramostim, satumomab, secretin, sipuleucel-T, sizofiran, sobuzoxane, sodium glycididazole, sorafenib, stanozolol, streptozocin, sunitinib, talaporfin, tamibarotene, tamoxifen, tapentadol, tasonermin, teceleukin, technetium (99mTc) nofetumomab merpentan, 99mTc-HYNIC-[Tyr3]-octreotide, tegafur, tegafur + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, thyrotropin alfa, tioguanine, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, tramadol, trastuzumab, trastuzumab emtansine, treosulfan, tretinoin, trifluridine + tipiracil, trilostane, triptorelin, trametinib, trofosfamide, thrombopoietin, tryptophan, ubenimex, valatinib , valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vismodegib, vorinostat, vorozole, yttrium-90 glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid, zorubicin. Based upon standard laboratory techniques known to evaluate compounds useful for the treatment of hyperproliferative and/or inflammatory 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 active ingredients or medicaments that are used to treat these conditions, the effective dosage of the compounds of the present 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, it is possible for "drug holidays", in which a patient is not dosed with a drug for a certain period of time, to be beneficial to the overall balance between pharmacological effect and tolerability. It is possible for a unit dosage to 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.
EXPERIMENTAL SECTION
EXPERIMENTAL SECTION - GENERAL PART
The following Table 1 lists the abbreviations used herein, in particular in the Compounds part and the Examples part of the Experimental Section:
Table 1
Figure imgf000310_0001
DMF /V,/V-dimethylformamide
DIC Diisopropyl carbodiimide
DMSO dimethyl sulfoxide
Dppf 1 ,1 '-bis(diphenylphosphino)ferrocene
EDC, EDCI N-[3-(dimethylamino)propyl]-N'-ethylcarbodiimide hydrochloride
Eq equivalent
ESI electrospray ionisation
A -[(dimethylamino)(3H-[1 ,2,3]triazolo[4,5-ib]pyridin-3-yloxy)-
HATU
methylene]-/V-methylmethanaminium hexafluorophosphate
Hunig Base /V,/V-diisopropylethylamine m multiplet m.p. melting point in Ό
MS mass spectrometry
MW molecular weight
NaOtBu sodium fert-butoxide; sodium 2-methylpropan-2-olate
NBS 2-bromo-1 H-isoindole-1 ,3(2H)-dione
NMM N-Methyl morpholine
NMP /V-methylpyrrolidinone nuclear magnetic resonance spectroscopy: chemical shifts (δ) are
NMR
given in ppm.
PdCI2(PPh3)2 dichlorobis(triphenylphosphine)palladium(l l)
Pd(dba)2 bis-(dibenzylideneacetone)palladium(0) complex
Pd2(dba)3 tris-(dibenzylideneacetone)dipalladium(0) chloroform complex Pd(dppf)CI2 dichloro[1 ,1 '-bis(diphenylphosphino)ferrocene]palladium(ll)
Pd(dppf)CI2 dichloro[1 , 1 '-bis(diphenyIphosphino)ferrocene]palladium(ll) CH2CI2 dichloromethane adduct
Pd-Brett-Phos- chloro[2-(dicyclohexylp osphino)-3,6-dimethoxy-2'-4'-6'-tri-iso- pre-cat propyl-1 ,1'-biphenyl][2-(2-aminoethyl)phenyl]palladium(ll)
Pd-tBu-X-Phos- chloro(2-di-fe/ -butylphosphino-2',4',6'-tri-isopropyl-1 ,1 '-biphenyl)[2- pre-cat (2-aminoethyl)phenyl] palladium(ll)
Pd-X-Phos-pre- chloro(2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1 ,1 '-biphenyl)[2- cat (2-aminoethyl)phenyl] palladium(ll) methyl-iert-butylether adduct
PPh3 triphenylphosphine
P(oTol)3 tri-o-tolylphosphine benzotriazol-1 -yl-oxytripyrrolidinophosphonium
PyBOP
hexafluorophosphate q quartet quin quintett
Rac racemic r.t. room temperature
Rt retention time in minutes s singlet
S-Phos dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine t triplet
T3P 2,4,6-tripropyl-1 ,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide
TBAF tetrabutylammoniumfluoride tBu-X-Phos 2-di-fert-butylphosphino-2',4',6'-tri-isopropyl-1 ,1 '-biphenyl
TBDPS ferf-butyldiphenylsilyl /V-[(1 H-benzotriazol-1-yloxy)(dimethylamino)methylene]-/V-
TBTU
methylmethanaminium tetrafluoroborate
TEA triethylamine
TCDI di-1 H-imidazol-1 -ylmethanethione (Thiocarbonyldiimidazole)
TFA trifluoroacetic acid
THF tetrahydrofuran
TMS trimethylsilyl
Ts para toluenesulfonyl; (tosyl)
UPLC ultra performance liquid chromatography
X-Phos 2-dicyclohexylphosphino-2',4',6,-triisopropylbiphenyl
4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene;
Xantphos
CAS RN: 161265-03-8
All reagents, for which the synthesis is not described in the experimental part, are either commercially available, or are known compounds or may be formed from known compounds by known methods by a person skilled in the art.
Wherever specified, NMR peak multiplicities and peak forms are stated as they appear in the spectra. Possible higher order effects have not been considered.
The 1H-NMR data of selected compounds and examples are listed in the form of 1H-NMR peaklists. For each signal peak the δ value in ppm is given, followed by the signal intensity, reported in round brackets. The δ value-signal intensity pairs from different peaks are separated by commas. Therefore, a peaklist is described by the general form: δι (intensityi), 62 (intensity2), ... , δ, (intensity,), ... , δη (intensity,,).
The intensity of a sharp signal correlates with the height (in cm) of the signal in a printed NMR spectrum. When compared with other signals, this data can be correlated to the real ratios of the signal intensities. In the case of broad signals, more than one peak, or the center of the signal along with their relative intensity, compared to the most intense signal displayed in the spectrum, are shown. A 1H-NMR peaklist is similar to a classical 1H-NMR readout, and thus usually contains all the peaks listed in a classical NMR interpretation. Moreover, similar to classical 1H-NMR printouts, peaklists can show solvent signals, signals derived from stereoisomers of target compounds (also the subject of the invention), and/or peaks of impurities. The peaks of stereoisomers, and/or peaks of impurities are typically displayed with a lower intensity compared to the peaks of the target compounds (e.g., with a purity of >90%). Such stereoisomers and/or impurities may be typical for the particular manufacturing process, and therefore their peaks may help to identify the reproduction of our manufacturing process on the basis of "by-product fingerprints". An expert who calculates the peaks of the target compounds by known methods (MestReC, ACD simulation, or by use of empirically evaluated expectation values), can isolate the peaks of target compounds as required, optionally using additional intensity filters. Such an operation would be similar to peak-picking in classical 1 H- NMR interpretation. A detailed description of the reporting of NMR data in the form of peaklists can be found in the publication "Citation of NMR Peaklist Data within Patent Applications" (cf. Research Disclosure Database Number 605005, 2014, 01 Aug 2014, or http://www.researchdisclosure.com/searching-disclosures). In the peak picking routine, as described in the Research Disclosure Database Number 605005, the parameter "MinimumHeight" can be adjusted between 1 % and 4%. Depending on the chemical structure and/or depending on the concentration of the measured compound it may be reasonable to set the parameter "MinimumHeight" <1 %.
The examples and compounds produced according to the methods of the invention may require purification. Purification of organic compounds is well known to the person skilled in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. In some cases, the examples and compounds may be purified by crystallisation. In some cases, impurities may be removed by trituration using a suitable solvent or solvent mixture. In some cases, the examples and compounds may be purified by chromatography, particularly flash chromatography, using for example pre-packed silica gel cartridges, e.g. Isolute® Flash silica gel (Separtis) or SNAP cartridges KP-Sil® (Biotage) for purifications referred to herein as "silicagel chromatography"; or using e.g. Isolute® Flash NH2 silica gel (Separtis) or SNAP cartridges KP-NH® (Biotage), for purifications referred to herein as "aminophase silicagel chromatography", said cartridges being used in combination with a suitable chromatographic system such as a Flashmaster II (Separtis) or an Isolera® system (Biotage) and eluents such as, for example, gradients of hexane/ethyl acetate or DCM/methanol. In some cases, the examples and compounds may be purified by preparative HPLC using standard commercial HPLC equipment, such as a Waters autopurifier equipped with a diode array detector and/or on-line electrospray ionisation mass spectrometer in combination with a suitable pre-packed reverse phase column, and eluants such as, for example, gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia. In some cases, purification methods as described above can provide those compounds of the present invention which possess a sufficiently basic or acidic functionality in the form of a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt for example. A salt of this type can either be transformed into its free base or free acid form, respectively, by various methods known to the person skilled in the art, or be used as salts in subsequent biological assays. It is to be understood that the specific form (e.g. salt, free base etc.) of a compound of the present invention as isolated and as described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity.
Chemical names were generated using the ACD/ ame software from ACD/Labs. In some cases generally accepted names of commercially available reagents were used in place of ACD/Name generated names.
Optical rotations were measured using a JASCO P2000 Polarimeter. Typical, a solution of the compound with a concentration of 1 mg/mL to 15 mg/mL was used for the measurement. The specific rotation [a]o was calculated according to the following formula:
In this equation, a is the measured rotation in degrees; d is the path length in decimetres and β is the concentration in g/mL.
UPLC-MS Standard Procedures
Analytical UPLC-MS was performed as described below.
Method :
Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1.7 pm, 50x2.1 mm; eluent A: water + 0.1 vol % formic acid (99%), eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 mlJmin; temperature: 60 "C; DAD scan: 210-400 nm. Method 2:
Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1.7 μιτι, 50x2.1 mm; eluent A: water + 0.2 vol % aqueous ammonia (32%), eluent B: acetonitrile; gradient: 0-1.6 min 1 -99% B, 1.6-2.0 min 99% B; flow 0.8 mL/min; temperature: 60 Ό; DAD scan: 210-400 nm.
Method 3:
Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1 .7 50x2.1 mm; eluent A: water + 0.1 vol % formic acid (99%), eluent 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; DAD scan: 210-400 nm.
Method 4:
Instrument: Waters Acquity UPLCMS SingleQuad; Colum: Acquity UPLC BEH C18 1.7 50x2.1 mm; eluent A: water + 0.2 vol % aqueous ammonia (32%), eluent 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; DAD scan: 210-400 nm.
Method 5:
column: Ascentis Express C18, 2.7 pm, 3 cm x 2.1 mm
column temp.: 30 "C
injection volume: 1 μΙ
detection: MM-ES + APCI +DAD (254
fragment.potential: 50 V
mass range 80-800 m/z
mobile phase A: water / 0.1 % formic acid
mobile phase B: methanol / 0.1 % formic acid
system time delay: 0.2 min
gradient:
Figure imgf000316_0001
1.0 95 5 0.8
4.0 0 100 0.8
5.0 0 100 0.8
6.0 95 5 0.8
6.5 95 5 0.8
Method 6:
Instrument: Waters Acquity UPLCMS SingleQuad; Colum: Chiralpak IF 3μ 100x4.6; solvent: 20-50% EtOH/Hexan; buffer: + 0.1 % DEA; gradient: S6_20_ethanol hexane DEA; solution: 1 mg/mL, flow 1.4 mL/min; DAD scan: 254 nm; run time: 10 min.; injection volum: 5.0 pL.
Method 7:
Instrument MS: Waters ZQ; Instrument HPLC: Waters UPLC Acquity; Column: Acquity BEH C18 (Waters), 50mm x 2.1 mm, 1.7pm; eluent A: water +0, 1 ol% formic acid, eluent B: acetonitrile (Lichrosolv Merck); gradient: 0.0 min 99% A-1.6min 1 % A-1.8 min 1 %A - 1.81 min 99% A - 2.0min 99 % A; temperature: 60"C; flow: 0.8 mL/min; UV-Detection PDA 210-400nm.
EXPERIMENTAL SECTION - DESCRIPTION OF COMPOUNDS
Compound 01.01
4-(bromomethyl)pyridin-2-amine hydrobromide
Figure imgf000318_0001
x HBr
A mixture of (2-aminopyridin-4-yl)methanol (5.00 g, 40.3 mmol) and aqueous hydrobromic acid (50 mL, c =. 48 % , 440 mmol) was heated at 100°C for 24 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. Ethyl acetate was added to the crude product and the resulting solid was filtered, washed with ethyl acetate and dried under reduced pressure to give 7.70 g (71 %) of the title compound as a crude product that was used without further purification.
LC- S (Method 2): R, = 0.68 min; MS (ESIpos): m/z = 186; 188 [M+H]+
1H-NMR (400 MHz, d6-DMSO): δ [ppm] = 8.10 (brs, 2H), 7.90 (d, J = 6.9 Hz, 1 H), 6.98 (s, 1 H), 6.84 (dd, J = 1.8 and 6.9 Hz, 1 H), 4.65 (s, 2H).
Compound 01.02
tert-butyl 4-[(2-aminopyridin-4-yl)methyl]piperazine-1 -carboxylate
Figure imgf000318_0002
To a stirred suspension of 4-(bromomethyl)pyridin-2-amine hydrobromide (9.90 g, 36.9 mmol)in acetonitrile (75 mL) was added potassium carbonate (15.6 g, 113 mmol) and tert-butyl piperazine-1-carboxylate (7.50 g, 40.3 mmol). The mixture was stirred at 75° C for 2 h. Direct silicagel chromatography of the reaction mixture gave 10.3 g ( 95 % yield) of the title compound.
LC-MS (Method 2): R, = 1.00 min; MS (ESIpos): m/z = 293 [M+H]+
H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.386 (16.00), 1.392 (3.05), 2.278 (0.86), 2.291 (1.25), 2.303 (0.96), 5.815 (1.05), 6.383 (0.87), 6.385 (0.70), 6.407 (0.54), 6.419 (0.52), 7.802 (0.68), 7.815 (0.66), 7.817 (0.66). Compound 01.03
4-(4,4,5,5-tetramethyl-1 ,3,2-i dioxaborolan-2-yl)benzene-1 ,2-diamine
Figure imgf000319_0001
To a solution of 4-bromobenzene-1 ,2-diamine (25.3 g, 135 mmol) and 4, 4,4', 4', 5, 5,5', 5'- octamethyl-2,2'-bi-1 ,3,2-dioxaborolane (42.9 g, 169 mmol) in dioxane (120 ml.) was added potassium acetate (19.9 g, 203 mmol), the mixture was purged with Argon, dichloropalladium - tricyclohexylphosphane (1 :2) (5.00 g, 6.77 mmol) was added and the mixture was stirred at ^ 00 for 5 h. Diethyl ether was added and the mixt ure was filtered through celite and the solvent was removed in vacuum. Silicagel chromatography gave 21.7 g (65 % yield) of the title compound.
LC-MS (METHOD 5): Rt = 2.49 min; MS (ESIpos): m/z = 235 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.077 (8.15), 1.161 (4.45), 1.176 (0.50), 1.231 (16.00), 1.988 (0.71 ), 6.457 (1 .17), 6.476 (1.28), 6.765 (0.68), 6.768 (0.71 ), 6.784 (0.57), 6.787 (0.63), 6.889 (1.18), 6.892 (1.12).
Compound 01.04
tert-butyl 4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-benzimidazol-2- y l]ami no}pyrid i n-4-yl)methyl] pi perazi ne-1 -carboxylate
Figure imgf000319_0002
To a stirred solution of di-1 H-imidazol-1 -ylmethanethione (2.14 g, 12.0 mmol) and imidazole (159 mg, 2.34 mmol) in dichloromethane (30 mL) was added tert-butyl 4-[(2-aminopyridin-4- yl)methyl]piperazine-1 -carboxylate (3.18 g, 10.9 mmol), dissolved in dichloromethane (30 mL), at 0° C. The mixture was stirred at 0° C for 4 h. 4 -(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzene-1 ,2-diamine (2.55 g, 10.9 mmol), dissolved in dichloromethane (20 mL), was added and the mixture was stirred at r.t. for 18 h. Water was added and the mixture was extracted with dichloromethane.
The organic phase was dried (magnesium sulfate) and filtered. N,N'-dipropan-2-ylcarbodiimide (2.6 mL, 17 mmol) was added and the mixture was stirred at 40° C for 24 h. Saturated ammonium chloride solution was added, the mixture was stirred for 30 minutes and the mixture was extracted with dichloromethane. The organic phase was dried (magnesium sulfate) and the solvent was removed in vacuum. Silicagel chromatography gave a solid that was triturated with diethyl ether to give 2.22 g (38 % yield) of the title compound.
LC-MS (Method 5): Rt = 3.30 min; MS (ESIpos): m/z = 535[M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.086 (0.41 ), 1.171 (0.44), 1.299 (16.00), 1.392 (15.47), 1.984 (0.91 ), 2.336 (1.27), 2.348 (1.85), 2.360 (1.33), 2.495 (0.68), 2.499 (0.91 ), 2.504 (0.68), 3.320 (3.52), 3.342 (1.92), 3.368 (0.48), 3.481 (2.17), 6.901 (0.63), 6.914 (0.66), 8.235 (0.89), 8.248 (0.89).
Compound 01.05
6-(2-methylpyridin-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H-benzimidazol-2- amine hydrochloride
Figure imgf000320_0001
To a stirred solution of tert-butyl 4-[(2-{[6-(2-methylpyridin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate (388 mg, 777 pmol) in dichloromethane (10 mL) and methanol (1.6 mL) was added HCI in dioxane (2.9 mL, 4.0 M, 12 mmol). The mixture was stirred at room temperature for 16 h. The solvent was removed in vacuum to give 326 mg of the title compound as crude product that was used for the next step without purification. LC-MS (Method 2): R, = 0.92 min; MS (ESIneg): m/z = 398 [M-H]+
Compound 02.01
4-(2-methoxypyridin-4-yl)-2-nitroaniline
Figure imgf000321_0001
To a stirred solution of 4-bromo-2-nitroaniline (3.00 g, 13.8 mmol) in 1-propanol (130 ml_) was added potassium carbonate solution (21 mL, 2.0 M, 41 mmol), (2-methoxypyridin-4-yl)boronic acid (4.23 g, 27.6 mmol), triphenylphosphine (181 mg, 691 pmol) and PdCI2(PPh3)2 (485 mg, 691 μιτιοΙ).Τΐιβ mixture was heated to reflux for 2 h, the solvent was removed in vacuum, water was added and the mixture was extracted with ethyl acetate. The organic phase was dried (sodium sulfate), filtered and the solvent was removed in vacuum. Silicagel chromatography gave a solid that was triturated with warm ethanol to give 2.20 g (65 % yield) of the title compound.
LC-MS (Method 2): Rt = 1.05 min; MS (ESIpos): m/z = 246 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.309 (16.00), 3.903 (0.89), 5.752 (0.76), 7.058 (6.56), 7.062 (7.47), 7.119 (7.28), 7.141 (7.58), 7.271 (4.73), 7.275 (4.50), 7.285 (4.72), 7.289 (4.72), 7.666 (8.49), 7.862 (3.74), 7.867 (3.82), 7.884 (3.49), 7.889 (3.62), 8.169 (6.51 ), 8.183 (6.28), 8.339 (7.41 ), 8.345 (7.24).
Compound 02.02
4-(2-methoxypyridin-4-yl)benzene-1 ,2-diamine
Figure imgf000321_0002
To a stirred solution of 4-(2-methoxypyridin-4-yl)-2-nitroaniline (2.20 g, 8.97 mmol) in ethanol (30 mL) was added Raney Nickel (53 mg) and the mixture was stirred at r.t. in a hydrogen atmosphere for 144 h. The mixture was filtered, and the solution was concentrated in vacuum to give 1.90 g (98 % yield) mg of the title compound as crude product, that was used for the next step without purification.
LC-MS (Method 2): Rt = 0.83 min; MS (ESIpos): m/z = 216 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.334 (5.14), 4.828 (8.22), 5.752 (5.73), 6.587 (8.30), 6.844 (16.00), 6.947 (10.92), 7.103 (11.29), 7.683 (0.89), 8.070 (9.76).
Compound 02.03
6-(2-methoxypyridin-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H-benzimidazol-2- amine hydrochloride
Figure imgf000322_0001
Starting with tert-butyl 4-[(2-{[6-(2-methoxypyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate (575 mg, 1.12 mmol) Compound 02.03 was prepared analogously to the procedure for the preparation of Compound 01.05.
Yield: 540 mg of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): R, = 1.07 min; MS (ESIneg): m/z = 414 [M-H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.162 (8.02), 3.442 (1.95), 3.561 (16.00), 3.934 (15.50), 4.507 (2.69), 5.751 (2.51 ), 7.135 (2.88), 7.139 (2.96), 7.333 (1.77), 7.336 (1.71 ), 7.346 (1.74), 7.350 (1.75), 7.591 (2.75), 7.648 (1.24), 7.661 (1.38), 7.786 (6.74), 7.788 (6.71 ), 8.021 (2.19), 8.024 (3.45), 8.027 (2.12), 8.272 (2.66), 8.286 (2.55), 8.560 (2.19), 8.574 (2.06), 9.976 (0.86). Compound 03.01
4-(5-fluoro-2-methoxypyridin-4-yl)-2-nitroaniline
Figure imgf000323_0001
Starting with 4-bromo-2-nitroaniline (3.00 g, 13.5 mmol) and (5-fluoro-2-methoxypyridin-4- yl)boronic acid (2.55 g, 14.9 mmol), Compound 03.01 was prepared analogously to the procedure for the preparation of Compound 02.01.
Yield: 1.70 g (48 %) of the title compound.
LC-MS (Method 2): R, = 1.16 min; MS (ESIpos): m/z = 264 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.319 (16.00), 7.024 (1.93), 7.038 (1.89), 7.126 (1.91 ), 7.148 (1.99), 7.724 (0.87), 7.730 (1.58), 7.734 (2.38), 7.747 (0.85), 7.752 (0.85), 8.201 (1.92), 8.209 (1.93), 8.300 (1.24), 8.302 (1.31 ), 8.306 (1.29), 8.308 (1.14).
Compound 03.02
4-(5-fluoro-2-methoxypyridin-4- l)benzene-1 ,2-diamine
Figure imgf000323_0002
To a stirred solution of 4-(5-fluoro-2-methoxypyridin-4-yl)-2-nitroaniline (1.70 g, 6.46 mmol) in ethanol (200 mL) and dichloromethane (70 mL) was added palladium on carbon (10 % w/w palladium) (344 mg, 323 pmol) and the mixture was stirred at r.t. in a hydrogen atmosphere for 14 h. The mixture was filtered through aminophase silicagel, and the solution was
concentrated in vacuum to give 1.50 g (100 % yield) of the title compound as crude product, that was used for the next step without purification.
LC-MS (Method 2): R, = 0.87 min; MS (ESIpos): m/z = 234 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.037 (0.99), 1.054 (2.00), 1.071 (1.74), 1.089 (2.01 ), 1.106 (0.86), 3.321 (16.00), 3.371 (0.86), 3.389 (0.95), 3.424 (0.47), 3.436 (0.48), 3.454 (0.42), 4.344 (0.63), 4.628 (2.93), 4.920 (3.66), 6.573 (2.89), 6.593 (3.49), 6.744 (0.88), 6.749 (1.52), 6.754 (0.97), 6.764 (0.78), 6.769 (1.65), 6.772 (3.61 ), 6.786 (3.01 ), 6.859 (1.59), 6.863 (2.64), 6.868 (1.43), 7.546 (0.79), 7.549 (0.71 ), 7.554 (0.65), 7.557 (0.65), 7.564 (0.94), 7.566 (0.71 ), 7.572 (0.68), 7.597 (1.01 ), 7.614 (0.92), 7.622 (0.90), 7.626 (1.33), 7.631 (0.64), 7.643 (0.64), 8.079 (3.09), 8.087 (3.02).
Compound 03.03
tert-butyl 4-[(2-{[6-(5-fluoro-2-methoxypyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin- 4-yl)methyl]piperazine-1-carboxylate
Figure imgf000324_0001
To a stirred solution of 1 H-imidazole (61.3 mg, 900 μιτιοΙ) and di-1 H-imidazol-1- ylmethanethione (844 mg, 95 % purity, 4.50 mmol) in dichloromethane (30 ml_) was added tert-butyl 4-[(2-aminopyridin-4-yl)methyl]piperazine-1 -carboxylate (1.32 g, 4.50 mmol) dissolved in dichloromethane (50 mL), at 0° C. The mixture was stirred at r.t. for 14 h. 4-(5- fluoro-2-methoxypyridin-4-yl)benzene-1 ,2-diamine (1.50 g, 70 % purity, 4.50 mmol) , dissolved in dichloromethane (10 mL), was added and the mixture was stirred at r.t. for 65 h. Water was added and the mixture was extracted with dichloromethane.
The organic phase was dried (sodium sulfate) and filtered. N,N'-dipropan-2-ylcarbodiimide (2.8 mL, 18 mmol) was added and the mixture was stirred at r.t. for 1 h. Further N,N'-dipropan-2- ylcarbodiimide (2.8 mL, 18 mmol) was added and the mixture was stirred at r.t. for 2 h. Again, further N,N'-dipropan-2-ylcarbodiimide (2.8 mL, 18 mmol) was added and the mixture was stirred at r.t. for 14 h. Saturated ammonium chloride solution was added, the mixture was stirred for 30 minutes and the mixture was extracted with dichloromethane. The organic phase was dried (sodium sulfate) and the solvent was removed in vacuum. Silicagel chromatography gave a solid that was triturated with ethanol. The solid was removed by filtration and was discarded. The solution was concentrated in vacuum. Aminophase-silicagel chromatography followed by silicagel chromatography gave 1.20 g of the title compound as a crude product, that was used without further purification.
LC-MS (Method 2): R, = 1.38 min; MS (ESIpos): m/z = 534 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.993 (4.37), 1.009 (4.35), 1.038 (0.52), 1.056 (0.95), 1.073 (0.53), 1.387 (2.07), 1.396 (16.00), 1.987 (0.43), 2.350 (0.95), 2.362 (1.36), 2.374 (1.00), 3.351 (1.15), 3.503 (1.68), 3.845 (0.47), 3.879 (5.30), 6.930 (0.56), 7.187 (0.65), 8.201 (0.63), 8.208 (0.62), 8.261 (0.77), 8.274 (0.76).
Compound 03.04
6-(5-fluoro-2-methoxypyridin-4-yl)-N-[4-(piperazin-1-ylmethyl)pyridin
benzimidazol-2-amine hydrochloride
Figure imgf000325_0001
Starting with tert-butyl 4-[(2-{[6-(5-fluoro-2-methoxypyridin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate (1 .20 g, 1.80 mmol), Compound 03.04 was prepared analogously to the procedure for the preparation of Compound 01.05.
Yield: 0.58 g of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): R, = 1.13 min; MS (ESIpos): m/z = 434 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.968 (1.58), 0.985 (1 .59), 2.296 (2.44), 2.300 (2.59), 2.304 (2.49), 2.309 (2.10), 2.684 (3.09), 2.696 (4.52), 2.708 (2.73), 3.410 (5.47), 3.856 (16.00), 5.733 (0.91 ), 6.893 (1.33), 6.896 (1.35), 6.906 (1.39), 6.909 (1.37), 7.148 (2.37), 8.182 (2.25), 8.188 (2.15), 8.226 (2.29), 8.239 (2.17).
Compound 04.01
4-(3-methoxypyridin-4-yl)-2-nitroaniline
Figure imgf000326_0001
Starting with 4-bromo-2-nitroaniline (2.40 g, 1 1.1 mmol) and (3-methoxypyridin-4-yl)boronic acid (3.38 g, 22.1 mmol), Compound 04.01 was prepared analogously to the procedure for the preparation of Compound 02.01.
Yield: 2.20 g (73 %) of the title compound.
LC-MS (Method 1 ): R, = 0.64 min; MS (ESIpos): m/z = 246 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.917 (16.00), 7.082 (2.37), 7.105 (2.52), 7.382 (2.44), 7.394 (2.50), 7.613 (2.41 ), 7.677 (1.37), 7.683 (1.37), 7.699 (1.24), 7.705 (1.27), 8.240 (3.19), 8.252 (2.99), 8.271 (2.48), 8.277 (2.46), 8.437 (4.31 ).
Compound 04.02
4-(3-methoxypyridin-4-yl)benzene-1,2-diamine
Figure imgf000326_0002
To a stirred solution of 4-(3-methoxypyridin-4-yl)-2-nitroaniline (2.10 g, 8.56 mmol) in ethanol (30 mL) was added Raney Nickel (50 mg) and the mixture was stirred at r.t. in a hydrogen atmosphere for 16 h. The mixture was filtered, and the solution was concentrated in vacuum to give 1.80 g (88 % yield) of the title compound as crude product, that was used for the next step without purification.
LC-MS (Method 2): Rt = 0.69 min; MS (ESIpos): m/z = 216 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.315 (4.62), 4.614 (1.94), 5.752 (0.66), 6.541 (8.22), 6.562 (10.75), 6.689 (5.56), 6.694 (5.89), 6.709 (4.10), 6.714 (4.55), 6.828 (10.07), 6.833 (9.39), 7.192 (8.70), 7.204 (9.09), 8.150 (10.53), 8.162 (10.08), 8.322 (16.00). Compound 04.03
4-({[tert-butyl(dimethyl)silyl]oxy}methyl)pyridin
Figure imgf000327_0001
To a stirred solution of (2-aminopyridin-4-yl)methanol (10.0 g, 97 % purity, 78.1 mmol) and 1 H- imidazole (5.32 g, 78.1 mmol) in DMF (70 ml_), was added tert-butyl(chloro)dimethylsilane (12.1 g, 97 % purity, 78.1 mmol) at 0°C and the mi xture was stirred at r.t. for 14 h. The solvent was removed in vacuum. Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried (sodium sulfate), filtered and the solvent was removed in vacuum. Silicagel chromatography gave 16.0 g (86% yield) of the title compound.
LC-MS (Method 2): R, = 1.29 min; MS (ESIpos): m/z = 239 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.061 (0.42), 0.059 (1 1.41 ), 0.822 (0.66), 0.881 (0.84), 0.889 (16.00), 0.896 (0.76), 4.539 (1.92), 5.830 (0.78), 6.370 (0.66), 6.372 (0.76), 7.780 (0.59), 7.782 (0.52), 7.793 (0.56), 7.795 (0.54).
Compound 04.04
N-[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)pyridin-2-yl]-6-(3-methoxypyridin-4-yl)-1 H benzimidazol-2-amine
To a stirred solution of 1 H-imidazole (92.0 mg, 1.35 mmol) and di-1 H-imidazol-1 - ylmethanethione (1.52 g, 95 % purity, 8.11 mmol) in dichloromethane (200 mL) was added 4- ({[tert-butyl(dimethyl)silyl]oxy}methyl)pyridin-2-amine (1.61 g, 6.76 mmol) , dissolved in dichloromethane (200 mL) at 0°C. The mixture was s tirred at r.t. for 14 h. 4-(3-methoxypyridin- 4-yl)benzene-1 ,2-diamine (1.80 g, 97 % purity, 8.1 1 mmol) , dissolved in dichloromethane was added and the mixture was stirred at r.t. for 4 h. Water was added and the mixture was extracted with dichloromethane / methanol (10:1 ).
The organic phase was dried (sodium sulfate) and filtered. N,N'-dipropan-2-ylcarbodiimide (3.1 mL, 20 mmol) was added and the mixture was stirred at r.t. for 14 h. Saturated ammonium chloride solution was added, the mixture was stirred for 30 minutes and the mixture was extracted with dichloromethane. The organic phase was dried (sodium sulfate) and the solvent was removed in vacuum. Silicagel chromatography gave a solid that was triturated with ethyl acetate. The solid was removed by filtration and was discarded. The solution was concentrated in vacuum. Aminophase-silicagel chromatography gave 1.10 g of the title compound as a crude product, that was used without further purification.
LC-MS (Method 2): F¾ = 1.51 min; MS (ESIpos): m/z = 462 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.150 (12.43), 0.970 (1.01 ), 0.978 (16.00), 0.985 (0.93), 1.015 (0.74), 1.031 (0.76), 1.196 (0.72), 2.010 (1.31 ), 3.930 (3.13), 4.766 (1.90), 7.394 (0.57), 8.266 (0.79), 8.272 (0.94), 8.280 (0.86), 8.284 (0.91 ), 8.458 (1.50).
Compound 04.05
(2-{[6-(3-methoxypyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4-yl)methanol
Figure imgf000328_0001
To a stirred solution of crude N-[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)pyridin-2-yl]-6-(3- methoxypyridin-4-yl)-1 H-benzimidazol-2-amine (1.10 g, approx. 2.38 mmol) in THF (27 mL), was added tetra-n-butylammoniumfluoride (4.8 mL, 1.0 M, 4.8 mmol), and the mixture was stirred at r.t. for 1 h. Water was added, the mixture was stirred for 30 minutes and the mixture was extracted with ethyl acetate and then with dichloromethane / methanol (100:1 ). The combined organic phases were dried (sodium sulfate), filtered and the solvent was removed in vacuum. The solid was triturated with ethanol to give 700 mg (76 % yield) of the title compound.
LC-MS (Method 2): Rt = 0.87 min; MS (ESIpos): m/z = 348 [M+H]+ 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.172 (0.73), 1.986 (1.45), 3.906 (16.00), 4.517 (4.1 1 ), 4.531 (4.20), 5.430 (1.79), 5.444 (3.84), 5.458 (1.68), 5.755 (0.46), 6.880 (1.85), 6.884 (1.82), 6.894 (1.88), 6.897 (1.84), 7.202 (2.63), 7.268 (0.62), 7.360 (2.65), 7.372 (2.73), 8.236 (2.92), 8.248 (6.20), 8.260 (3.55), 8.434 (6.22), 10.666 (1.23), 12.194 (0.86).
Compound 04.06
N-[4-(chloromethyl)pyridin-2-yl]-6-(3-methoxypyridin-4-yl)-1 H-benzimidazol-2-amine
Figure imgf000329_0001
To a suspension of (2-{[6-(3-methoxypyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methanol (700 mg, 2.02 mmol) in dioxane (50 mL, 580 mmol) was added thionyl dichloride (590 μΙ, 8.1 mmol) and the mixture was stirred for 86 h. A solution of sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The organic phase was dried (sodium sulfate), filtered and the solvent was removed in vacuum to give 870 mg of the title compound as a crude product.
LC-MS (Method 2): R, = 1.08 min; MS (ESIpos): m/z = 366 [M+H]+
1H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.355 (0.44), 3.311 (16.00), 3.908 (8.77), 4.779 (6.30), 7.007 (1.14), 7.010 (1.09), 7.017 (1.09), 7.020 (1.15), 7.301 (1.13), 7.363 (1.37), 7.372 (1.37), 8.251 (2.25), 8.261 (2.07), 8.321 (1.72), 8.332 (1.63), 8.437 (3.54).
Compound 04.07
6-(3-methoxypyridin-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1H-benzimidaz amine hydrochloride
Figure imgf000330_0001
Starting with tert-butyl 4-[(2-{[6-(3-methoxypyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate (800 mg, 1.55 mmol), Compound 04.07 was prepared analogously to the procedure for the preparation of Compound 01.05.
Yield: 0.80 g of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): R, = 0.90 min; MS (ESIpos): m/z = 460 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.523 (1.48), 2.526 (1.48), 2.728 (1.49), 2.889 (1.73), 3.258 (0.93), 3.401 (2.10), 4.048 (16.00), 4.322 (0.66), 7.555 (2.55), 7.650 (1.48), 7.654 (1.39), 7.671 (1.78), 7.675 (1.84), 7.795 (2.28), 7.815 (1.71 ), 7.942 (1.81 ), 7.956 (1 .94), 8.036 (2.43), 8.040 (2.42), 8.529 (1.27), 8.543 (1.19), 8.589 (2.47), 8.603 (2.36), 8.744 (4.60).
Compound 05.01
4-bromo-3-(2,2,2-trifluoroethoxy)pyri ine
Figure imgf000330_0002
To a stirred solution of 4-bromopyridin-3-ol (1.00 g, 95 % purity, 5.46 mmol) in DMA (15 mL) was added potassium carbonate (981 mg, 7.10 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.2 mL, 97 % purity, 8.2 mmol). The mixture was stirred at r.t. for 48 h. Water was added (250 mL) and ammonium chloride was added until pH7 was reached. The mixture was extracted with ethyl acetate. The organic phase was washed with half-saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum to give 1.43 g of the title compound as crude product, that was used without further purification. LC-MS (Method 2): R, = 1.06 min; MS (ESIpos): m/z = 256 [M+H]+
1 H-NMR (500 MHz, DMSO-d6) δ [ppm]: 4.663 (0.53), 4.682 (1.51 ), 4.700 (1.45), 4.718 (0.46), 4.910 (0.99), 4.928 (0.93), 4.997 (4.67), 5.015 (13.93), 5.033 (13.29), 5.050 (4.20), 6.310 (1.35), 6.325 (1.31 ), 7.739 (10.77), 7.749 (1 1.23), 7.845 (0.86), 7.850 (0.75), 8.156 (10.52), 8.166 (10.05), 8.51 1 (16.00).
Compound 05.02
2-nitro-4-[3-(2,2,2-trifluoroethoxy)pyridin
Figure imgf000331_0001
Starting with crude 4-bromo-3-(2,2,2-trifluoroethoxy)pyridine (1.43 g, approx. 5.03 mmol) and 2-nitro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)aniline (1.37 g, 97 % purity, 5.03 mmol), Compound 05.02 was prepared analogously to the procedure for the preparation of Compound 02.01.
Yield: 1.25 g of the title compound.
LC-MS (Method 2): R, = 1.01 min; MS (ESIpos): m/z = 314 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.069 (4.06), 2.327 (0.66), 2.523 (1.31 ), 2.669 (0.61 ), 3.162 (0.58), 3.175 (0.61 ), 3.912 (0.67), 4.909 (3.12), 4.931 (9.05), 4.953 (8.56), 4.975 (2.54), 5.752 (1.17), 7.091 (7.76), 7.1 13 (8.10), 7.470 (7.97), 7.482 (8.31 ), 7.525 (0.91 ), 7.528 (1.46), 7.533 (1.18), 7.536 (1.28), 7.540 (1.01 ), 7.544 (2.45), 7.547 (3.52), 7.549 (3.47), 7.555 (2.81 ), 7.558 (2.69), 7.564 (4.23), 7.572 (3.19), 7.592 (2.66), 7.597 (5.22), 7.605 (2.18), 7.610 (2.99), 7.614 (4.87), 7.618 (2.57), 7.623 (5.80), 7.626 (8.20), 7.631 (7.26), 7.637 (9.43), 7.644 (6.29), 7.647 (3.90), 7.651 (1.34), 7.673 (4.28), 7.679 (4.38), 7.696 (3.89), 7.701 (3.93), 8.327 (9.81 ), 8.340 (16.00), 8.346 (8.10), 8.51 1 (14.24).
Compound 05.03
4-[3-(2,2,2-trifluoroethoxy)pyridin-4-yl]benzene-1 ,2-diamine
Figure imgf000332_0001
To a stirred solution of 2-nitro-4-[3-(2,2,2-trifluoroethoxy)pyridin-4-yl]aniline (1.25 g, 3.99 mmol) in ethanol (20 mL) and dichloromethane (40 mL) was added palladium on carbon (10 % w/w palladium) (425 mg) and the mixture was stirred at r.t. in a hydrogen atmosphere for 3 h. The mixture was filtered, and the solution was concentrated in vacuum. Aminophase-silicagel chromatography gave 0.74 g (65 % yield) of the title compound.
LC-MS (Method 2): R, = 0.82 min; MS (ESIpos): m/z = 284 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 4.514 (8.54), 4.758 (3.76), 4.780 (14.97), 4.785 (1 1.17), 4.802 (10.43), 4.824 (3.10), 5.752 (16.00), 6.545 (7.92), 6.565 (9.38), 6.753 (4.60), 6.758 (5.54), 6.773 (3.47), 6.778 (4.69), 6.802 (9.61 ), 6.807 (7.41 ), 7.262 (8.62), 7.274 (8.94), 7.525 (0.59), 7.528 (1.02), 7.533 (0.81 ), 7.536 (0.90), 7.544 (1.71 ), 7.547 (2.38), 7.549 (2.42), 7.555 (2.01 ), 7.558 (1.77), 7.564 (2.85), 7.566 (2.29), 7.572 (2.19), 7.574 (2.08), 7.594 (1.83), 7.598 (3.47), 7.604 (1.71 ), 7.607 (1.27), 7.61 1 (1.89), 7.615 (2.51 ), 7.619 (1.68), 7.624 (3.79), 7.626 (4.54), 7.631 (2.38), 7.640 (1.20), 7.644 (2.45), 7.647 (1.89), 8.240 (1 1.48), 8.252 (10.23), 8.392 (15.29).
Compound 05.04
tert-butyl 4-{[2-({6-[3-(2,2,2-trifluoroethoxy)pyridin-4-yl]-1H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate
Figure imgf000332_0002
To a stirred solution of 1 H-imidazole (43.3 mg, 635 pmol) and di-1 H-imidazol-1 - ylmethanethione (596 mg, 95 % purity, 3.18 mmol) in dichloromethane (35 mL) was added tert-butyl 4-[(2-aminopyridin-4-yl)methyl]piperazine-1 -carboxylate (929 mg, 3.18 mmol), dissolved in dichloromethane (18 mL), at 0° C. The mixture was stirred at r.t. for 14 h. 4-[3- (2,2,2-trifluoroethoxy)pyridin-4-yl]benzene-1 ,2-diamine (900 mg, 3.18 mmol), dissolved in dichloromethane (18 mL), was added and the mixture was stirred at r.t. for 3 h. Water was added and the mixture was extracted with dichloromethane.
The organic phase was dried (sodium sulfate) and filtered. N,N'-dipropan-2-ylcarbodiimide (1.4 mL, 9.2 mmol) was added and the mixture was stirred at r.t. for 56 h. Saturated ammonium chloride solution was added, the mixture was stirred for 30 minutes and the mixture was extracted with dichloromethane. The organic phase was dried (sodium sulfate) and the solvent was removed in vacuum. Aminophase-silicagel chromatography gave 130 mg of the title compound as a crude product, that was used without further purification.
LC-MS (Method 2): R, = 1.29 min; MS (ESIpos): m/z = 584 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.385 (1.81 ), 1.389 (1 1.21 ), 1.394 (16.00), 2.322 (0.78), 2.327 (0.86), 2.332 (0.98), 2.336 (0.95), 2.346 (1.29), 2.359 (1 .27), 2.371 (0.95), 2.518 (3.42), 2.523 (2.13), 3.499 (1.96), 5.760 (1.92), 8.210 (0.46), 8.212 (0.47), 8.224 (0.47), 8.258 (0.70), 8.272 (0.70), 8.513 (1.10).
Compound 05.05
N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-6-[3-(2,2,2-trifluoroethoxy)pyridin
benzimidazol-2-amine hydrochloride
Figure imgf000333_0001
Starting with tert-butyl 4-{[2-({6-[3-(2,2,2-trifluoroethoxy)pyridin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate (130 mg, 223 pmol), Compound 05.05 was prepared analogously to the procedure for the preparation of Compound 01.05.
Yield: 159 mg of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): Rt = 1.02 min; MS (ESIpos): m/z = 484 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.003 (0.46), 2.083 (0.49), 2.323 (1.09), 2.327 (1.51 ), 2.332 (1.14), 2.523 (10.22), 2.665 (1.46), 2.669 (1.82), 2.673 (1.41 ), 3.162 (1.94), 3.296 (1.97), 3.485 (1.19), 3.561 (2.67), 3.563 (16.00), 4.366 (1.24), 5.023 (1.82), 5.045 (4.52), 5.067 (4.35), 5.088 (1.72), 5.760 (4.81 ), 7.558 (3.59), 7.616 (2.50), 7.620 (2.43), 7.637 (2.79), 7.641 (3.03), 7.778 (3.71 ), 7.787 (2.38), 7.799 (4.71 ), 7.913 (4.37), 8.376 (1.36), 8.390 (1.41 ), 8.547 (1.77), 8.560 (1.89), 8.583 (3.71 ), 8.596 (3.54), 8.782 (5.97), 9.690 (1.09).
Compound 06.01
4-bromo-3-(propan-2-yloxy)pyridine
Figure imgf000334_0001
To a stirred solution of 4-bromopyridin-3-ol (5.00 g, 28.7 mmol) in DMA (150 mL) was added potassium carbonate (11.9 g, 86.2 mmol) and 2-iodopropane (4.3 mL, 43 mmol) and the mixture was stirred at 70° C for 3 h. Water was add ed and the mixture was extracted with ethyl acetate. The organic phase was washed with half-saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Aminophase-silicagel chromatography gave 4.41 g (71 % yield) of the title compound.
LC-MS (Method 2): Rt = 1.07 min; MS (ESIpos): m/z = 216 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.307 (15.82), 1.31 1 (2.09), 1.322 (16.00), 1.326 (1.88), 4.803 (0.88), 4.818 (1.18), 4.833 (0.88), 7.662 (2.23), 7.674 (2.33), 8.030 (2.72), 8.042 (2.52), 8.413 (3.82).
Compound 06.02
2-nitro-4-[3-(propan-2-yloxy)pyridin
Figure imgf000335_0001
Starting with 4-bromo-3-(propan-2-yloxy)pyridine (1.78 g, 8.07 mmol) and (4-amino-3- nitrophenyl)boronic acid (2.64 g, 14.5 mmol), Compound 06.02 was prepared analogously to the procedure for the preparation of Compound 02.01.
Yield: 1.10 g (45 %) of the title compound.
LC-MS (Method 2): R, = 1.04 min; MS (ESIpos): m/z = 274 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.263 (15.64), 1.279 (16.00), 4.716 (0.97), 4.731 (1.31 ), 4.747 (0.97), 7.077 (2.39), 7.099 (2.51 ), 7.404 (2.46), 7.417 (2.51 ), 7.546 (0.77), 7.549 (0.76), 7.554 (0.62), 7.564 (0.86), 7.566 (0.70), 7.571 (0.69), 7.596 (1.10), 7.609 (0.93), 7.613 (1.53), 7.622 (3.99), 7.625 (4.03), 7.630 (1.72), 7.638 (0.70), 7.643 (0.88), 7.712 (1.42), 7.718 (1.37), 7.735 (1.30), 7.740 (1.27), 8.206 (3.03), 8.218 (2.82), 8.412 (3.15), 8.417 (6.33).
Compound 06.03
4-[3-(propan-2-yloxy)pyridin-4-yl]benzene-1 ,2-diamine
Figure imgf000335_0002
To a stirred solution of 2-nitro-4-[3-(propan-2-yloxy)pyridin-4-yl]aniline (1.10 g, 4.02 mmol) in ethanol (16 mL) was added palladium on carbon (10 % w/w palladium) (428 mg, 402 pmol) and the mixture was stirred at r.t. in a hydrogen atmosphere for 48 h. The mixture was filtered, and the solution was concentrated in vacuum. Silicagel chromatography gave 840 mg (77 % yield) of the title compound.
LC-MS (Method 2): Rt = 0.80 min; MS (ESIpos): m/z = 244 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.207 (15.79), 1.222 (16.00), 2.083 (0.57), 4.492 (1.02), 4.507 (1.80), 4.516 (2.48), 4.522 (1.99), 4.713 (2.77), 5.751 (0.60), 6.542 (2.17), 6.562 (2.55), 6.744 (1.35), 6.749 (1.48), 6.764 (1.10), 6.769 (1.18), 6.872 (2.44), 6.877 (2.25), 7.198 (2.30), 7.210 (2.34), 7.545 (0.63), 7.548 (0.73), 7.553 (0.64), 7.562 (0.72), 7.565 (0.70), 7.570 (0.61 ), 7.572 (0.57), 7.598 (1.01 ), 7.603 (0.58), 7.615 (0.62), 7.625 (1.28), 7.630 (0.72), 7.646 (0.70), 8.127 (3.1 1 ), 8.139 (3.13), 8.270 (4.43).
Compound 06.04
tert-butyl 4-{[2-({6-[3-(propan-2-yloxy)pyridin-4-yl]-1 H-benzimidazol-2-yl}amino)pyridin-4- yl]methyl}piperazine-1 -carboxylate
Figure imgf000336_0001
To a stirred solution of 1 H-imidazole (39.6 mg, 582 pmol) and di-1 H-imidazol-1 - ylmethanethione (692 mg, 90 % purity, 3.49 mmol) in dichloromethane (20 mL) was added tert-butyl 4-[(2-aminopyridin-4-yl)methyl]piperazine-1 -carboxylate (851 mg, 2.91 mmol) , dissolved in dichloromethane (20 mL), at 0° C. The mixture was stirred at r.t. for 14 h. 4-[3- (propan-2-yloxy)pyridin-4-yl]benzene-1 ,2-diamine (840 mg, 97 % purity, 3.35 mmol), dissolved in dichloromethane (15 mL), was added and the mixture was stirred at r.t. for 2 h. Water was added and the mixture was extracted with dichloromethane
The organic phase was dried (sodium sulfate) and filtered. N,N'-dipropan-2-ylcarbodiimide (620 μΙ, 4.0 mmol) was added. The mixture was stirred at r.t. for 14 h. Further N,N'-dipropan-2- ylcarbodiimide (230 μΙ, 1.5 mmol) was added and the mixture was stirred at r.t. for 14 h. Saturated ammonium chloride solution was added, the mixture was stirred for 30 minutes and was extracted with dichloromethane. Aminophase-silicagel chromatography gave 240 mg of the title compound as a crude product, that was used without further purification.
LC-MS (Method 2): R, = 1.32 min; MS (ESIpos): m/z = 544 [M+H]+
H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.054 (1.16), 1.227 (2.03), 1.241 (2.01 ), 1.391 (7.80), 1.396 (16.00), 2.349 (1.18), 2.362 (1.33), 2.374 (0.96), 3.349 (1.19), 3.501 (1.96), 8.222 (1.22), 8.234 (0.98), 8.396 (1.66). Compound 06.05
N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-6-[3-(propan-2-yloxy)pyridin-4-yl]-1 H
benzimidazol-2-amine hydrochloride
Figure imgf000337_0001
Starting with tert-butyl 4-{[2-({6-[3-(propan-2-yloxy)pyridin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate (240 mg, 441 μιτιοΙ), Compound 06.05 was prepared analogously to the procedure for the preparation of Compound 01.05.
Yield: 340 mg of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): Rt = 1.03 min; MS (ESIpos): m/z = 444 [M+H]+
Compound 07.01
2-methyl-5-{[2-(trimethylsilyl)ethoxy]methoxy}pyridine
Figure imgf000337_0002
To a stirred suspension of 6-methylpyridin-3-ol (15.7 g, 144 mmol) in dichloromethane (130 mL), was added N,N-diisopropylethylamine (30 mL, 170 mmol), and [2- (chloromethoxy)ethyl](trimethyl)silane (26 mL, 150 mmol) and the mixture was stirred at r.t. for 19 h. The mixture was washed with water and the organic phase was dried (magnesium sulfate), filtered and the solvent was removed in vacuum. Silicagel chromatography gave 32.8 g (95 % yield) of the title compound.
LC-MS (Method 5): R, = 3.26 min; MS (ESIpos): m/z = 240 [M+H]+ 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.042 (2.31 ), -0.025 (2.20), 0.000 (1.67), 0.858 (2.60), 0.879 (2.81 ), 0.881 (2.00), 0.899 (2.80), 2.390 (16.00), 2.498 (0.68), 2.502 (0.97), 2.506 (0.66), 3.315 (6.15), 3.681 (2.75), 3.699 (2.28), 3.701 (3.30), 3.703 (2.44), 3.721 (2.80), 5.237 (13.03), 7.155 (1.62), 7.176 (2.32), 7.322 (1.60), 7.329 (1.74), 7.344 (1.25), 7.350 (1.42), 8.184 (1.85), 8.191 (2.16).
Compound 07.02
4-iodo-2-methyl-5-{[2-(trimethylsilyl)ethoxy]methoxy}pyridine
Figure imgf000338_0001
To a stirred solution of 2-methyl-5-{[2-(trimethylsilyl)etfioxy]methoxy}pyridine (22.5 g, 94.0 mmol) in diethyl ether (360 mL) was added a solution of tert-butyllithium in pentane (55 ml_, 1.9 M, 100 mmol) at -70 Ό. The solution was stirred at -78 for 5 minutes. Iodine (24.3 g, 95.7 mmol), dissolved in THF (50 mL) was added at -70 V , and the mixture was stirred at -78 Ό for 0.5 h and then allowed to warm up to room temperature. An aqueous solution of disodium sulfurothioate (c = 1 M; 300 mL) was added and the reaction mixture was stirred for 5 minutes. The phases were separated and the aqueous phase was extracted with diethyl ether.The combined organic phases were dried (magnesium sulfate), filtered and the solvent was removed in vacuum. The residue was crystallized from pentane to give 24.8 g (72 % yield) of the title compound.
Compound 07.03
4-iodo-6-methylpyridin-3-ol
Figure imgf000339_0001
To a stirred solution of 4-iodo-2-methyl-5-{[2-(trimethylsilyl)ethoxy]methoxy}pyridine (24.8 g, 67.9 mmol) in dioxane (120 mL) was added aqueous hydrochloric acid (15 mL, 37 %, 180 mmol). The mixture was stirred at 60 Ό for 0.5 h. Sodium bicarbonate (45 g) was added and the mixture was stirred for 30 minutes. THF (300 mL) was added, the mixture was filtered through sodium sulfate and the solvent was removed in vacuum. Diethyl ether was added to the residue, solids were removed by filtration and the solvent was removed in vacuum to give 15.1 g (95 % yield) of the title compound.
LC-MS (Method 5): Rt = 0.38 min; MS (ESIpos): m/z = 236 [M+H]+
Compound 07.04
4-iodo-5-methoxy-2-methylpyrid
Figure imgf000339_0002
To a stirred solution of 4-iodo-6-methylpyridin-3-ol (4.80 g, 20.4 mmol) in dichloromethane (60 mL) and methanol (30 mL) was added (diazomethyl)(trimethyl)silane (12 mL, 2.0 M solution in hexane, 24 mmol). The mixture was stirred at r.t. for 1 h. The solvent was removed in vacuum. Silicagel chromatography gave 3.5 g (69 % yield) of the title compound.
LC-MS (Method 5): R, = 0.90 min; MS (ESIpos): m/z = 250 M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.357 (14.33), 2.493 (0.60), 2.499 (0.80), 2.503 (0.59), 3.310 (3.81 ), 3.891 (16.00), 7.697 (3.86), 8.070 (4.16). Compound 07.05
tert-butyl 4-[(2^[6-(5-methoxy-2-methylpyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin- 4-yl)methyl]piperazine-1 -carboxylate
Figure imgf000340_0001
To a stirred solution of tert-butyl 4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate (1.10 g, 2.06 mmol) and 4-iodo-5-methoxy-2-methylpyridine (600 mg, 2.41 mmol) in dioxane (10 mL) and water (2.0 mL) was added sodium carbonate (660 mg, 6.23 mmol) and Pd(dppf)Cl2 . CH2CI2 (250 mg, 306 pmol). The mixture was heated to reflux for 24 h. Chloroform was added, the mixture was dried (magnesium sulfate), filtered and the solvent was removed in vacuum. Silicagel chromatography gave 915 mg (84 % yield) of the title compound.
LC-MS (Method 5): R, = 2.56 min; MS (ESIpos): m/z = 530 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.142 (1.07), 1.394 (16.00), 1.909 (0.53), 2.081 (2.48), 2.1 15 (0.47), 2.354 (0.96), 2.367 (1.45), 2.379 (1.07), 2.451 (4.85), 2.495 (0.89), 2.500 (1.23), 2.505 (0.94), 3.340 (1.1 1 ), 3.351 (1.50), 3.364 (1.12), 3.503 (1.71 ), 3.853 (5.50), 6.915 (0.54), 6.918 (0.56), 6.928 (0.56), 6.931 (0.57), 7.196 (0.97), 7.233 (1.62), 7.242 (0.59), 7.246 (0.56), 7.263 (0.59), 7.267 (0.62), 7.444 (0.62), 7.465 (0.53), 7.661 (0.65), 8.254 (0.85), 8.270 (2.02).
Compound 07.06
6-(5-methoxy-2-methylpyridin-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H benzimidazol-2-amine
Figure imgf000341_0001
To a stirred solution tert-butyl 4-[(2-{[6-(5-methoxy-2-methylpyridin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazine-1-carboxylate (900 mg, 1 .70 mmol) in dioxane (8 mL) was added aqueous hydrochloric acid (1.4 mL, 6.0 M, 8.4 mmol). The mixture was stirred at room temperature for 2 h. Sodium bicarbonate (5.0 g) was added and the mixture was stirred for 30 minutes. THF (50 mL) was added, the mixture was filtered through magnesium sulfate and the solvent was removed in vacuum. Diethyl ether was added to the residue, solids were removed by filtration and the solvent was removed in vacuum to give 695 mg (95 % yield) of the title compound.
LC-MS (Method 5): R, = 3.30 min; MS (ESIpos): m/z = 535[M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.062 (4.84), 1 .079 (9.70), 1.097 (4.89), 1.215 (1.04), 1.730 (2.43), 1.737 (3.18), 1.746 (6.66), 1.754 (3.18), 1.763 (2.43), 2.442 (15.71 ), 2.495 (5.78), 2.499 (7.44), 2.503 (6.92), 2.508 (5.84), 2.517 (5.16), 2.938 (4.94), 3.163 (1.92), 3.344 (2.08), 3.362 (5.49), 3.379 (5.47), 3.397 (2.1 1 ), 3.505 (5.84), 3.573 (3.33), 3.589 (6.93), 3.596 (3.22), 3.606 (2.92), 3.845 (16.00), 6.890 (0.40), 6.905 (2.05), 6.919 (2.00), 7.219 (5.34), 7.249 (4.53), 7.439 (0.74), 7.648 (0.44), 8.243 (2.62), 8.259 (6.56).
Compound 08.01
{4-[(2-aminopyridin-4-yl)methyl]piperazin-1-yl}(cyclopropyl)methanone
Figure imgf000342_0001
To a stirred suspension of 4-(bromomethyl)pyridin-2-amine hydrobromide (10.0 g, 37.3 mmol) in acetonitrile (75 mL) was added potassium carbonate (16.0 g, 1 16 mmol) and cyclopropyl(piperazin-1 -yl)methanone (6.10 g, 39.6 mmol) (CAS-RN 59878-57-8 ) The mixture was stirred at 75° C for 2 h. Direct silicagel chro matography of the reaction mixture gave a solid which was triturated with ether to give 7.20 g (74 % yield) of the title compound.
LC-MS (Method 5): R, = 0.14 min; MS (ESIpos): m/z = 261 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.655 (0.49), 0.667 (1.47), 0.674 (3.50), 0.680 (2.08), 0.687 (1.70), 0.694 (4.26), 0.699 (3.30), 0.705 (3.66), 0.712 (3.58), 0.717 (4.34), 0.724 (1.98), 0.737 (0.54), 1.905 (0.42), 1.917 (0.87), 1.924 (0.93), 1.928 (0.69), 1.936 (1.55), 1.942 (0.73), 1.948 (0.90), 1.956 (0.83), 2.304 (1.43), 2.376 (1.45), 2.490 (0.57), 2.495 (1.18), 2.500 (1.61 ), 2.504 (1.18), 2.509 (0.57), 3.332 (16.00), 3.355 (0.68), 3.462 (1.29), 3.599 (0.53), 3.615 (0.43), 3.661 (1.28), 5.805 (4.16), 6.408 (3.74), 6.428 (2.21 ), 6.431 (1.88), 6.441 (2.19), 6.444 (1.89), 7.815 (2.34), 7.828 (2.29).
Compound 08.02
cyclopropyl{4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}methanone
Figure imgf000342_0002
To a stirred solution of di-1 H-imidazol-1 -ylmethanethione (5.20 g, 29.2 mmol) and imidazole (400 mg, 5.88 mmol) in dichloromethane (50 mL) was added {4-[(2-aminopyridin-4- yl)methyl]piperazin-1 -yl}(cyclopropyl)methanone (7.20 g, 27.7 mmol) , dissolved in dichloromethane (50 mL) at 0° C. The mixture was st irred at 0° C for 4 h. 4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzene-1 ,2-diamine (6.50 g, 27.8 mmol) dissolved in dichloromethane (50 mL) was added and the mixture was stirred at r.t. for 18 h. Water was added and the mixture was extracted with chloroform.
The organic phase was dried (magnesium sulfate) and filtered. N,N'-dipropan-2-ylcarbodiimide (6.0 mL, 39 mmol) was added and the mixture was stirred at 40° C for 8 h. Direct silicagel chromatography of the crude mixture gave 5.25 g (38 % yield) of the title compound.
LC-MS (Method 5): Rt = 2,94 min; MS (ESIpos): m/z = 503 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.666 (0.49), 0.673 (0.85), 0.678 (0.68), 0.686 (0.56), 0.694 (0.98), 0.706 (0.71 ), 0.71 1 (0.96), 0.718 (1.06), 0.722 (1.13), 0.730 (0.61 ), 1.298 (16.00), 1.931 (0.44), 2.360 (0.56), 2.421 (0.56), 2.495 (0.71 ), 2.499 (0.84), 2.503 (0.58), 3.334 (8.1 1 ), 3.501 (2.68), 6.916 (0.70), 6.929 (0.67), 7.185 (0.49), 7,379 (0.50), 8.244 (0.93), 8.257 (0.88).
Compound 08.03
2-(hydroxymethyl)-5-methoxy-4H-pyran
Figure imgf000343_0001
To a solution of potassium hydroxide (4.50 g, 80.2 mmol) in 40 mL water was added 5- hydroxy-2-(hydroxymethyl)-4H-pyran-4-one (10.0 g, 70.4 mmol, CAS-RN 6269-25-6) and the mixture was stirred at r.t. until a solution had formed. Dimethyl sulfate (6.7 mL, 71 mmol) was added slowly, and the mixture was stirred at 23° C for 1 h and then at 0° C for 1 h. A solid precipitated and was collected by filtration, washed with water, and dried to give 7.35 g (67% yield) of the title compound.
LC-MS (Method 5): Rt = 0.25 min; MS (ESIpos): m/z = 157 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.499 (0.58), 2.503 (0.45), 3.313 (2.22), 3.644 (16.00), 4.285 (2.03), 4.298 (2.05), 5.657 (0.84), 6.285 (1.58), 6.287 (3.03), 6.289 (1.50), 8.070 (5.73). Compound 08.04
2-(hydroxymethyl)-5-methoxypyridin-4-ol
H3
Figure imgf000344_0001
To a stirred mixture of 2-(hydroxymethyl)-5-methoxy-4H-pyran-4-one (6.68 g, 42.8 mmol) in methanol (10 mL) was added aqueous ammonium hydroxide solution (20 ml_, c = 25 %, 130 mmol). The mixture was heated to 100°C in a sealed tube for 6 h. The solvent was removed in vaccum. Silicagel chromatography gave 4.97 g (75 % yield) of the title compound.
LC-MS (Method 5): Rt = 0.14 min; MS (ESIpos): m/z = 156 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.490 (0.83), 2.495 (1 .96), 2.499 (2.75), 2.503 (1.80), 2.509 (0.83), 3.320 (16.00), 3.643 (1.52), 4.330 (2.40), 4.343 (2.35).
Compound 08.05
4-hydroxy-5-methoxypyridine-2-carboxylic acid
Figure imgf000344_0002
Concentrated nitric acid (25 mL, c = 65 %) and fuming nitric acid (5.0 mL, c = 90 %) were added to 2-(hydroxymethyl)-5-methoxypyridin-4-ol (4.97 g, 32.0 mmol) . The mixture was stirred at r.t. for 1 day, then poured into icewater. The precipitate was collected by filtration and the dissolved in diluted sodium hydroxide solution. Hydrochloric acid (c = 2N) was added until pH4 was reached. A solid precipitated and was collected by filtration to give 2.90 g of the title compound.
LC-MS (Method 5): Rt = 0.17 min; MS (ESIpos): m/z = 170 [M+H]+ Compound 08.06
4-bromo-5-methoxy-N,N-dimethylpyridine-2-carboxamide
Figure imgf000345_0001
To a solution of 4-hydroxy-5-methoxypyridine-2-carboxylic acid (1.00 g, 5.91 mmol) in DMF (20 mL, 260 mmol),was slowly added phosphorus tribromide (2.0 mL, 21 mmol) with water bath cooling. The mixture was stirred at 23° C for 1 h, and then slowly added to an aqueous solution of N-methylmethanamine-(20 mL, c = 40 %, 160 mmol) with water bath cooling. The mixture was stirred at 23'C for 1 h. A saturated so dium chloride solution, was added and the mixture was extracted with ethyl acetate, dried (magnesium sulfate) and the solvent was removed in vacuum. The residue was crystallized from cyclohexane to give 535 mg (35 % yield) of the title compound.
LC-MS (Method 5): R, = 2.70 min; MS (ESIpos): m/z = 259 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.495 (0.70), 2.500 (0.96), 2.505 (0.71 ), 2.989 (1 1.95), 2.996 (12.87), 3.314 (9.25), 4.023 (16.00), 4.028 (1.69), 7.831 (5.65), 8.371 (4.82).
Compound 09.01
5-ethoxy-4-iodo-2-methylpyridine
Figure imgf000345_0002
To a stirred solution of 4-iodo-6-methylpyridin-3-ol (4.00 g, 17.0 mmol) in DMF (10 mL) was added potassium carbonate (5.00 g, 36.2 mmol) and iodoethane (2.0 mL, 25 mmol). The mixture was stirred at r.t. for 3 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with half-saturated sodium chloride solution, dried (magnesium sulfate) and the solvent was removed in vacuum. Silicagel chromatography gave 2.54 g (57 % yield) of the title compound.
LC-MS (Method 5): R, = 2.38 min; MS (ESIpos): m/z = 264 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.337 (4.18), 1.355 (9.04), 1.373 (4.31 ), 2.352 (16.00), 2.495 (0.65), 2.499 (0.91 ), 2.503 (0.65), 3.310 (5.16), 4.126 (1.41 ), 4.144 (4.20), 4.162 (3.90), 4.178 (1.24), 7.694 (4.21 ), 8.050 (4.86).
Compound 09.02
tert-butyl 4-[(2-{[6-(5-ethoxy-2-methylpyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1-carboxylate
Figure imgf000346_0001
To a stirred solution of tert-butyl 4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)methyl]piperazine-1-carboxylate (1.10 g, 2.06 mmol) and 5-ethoxy-4-iodo-2-methylpyridine (700 mg, 2.66 mmol) in dioxane ( 0 mL) and water (2.0 mL) was added sodium carbonate (660 mg, 6.23 mmol) and Pd(dppf)CI2 . CH2CI2 (250 mg, 306 pmol). The mixture was heated to reflux for 24 h. Chloroform was added, the mixture was dried (magnesium sulfate), filtered and the solvent was removed in vacuum. Silicagel chromatography gave 790 mg (70 % yield) of the title compound.
LC-MS (Method 5): Rt = 2.68 min; MS (ESIpos): m/z = 544 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.072 (0.43), 1.141 (2.99), 1.155 (0.73), 1.264 (1.16), 1.281 (2.53), 1.299 (1.27), 1.391 (16.00), 2.079 (1.77), 2.1 13 (1.18), 2.342 (1.05), 2.354 (1.52), 2.366 (1.07), 2.441 (4.84), 2.480 (0.75), 2.495 (0.66), 2.499 (0.90), 2.503 (0.63), 3.334 (2.49), 3.344 (2.36), 3.488 (1.91 ), 4.069 (0.45), 4.087 (1.36), 4.103 (1.35), 6.904 (0.58), 6.917 (0.58), 7.194 (0.99), 7.229 (1.49), 8.241 (1.75), 8.250 (0.94), 8.264 (0.85). Compound 09.03
6-(5-ethoxy-2-methylpyridin-4-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]-1 H
benzimidazol-2-amine
Figure imgf000347_0001
Starting with tert-butyl 4-[(2-{[6-(5-ethoxy-2-methylpyridin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate (780 mg, 1.43 mmol) , Compound 09.03 was prepared analogously to the procedure for the preparation of Example 07.06
Yield: 500 mg (79 % of the title compound.
LC-MS (Method 5): Rt = 1.99 min; MS (ESIpos): m/z = 444 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.066 (0.71 ), 1.083 (1.41 ), 1.101 (0.74), 1.265 (3.53), 1.283 (7.33), 1.300 (3.82), 2.343 (4.05), 2.442 (16.00), 2.491 (1.40), 2.495 (2.68), 2.500 (3.55), 2.504 (2.68), 2.509 (1.41 ), 2.754 (4.84), 3.348 (3.72), 3.366 (3.58), 3.383 (2.82), 3.401 (1.80), 3.434 (7.34), 4.070 (1.38), 4.087 (4.27), 4.105 (4.28), 4.122 (1.41 ), 6.897 (1.89), 6.910 (1.95), 7.184 (3.19), 7.229 (4.01 ), 7.281 (1.14), 7.301 (1.42), 7.445 (0.55), 8.242 (7.80), 8.256 (2.66).
Compound 09.04
cyclopropylacetyl chloride
Figure imgf000347_0002
To a stirred solution of cyclopropyiacetic acid (930 μΙ, 10 mmol) in dichloromethane (4 mL) was added ethanedioyi dichloride (500 μΙ, 5.7 mmol) and the mixture was stirred at r.t. for 4 h. The mixture was carefully concentrated in vacuum to give 1.00 g of the title compound as crude product that was used without purification. Compound 10.01
4-iodo-2-methoxy-3-methyl py ridi ne
Figure imgf000348_0001
To a stirred solution of 2-fluoro-4-iodo-3-methylpyridine (250 mg, 1.05 mmol) in methanol (100 mL) was added lithium methoxide (1.00 g, 26.3 mmol), and the mixture was heated to reflux for 30 minutes. The reaction mixture was cooled down and water was added. A solid precipitated and was collected by filtration, washed with water, and dried to give 260 mg (99 % yield) of the title compound.
LC-MS (Method 5): Rt = 3.78 min; MS (ESIpos): m/z = 250 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.253 (1 1.45), 2.493 (0.56), 2.499 (0.76), 2.503 (0.56), 3.319 (15.44), 3.851 (16.00), 7.391 (1.89), 7.404 (2.16), 7.645 (1.63), 7.658 (1.48).
Compound 11.01
4-iodo-3-methyl-2-(propan-2-yloxy)pyridine
Figure imgf000348_0002
Sodium hydride (500 mg, 60 % in oil, 12.5 mmol) was carefully added to propan-2-ol (10 mL, 130 mmol). After stirring for 15 minutes, 2-fluoro-4-iodo-3-methylpyridine (250 mg, 1.05 mmol) was added, and the mixture was stirred at reflux for 30 minutes. The reaction mixture was cooled down and water (50 mL) was added. The mixture was extracted with diethyl ether, the organic phase was dried (sodium sulfate), filtered and the solvent was removed in vacuum to give 210 mg of the title compound as a crude product that was used without purification.
LC-MS (Method 5): Rt = 0.32 min; MS (ESIpos): m/z = 186 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.089 (0.80), 1.273 (0.76), 1.278 (7.25), 1.295 (7.12), 1.354 (0.43), 2.235 (5.53), 2.490 (0.85), 2.495 (1.64), 2.499 (2.12), 2.504 (1.45), 2.509 (0.68), 3.285 (1.16), 3.309 (16.00), 5.200 (0.48), 5.215 (0.64), 5.231 (0.47), 7.356 (1.00), 7.369 (1.11 ), 7.624 (0.72), 7.639 (0.71 ). Compound 12.01
6-(6-methylpyridin-2-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H-benzimidazol-2 amine hydrochloride
Figure imgf000349_0001
Starting with tert-butyl 4-[(2-{[6-(6-methylpyridin-2-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate (380 mg, 761 pmol), Compound 12.01 was prepared analogously to the procedure for the preparation of Compound 01.05.
Yield: 350 mg of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): R, = 1.03 min; MS (ESIpos): m/z = 400 [M+H]+
Compound 13.01
4-(6-methoxypyridin-3-yl)benzene-1 ,2-diamine
Figure imgf000349_0002
To a stirred solution of 5-bromo-2-methoxypyridine (350 μΙ, 95 % purity, 2.5 mmol) in 1- propanol (12 ml_) was added a potassium carbonate solution (3.8 ml_, 2.0 M, 7.6 mmol), 4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzene-1 ,2-diamine (660 mg, 90 % purity, 2.54 mmol) triphenylphosphine (66.6 mg, 254 pmol) and PdCI2(PPh3)2 (178 mg, 254 pmol) The mixture was heated to 120 *C in a sealed tube for 1 4 h. The mixture was filtered and the solvent was removed in vacuum. Aminophase-silicagel chromatography gave 500 mg (82 % yield) of the title compound.
LC-MS (Method 1 ): R, = 0.61 min; MS (ESIpos): m/z = 216 [M+H]+ 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.067 (4.34), 1.154 (0.74), 1.172 (1.54), 1.189 (0.76), 1.988 (2.57), 3.337 (16.00), 3.908 (2.00), 3.943 (0.72), 4.017 (0.59), 4.035 (0.59), 4.567 (1.80), 4.602 (2.04), 5.760 (2.04), 6.555 (3.35), 6.575 (4.68), 6.656 (2.41 ), 6.661 (2.63), 6.675 (1.69), 6.680 (1.82), 6.775 (4.27), 6.780 (3.75), 6.797 (3.17), 6.799 (2.96), 6.818 (3.24), 6.820 (2.94), 7.528 (0.77), 7.536 (0.79), 7.544 (1.44), 7.547 (2.01 ), 7.549 (1.90), 7.552 (1.40), 7.555 (1.73), 7.558 (1.65), 7.564 (2.49), 7.566 (1.92), 7.572 (1.83), 7.574 (1.71 ), 7.592 (1.50), 7.596 (2.56), 7.605 (1.07), 7.610 (1.42), 7.614 (2.27), 7.617 (1.25), 7.622 (2.84), 7.626 (3.62), 7.631 (1.69), 7.639 (1.24), 7.643 (1.96), 7.646 (1.49), 7.762 (2.51 ), 7.769 (2.45), 7.784 (2.32), 7.790 (2.37), 8.249 (2.86), 8.251 (3.09), 8.256 (3.04).
Compound 13.02
6-(6-methoxypyridin-3-yl)-N-t4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1H-benzimi
amine hydrochloride
Figure imgf000350_0001
Starting with tert-butyl 4-[(2-{[6-(6-methoxypyridin-3-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1-carboxylate (110 mg, 213 pmol), Compound 13.02 was prepared analogously to the procedure for the preparation of Compound 01.05.
Yield: 1 10 mg of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): Rt = 1.05 min; MS (ESIpos): m/z = 416 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.022 (5.63), 3.358 (1.08), 3.500 (0.69), 3.527 (16.00), 3.878 (9.50), 4.438 (0.98), 6.495 (1.32), 6.520 (1.35), 6.922 (0.98), 6.924 (1.01 ), 6.944 (1.04), 7.508 (0.90), 7.512 (1.01 ), 7.523 (1.65), 7.530 (2.24), 7.534 (1.97), 7.599 (1.14), 7.603 (0.93), 7.619 (0.87), 7.624 (0.91 ), 7.649 (1.47), 7.670 (1.07), 7.709 (1.98), 7.713 (1.43), 7.730 (2.31 ), 7.735 (1.66), 7.814 (0.90), 7.821 (0.81 ), 7.838 (1.86), 7.845 (0.92), 7.978 (0.78), 7.984 (0.77), 7.999 (0.69), 8.006 (0.73), 8.450 (1.07), 8.452 (1.04), 8.456 (1.02), 8.458 (1.04), 8.51 1 (1.03), 8.523 (1 .45), 8.535 (0.77). Compound 14.01
tert-butyl 4-[(2-{[6-(4-methoxypyridin-3-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 - arboxylate
Figure imgf000351_0001
To a stirred solution of tert-butyl 4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate (400 mg, 748 μιηοΙ) and 3-bromo-4-methoxypyridine (169 mg, 898 pmol) in dioxane (4 mL) and water (0.7 mL) was added sodium carbonate (238 mg, 2.25 mmol) and Pd(dppf)CI2 . CH2CI2 (91.7 mg, 1 12 μιτιοΙ). The mixture was heated to reflux for 24 h. Further 3-bromo-4-methoxypyridine (70 mg) was added and the mixture was heated to reflux for 24 h. Dichloromethane was added, the mixture was dried (magnesium sulfate), filtered and the solvent was removed in vacuum. Silicagel chromatography gave 16.0 mg (4% yield) of the title compound as a crude product that was used without further purification.
LC-MS (Method 2): R, = 1.20 min; MS (ESIpos): m/z = 516 [M+H]+
1H-NMR (400 MHz, CHLOROFORM-d) δ [ppm]: 1.261 (0.74), 1.468 (16.00), 2.330 (1.89), 3.394 (1.99), 3.444 (1.92), 3.927 (1.16), 6.927 (0.58), 6.941 (0.64), 6.953 (0.79), 6.965 (0.70), 7.081 (1.09), 8.283 (0.78), 8.296 (0.74), 8.483 (0.57), 8.497 (0.56), 8.540 (1.04).
Compound 14.02
6-(4-methoxypyridin-3-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]-1 H-benzim
amine hydrochloride
Figure imgf000352_0001
Starting with tert-butyl 4-[(2-{[6-(4-methoxypyridin-3-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate (173 mg, 336 pmol), Compound 14.02 was prepared analogously to the procedure for the preparation of Compound 01.05.
Yield: 203 mg of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): Rt = 0.87 min; MS (ESIpos): m/z = 416 [M+H]+
Compound 15.01
tert-butyl 4-[(2-{[6-(2-methoxypyridin-3-yl)-1 H-benzimidazol-2-yl]amino}pyridin yl)methyl]piperazine-1-carboxylate
Figure imgf000352_0002
To a stirred solution of tert-butyl 4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate (300 mg, 561 pmol) and 3-iodo-2-methoxypyridine (158 mg, 674 μιτιοΙ) in dioxane (3 mL) and water (0.55 ml_) was added sodium carbonate (178 mg, 1.68 mmol) and Pd(dppf)CI2 . CH2CI2 (68.8 mg, 84.2 μιηοΙ). The mixture was heated to reflux for 24 h. Dichloromethane was added, the mixture was dried (magnesium sulfate), filtered and the solvent was removed in vacuum. Silicagel chromatography gave 125 mg (43 % yield) of the title compound.
LC-MS (Method 2): F¾ = 1.03 min; MS (ESIpos): m/z = 400 [M+H]+
Compound 15.02
6-(2-methoxypyridin-3-yl)-N-[4-(piperazin-1-ylm
amine hydrochloride
Figure imgf000353_0001
Starting with tert-butyl 4-[(2-{[6-(2-methoxypyridin-3-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate (124 mg, 240 pmol), Compound 15.02 was prepared analogously to the procedure for the preparation of Compound 01.05.
Yield: 133 mg of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): R, = 1.03 min; MS (ESIpos): m/z = 416 [M+H]+
Compound 16.01
methyl 2-{[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)pyridin-2-yl]amino}'
benzimidazole-5-carboxylate
Figure imgf000353_0002
To a stirred solution of 1 H-imidazole (474 mg, 6.96 mmol) and di-1 H-imidazol-1- ylmethanethione (9.65 g, 90 % purity, 48.7 mmol) in dichloromethane (200 mL) was added 4- ({[tert-butyl(dimethyl)silyl]oxy}methyl)pyridin-2-amine (8.30 g, 34.8 mmol) , dissolved in dichloromethane (100 mL) at 0° C. The mixture was s tirred at r.t. for 18 h. Methyl 3,4- diaminobenzoate (8.95 g, 97 % purity, 52.2 mmol), dissolved in dichloromethane (10 mL), was added and the mixture was stirred at r.t. for 16 h. Water was added and the mixture was extracted with dichloromethane.
The organic phase was dried (sodium sulfate) and filtered. N,N'-dipropan-2-ylcarbodiimide (6.5 mL, 42 mmol) was added and the mixture was stirred at r.t. for 48 h. Saturated ammonium chloride solution was added, the mixture was stirred for 30 minutes and the mixture was extracted with dichloromethane. The organic phase was dried (sodium sulfate) and the solvent was removed in vacuum. Silicagel chromatography gave 18.3 g of the title compound as a crude product, that was used without further purification.
LC-MS (Method 2): R, = 1.49 min; MS (ESIpos): m/z = 413 [M+H]+
1H-NMR (300 MHz, DMSO-d6) δ [ppm]: 0.000 (0.95), 0.055 (1.12), 0.822 (0.79), 0.829 (1.03), 0.873 (16.00), 0.883 (2.39), 0.91 1 (4.69), 0.932 (4.64), 0.994 (2.85), 1.016 (2.90), 3.762 (4.24), 4.667 (2.03), 5.680 (0.82), 8.175 (0.58), 8.192 (0.54).
Compound 16.02
methyl 2-{[4-(hydroxymethyl)pyridin-2-yl]amino}-1 H-benzimidazole-6-carboxylate
Figure imgf000354_0001
To a stirred solution of methyl 2-{[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)pyridin-2-yl]amino}- 1 H-benzimidazole-6-carboxylate (18.3 g, approx. 31.9 mmol) in THF (780 mL), was added tetra-n-butylammoniumfluoride (48 mL, 1.0 M, 48 mmol), and the mixture was stirred at r.t. for 1 h. A sodium bicarbonate solution was added, the mixture was stirred for 30 minutes and the mixture was extracted with ethyl acetate. The organic phase was dried (sodium sulfate), filtered and the solvent was removed in vacuum. The solid was triturated with ethanol to give 4.30 g of the title compound.
LC-MS (Method 1 ): R, = 0.66 min; MS (ESIpos): m/z = 299 [M+H]+ 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.523 (0.90), 3.311 (16.00), 4.519 (5.40), 4.532 (5.60), 5.421 (1.89), 5.435 (4.13), 5.450 (1.83), 6.907 (2.02), 6.921 (2.10), 7.179 (4.42), 7.704 (1.10), 8.247 (3.52), 8.260 (3.44), 10.840 (0.74), 12.396 (1.46).
Compound 16.03
methyl 2-{[4-(chloromethyl)pyridin-2-yl]amino}-1 H-benzimidazole-6-carboxylate
Figure imgf000355_0001
To a suspension of methyl 2-{[4-(hydroxymethyl)pyridin-2-yl]amino}-1 H-benzimidazole-6- carboxylate (4.79 g, 16.1 mmol) in dichloromethane (70 mL) and DMF (100 mL) was added thionyl dichloride (2.3 mL, 32 mmol) and the mixture was stirred for 72 h. A solution of sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The organic phase was washed with water, dried (sodium sulfate), filtered and the solvent was removed in vacuum to give 4.46 g of the title compound as a crude product.
LC-MS (Method 1 ): Rt = 0.90 min; MS (ESIpos): m/z = 317 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.523 (1.18), 3.842 (16.00), 4.784 (7.77), 7.031 (1.30), 7.034 (1.26), 7.044 (1.25), 7.048 (1.17), 7.271 (2.54), 7.709 (0.95), 7.730 (0.79), 8.330 (2.10), 8.344 (1.97).
Compound 16.04
methyl 2-[(4-{[4-(tert-butoxycarbonyl)piperazin-1 -yl]methyl}pyridin-2-yl)amino]-1 H- benzimidazole-6-carboxylate
Figure imgf000356_0001
To a stirred solution of methyl 2-{[4-(chloromethyl)pyridin-2-yl]amino}-1 H-benzimidazole-6- carboxylate (2.00 g, 6.31 mmol) in DMF (120 mL) was added potassium carbonate (4.36 g, 31.6 mmol) and tert-butyl piperazine-1-carboxylate (2.35 g, 12.6 mmol). The mixture was stirred at r.t. for 14 h. Further tert-butyl piperazine-1-carboxylate (290 mg) was added and the mixture was stirred at r.t. for 14 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with half-saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silicagel chromatography gave a solid that was triturated with dichloromethane/hexane to LC-MS (Method 2): Rt = 1.27 min; MS (ESIpos): m/z = 467 [M+H]+
H-NMR (300 MHz, DMSO-d6) δ [ppm]: 1.393 (16.00), 1.417 (1.02), 2.354 (1.79), 2.369 (1.32), 3.500 (2.12), 3.838 (5.36), 6.941 (0.53), 7.158 (1.22), 8.264 (0.74), 8.281 (0.75), 12.382 (0.53).
Compound 16.05
2-[(4-{[4-(tert-butoxycarbonyl)piperazin-1 -yl]methyl}pyridin-2-yl)amino]-1 H- benzimidazole-6-carboxylic acid
Figure imgf000356_0002
To a stirred solution of methyl 2-[(4-{[4-(tert-butoxycarbonyl)piperazin-1 -yl]methyl}pyridin-2- yl)amino]-1 H-benzimidazole-6-carboxylate (12.0 g, 25.7 mmol) in methanol (380 mL, 9.5 mol) and THF (130 mL, 1.6 mol) was added an aqueous solution of sodium hydroxide (130 mL, 2.0 M, 260 mmol). The mixture was stirred at 70 for 14 h. The solution was cooled to room temperature, hydrochloric acid was added until pH 7 was reached and the solvent was removed in vacuum. Toluene and dichloromethane were added, the mixture was stirred for 10 minutes and the solvent was removed in vacuum. The solid was dried in a vacuum oven at 60Ό overnight, to give 26.4g (purity approx. 47%) of the title compound as a crude product that was used for the next step without purification.
LC-MS (Method 2): Rt = 0.66 min; MS (ESIpos): m/z = 453 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.396 (16.00), 3.361 (0.71 ), 3.409 (0.69), 7.252 (0.73), 7.696 (0.71 ), 7.700 (0.70), 7.717 (0.58), 7.721 (0.61 ), 8.293 (0.59), 8.306 (0.56).
Compound 16.06
tert-butyl 4-({2-[(6-{[(ethanimidoylamino)oxy]carbonyl}-1H-benzimidazol-2
yl)amino]pyridin-4-yl}methyl)piperazine-1 -carboxylate
Figure imgf000357_0001
To a stirred solution of 2-[(4-{[4-(tert-butoxycarbonyl)piperazin-1 -yl]methyl}pyridin-2-yl)amino]- 1 H-benzimidazole-6-carboxylic acid (26.4 g, approx. 25.7 mmol) in DMA (250 mL) was added DIPEA (18 mL, 100 mmol), (IZ)-N'-hydroxyethanimidamide (2.85 g, 38.5 mmol) and PyBOP (20.0 g, 38.5 mmol). The mixture was stirred at r.t. for 1 h. An aqueous sodium bicarbonate solution was added, the mixture was stirred for 15 minutes and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate), filtered and the solvent was removed in vacuum to give a solid. The solid was triturated with dichloromethane to give 12.1 g of the title compound.
LC-MS (Method 2): R, = 1.05 min; MS (ESIpos): m/z = 509 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.172 (0.56), 1.394 (16.00), 1.822 (4.66), 1.986 (0.98), 2.344 (0.81 ), 2.357 (1.19), 2.369 (0.85), 3.324 (4.96), 3.336 (0.82), 3.348 (0.97), 3.362 (0.65), 5.755 (3.12), 7.193 (0.72), 8.258 (0.74), 8.272 (0.71 ). Compound 16.07
6-(3-methyl-1,2,4-oxadiazol-5-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride
Figure imgf000358_0001
Starting with tert-butyl 4-[(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate (8.30 g, 16.9 mmol), Compound 16.07 was prepared analogously to the procedure for the preparation of Compound 01.05.
Yield: 8.50 g of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): R, = 0.92 min; MS (ESIpos): m/z = 391 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.952 (0.54), 2.428 (15.44), 2.938 (0.58), 3.160 (16.00), 3.331 (1.01 ), 3.352 (1.18), 3.444 (2.47), 3.455 (1.91 ), 3.466 (1.15), 3.560 (3.34), 7.585 (2.37), 7.823 (1.72), 7.844 (2.03), 8.037 (1.93), 8.041 (1.88), 8.058 (1.49), 8.063 (1.63), 8.341 (2.28), 8.344 (2.31 ), 8.536 (1.41 ), 8.550 (1.38).
Compound 16.08
tert-butyl (2R,5S)-4-[(2-aminopyridin-4-yl)methyl]-2,5-dimethylpiperazine-1 -carboxylate
Figure imgf000358_0002
To a stirred suspension of 4-(bromomethyl)pyridin-2-amine hydrobromide (2.00 g, 7.46 mmol) in acetonitrile (16 mL) was added potassium carbonate and tert-butyl (2R,5S)-2,5- dimethylpiperazine-1 -carboxylate (1.76 g, 8.21 mmol). The mixture was stirred at r.t. for 14 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with half-saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silicagel chromatography gave 1.72 g (65 % yield) of the title compound.
LC-MS (Method 2): F¾ = 1.18 min; MS (ESIpos): m/z = 321 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.874 (1.89), 0.890 (1.97), 1.160 (2.09), 1 .177 (2.13), 1.381 (1.15), 1.389 (16.00), 5.805 (1.23), 7.796 (0.77), 7.809 (0.78).
Compound 16.09
methyl 2-[(4-{[(2S,5R)-4-(tert-butoxycarbonyl)-2,5-dimethylpiperazin-1 -yl]methyl}pyridin- 2-yl)amino]-1 H-benzimidazole-6-carboxylate
Figure imgf000359_0001
To a stirred solution of 1 H-imidazole (72.2 mg, 1.06 mmol) and di-1 H-imidazol-1- ylmethanethione (1.26 g, 90 % purity, 6.37 mmol) in dichloromethane (45 mL) was added tert- butyl (2R,5S)-4-[(2-aminopyridin-4-yl)methyl]-2,5-dimethylpiperazine-1 -carboxylate (1.70 g, 5.31 mmol), dissolved in dichloromethane (25 mL) at 0°C. The mixture was stirred at r.t. for 14 h. Methyl 3,4-diaminobenzoate (1.36 g, 97 % purity, 7.96 mmol), dissolved in dichloromethane (30 mL) was added and the mixture was stirred at r.t. for 2 h. Water was added and the mixture was extracted with dichloromethane.
The organic phase was dried (sodium sulfate) and filtered. N,N'-dipropan-2-ylcarbodiimide (1.18 mL, 7.4 mmol) was added. The mixture was stirred at r.t. for 14 h. Further Ν,Ν'-dipropan- 2-ylcarbodiimide (0.42 mL, 2.6 mmol) was added and the mixture was stirred at r.t. for 14 h. Saturated ammonium chloride solution was added, the mixture was stirred for 30 minutes and was extracted with dichloromethane. Aminophase-silicagel chromatography followed by silicagel chromatography gave 564 mg (21 % yield) of the title compound.
LC-MS (Method 2): R, = 1.41 min; MS (ESIpos): m/z = 495 [M+H]+
1 H-NMR (600 MHz, DMSO-d6) δ [ppm]: 0.921 (2.33), 0.932 (2.35), 1.227 (2.34), 1.238 (2.33), 1.398 (16.00), 3.448 (0.76), 3.835 (5.47), 7.262 (0.83), 8.250 (0.76), 8.259 (0.74). Compound 16.10
2-[(4-{[(2S,5R)-4-(tert^utoxycarbonyl)-2,5-dimethylpiperazin-1-yl]methyl}pyridin-2- yl)amino]-1H-benzimidazole-6-carboxylic acid
Figure imgf000360_0001
To a stirred solution of methyl 2-[(4-{[(2S,5R)-4-(tert-butoxycarbonyl)-2,5-dimethylpiperazin-1- yl]methyl}pyridin-2-yl)amino]-1 H-benzimidazole-6-carboxylate (560 mg, 1 .13 mmol) in methanol (17 mL) and THF (5.6 mL) was added an aqueous solution of sodium hydroxide (5.7 mL, 2.0 M, 1 1 mmol). The mixture was stirred at 70 *C for 14 h. The solution was cooled to room temperature, hydrochloric acid was added until pH 7 was reached and the solvent was removed in vacuum. Toluene and dichloromethane were added, the mixture was stirred for 10 minutes and the solvent was removed in vacuum. The solid was dried in a vacuum oven at 60Ό overnight, to give 1.15 g (purity approx. 47%) of the title compound as a crude product that was used for the next step without purification.
LC-MS (Method 2): R, = 0.74 min; MS (ESIpos): m/z = 481 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.916 (1.78), 0.933 (1.81 ), 0.980 (0.75), 0.997 (0.79), 1.227 (1.90), 1.244 (1.92), 1.394 (16.00), 8.205 (0.83), 8.218 (0.78).
Compound 16.11
tert-butyl (2R,5S)-4-({2-[(6-{[(ethanimidoylamino)oxy]carbonyl}-1 H-benzimidazol-2 yl)amino]pyridin-4-yl}methyl)-2,5-dimethylpiperazine-1 -carboxylate
Figure imgf000360_0002
Starting with 2-[(4-{[(2S,5R)-4-(tert-butoxycarbonyl)-2,5-dimethylpiperazin-1 -yl]methyl}pyridin- 2-yl)amino]-1 H-benzimidazole-6-carboxylic acid (1.15 g, approx. 1.12 mmol) and (1Ζ)-Ν'- hydroxyethanimidamide (124 mg, 1.68 mmol), Compound 16.1 1. was prepared analogously to the procedure for the preparation of Compound 16.06.
Yield: 508 mg of the title compound.
LC-MS (Method 2): R, = 1.21 min; MS (ESIpos): m/z = 537 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.921 (1.98), 0.937 (2.00), 1.225 (2.06), 1.242 (2.1 1 ), 1.400 (16.00), 1.819 (4.52), 5.758 (2.55), 8.248 (0.85), 8.261 (0.82).
Compound 16.12
N-(4-{[(2S,5R)-2,5-dimethylpiperazin-1-yl]methyl}pyridin-2-yl)-6-(3-methyl^
oxadiazol-5-yl)-1 H-benzimidazol-2-amine hydrochloride
Figure imgf000361_0001
Starting with tert-butyl (2R,5S)-2,5-dimethyl-4-[(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate (360 mg, 694 pmol), Compound 16.12 was prepared analogously to the procedure for the preparation of Compound 01.05.
Yield: 392 mg of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): R, = 1.01 min; MS (ESIpos): m/z = 419 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.218 (4.02), 1.234 (4.10), 2.433 (16.00), 3.161 (0.73), 5.759 (10.36), 7.540 (1.48), 7.81 1 (1.53), 7.832 (1.73), 8.044 (1.83), 8.048 (1.82), 8.065 (1.47), 8.069 (1.54), 8.332 (2.19). Compound 16.13
tert-butyl (3R)-4-[(2-aminopyridin-4-yl)methyl]-3-methylpiperazine-1-carboxylate
Figure imgf000362_0001
To a stirred suspension of 4-(bromomethyl)pyridin-2-amine hydrobromide (2.00 g, 7.46 mmol) in acetonitrile (16 ml_) was added potassium carbonate and tert-butyl (3R)-3-methylpiperazine- 1 -carboxylate (1.64 g, 8.21 mmol). The mixture was stirred at r.t. for 14 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with half- saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Aminophase silicagel chromatography gave 1.41 g (55 % yield) of the title compound. LC-MS (Method 2): R, = 1.07 min; MS (ESIpos): m/z = 307 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.913 (0.82), 0.929 (0.82), 0.995 (1.59), 1.01 1 (1.61 ), 1.386 (16.00), 3.307 (1.84), 5.751 (1.86), 5.784 (0.94), 6.401 (0.75), 7.793 (0.57), 7.807 (0.57).
Compound 16.14
methyl 2-[(4-{[(2R)-4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl]methyl}pyridin-2- yl)amino]-1 H-benzimidazole-6-carboxylate
Figure imgf000362_0002
To a stirred solution of 1 H-imidazole (62.2 mg, 914 pmol) and di-1 H-imidazol-1 - ylmethanethione (1.18 g, 90 % purity, 5.94 mmol) in dichloromethane (35 mL) was added tert- butyl (3R)-4-[(2-aminopyridin-4-yl)methyl]-3-methylpiperazine-1 -carboxylate (1.40 g, 4.57 mmol), dissolved in dichloromethane (35 mL) at 0° C . The mixture was stirred at r.t. for 14 h. Further di-1 H-imidazol-1 -ylmethanethione (1.18 g, 90 % purity, 5.94 mmol) was added and the mixture was stirred at r.t. for 14 h. Methyl 3,4-diaminobenzoate (2.04 g, 97 % purity, 1 1.9 mmol), dissolved in dichloromethane (30 mL) was added and the mixture was stirred at r.t. for 2 h. Water was added and the mixture was extracted with dichloromethane.
The organic phase was dried (sodium sulfate) and filtered. N,N'-dipropan-2-ylcarbodiimide (1.03 mL, 6.4 mmol) was added. The mixture was stirred at r.t. for 72 h. Further N,N'-dipropan- 2-ylcarbodiimide (0.37 mL, 2.3 mmol) was added and the mixture was stirred at r.t. for 14 h. Saturated ammonium chloride solution was added, the mixture was stirred for 30 minutes and was extracted with dichloromethane. Aminophase-silicagel chromatography gave 583 mg of the title compound as a crude product, that was used without further purification.
LC-MS (Method 2): R, = 1.31 min; MS (ESIpos): m/z = 481 [M+H]+
1H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.026 (2.36), 1.039 (2.36), 1.394 (16.00), 3.839 (6.00), 5.752 (3.00), 7.190 (0.86), 8.253 (0.81 ), 8.264 (0.76).
Compound 16.15
2-[(4-{[(2R)-4-(tert-butoxycarbonyl)-2-methylpiperazin-1 -yl]methyl}pyridin
1 H-benzimidazole-6-carboxylic acid
Figure imgf000363_0001
To a stirred solution of methyl 2-[(4-{[(2R)-4-(tert-butoxycarbonyl)-2-methylpiperazin-1- yl]methyl}pyridin-2-yl)amino]-1 H-benzimidazole-6-carboxylate (580 mg, 1.21 mmol) in methanol (18 mL, 440 mmol) and THF (6.0 mL, 74 mmol) was added an aqueous solution of sodium hydroxide (6.0 mL, 2.0 M, 12 mmol). The mixture was stirred at 70 for 14 h. The solution was cooled to room temperature, hydrochloric acid was added until pH 7 was reached and the solvent was removed in vacuum. Toluene and dichloromethane were added, the mixture was stirred for 10 minutes and the solvent was removed in vacuum. The solid was dried in a vacuum oven at 60Ό overnight to give 1. 4 g (purity: approx.40%) of the title compound as a crude product that was used for the next step without purification.
LC-MS (Method 2): Rt = 0.79 min; MS (ESIpos): m/z = 467 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.396 (16.00), 5.758 (3.59), 7.707 (0.70), 7.71 1 (0.70), 7.728 (0.58), 7.732 (0.61 ). Compound 16.16
tert-butyl (3R)-4-({2-[(6-{[(ethanimidoylamino)oxy]carbonyl}-1 H-benzimidazol-2 yl)amino]pyridin-4-yl}methyl)-3-methylpiperazine-1 -carboxylate
Figure imgf000364_0001
To a stirred solution of 2-[(4-{[(2R)-4-(tert-butoxycarbonyl)-2-methylpiperazin-1- yl]methyl}pyridin-2-yl)amino]-1 H-benzimidazole-6-carboxylic acid (1.40 g, approx. 1.20 mmol) in DMA (12 mL) was added DIPEA (840 μΙ, 4.8 mmol), (I Z)-N'-hydroxyethanimidamide (133 mg, 1.80 mmol) and PyBOP (937 mg, 1.80 mmol). The mixture was stirred at room temperature for 1 h. A sodium bicarbonate solution was added, the mixture was stirred for 15 minutes and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate), filtered and the solvent was removed in vacuum. Aminophase-Silicagel chromatography gave 514 mg of the title compound.
LC-MS (Method 2): F¾ = 1.12 min; MS (ESIpos): m/z = 523 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.026 (2.27), 1.036 (1.39), 1.042 (2.35), 1.054 (1.99), 1.071 (0.87), 1.393 (16.00), 1.821 (5.17), 5.755 (2.41 ), 7.199 (1.00), 8.249 (0.93), 8.262 (0.88).
Compound 16.17
tert-butyl (3R)-3-methyl-4-[(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazine-1-carboxylate
Figure imgf000365_0001
A mixture of tert-butyl (3R)-4-({2-[(6-{[(ethanimidoylamino)oxy]carbonyl}-1 H-benzimidazol-2- yl)amino]pyridin-4-yl}methyl)-3-methylpiperazine-1-carboxylate (510 mg, 976 pmol) and sodium acetate (88.1 mg, 1.07 mmol) in 1 -propanol (20 mL) and water (10 mL) was heated to 100° C for 40 h. The solvent was removed in vacuum. Aminophase-silicagel chromatography gave 310 mg (57 % yield) of the title compound.
LC-MS (Method 2): R, = 1.33 min; MS (ESIpos): m/z = 505 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.029 (2.19), 1.045 (2.23), 1.396 (16.00), 2.085 (3.57), 2.398 (5.85), 7.206 (0.89), 8.273 (0.76), 8.286 (0.73).
Compound 16.18
6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-N-(4-{[(2R)-2-methylpiperazin-1 -yl]methyl}pyridin-2-yl)- 1 H-benzimidazol-2-amine hydrochloride
Figure imgf000365_0002
Starting with tert-butyl (3R)-3-methyl-4-[(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol- 2-yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate (300 mg, 595 pmol), Compound 16.18 was prepared analogously to the procedure for the preparation of Compound 01.05. Yield: 310 mg of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): R, = 0.99 min; MS (ESIpos): m/z = 405 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.473 (1.02), 2.432 (16.00), 3.332 (0.67), 3.371 (0.83), 3.486 (0.73), 3.488 (0.73), 3.498 (0.72), 5.755 (1.37), 7.575 (1.61 ), 7.815 (1.54), 7.836 (1.75), 8.042 (1.77), 8.046 (1.80), 8.063 (1.40), 8.067 (1.49), 8.335 (2.06), 8.339 (2.02), 8.527 (0.95), 8.540 (0.87).
Compound 16.19
tert-butyl 4-[(2-aminopyridin-4-yl)methyl]-3,3-dimethylpiperazine-1-carboxylate
Figure imgf000366_0001
To a stirred solution of 4-(bromomethyl)pyridin-2-amine hydrobromide (2.50 g, 9.33 mmol) in DMF (30 ml_) was added potassium carbonate (5.16 g, 37.3 mmol) and tert-butyl 3,3- dimethylpiperazine-1 -carboxylate (2.40 g, 1 1.2 mmol). The mixture was stirred at r.t. for 14 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with half-saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Aminophase-silicagel chromatography followed by silicagel chromatography gave 2.20 g (74 % yield) of the title compound.
LC-MS (Method 2): R, = 1.16 min; MS (ESIpos): m/z = 321 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.004 (9.22), 1.027 (0.55), 1.042 (0.53), 1 .390 (16.00), 2.276 (0.67), 3.126 (0.69), 3.335 (3.19), 5.788 (1.25), 6.414 (0.98), 6.423 (0.68), 6.435 (0.58), 7.775 (0.78), 7.777 (0.73), 7.788 (0.73), 7.790 (0.73). Compound 16.20
4-(3-methyl-1,2,4-oxadiazol-5-yl)benzene-1 ,2-diamine
Figure imgf000367_0001
To a stirred suspension of methyl 3,4-diaminobenzoate (10.0 g, 60.2 mmol) and N- hydroxyethanimidamide (10.6 g, 95 % purity, 135 mmol) in dioxane (20 mL) was added caesium carbonate (19.6 g, 60.2 mmol) and the mixture was stirred at 110° C for 2 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried (sodium sulfate), filtered and the solvent was removed in vacuum to give a solid that was triturated with methanol to give 8.00 g (70 % yield) of the title compound.
LC-MS (Method 2): R, = 0.67 min; MS (ESIpos): m/z = 191 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.308 (16.00), 4.831 (2.74), 5.429 (3.11 ), 6.583 (2.69), 6.603 (2.81 ), 7.148 (1.50), 7.153 (1.72), 7.169 (1.30), 7.174 (1.62), 7.212 (3.04), 7.217 (2.53).
Compound 16.21
N-{4-[(2,2-dimethylpiperazin-1 -yl)methyl]pyridin-2-yl}-6-(3-methyl-1,2,4-oxadiazol-5-yl)- 1 H-benzimidazol-2-amine hydrochloride
Figure imgf000367_0002
Starting with tert-butyl 3,3-dimethyl-4-[(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol- 2-yl]amino}pyridin-4-yl)methyl]piperazine-1-carboxylate (980 mg, 1.89 mmol), Compound 16.21 was prepared analogously to the procedure for the preparation of Compound 01.05. Yield: 1.06 g of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): R, = 1.07 min; MS (ESIpos): m/z = 419 [M+H]+ 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.431 (16.00), 2.523 (0.93), 7.616 (1.03), 7.824 (1.32), 7.845 (1.53), 8.047 (1.81 ), 8.051 (1.86), 8.068 (1.46), 8.072 (1.56), 8.342 (1.90).
Compound 16.22
2-(4-ethylpyridin-2-yl)-1H-isoindole-1 ,3(2H)-dione
Figure imgf000368_0001
To a stirred solution of 4-ethylpyridin-2-amine (20.0 g, 164 mmol) in dichloromethane (600 mL) was added benzene-1 ,2-dicarbonyl dichloride (26 mL, 180 mmol), followed by triethylamine (60 mL, 430 mmol) with water bath cooling. The mixture was stirred at r.t. for 1 h. The mixture was washed with water, the organic phase was separated, dried (magnesium sulfate), filtered and the solvent was removed in vacuum. Silicagel chromatography gave 37.0 g (90 % yield) of the title compound.
LC-MS (Method 5): R, = 3.21 min; MS (ESIpos): m/z = 253 [M+H]+
Compound 16.23
(rac)-2-{4-[1 -bromoethyl]pyridin-2-yl}-1 H-isoindo!e-1 ,3(2H)-dione
Figure imgf000368_0002
To a stirred suspension of 2-(4-ethylpyridin-2-yl)-1 H-isoindole-1 ,3(2H)-dione (24.7 g, 97.9 mmol) and NBS (19.0 g, 107 mmol) in dichloroethane (300 mL) was added AIBN (800 mg, 4.87 mmol), and the mixture was stirred at reflux for 1 h. The mixture was washed with water, the organic phase was separated, dried (magnesium sulfate), filtered and the solvent was removed in vacuum. Diethyl ether was added and the mixture was stirred at r.t. for 19 h. A precipitated solid was collected by filtration to give 27.8 g (86 % yield) of the title compound. LC-MS (Method 5): Rt = 3.34 min; MS (ESIpos): m/z = 331 [M+H]+ Compound 16.24
(rac)-tert-butyl 4-[1-{2-[(2-{[4-(tert-butoxycarbonyl)piperazin-1 - yl]carbonyl}benzoyl)amino]pyridin-4-yl}ethyl]piperazine-1 -carboxylate
Figure imgf000369_0001
To a stirred suspension of (rac)-2-{4-[1 -bromoethyl]pyridin-2-yl}-1 H-isoindole-1 ,3(2H)-dione (41.7 g, 126 mmol)in acetonitrile (200 mL) was added potassium carbonate (22.0 g, 159 mmol) and tert-butyl piperazine-1 -carboxylate (53.0 g, 285 mmol). The mixture was stirred at 75° C for 1 h. The solvent was removed in vacuum. Water was added and the mixture was extracted with diethyl ether. The organic phase was washed with halfsaturated sodium chloride solution, dried (magnesium sulfate) and the solvent was removed in vacuum to give 91.6 g of the title compound as a crude product, that was used for the next step without further purification.
LC- S (Method 5): Rt = 3.36 min; MS (ESIpos): m/z = 623 [M+H]+
Compound 16.25
(rac)-tert-butyl 4-[1-(2-aminopyridin-4-yl)ethyl]piperazine-1 -carboxylate
Figure imgf000369_0002
To a stirred solution of (rac)-tert-butyl 4-[1-{2-[(2-{[4-(tert-butoxycarbonyl)piperazin-1- yl]carbonyl}benzoyl)amino]pyridin-4-yl}ethyl]piperazine-1-carboxylate (91.6 g, approx. 1 13 mmol) in dioxane (350 mL) was added hydrazine hydrate (50 mL, 1.0 mol), and the mixture was stirred at reflux for 3 h. The mixture was cooled to r.t., and a precipitate was removed by filtration. Diethyl ether was added and the mixture was washed with water. The organic phase was separated, dried (magnesium sulfate), filtered and the solvent was removed in vacuum. Silicagel chromatography gave 32.35 g of the title compound.
LC-MS (Method 5): Rt = 0.71 min; MS (ESIpos): m/z = 307 [M+H]+
Compound 16.26
(rac)-6-(3-methyl-1,2,4-oxadiazol-5-yl)-N-{4-[1 -(piperazin-1 -yl)ethyl]pyridin-2-yl}-1 H- benzimidazol-2-amine hydrochloride
Figure imgf000370_0001
x HCI
Starting with tert-butyl (rac)-4-[1-(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazine-1-carboxylate (20.1 g, 39.8 mmol) , Compound 16.26 was prepared analogously to the procedure for the preparation of Compound 01.05.
Yield: 23.3 g of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): Rt = 1.01 min; MS (ESIpos): m/z = 405 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.432 (16.00), 7.568 (1.28), 7.818 (1.34), 7.839 (1.61 ), 8.045 (1 .77), 8.048 (1.67), 8.066 (1.34), 8.070 (1.39), 8.338 (1.75), 8.342 (1.72).
Compound 16.27
6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-N-{4-[(1R or 1S)-1 -(piperazin-1 -yl)ethyl]pyridin-2-yl}-1H- benzimidazol-2-amine hydrochloride
Figure imgf000371_0001
Starting with tert-butyl 4-[(1 R or 1 S)-1-(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol- 2-yl]amino}pyridin-4-yl)ethyl]piperazine-1 -carboxylate (100 mg, 198 pmol), Compound 16.27 was prepared analogously to the procedure for the preparation of Compound 01.05.
Yield: 100 mg of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): R, = 1.02 min; MS (ESIpos): m/z = 405 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.085 (0.81 ), 1.104 (0.65), 1.678 (1.45), 2.434 (16.00), 3.367 (0.61 ), 3.385 (0.67), 3.452 (0.88), 5.760 (0.52), 7.583 (1.64), 7.830 (1.64), 7.851 (1.88), 8.057 (2.08), 8.060 (1.97), 8.078 (1.56), 8.082 (1.62), 8.347 (2.10), 8.350 (2.06), 8.573 (1.12), 8.586 (1.05).
Compound 16.28
N-[4-({[tert^utyl(dimethyl)silyl]oxy}methyl)pyridin-2-yl]-6-(3-methyl-1 ,2,4-oxadiazol-5 1 H-benzimidazol-2-amine
Figure imgf000371_0002
To a stirred solution of 1 H-imidazole (143 mg) and di-1 H-imidazol-1 -ylmethanethione (2.18 g, 90 % purity) in dichloromethane (10 mL) was added 4-({[tert- butyl(dimethyl)silyl]oxy}methyl)pyridin-2-amine (2.50 g, see Compound 04.03), dissolved in dichloromethane (20 mL) at 0° C. The mixture was st irred at r.t. for 18 h. 4-(3-methyl-1 ,2,4- oxadiazol-5-yl)benzene-1 ,2-diamine (2.06 g, 97 % purity; see Compound 16.20), dissolved in dichloromethane (20 mL), was added and the mixture was stirred at r.t. for 16 h. Water was added and the mixture was extracted with dichloromethane. The organic phase was separated and filtered through a silicagel to give 4.7 g of a solid that was dissolved in dichloromethane ( 50 mL). N,N'-dipropan-2-ylcarbodiimide (3.0 ml) was added and the mixture was stirred at r.t. for 16 h. Further N,N'-dipropan-2-ylcarbodiimide (3.0 ml) was added and the mixture was stirred for 3 h. The solvent was removed in vacuum. Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried (sodium sulfate), filtered and the solvent was removed in vacuum. Silicagel chromatography gave a solid that was triturated with ethanol to give 1.7 g of the title compound as a crude product, that was used without further purification.
LC-MS (Method 2): Rt = 1.52 min; MS (ESIpos): m/z = 436 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.150 (13.83), 0.970 (1.53), 0.978 (16.00), 2.424 (3.52), 4.777 (1.65).
Compound 16.29
(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4-yl)methanol
Figure imgf000372_0001
To a stirred solution of crude N-[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)pyridin-2-yl]-6-(3- methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2-amine (1.70 g) in THF (51 mL) and ethanol (17 mL), was added aqueous hydrochloric acid (5.8 ml, 2.0 M) and the solution was stirred for 1 h. Water was added and the mixture was extracted with ethyl acetate and hexane (1 : 1 mixture). The organic phase was removed. An aqueous 2 M solution of sodium hydroxide was added to the aqueous phase until pH 6.5 was reached, and the solution was extracted with ethyl acetate. The organic phase was dried (sodium sulfate), filtered and the solvent was removed in vacuum. The gummy material was suspended in chloroform and concentrated in vacuum for two times to give 2.2 g of the crude product, that was used for the next step without further purification. LC-MS (Method 2): Rt = 0.86 min; MS (ESIpos): m/z = 322 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.688 (16.00), 2.390 (12.03), 4.529 (4.87), 6.898 (1.15), 6.901 (1.15), 6.912 (1.17), 6.915 (1.15), 7.498 (1.28), 7.519 (1.51 ), 7.552 (0.99), 7.744 (1.31 ), 7.749 (1.31 ), 7.765 (1.08), 7.769 (1.09), 8.084 (1.35), 8.225 (1.78), 8.237 (1.77).
Compound 16.30
N-[4-(chloromethyl)pyridin-2-yl]-6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2-amine
Figure imgf000373_0001
To a suspension of crude (2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methanol (2.20 g) in dichloromethane (100 mL) was added thionyl dichloride (570 μΙ) and the mixture was stirred for 19 h. An aqueous solution of sodium bicarbonate was added and the mixture was extracted with a mixture of dichloromethane and methanol (10:1 ) and afterwards with a mixture of chloroform and methanol (5: 1 ). The organic phases were combined, dried (sodium sulfate), filtered and the solvent was removed in vacuum. The residue was triturated with ethanol to give 900 mg of the title compound.
LC-MS (Method 1 ): Rt = 0.89 min; MS (ESIpos): m/z = 340 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.155 (5.25), 2.399 (16.00), 4.793 (6.94), 5.134 (1.31 ), 7.049 (0.91 ), 7.062 (0.91 ), 7.272 (2.1 1 ), 8.352 (1.10), 8.365 (1.03). Compound 17.01
tert-butyl 4-[(2-{[6-({[(cyclopropylcarbonoimidoyl)amino]oxy}carbonyl)-1H-benzimidazol- 2-yl]amino}pyridin-4-yl)methyl]piperazine-1-carboxylate
Figure imgf000374_0001
To a stirred solution of 2-[(4-{[4-(tert-butoxycarbonyl)piperazin-1 -yl]methyl}pyridin-2-yl)amino]- 1 H-benzimidazole-6-carboxylic acid (18.6 g, approx. 19.3 mmol) in DMA (440 ml_) was added DIPEA (67 mL, 390 mmol), N'-hydroxycyclopropanecarboximidamide (5.80 g, 57.9 mmol) and PyBOP (15.1 g, 29.0 mmol). The mixture was stirred at r.t. for 14 h. Further PyBOP (15.1 g, 29.0 mmol) was added and the mixture was stirred at r.t. for 1 h. A sodium bicarbonate solution was added, the mixture was stirred for 15 minutes and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate), filtered and the solvent was removed in vacuum. Silicagel chromatography gave 7.50 g of the title compound.
LC-MS (Method 2): R, = 1.12 min; MS (ESIpos): m/z = 535 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.743 (0.52), 0.749 (0.69), 0.764 (0.53), 0.770 (0.72), 0.830 (0.73), 0.835 (0.76), 0.842 (0.81), 0.849 (0.68), 1.394 (16.00), 1.513 (0.46), 2.083 (4.98), 2.343 (0.85), 2.356 (1.30), 2.369 (0.95), 3.323 (3.31 ), 3.502 (1.61 ), 5.755 (1.09), 7.182 (0.88), 8.259 (0.78), 8.272 (0.74).
Compound 17.02
6-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-N-[4-(piperazin-1-ylmethyl)pyridin
benzimidazol-2-amine hydrochloride
Figure imgf000374_0002
Starting with tert-butyl 4-[(2-{[6-(3-cyclopropyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate (6.40 g, 12.4 mmol), Compound 17.02 was prepared analogously to the procedure for the preparation of Compound 01.05.
Yield: 6.1 1 g of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): R, = 1 .05 min; MS (ESIpos): m/z = 417 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.985 (0.72), 0.995 (2.52), 1.002 (2.55), 1.007 (2.47), 1.014 (2.28), 1.023 (0.89), 1.107 (0.89), 1.1 16 (2.27), 1.122 (1.78), 1.127 (1.43), 1.137 (2.33), 1.143 (1.84), 2.180 (0.86), 2.188 (0.94), 2.201 (1.58), 2.213 (0.81 ), 2.221 (0.74), 3.159 (1.66), 3.165 (16.00), 3.218 (1.33), 3.381 (2.84), 3.565 (2.36), 7.533 (2.14), 7.785 (1.79), 7.806 (2.06), 7.994 (2.23), 7.999 (1.96), 8.016 (1.68), 8.019 (1.65), 8.305 (2.44), 8.505 (1.49), 8.517 (1 .38).
Compound 17.03
methyl 2-[(4-{[(methylsulfonyl)oxy]methyl}pyridin-2-yl)amino]-1 H-benzimidazole-6- carboxylate
Figure imgf000375_0001
To a stirred solution of methyl 2-{[4-(hydroxymethyl)pyridin-2-yl]amino}-1 H-benzimidazole-6- carboxylate (4.30 g, 14.4 mmol) and DIPEA (25 mL, 140 mmol) in dichloromethane (71 mL), methanesulfonyl chloride (1.7 mL, 22 mmol) was added at 0 . The mixture was stirred at r.t. for 1 h. Further methanesulfonyl chloride (1.7 mL, 22 mmol) was added and the mixture was stirred at r.t. for 2 h. Aqueous sodium bicarbonate solution was added and the mixture was extracted with dichloromethane. The organic phase was dried (sodium sulfate), filtered, and the solvent was removed in vacuum to give 8.10 g of the title compound as a crude product that was used without further purification.
LC-MS (Method 2): R, = 1.11 min; MS (ESIneg): m/z = 375 [M-H]+ Compound 17.04
methyl 2-[(4-{[4-(2-chlorophenyl)piperazin-1 -yl]methyl}pyridin-2-yl)amino]-1 H- benzimidazole-6-carboxylate
Figure imgf000376_0001
To a stirred solution of methyl 2-[(4-{[(methylsulfonyl)oxy]methyl}pyridin-2-yl)amino]-1 H- benzimidazole-6-carboxylate (7.50 g, approx. 15.9 mmol) in DMF (120 mL) was added potassium carbonate (11.0 g, 79.7 mmol) and 1 -(2-chlorophenyl)piperazine (6.27 g, 31.9 mmol). The mixture was stirred at r.t. for 48 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with half-saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silicagel chromatography gave 1.65 g of the title compound.
LC-MS (Method 2): Rt = 1.41 min; MS (ESIpos): m/z = 477 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.156 (0.92), 1.174 (2.03), 1.192 (1 .05), 1.987 (3.67), 2.523 (1.28), 2.598 (2.17), 2.609 (1.96), 2.730 (7.89), 2.732 (7.36), 2.890 (9.81 ), 3.023 (2.71 ), 3.571 (4.51 ), 3.842 (16.00), 3.845 (5.51 ), 4.020 (0.79), 4.038 (0.80), 6.982 (0.90), 6.993 (0.85), 7.017 (0.89), 7.021 (0.95), 7.036 (1.45), 7.040 (1.55), 7.055 (1.06), 7.059 (1.1 1 ), 7.159 (1.28), 7.163 (1.32), 7.180 (1.94), 7.183 (1.64), 7.207 (2.42), 7.279 (1.26), 7.283 (1.30), 7.298 (1.23), 7.302 (1.51 ), 7.303 (1.31 ), 7.318 (0.81 ), 7.322 (0.93), 7.389 (2.38), 7.393 (2.27), 7.409 (2.01 ), 7.413 (1.82), 7.716 (0.67), 7.952 (1.30), 8.157 (0.67), 8.284 (1.38), 8.297 (1.33), 12.381 (1.03).
Compound 17.05
2-[(4-{[4-(2-chlorophenyl)piperazin-1-yl]methyl}pyridin-2-yl)amino]-1H-benzimidazole carboxylic acid
Figure imgf000377_0001
To a stirred solution of methyl 2-[(4-{[4-(2-chlorophenyl)piperazin-1-yl]methyl}pyridin-2- yl)amino]-1 H-benzimidazole-6-carboxylate (3.00 g, 6.29 mmol) in methanol (130 mL) and THF (42 mL) was added an aqueous solution of sodium hydroxide (42 mL, 2.0 M, 85 mmol). The mixture was stirred at 70 "C for 14 h. Water was ad ded and the mixture was stirred for 10 minutes and extracted with ethyl acetate. The organic phase was concentrated in vacuum to give 3.1 g of the title compound as a crude product that was used for the next step without purification.
LC-MS (Method 2): R, = 0.80 min; MS (ESIpos): m/z = 463 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.715 (1.69), 2.296 (1.01 ), 2.327 (0.61 ), 2.518 (4.70), 2.523 (3.85), 2.601 (8.03), 2.665 (0.92), 2.669 (1.02), 2.673 (0.79), 3.022 (10.32), 3.167 (16.00), 3.567 (15.58), 3.625 (0.72), 3.844 (0.68), 5.756 (9.34), 6.919 (5.22), 6.922 (5.09), 6.932 (5.24), 6.935 (5.17), 7.009 (3.42), 7.013 (3.64), 7.027 (5.24), 7.032 (5.50), 7.047 (4.23), 7.051 (4.39), 7.156 (5.01 ), 7.160 (5.24), 7.176 (7.20), 7.180 (6.40), 7.260 (1.62), 7.264 (1.80), 7.274 (5.92), 7.278 (6.21 ), 7.293 (5.97), 7.296 (6.19), 7.298 (5.25), 7.302 (1.47), 7.313 (3.23), 7.317 (3.23), 7.383 (8.45), 7.387 (8.10), 7.403 (8.10), 7.407 (7.33), 7.498 (3.31 ), 7.719 (3.82), 7.723 (3.74), 7.743 (3.49), 8.029 (2.18), 8.246 (8.37), 8.260 (7.70).
Compound 17.06
N-[({2-[(4-{[4-(2-chlorophenyl)piperazin-1-y
6-yl}carbonyl)oxy]cyclopropanecarboximidamide
Figure imgf000378_0001
To a stirred solution of 2-[(4-{[4-(2-chlorophenyl)piperazin-1 -yl]methyl}pyridin-2-yl)amino]-1 H- benzimidazole-6-carboxylic acid (200 mg, approx. 432 pmol) in DMA (5 mL) was added DIPEA (450 μΙ, 2.6 mmol), N'-hydroxycyclopropanecarboximidamide (38 μΙ, 97 % purity, 650 μιτιοΙ) and PyBOP (337 mg, 648 μιτιοΙ). The mixture was stirred at r.t. for 14 h. Further PyBOP (337 mg, 648 μιτιοΙ) and DIPEA (450 μΙ, 2.6 mmol) was added and the mixture was stirred at r.t. for 14 h. Water was added and a solid precipitated and was collected by filtration. A potassium carbonate solution was added to the solid and the mixture was extracted with dichloromethane / methanol (20:1 ). The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate), filtered and the solvent was removed in vacuum to give a solid. The solid was triturated with warm ethanol to give 160 mg of the title compound as a crude product that was used for the next step without purification.
LC-MS (Method 2): Rt = 1.25 min; MS (ESIneg): m/z = 543 [M-H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.732 (1.54), 0.744 (4.70), 0.751 (6.32), 0.759 (4.26), 0.766 (4.71 ), 0.771 (6.47), 0.780 (3.04), 0.787 (0.83), 0.795 (0.71 ), 0.800 (0.86), 0.816 (0.90), 0.823 (2.80), 0.831 (6.59), 0.837 (7.03), 0.844 (7.27), 0.850 (6.17), 0.855 (1.98), 0.863 (1.71 ), 1.090 (0.84), 1.107 (0.42), 1.481 (1.17), 1.494 (2.25), 1.503 (2.23), 1.507 (1.42), 1.515 (4.12), 1.523 (1.25), 1.528 (2.06), 1.536 (1.99), 1.549 (0.86), 2.322 (0.73), 2.327 (1.03), 2.331 (0.73), 2.523 (2.38), 2.664 (0.88), 2.669 (1.12), 2.674 (0.84), 3.024 (10.36), 3.391 (0.41 ), 3.481 (1.00), 3.573 (16.00), 6.242 (4.83), 6.959 (0.56), 6.976 (4.07), 6.989 (4.02), 7.017 (2.92), 7.021 (3.04), 7.036 (5.10), 7.039 (5.42), 7.055 (3.62), 7.058 (3.80), 7.159 (4.43), 7.163 (4.71 ), 7.180 (6.40), 7.183 (5.91 ), 7.236 (6.35), 7.279 (3.73), 7.283 (4.05), 7.298 (4.56), 7.302 (5.12), 7.318 (2.55), 7.322 (2.67), 7.389 (7.59), 7.393 (7.42), 7.408 (6.71 ), 7.412 (6.50), 7.810 (1.76), 8.174 (0.81 ), 8.277 (7.27), 8.290 (6.89), 10.774 (0.64), 12.323 (1.01 ). Compound 18.01
N-hydroxy-3-methylbutanimidamide
C H3 N H H
To a stirred mixture of 3-methylbutanenitrile (1.00 g, 98 % purity, 1 1.8 mmol) and hydroxylamine hydrochloride (1.84 g, 98 % purity, 25.9 mmol) in ethanol (12 mL) was added triethyl amine (3.8 mL, 27 mmol), and the mixture was heated to 75*0 for 14 h. The mixture was cooled to r.t. and a solid was removed by filtration. The solution was concentrated in vacuum. Ethyl acetate was added to the residue, the mixture was stirred and again, a solid was removed by filtration. The solution was concentrated in vacuum to give 0.60 g (44 % yield) of the title compound as a crude product that was used without further purification.
LC- S (Method 2): R, = 0.53 min; MS (ESIpos): m/z = 1 17 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.842 (15.79), 0.858 (16.00), 0.874 (0.68), 1.793 (2.16), 1.795 (2.19), 1.812 (4.22), 1.891 (0.72), 1.907 (1.14), 1.91 1 (0.68), 1.988 (0.44), 5.354 (1.03), 8.709 (0.81 ).
Compound 18.02
tert-butyl 4-[(2-{[6-({[(3-methylbutanimidoyl)amino]oxy}carbonyl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate
Figure imgf000379_0001
To a stirred solution of 2-[(4-{[4-(tert-butoxycarbonyl)piperazin-1 -yl]methyl}pyridin-2-yl)amino]- 1 H-benzimidazole-6-carboxylic acid (400 mg, approx. 407 pmol) in NMP (10 mL) was added DIPEA (1.4 mL, 8.1 mmol), crude N-hydroxy-3-methylbutanimidamide (142 mg) and PyBOP (635 mg, 1.22 mmol). The mixture was stirred at room temperature for 1 h. A sodium bicarbonate solution was added, the mixture was stirred for 15 minutes and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate), filtered and the solvent was removed in vacuum. Silicagel chromatography gave 190 mg of the title compound.
LC-MS (Method 2): R, = 1.23 min; MS (ESIpos): m/z = 551 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.929 (3.45), 0.944 (3.59), 1.396 (16.00), 1.713 (2.29), 1.721 (2.32), 1.729 (6.21 ), 1.738 (2.36), 1.746 (2.41 ), 1.989 (1.27), 2.348 (0.91 ), 2.360 (1.35), 2.372 (0.97), 2.992 (1.59), 2.998 (1.06), 3.001 (2.44), 3.008 (4.48), 3.012 (2.08), 3.015 (2.15), 3.018 (4.50), 3.021 (1.61 ), 3.025 (2.43), 3.028 (1.02), 3.034 (1.54), 3.351 (1.14), 3.505 (1.50), 7.187 (0.82), 8.259 (0.67), 8.273 (0.66).
Compound 18.03
tert-butyl 4-{[2-({6-[3-(2-methylpropyl)-1 ,2,4-oxadiazol-5-yl]-1 H-benzimidazoi-2- yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate
Figure imgf000380_0001
A mixture of tert-butyl 4-[(2-{[6-({[(3-methylbutanimidoyl)amino]oxy}carbonyl)-1 H-benzimidazol- 2-yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate (190 mg, 345 μιηοΙ) and sodium acetate (31.1 mg, 380 pmol) in 1-propanol (9 mL) and water (4.5 mL) was heated to 100°C for 14 h. The solvent was removed in vacuum. Silicagel chromatography gave 133 mg (72 % yield) of the title compound.
LC-MS (Method 2): R, = 1.51 min; MS (ESIpos): m/z = 533 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.974 (5.62), 0.991 (5.63), 1.396 (16.00), 1.712 (2.85), 1.721 (3.16), 1.729 (7.23), 1.737 (3.05), 1 .746 (2.79), 2.327 (0.58), 2.349 (1.21 ), 2.362 (1.74), 2.374 (1.25), 2.523 (1.53), 2.624 (1.61 ), 2.641 (1.47), 2.990 (1.91 ), 3.000 (3.08), 3.006 (5.08), 3.010 (3.00), 3.017 (5.10), 3.023 (2.87), 3.033 (1.74), 3.351 (1.62), 3.51 1 (2.00), 7.193 (0.59), 8.279 (0.76), 8.292 (0.71 ). Compound 18.04
6-[3-(2-methylpropyl)-1 ,2,4-oxadiazol-5-yl]-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride
Figure imgf000381_0001
Starting with tert-butyl 4-{[2-({6-[3-(2-methylpropyl)-1 ,2,4-oxadiazol-5-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate (133 mg, 250 pmol), Compound 18.04 was prepared analogously to the procedure for the preparation of Compound 01.05.
Yield: 139 mg of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): R, = 1.20 min; MS (ESIpos): m/z = 433 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.979 (15.36), 0.995 (16.00), 1.720 (5.48), 1.729 (5.52), 1.737 (14.93), 1.745 (5.57), 1.754 (5.66), 2.1 17 (0.80), 2.134 (1.03), 2.151 (0.79), 2.327 (0.57), 2.523 (1.24), 2.661 (4.05), 2.669 (1.10), 2.678 (3.82), 3.001 (4.02), 3.004 (1.82), 3.007 (2.55), 3.010 (5.85), 3.017 (1 1.15), 3.021 (4.90), 3.024 (4.97), 3.027 (11.03), 3.031 (3.65), 3.034 (5.78), 3.038 (2.36), 3.040 (1.75), 3.044 (3.67), 3.386 (1.76), 3.565 (1.12), 3.910 (0.94), 7.533 (1.44), 7.805 (1.18), 7.826 (1.36), 8.047 (1.40), 8.052 (1.43), 8.069 (1.17), 8.073 (1.22), 8.346 (1.72), 8.519 (0.95), 8.532 (0.93).
Compound 18.05
methyl 2-{[4-(piperazin-1 -ylmethyl)pyridin-2-yl]amino}-1 H-benzimidazole-6-carboxylate hydrochloride
Figure imgf000381_0002
Starting with methyl 2-[(4-{[4-(tert-butoxycarbonyl)piperazin-1 -yl]methyl}pyridin-2-yl)amino]-1 H- benzimidazole-6-carboxylate (5.00 g, 10.7 mmol), Compound 18.05 was prepared analogously to the procedure for the preparation of Compound 01.05.
Yield: 5.20g of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): R, = 0.92 min; MS (ESIpos): m/z = 367 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.518 (1.07), 2.523 (0.74), 3.892 (16.00), 7.543 (1.71 ), 7.726 (1.47), 7.747 (1.72), 7.949 (1.93), 7.952 (1.99), 7.969 (1.57), 7.973 (1.65), 8.258 (1.94), 8.261 (1.92), 8.514 (0.98), 8.527 (0.95).
Compound 18.06
methyl 2-[(4-{[4-(cyclopropylcarbonyl)piperazin-1 -yl]methyl}pyridin-2-yl)amino]-1 H- benzimidazole-6-carboxylate
Figure imgf000382_0001
To a stirred solution of methyl 2-{[4-(piperazin-1-ylmethyl)pyridin-2-yl]amino}-1 H- benzimidazole-6-carboxylate hydrochloride (2.10 g, approx. 5.21 mmol) in DMA (85 ml_) was added DIPEA (3.6 mL, 21 mmol), cyclopropanecarboxylic acid (650 μΙ, 95 % purity, 7.8 mmol) and PyBOP (4.07 g, 7.82 mmol). The mixture was stirred at room temperature for 14 h. A sodium bicarbonate solution was added, the mixture was stirred for 15 minutes and the mixture was extracted with dichloromethane / methanol (20:1 ). The organic phase was dried (sodium sulfate), filtered and the solvent was removed in vacuum. Silicagel chromatography followed by trituration with ethanol/water (1 : 1 ) gave 1.45 g of the title compound.
LC-MS (Method 2): Rt = 1.00 min; MS (ESIpos): m/z = 435 [M+H]+
H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.677 (0.96), 0.684 (2.29), 0.690 (1.36), 0.697 (1.07), 0.704 (2.77), 0.710 (2.23), 0.715 (2.35), 0.722 (2.34), 0.727 (2.83), 0.734 (1.28), 1.940 (0.57), 1.947 (0.59), 1 .959 (1.02), 1.971 (0.57), 1.979 (0.53), 2.327 (0.53), 2.367 (0.92), 2.442 (0.93), 2.523 (1.60), 3.527 (5.36), 3.703 (0.84), 3.841 (16.00), 6.959 (1.16), 6.971 (1.18), 7.192 (2.36), 7.700 (0.70), 8.273 (1.99), 8.287 (1.92). Compound 18.07
2-[(4-{[4-(cyclopropylcarbonyl)piperazin-1 -yl]methyl}pyridin-2-yl)amino]-1 H
benzimidazole-6-carboxylic acid
Figure imgf000383_0001
To a stirred solution of methyl 2-[(4-{[4-(cyclopropylcarbonyl)piperazin-1 -yl]methyl}pyridin-2- yl)amino]-1 H-benzimidazole-6-carboxylate (1.42 g, 3.27 mmol) in methanol (10 mL) and THF (26 mL) was added an aqueous solution of sodium hydroxide (15 mL, 2.0 M, 31 mmol). The mixture was stirred at 70 "C for 56 h. Hydrochloric acid was added until pH 7 was reached. The organic solvent was removed in vacuum and the aqueous mixture was lyophilized. The residue was dissolved in DMA (50 mL) and potassium carbonate (2.47 g, 17.9 mmol), cyclopropanecarboxylic acid (420 μΙ, 5.4 mmol) and HATU (1.77 g, 4.65 mmol) was added. The mixture was stirred at r.t. for 14 h. Water was added, the mixture was stirred for 30 minutes and the mixture was extracted with hexane. The aqueous phase was lyophilized to give 8.5 g (purity approx. 17 %) of the title compound as a crude product, that was used without purification.
LC-MS (Method 2): Rt = 0.59 min; MS (ESIpos): m/z = 421 [M+H]+
Compound 18.08
N-[({2-[(4-{[4-(cyclopropylcarbonyl)piperazin-1 -yl]methyl}pyridin-2-yl)amino]-1 H- benzimidazol-6-yl}carbonyl)oxy]-3-methylbutanimidamide
Figure imgf000383_0002
To a stirred solution of 2-[(4-{[4-(cyclopropylcarbonyl)piperazin-1 -yl]methyl}pyridin-2-yi)amino]- 1 H-benzimidazole-6-carboxylic acid (1.20 g, approx 485 pmol) in DMA (15 mL) was added DIPEA (1.7 mL, 9.7 mmol), crude N-hydroxy-3-methylbutanimidamide (169 mg, approx. 1.46 mmol) and PyBOP (757 mg, 1.46 mmol). The mixture was stirred at room temperature for 1 h. Further crude N-hydroxy-3-methylbutanimidamide (60 mg) and PyBOP (251 mg) was added and the mixture was stirred at r.t. for 56 h. A sodium bicarbonate solution was added, the mixture was stirred for 15 minutes and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate), filtered and the solvent was removed in vacuum. Silicagel chromatography gave 134 mg of the title compound.
LC-MS (Method 2): R, = 1.01 min; MS (ESIpos): m/z = 519 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.666 (0.50), 0.678 (1.55), 0.685 (3.64), 0.690 (2.19), 0.697 (1.70), 0.704 (4.39), 0.709 (3.70), 0.714 (3.96), 0.721 (3.64), 0.726 (4.32), 0.733 (1.95), 0.745 (0.44), 0.928 (15.47), 0.943 (16.00), 1.254 (0.54), 1.931 (0.44), 1.944 (0.93), 1.951 (1.02), 1.956 (0.94), 1.964 (2.24), 1.969 (2.08), 1.975 (2.46), 1.988 (5.61 ), 2.007 (1.1 1 ), 2.021 (1.01 ), 2.038 (0.62), 2.043 (0.48), 2.323 (0.75), 2.327 (1.05), 2.331 (0.87), 2.337 (0.65), 2.365 (1.56), 2.444 (1.59), 2.518 (3.06), 2.523 (2.10), 2.665 (0.64), 2.669 (0.89), 2.673 (0.64), 3.498 (1.54), 3.528 (6.67), 3.704 (1.47), 6.347 (0.62), 6.389 (1.08), 6.965 (1 .37), 7.200 (3.74), 7.351 (0.68), 7.372 (0.75), 7.842 (0.72), 7.863 (0.62), 8.098 (0.72), 8.222 (1 .15), 8.270 (2.80), 8.283 (2.66), 10.830 (0.76), 12.307 (1.30), 12.330 (0.82).
Compound 19.01
N-hydroxycyclopentanecarboximidamide
Figure imgf000384_0001
To a stirred mixture of cyclopentanecarbonitrile (1.00 g, 98 % purity, 10.3 mmol) and hydroxylamine hydrochloride (876 mg, 98 % purity, 12.4 mmol) in ethanol (10 mL) was added triethylamine (2.2 mL, 15 mmol), and the mixture was heated to 75'C for 14 h. The mixture was cooled to r.t., diethyl ether was added and a solid was removed by filtration. The solution was concentrated in vacuum. Diethyl ether was added to the residue, the mixture was stirred and again, a solid was removed by filtration. The solution was concentrated in vacuum to give 0.65 g of the title compound as a crude product that was used without further purification. LC-MS (Method 2): R, = 0.57 min; MS (ESIpos): m/z = 129 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.405 (0.46), 1 .410 (0.50), 1.414 (0.67), 1.417 (0.65), 1.421 (0.89), 1.425 (1.10), 1.432 (1.65), 1.441 (2.49), 1.445 (4.74), 1.448 (4.53), 1.455 (6.07), 1.458 (6.87), 1.462 (4.86), 1.465 (4.66), 1.472 (3.1 1 ), 1.475 (2.97), 1.481 (2.83), 1.483 (2.79), 1.488 (2.65), 1.495 (1.88), 1.500 (1.64), 1.505 (1.30), 1.512 (1.03), 1.517 (1.26), 1.520 (1.29), 1.526 (2.12), 1.533 (2.56), 1.535 (3.01 ), 1.538 (3.27), 1.541 (3.73), 1.546 (4.38), 1.549 (4.07), 1.552 (4.53), 1.554 (5.91 ), 1.557 (6.02), 1.559 (5.09), 1.562 (5.68), 1.566 (7.60), 1.571 (8.03), 1.576 (9.74), 1.583 (16.00), 1.587 (13.59), 1.591 (13.44), 1.597 (8.52), 1.605 (6.46), 1.609
(5.18) , 1.61 1 (4.77), 1.618 (3.33), 1.622 (2.81 ), 1.628 (3.65), 1.635 (2.16), 1.638 (2.30), 1.642 (2.10), 1.646 (2.59), 1.648 (2.59), 1.653 (2.33), 1.658 (4.23), 1.663 (7.67), 1.669 (6.27), 1.677
(4.23), 1.679 (3.96), 1.688 (8.76), 1.693 (6.26), 1.703 (7.30), 1.705 (6.79), 1.707 (6.87), 1.715 (2.99), 1.718 (3.28), 1.721 (3.66), 1.726 (2.39), 1.728 (2.29), 1.732 (1.80), 1.736 (1.73), 1.739
(1.19) , 1.743 (0.82), 1.885 (1.39), 1.900 (0.48), 1.905 (0.70), 1 .908 (1.01 ), 1.914 (1.52), 1.918 (1.25), 1.920 (1.09), 1.923 (1.34), 1.925 (1.60), 1.928 (2.55), 1.933 (1.93), 1.938 (0.90), 1.941 (1.05), 1.943 (1.11 ), 1.947 (2.19), 1.957 (1.48), 1 .961 (0.96), 1.964 (0.61 ), 1.969 (0.77), 1.973 (0.47), 1.976 (0.62), 1.978 (0.66), 1.980 (0.65), 2.349 (1.24), 2.351 (0.64), 2.355 (0.59), 2.358 (0.57), 2.368 (3.27), 2.376 (1.38), 2.380 (1.50), 2.382 (1.58), 2.388 (4.88), 2.396 (2.01 ), 2.403 (1.49), 2.409 (2.89), 2.414 (1.03), 2.423 (0.50), 2.430 (1.1 1 ), 2.496 (1.18), 2.500 (0.79), 2.517 (4.88), 2.872 (0.84), 2.889 (1.64), 2.893 (1.35), 2.895 (0.57), 2.906 (1.23), 2.910 (2.12), 2.913 (0.98), 2.926 (1.33), 2.930 (0.88), 2.946 (0.54), 5.241 (9.25), 8.733 (6.43).
Compound 19.02
N_[({2-[(4-{[4-(cyclopropylcarbonyl)piperazin-1-yl]methyl}pyridin-2-yl)amino]-1 H- benzimidazol-6-yl}carbonyl)oxy]cyclopentanecarboximidamide
Figure imgf000385_0001
To a stirred solution of crude 2-[(4-{[4-(cyclopropylcarbonyl)piperazin-1 -yl]methyl}pyridin-2- yl)amino]-1 H-benzimidazole-6-carboxylic acid (1.20 g, approx. 485 pmol) in DMA (15 mL) was added DIPEA (1.7 mL, 9.7 mmol), crude N-hydroxycyclopentanecarboximidamide (187 mg, approx. 1.46 mmol) and PyBOP (252 mg, 485 Mmol). The mixture was stirred at room temperature for 14 h. Further crude N-hydroxycyclopentanecarboximidamide (62 mg) and PyBOP (252 mg, 485 pmol) was added and the mixture was stirred at r.t. for 5 h. A sodium bicarbonate solution was added, the mixture was stirred for 15 minutes and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate), filtered and the solvent was removed in vacuum. Silicagel chromatography gave 140 mg of the title compound.
LC-MS (Method 2): R, = 1.00 min; MS (ESIpos): m/z = 531 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.667 (1.11 ), 0.679 (3.59), 0.686 (8.58), 0.691 (5.07), 0.699 (4.01 ), 0.706 (10.1 1 ), 0.710 (8.37), 0.716 (9.05), 0.723 (8.30), 0.728 (10.16), 0.735 (4.55), 0.747 (1.01 ), 1.236 (0.65), 1.540 (3.44), 1.552 (4.58), 1.557 (4.14), 1.639 (1.40), 1.708 (7.39), 1.718 (9.20), 1.757 (3.00), 1.824 (2.35), 1.843 (4.14), 1.863 (3.46), 1.908 (0.59), 1.929 (0.96), 1.942 (2.09), 1.949 (2.27), 1.961 (3.77), 1.973 (2.12), 1.980 (1.94), 1.992 (0.90), 2.322 (1.34), 2.327 (1.91 ), 2.331 (1.55), 2.373 (3.46), 2.449 (3.59), 2.523 (3.72), 2.559 (1.99), 2.580 (2.69), 2.600 (1.76), 2.664 (1.03), 2.669 (1.60), 2.674 (1.14), 3.532 (16.00), 3.703 (3.13), 5.752 (12.23), 6.268 (2.87), 6.961 (3.75), 6.973 (3.80), 7.206 (9.18), 7.369 (0.83), 7.830 (1.50), 8.212 (1.01 ), 8.271 (7.78), 8.285 (7.42), 10.799 (0.85), 12.308 (1.58).
Compound 20.01
N-hydroxy-2-methylbutanimidamide
Figure imgf000386_0001
To a stirred mixture of 2-methylbutanenitrile (1.00 g, 98 % purity, 1 1.8 mmol) and hydroxylamine hydrochloride (1.00 g, 98 % purity, 14.1 mmol) in ethanol (12 mL) was added triethyl amine (2.5 mL, 18 mmol), and the mixture was heated to 75Ό for 14 h. The mixture was cooled to r.t., diethyl ether was added and a solid was removed by filtration. The solution was concentrated in vacuum. Diethyl ether was added to the residue, the mixture was stirred and again, a solid was removed by filtration. The solution was concentrated in vacuum to give 0.54 g (39 % yield) of the title compound as a crude product that was used without further purification.
LC-MS (Method 2): R, = 0.52 min; MS (ESIpos): m/z = 1 17 [M+H]+ Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.783 (6.25), 0.789 (1.05), 0.802 (15.54), 0.808 (2.07), 0.821 (7.30), 0.826 (1.00), 0.955 (1.44), 0.972 (1.42), 1.014 (14.96), 1.032 (16.00), 1.301 (0.82), 1.317 (1.17), 1.319 (0.98), 1.335 (1.66), 1.351 (1.34), 1.353 (1.43), 1.369 (1.08), 1.489 (1.17), 1.509 (1.59), 1.522 (0.95), 1.527 (1.34), 1.543 (1.18), 1.561 (0.89), 1.903 (0.42), 1.970 (0.97), 1.987 (1.52), 2.007 (1.44), 2.024 (0.81 ), 5.204 (2.90), 8.644 (6.67).
Compound 20.02
N-[({2-[(4-{[4-(cyclopropylcarbonyl)piperazin-1 -yl]methyl}pyridin-2-yl)amino]-1 H benzimidazol-6-yl}carbonyl)oxy]-2-methylbutanimidamide
Figure imgf000387_0001
To a stirred solution of 2-[(4-{[4-(cyclopropylcarbonyl)piperazin-1 -yl]methyl}pyridin-2-yl)amino]- 1 H-benzimidazole-6-carboxylic acid (1.20 g, approx. 485 pmol) in DMA (15 mL) was added DIPEA (1.7 mL, 9.7 mmol), crude N-hydroxy-2-methylbutanimidamide (169 mg, approx. 1.46 mmol) and PyBOP (757 mg, 1.46 mmol). The mixture was stirred at room temperature for 14 h. Further crude N-hydroxy-2-methylbutanimidamide (56 mg) and PyBOP (251 mgl) was added and the mixture was stirred at r.t. for 5 h. A sodium bicarbonate solution was added, the mixture was stirred for 15 minutes and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate), filtered and the solvent was removed in vacuum. Silicagel chromatography gave 194 mg of the title compound.
LC-MS (Method 2): R, = 0.97 min; MS (ESIpos): m/z = 519 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.682 (2.06), 0.690 (4.66), 0.702 (2.35), 0.710 (5.65), 0.713 (5.14), 0.718 (5.39), 0.725 (4.78), 0.730 (5.60), 0.737 (2.45), 0.750 (0.59), 0.871 (6.74), 0.889 (16.00), 0.908 (7.36), 1.144 (13.99), 1.162 (14.42), 1.234 (0.62), 1.431 (0.85), 1.448 (1.37), 1.466 (1.96), 1.483 (1.72), 1.500 (1.05), 1.599 (1.12), 1.620 (1.55), 1.638 (1.37), 1.654 (1.12), 1.672 (0.78), 1.932 (0.57), 1.944 (1.16), 1.951 (1.28), 1.964 (2.08), 1.976 (1.21 ), 1.983 (1.10), 2.160 (1.08), 2.178 (1.76), 2.199 (1.64), 2.215 (0.98), 2.322 (1.12), 2.327 (1.46), 2.332 (1 .17), 2.400 (1.32), 2.523 (2.65), 2.664 (0.76), 2.669 (1.07), 2.674 (0.76), 3.169 (1.42), 3.545 (2.01 ), 3.71 1 (1.32), 5.752 (4.20), 6.278 (2.99), 6.971 (2.08), 6.985 (2.13), 7.214 (3.82), 7.832 (1.62), 7.853 (1.46), 8.180 (0.80), 8.281 (2.52), 8.294 (2.51 ), 10.821 (0.59).
Compound 21.01
N-hydroxy-2-phenylethanimidamide
Figure imgf000388_0001
To a stirred mixture of phenylacetonitrile (1.00 g, 98 % purity, 8.37 mmol) and hydroxylamine hydrochloride (712 mg, 98 % purity, 10.0 mmol) in ethanol (9 ml_) was added triethyl amine (1.7 ml_, 13 mmol), and the mixture was heated to 75*C for 14 h. The mixture was cooled to r.t., diethyl ether was added and a solid was removed by filtration. The solution was concentrated in vacuum. Diethyl ether was added to the residue, the mixture was stirred and again, a solid was removed by filtration. The solution was concentrated in vacuum to give 0.98 g (78 % yield) of the title compound as a crude product that was used without further purification.
LC-MS (Method 2): R, = 0.63 min; MS (ESIpos): m/z = 151 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.327 (2.14), 4.035 (7.91 ), 5.366 (2.52), 7.184 (0.84), 7.188 (0.59), 7.195 (1.50), 7.206 (1.41 ), 7.208 (1.14), 7.217 (1.07), 7.260 (0.81 ), 7.271 (16.00), 7.275 (2.33), 7.282 (9.43), 7.327 (1.32), 7.334 (0.89), 7.336 (1.18), 7.340 (1.88), 7.342 (1.67), 7.344 (1.43), 7.346 (1.39), 7.348 (1.45), 7.357 (3.49), 7.360 (2.33), 7.362 (1.84), 7.379 (0.97), 7.381 (2.35), 7.383 (3.05), 7.389 (1.05), 7.398 (1.78), 7.401 (2.45), 7.404 (1.62), 7.419 (0.99), 7.422 (0.63), 8.869 (6.19).
Compound 21.02
N-[({2-[(4-{[4-(cyclopropylcarbonyl)piperazin-1 -yl]methyl}pyridin-2-yl)amino]-1H- benzimidazol-6-yl}carbonyl)oxy]-2-phenylethanimidamide
Figure imgf000389_0001
To a stirred solution of crude 2-[(4-{[4-(cyclopropylcarbonyl)piperazin-1-yl]methyl}pyridin-2- yl)amino]-1 H-benzimidazole-6-carboxylic acid (1 .20 g, approx. 485 μιτιοΙ) in DMA (15 mL) was added DIPEA (1.7 mL, 9.7 mmol), crude N-hydroxy-2-phenylethanimidamide (219 mg, approx. 1.46 mmol) and PyBOP (757 mg, 1.46 mmol). The mixture was stirred at room temperature for 14 h. Further crude N-hydroxy-2-phenylethanimidamide (73 mg) and PyBOP (251 mg) was added and the mixture was stirred at r.t. for 5 h. A sodium bicarbonate solution was added, the mixture was stirred for 15 minutes and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate), filtered and the solvent was removed in vacuum. Silicagel chromatography gave 239 mg of the title compound.
LC-MS (Method 2): R, = 1.00 min; MS (ESIpos): m/z = 553 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.665 (1 .1 1 ), 0.677 (3.37), 0.685 (8.15), 0.690 (4.78), 0.697 (3.75), 0.705 (9.57), 0.709 (8.1 1 ), 0.714 (8.57), 0.722 (8.08), 0.727 (9.45), 0.734 (4.29), 0.746 (1.03), 1.242 (0.96), 1.258 (0.84), 1.714 (0.77), 1.730 (2.22), 1.747 (0.80), 1.908 (0.61 ), 1.927 (0.96), 1.940 (1.88), 1.948 (2.03), 1.960 (3.56), 1.972 (1.99), 1.979 (1.80), 1.991 (0.92), 2.322 (1.57), 2.327 (2.18), 2.332 (1.80), 2.366 (3.37), 2.444 (3.25), 2.523 (4.48), 2.665 (1.26), 2.669 (1.68), 2.674 (1.26), 3.009 (1.42), 3.019 (1.45), 3.162 (0.57), 3.175 (0.65), 3.443 (16.00), 3.528 (15.08), 3.703 (3.06), 5.752 (3.22), 6.518 (2.26), 6.962 (2.95), 7.204 (8.54), 7.236 (1.80), 7.248 (1.26), 7.254 (5.47), 7.259 (1.80), 7.272 (4.29), 7.319 (6.28), 7.334 (5.40), 7.338 (12.71 ), 7.351 (3.25), 7.356 (7.66), 7.396 (12.56), 7.414 (7.31 ), 7.418 (5.36), 7.537 (0.80), 7.850 (1.34), 8.1 10 (1.19), 8.225 (1.88), 8.268 (7.08), 8.282 (6.66), 10.818 (1.26), 12.299 (2.07). Compound 22.01
2^[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)pyridin-2-yl]amino}-1 H-benzimidazole carbonitrile
Figure imgf000390_0001
To a stirred solution of 1 H-imidazole (383 mg, 5.62 mmol) and di-1 H-imidazol-1- ylmethanethione (6.68 g, 90 % purity, 33.7 mmol) in dichloromethane (100 ml_) was added 4- ({[tert-butyl(dimethyl)silyl]oxy}methyl)pyridin-2-amine (6.70 g, 28.1 mmol), dissolved in dichloromethane (100 mL) at 0° C. The mixture was s tirred at r.t. for 3 h. 3,4- diaminobenzonitrile (4.63 g, 97 % purity, 33.7 mmol) was added and the mixture was stirred at r.t. for 1 h. Water was added and the mixture was extracted with dichloromethane. The organic phase was dried (sodium sulfate) and filtered. N,N'-dipropan-2-ylcarbodiimide (4.9 mL, 32 mmol) was added and the mixture was stirred at r.t. for 14 h. Saturated ammonium chloride solution was added, the mixture was stirred for 30 minutes and the mixture was extracted with dichloromethane. The organic phase was dried (sodium sulfate) and the solvent was removed in vacuum. Silicagel chromatography gave a solid that was triturated with warm methanol to give 3.6 g of the title compound.
LC-MS (Method 2): R, = 1.51 min; MS (ESIpos): m/z = 380 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.150 (12.85), 0.970 (0.98), 0.977 (16.00), 0.985 (0.93), 3.353 (2.20), 4.777 (1.37).
Compound 22.02
2-{[4-(hydroxymethyl)pyridin-2-yl]amino}-1 H-benzimidazole-6-carbonitrile
Figure imgf000391_0001
To a stirred solution 2-{[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)pyridin-2-yl]amino}-1 H- benzimidazole-6-carbonitrile (9.00 g, 23.7 mmol) in dioxane (230 mL) was added HCI in dioxane (36 mL, 4.0 M, 140 mmol). The mixture was stirred at 50° C for 14 h. Further HCI (10 mL, 4.0 M, 40 mmol) in dioxane was added and the mixture was stirred at 50° C for 14 h. Sodium bicarbonate (5.0 g) was added and the mixture was stirred for 30 minutes. THF (50 mL) was added, the mixture was filtered through magnesium sulfate and the solvent was removed in vacuum. Diethyl ether was added and a solid precipitated and was collected by filtration to give 8.20 g of the title compound as a salt that was used for the next step without purification.
LC-MS (Method 1 ): Rt = 0.67 min; MS (ESIpos): m/z = 266 [M+H]+
1H-NMR (300 MHz, DMSO-d6) δ [ppm]: 0.000 (0.83), 0.178 (1.17), 0.884 (1.14), 0.993 (1.55), 3.627 (1.26), 4.650 (16.00), 7.184 (3.79), 7.205 (3.96), 7.428 (6.96), 7.728 (1.15), 7.756 (7.13), 7.761 (8.49), 7.768 (8.76), 7.796 (1.58), 8.031 (7.18), 8.420 (4.31 ), 8.438 (4.37).
Compound 22.03
2-{[4-(chloromethyl)pyridin-2-yl]amino}-1 H-benzimidazole-6-carbonitrile
Figure imgf000391_0002
To a suspension of 2-{[4-(hydroxymethyl)pyridin-2-yl]amino}-1 H-benzimidazole-6-carbonitrile hydrochloride (6.00 g, 19.9 mmol) in dichloromethane (400 mL) and DMF (15 mL, 190 mmol) was added thionyl dichloride (2.9 mL, 40 mmol) and the mixture was stirred at r.t. for 14 h. A solution of potassium carbonate was added and the mixture was extracted with dichloromethane / methanol (20: 1 ). A solid precipitated and was collected. The organic phase was separated, dried (sodium sulfate), filtered and the solvent was removed in vacuum to give a second solid batch. Both solids were combined and triturated with ethanol to give 4.50 g (80 % yield) of the title compound.
LC-MS (Method 2): R, = 1.06 min; MS (ESIpos): m/z = 284 [M+H]+
1H-NMR (300 MHz, DMSO-d6) δ [ppm]: 2.525 (1.09), 4.790 (16.00), 5.756 (2.25), 7.052 (2.82), 7.057 (2.80), 7.069 (2.89), 7.074 (2.90), 7.276 (5.26), 7.425 (2.15), 7.430 (2.17), 7.452 (3.55), 7.457 (3.57), 7.533 (1.13), 7.825 (3.89), 8.346 (4.38), 8.364 (4.23), 1 1.063 (1.26).
Compound 22.04
2-[(4-{[4-(2-chlorophenyl)piperazin-1-yl]methyl}pyridin-2-yl)amino]-1 H-benzimidazole-6- carbonitrile
Figure imgf000392_0001
To a stirred solution of 2-{[4-(chloromethyl)pyridin-2-yl]amino}-1 H-benzimidazole-6-carbonitrile (1.00 g, 3.52 mmol) in DMF (30 mL) was added potassium carbonate (2.44 g, 17.6 mmol) and 1 -(2-chlorophenyl)piperazine (1.73 g, 8.81 mmol). The mixture was stirred at 60*0 for 2 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with half-saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silicagel chromatography gave a solid that was triturated with ethanol to give 1.30 g (83 % yield) of the title compound.
LC-MS (Method 2): Rt = 1 .40 min; MS (ESIpos): m/z = 444 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.038 (0.69), 1.055 (1.42), 1.073 (0.75), 2.322 (0.42), 2.327 (0.59), 2.331 (0.43), 2.523 (2.21 ), 2.596 (8.11 ), 2.665 (0.63), 2.669 (0.80), 2.674 (0.58), 2.731 (0.45), 2.889 (0.56), 3.021 (9.78), 3.575 (16.00), 4.331 (0.42), 7.000 (3.25), 7.015 (5.11 ), 7.019 (4.03), 7.034 (4.70), 7.038 (4.89), 7.053 (3.29), 7.057 (3.44), 7.156 (3.89), 7.160 (4.13), 7.176 (5.48), 7.180 (5.06), 7.218 (8.23), 7.278 (3.35), 7.281 (3.67), 7.296 (4.01 ), 7.300 (4.57), 7.316 (2.30), 7.320 (2.26), 7.387 (6.39), 7.391 (6.28), 7.407 (6.65), 7.41 1 (6.45), 7.441 (2.92), 7.630 (0.62), 7.775 (0.77), 7.856 (1.10), 8.300 (3.08), 8.312 (3.02), 10.932 (0.69), 12.485 (0.98). Compound 22.05
2-[(4-{[4-(2-chlorophenyl)piperazin-1-yl]methyl}pyridin-2-yl)amino]-N'-hydroxy-1H benzimidazole-6-carboximidamide
Figure imgf000393_0001
To a stirred suspension of 2-[(4-{[4-(2-chlorophenyl)piperazin-1 -yl]methyl}pyridin-2-yl)amino]- 1 H-benzimidazole-6-carbonitrile (500 mg, 1.13 mmol)and triethylamine (360 μΙ, 2.6 mmol) in DMSO (15 mL, 210 mmol) was added hydroxylamine hydrochloride (176 mg, 98 % purity, 2.48 mmol). The mixture was stirred at 75Ό for 14 h. Wa ter was added, a solid precipitated and was collected by filtration and washed with water. The solid was dissolved in ethyl acetate/ethanol (1 : 1 ), filtered and the solvent was removed in vacuum to give 670 mg of the title compound as a crude product that was used without purification.
LC-MS (Method 2): R, = 1.17 min; MS (ESIpos): m/z = 477 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.539 (16.00), 3.560 (0.97), 7.387 (0.73), 7.391 (0.68), 7.407 (0.52).
Compound 22.06
2-[(4-{[4-(2-chlorophenyl)piperazin-1-yl]methyl}pyridin-2-yl)amino]-N'
[(cyclopropylcarbonyl)oxy]-1 H-benzimidazole-6-carboximidamide
Figure imgf000393_0002
To a stirred solution of crude 2-[(4-{[4-(2-chlorophenyl)piperazin-1 -yl]methyl}pyridin-2- yl)amino]-N'-hydroxy-1 H-benzimidazole-6-carboximidamide (330 mg, approx. 553 pmol) in DMA (5 mL) was added DIPEA (390 μΙ, 2.2 mmol), cyclopropanecarboxylic acid (69 μΙ, 95 % purity, 830 pmol) and PyBOP (432 mg, 830 pmol). The mixture was stirred at room temperature for 3 h. Water was added and a solid precipitated and was collected by filtration. The solid was triturated with ethanol. Aminophase-Silicagel chromatography gave 160 mg of the title compound.
LC-MS (Method 2): R, = 1.30 min; MS (ESIpos): m/z = 545 [M+H]+
H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.067 (0.54), 0.799 (0.60), 0.816 (0.63), 0.822 (0.70), 0.852 (0.92), 0.860 (1.14), 0.874 (3.79), 0.882 (7.87), 0.885 (7.27), 0.894 (8.70), 0.900 (9.26), 0.907 (3.86), 0.915 (3.95), 0.920 (7.18), 0.928 (3.13), 0.941 (0.92), 1.037 (0.57), 1.054 (1.17), 1.071 (0.70), 1.232 (2.59), 1.257 (1.1 1 ), 1.296 (0.57), 1.712 (1.20), 1.720 (1.33), 1.728 (3.26), 1.737 (1.26), 1.745 (1.20), 1.888 (0.85), 1.901 (1.71 ), 1.908 (1.87), 1.920 (2.94), 1.932 (1.74), 1.939 (1.55), 1.955 (1.93), 1.986 (0.44), 2.084 (0.73), 2.322 (1.42), 2.326 (1 .96), 2.331 (1.36), 2.523 (4.46), 2.539 (1.52), 2.596 (8.66), 2.664 (1.77), 2.668 (2.21 ), 2.673 (1.71 ), 2.782 (1.64), 2.942 (2.15), 2.990 (2.34), 3.006 (8.70), 3.016 (1 1.95), 3.022 (12.02), 3.565 (16.00), 5.169 (0.54), 5.755 (0.76), 6.701 (2.88), 6.958 (4.52), 6.971 (4.52), 7.017 (3.04), 7.021 (3.13), 7.036 (5.50), 7.040 (5.38), 7.055 (3.76), 7.059 (3.73), 7.098 (0.66), 7.161 (4.71 ), 7.165 (4.84), 7.181 (6.61 ), 7.185 (5.94), 7.215 (3.42), 7.280 (3.79), 7.284 (3.98), 7.303 (5.38), 7.318 (2.94), 7.322 (2.75), 7.357 (1.23), 7.390 (8.09), 7.394 (7.65), 7.410 (8.92), 7.414 (7.84), 7.484 (1.39), 7.612 (0.63), 7.713 (1.52), 7.864 (1.64), 8.264 (4.90), 8.277 (5.03), 10.701 (2.37), 12.231 (2.75).
Compound 22.07
2-[(4-{[4-(2-chlorophenyl)piperazin-1-yl]methyl}pyridin-2-yl)amino]-N'-[(3,3- dimethylbutanoyl)oxy]-1 H-benzimidazole-6-carboximidamide
Figure imgf000394_0001
To a stirred solution of 2-[(4-{[4-(2-chlorophenyl)piperazin-1 -yl]methyl}pyridin-2-yl)amino]-N'- hydroxy-1 H-benzimidazole-6-carboximidamide (330 mg, approx. 553 pmol) in DMA (5 mL) was added DIPEA (390 μΙ, 2.2 mmol), 3,3-dimethylbutanoic acid (110 μΙ, 98 % purity, 830 pmol) and PyBOP (432 mg, 830 μηιοΙ). The mixture was stirred at room temperature for 3 h. A sodium bicarbonate solution was added, the mixture was stirred for 15 minutes and the mixture was extracted with dichloromethane / methanol (20:1 ). The organic phase was dried (sodium sulfate), filtered and the solvent was removed in vacuum. Aminophase-silicagel chromatography gave 130 mg of the title compound.
LC-MS (Method 2): R, = 1.43 min; MS (ESIpos): m/z = 575 [M+H]+
H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.040 (16.00), 2.346 (3.10), 2.598 (0.83), 3.018 (0.98), 3.025 (1.07), 3.567 (1.59), 7.036 (0.53), 7.040 (0.50), 7.058 (0.41 ), 7.161 (0.46), 7.165 (0.47), 7.182 (0.68), 7.185 (0.59), 7.280 (0.41 ), 7.284 (0.42), 7.389 (0.80), 7.393 (0.76), 7.409 (0.96), 7.413 (0.91 ), 8.265 (0.63), 8.279 (0.59).
Compound 23.01
tert-butyl 4-[(2-{[6-(pyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4'
yl)methyl]piperazine-1-carboxylate
Figure imgf000395_0001
To a stirred solution of tert-butyl 4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate (500 mg, 936 pmol) and 4-bromopyrimidine (208 mg, 1.31 mmol) in dioxane (5 mL) and water (0.9 mL) was added sodium carbonate (297 mg, 2.81 mmol) and Pd(dppf)CI2 (1 15 mg, 140 μπιοΙ) CH2CI2 . The mixture was heated to reflux for 19 h. Another 0.5 equivalents of 4-bromopyrimidine (74 mg, 0.47 mmol) were added and the reaction mixture was stirred for 24 h at 105Ό. After cooling to r.t., dichloromethane was added, the mixture was dried (magnesium sulfate), filtered and the solvent was removed in vacuum. Silicagel chromatography gave 290 mg (64 % yield) of the title compound.
LC-MS (Method 2): Rt = 1 .17 min; MS (ESIpos): m/z = 487 [M+H]+ Compound 23.02
N 4-(piperazin-1-ylmethyl)pyridin-2-yl]-6-(pyrimidin-4-yl)-1 H^enzimidazol-2
hydrochloride
Figure imgf000396_0001
Starting with tert-butyl 4-[(2-{[6-(pyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate (290 mg, 596 pmol), Compound 23.02 was prepared analogously to the procedure for the preparation of Compound 01.05.
Yield: 288 mg of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): Rt = 0.81 min; MS (ESIpos): m/z = 387 [M+H]+
Compound 23.03
(2-chloro-6-methylpyridin-4-yl)methanol
Figure imgf000396_0002
Methyl 2-chloro-6-methylpyridine-4-carboxylate (6.50 g, 35.0 mmol) was dissolved in dry THF (110 mL). Lithium aluminium hydride (1.65 g, 43.4 mmol) was added portionwise within 60 min. The reaction mixture was stirred at room temperature fort he next 1.5 hours. Afterwards 50 mL water and 100 mL of an aqueous sodium hydroxide solution (15%) were added. This mixture was stirred for another hour and extracted three times with dichloromethane. The organic phase was washed with saturated sodium carbonate solution, dried (Whatman filter) and the solvent was removed in vacuum to give 4.4 g (80 % yield) of the title compound which was used without further purification.
LC-MS (Method 2): Rt = 0.67 min; MS (ESIpos): m/z = 158 [M+H]+ 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.352 (0.50), 1.854 (0.64), 1 .859 (0.61 ), 2.427 (16.00), 2.437 (1.41 ), 2.523 (0.74), 3.158 (1.14), 3.172 (1.31 ), 3.386 (1.09), 4.499 (3.82), 4.513 (3.88), 5.491 (1.29), 5.506 (2.86), 5.520 (1.25), 7.185 (3.22), 7.200 (3.13).
Compound 23.04
{2-[(2,4-dimethoxybenzyl)amino]-6-methylpyridin-4-yl}methanol
Figure imgf000397_0001
To a stirred solution of 2-chloro-6-methylpyridin-4-yl)methanol (2.10 g, 13.3 mmol) and 1-(2,4- dimethoxyphenyl)methanamine (8.0 mL, 53 mmol) in dioxane (57 mL) was added tris- (dibenzylidenaceton)-dipalladium(O) (1.22 g, 1.33 mmol), Xantphos (1.54 g, 2.66 mmol) and cesium carbonate (6.51 g, 20.0 mmol). The mixture was heated for 4 h at 100 under an argon atmosphere. The reaction mixture was allowed to cool down to room temperature and stirred for another 10 hours at room temperature. Ethyl acetate was added and the precipitate was filtered off. Amino phase silicagel chromatography gave 2.1 g (55 % yield) of the title compound.
LC-MS (Method 2): R, = 0.98 min; MS (ESIpos): m/z = 289 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (1.09), 1.172 (2.08), 1.190 (1.07), 1.612 (1.86), 1.987 (4.10), 2.202 (7.99), 2.222 (2.21 ), 2.332 (1.98), 2.341 (0.64), 2.437 (0.65), 2.518 (1.15), 3.568 (1.26), 3.718 (2.13), 3.721 (16.00), 3.728 (3.92), 3.757 (3.16), 3.783 (0.91 ), 3.789 (2.88), 3.796 (10.81 ), 4.017 (0.95), 4.035 (0.94), 4.291 (2.41 ), 4.297 (2.61 ), 4.305 (2.61 ), 4.312 (2.25), 5.123 (0.61 ), 5.137 (1.33), 5.147 (1.21 ), 5.151 (1.05), 6.253 (3.87), 6.425 (1.12), 6.431 (1.02), 6.446 (1.29), 6.452 (1.1 1 ), 6.497 (0.71 ), 6.502 (0.75), 6.515 (1.01 ), 6.527 (0.97), 6.530 (2.54), 6.536 (1.79), 7.105 (1.64), 7.125 (1.51 ), 7.306 (0.68), 7.31 1 (0.85), 7.320 (0.79), 7.325 (0.77), 7.327 (0.69). Compound 23.05
4-(bromomethyl)-6-methylpyridin-2 -amine hydrobromide
Figure imgf000398_0001
{2-[(2,4-dimethoxybenzyl)amino]-6-methylpyridin-4-yl}methanol (1.96 g, 6.80 mmol) was dissolved in aqueous hydrobromic acid (48%; 7.7mL) and stirred for 3h at '\ 20 . The reaction mixture was cooled down with ice water and the precipitate was filtered off. The precipitate was washed with acetone. Ethanol was added. The further precipitated solid was filtered off and combined with the first precipitate and discharded. The pH of the aqueous filtrate was brought to a basic range with saturated soda solution, extracted with ethyl acetate and dichloro methane. The combined organic phases were dried (Whatman filter) and the solvent was removed in vacuum to give 500 mg (26 % yield) of the title compound.
LC-MS (Method 2): R, = 1.03 min; MS (ESIpos): m/z = 307 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.173 (0.74), 1.368 (0.64), 1.385 (16.00), 1.988 (1.43), 2.189 (3.79), 2.266 (0.77), 2.279 (1.12), 2.292 (0.82), 3.305 (0.85), 3.323 (5.02), 5.736 (1.04), 6.187 (0.80), 6.277 (0.85).
Compound 23.06
tert-butyl 4-[(2-amino-6-methylpyridin-4-yl)methyl]piperazine-1-carboxylate
Figure imgf000398_0002
To a stirred suspension of 4-(bromomethyl)-6-methylpyridin-2-amine hydrobromide (920 mg, 3.26 mmol) in acetonitrile (6.9 mL) was added potassium carbonate (1.35 g, 9.79 mmol) and tert-butyl piperazine-1 -carboxylate (668 mg, 3.59 mmol). The mixture was stirred at r.t. for 14 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with half-saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Aminophase-silicagel chromatography gave 1.00 g (100 % yield) of the title compound.
LC-MS (Method 2): f¾ = 1.03 min; MS (ESIpos): m/z = 307 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.173 (0.74), 1.368 (0.64), 1.385 (16.00), 1.988 (1.43), 2.189 (3.79), 2.266 (0.77), 2.279 (1.12), 2.292 (0.82), 3.305 (0.85), 3.323 (5.02), 5.736 (1.04), 6.187 (0.80), 6.277 (0.85).
Compound 23.07
tert-butyl 4-[(2-methyl-6-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate
Figure imgf000399_0001
To a stirred solution of 1 H-imidazole (63.5 mg, 933 pmol) and di-1 H-imidazol-1 - ylmethanethione (907 mg, 5.09 mmol) in dichloromethane (30 ml_) was added tert-butyl 4-[(2- amino-6-methylpyridin-4-yl)methyl]piperazine-1-carboxylate (1.30 g, 4.24 mmol) , dissolved in dichloromethane (30 mL) at 0° C. The mixture was st irred at r.t. for 14 h. 4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzene-1 ,2-diamine (1.19 g, 5.09 mmol) dissolved in dichloromethane (30 mL), was added and the mixture was stirred at r.t. for 5 h. Water was added and the mixture was extracted with dichloromethane. The organic phase was dried (sodium sulfate), and filtered. N,N'-dipropan-2-ylcarbodiimide (920 μΙ, 5.9 mmol) was added. The mixture was stirred at r.t. for 24 h. Further N,N'-dipropan-2-ylcarbodiimide (460 μΙ, 2.95 mmol) was added and the mixture was stirred at r.t. for 56 h. Saturated ammonium chloride solution was added, the mixture was stirred for 30 minutes and was extracted with dichloromethane. Silicagel chromatography gave 1.40 g (60 % yield) of the title compound as a crude product, that was used without further purification.
LC-MS (Method 2): Rt = 1.51 min; MS (ESIpos): m/z = 549 [M+H]+ 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.035 (1.25), 1.052 (2.99), 1.070 (1.37), 1.241 (0.80), 1.289 (1.14), 1.301 (10.12), 1.385 (16.00), 1.389 (6.94), 1.392 (13.65), 2.193 (3.72), 2.267 (0.78), 2.280 (1.14), 2.292 (0.84), 2.323 (1.05), 2.327 (1.18), 2.331 (1.11 ), 2.337 (1.25), 2.349 (0.79), 2.399 (0.61 ), 2.518 (2.12), 2.523 (1.51 ), 2.530 (2.10), 2.728 (0.85), 2.888 (1.05), 3.267 (1.73), 3.307 (1.04), 3.422 (0.66), 3.435 (1.71 ), 3.439 (1.67), 3.452 (0.61 ), 4.358 (0.69), 6.199 (0.74), 6.284 (0.80), 6.761 (0.62), 6.984 (0.59).
Compound 23.08
tert-butyl 4-[(2-methyl-6-{[6-(pyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1-carboxylate
Figure imgf000400_0001
To a stirred solution of tert-butyl 4-[(2-methyl-6-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)-1 H-benzimidazol-2-yl]amino}pyridin-4-yl)rnethyl]piperazine-1-carboxylate (700 mg, 1.28 mmol) and 4-bromopyrimidine (365 mg, 2.30 mmol) in dioxane (6 mL) and water (1.2 mL) was added sodium carbonate (406 mg, 3.83 mmol) and Pd(dppf)CI2 (156 mg, 191 μιηοΙ). The mixture was heated to reflux for 24 h. Further 4-bromopyrimidine (101 mg, 0.64 mmol) was added and the mixture was heated to reflux for 4 h. Dichioromethane was added, the mixture was dried (magnesium sulfate), filtered and the solvent was removed in vacuum. Silicagel chromatography followed by aminophase-silicagel chromatography gave 130 mg (20 % yield) of the title compound.
LC-MS (Method 2): Rt = 1.27 min; MS (ESIpos): m/z = 501 [M+H]+ Compound 23.09
N-[6-methyl-4-(piperazin-1 -ylmethyl)pyridin-2-yl]-6-(pyrimidin-4-yl)-1H-benzim
amine hydrochloride
Figure imgf000401_0001
Starting with tert-butyl 4-[(2-methyl-6-{[6-(pyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1-carboxylate (130 mg, 260 μιτιοΙ), Compound 23.09 was prepared analogously to the procedure for the preparation of Compound 01.05.
Yield: 137 mg of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): R, = 0.89 min; MS (ESIpos): m/z = 401 [M+H]+
Compound 23.10
{2-[(diphenylmethylidene)amino]-6-(trifluoromethyl)pyridin-4-yl}methanol
Figure imgf000401_0002
To a stirred solution of (2-chloro-6-trifluoromethyl-pyridin-4-yl)-methanol: (10.0 g, 47.3 mmol) and -1 ,1 -diphenylmethanimine (16 ml_, 95 mmol) in dioxane (340 mL) was added tris- (dibenzylidenaceton)-dipalladium(O) (5.89 g, 9.45 mmol), (R)-(+)-2,2'-bis(diphenylphosphino)- 1 ,1 '-binaphthyl (5.89 g, 9.45 mmol) and cesium carbonate (38.5 g, 1 18 mmol). The mixture was heated overnight at 80*0 under an argon atmosph ere. The reaction mixture was allowed to cool down to room temperature. The solvent was removed in vacuo and Amino phase silicagel chromatography gave 14.6 g (87 % yield) of the title compound.
LC-MS (Method 2): R, = 1.29 min; MS (ESIpos): m/z = 357 [M+H]+ Compound 23.11
[2-amino-6-(trifluoromethyl)pyridin-4-yl]methanol
Figure imgf000402_0001
{2-[(diphenylmethylidene)amino]-6-(trifluoromethyl)^^ (14.6 g, 41.0 mmol) was dissolved in THF and 1 12 mL aqueous HCI (1 M) were added. The reaction mixture was stirred at room temperature for 30 min. THF was removed in vacuo. The crude residue was dissolved in 1 N NaOH and extracted with saturated sodium chloride solution, dried (Whatman filter) and the solvent was removed in vacuo. Amino phase silicagel chromatography gave 1.4 g (18 % yield) of the title compound.
LC-MS (Method 2): R, = 0.67 min; MS (ESIpos): m/z = 193 [M+H]+
Compound 23.12
4-(bromomethyl)-6-(trifluoromethyl)pyridin-2-amine hydrobromide
Figure imgf000402_0002
[2-amino-6-(trifluoromethyl)pyridin-4-yl]methanol (1.40 g, 7.29 mmol) was dissolved in aqueous hydrobromic acid (48%; 16.5 mL) and stirred for 4h at 120Ό. The reaction mixture was allowed to cool down to room temperature. The pH of the reaction mixture was brought to a basic range with saturated sodium carbonate solution. The mixture was extracted with ethyl acetate and dichloromethane. The combined organic phases were dried (Whatman filter) and the solvent was removed in vacuum to give 1.7 g (69 % yield) of the title compound.
LC-MS (Method 2): Rt = 1.04 min; MS (ESIpos): m/z = 255 [M+H]+ Compound 23.13
(4-{[2-amino-6-(trifluoromethyl)pyridin-4-yl]methyl}piperazin-1- yl)(cyclopropyl)methanone
Figure imgf000403_0001
To a stirred suspension of 4-(bromomethyl)-6-(trifluoromethyl)pyridin-2-amine hydrobromide (2.10 g, 6.25 mmol) in acetonitrile (13 mL) was added potassium carbonate and cyclopropyl(piperazin-1-yl)methanone (1.06 g, 6.88 mmol). The mixture was stirred at r.t. for 14 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with half-saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Ssilicagel chromatography gave 2.00 g (98 % yield) of the title compound.
LC-MS (Method 2): R, = 0.94 min; MS (ESIpos): m/z = 329 [M+H]+
Compound 23.14
cyclopropyl(4-{[2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-benzimidazol-2- yl]amino}-6-(trifluoromethyl)pyridin-4-yl]methyl}piperazin-1 -yl)methanone
Figure imgf000403_0002
To a stirred solution of 1 H-imidazole (91.2 mg, 1.34 mmol) and di-1 H-imidazol-1- ylmethanethione (1.30 g, 7.31 mmol) in dichloromethane (50 mL) was added (4-{[2-amino-6- (trifluoromethyl)pyridin-4-yl]methyl}piperazin-1 -yl)(cyclopropyl)methanone (2.00 g, 6.09 mmol), dissolved in dichloromethane (50 mL) at 0° C. The m ixture was stirred at r.t. for 14 h. Further di-1 H-imidazol-1 -ylmethanethione (6.09 mmol) dissolved in dichloromethane was added and the mixture was stirred at r.t. for 14 h. 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzene- 1 ,2-diamine (1.71 g, 7.31 mmol) dissolved in dichloromethane (50 mL) was added and the mixture was stirred at r.t. for 56 h. Water was added and the mixture was extracted with dichloromethane. The organic phase was dried (sodium sulfate) and filtered. N,N'-dipropan-2- ylcarbodiimide (2.8 mL, 18 mmol) was added. The mixture was stirred at r.t. for 14 h. Further N,N'-dipropan-2-ylcarbodiimide (1.4 mL, 9.0 mmol) was added and the mixture was stirred at r.t. for 5 h. Saturated ammonium chloride solution was added, the mixture was stirred for 30 minutes and was extracted with dichloromethane. Silicagei chromatography gave 2.10 g of the title compound as a crude product, that was used without further purification.
LC-MS (Method 2): R, = 1.41 min; MS (ESIpos): m/z = 571 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.686 (0.81 ), 0.705 (1.06), 0.710 (0.83), 0.716 (0.94), 0.724 (0.85), 0.728 (0.99), 1.035 (0.79), 1.052 (1.78), 1.065 (16.00), 1.070 (1.68), 1.272 (5.52), 1.289 (1.55), 1.301 (13.37), 3.439 (0.42), 3.452 (0.42), 3.654 (1.77), 3.942 (2.75), 4.360 (0.53), 7.370 (0.86).
Compound 23.15
(rac)-tert-butyl 4-[1 -(2-{[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H-benzimidazol- 2-yl]amino}pyridin-4-yl)ethyl]piperazine-1 -carboxylate
Figure imgf000404_0001
To a stirred solution of 1 H-imidazole (502 mg, 7.37 mmol) and di-1 H-imidazol-1 - ylmethanethione (6.56 g, 36.8 mmol) in dichloromethane (90 mL) was added (rac)-tert-butyl 4- [1 -(2-aminopyridin-4-yl)ethyl]piperazine-1 -carboxylate (10.3 g, 33.5 mmol), dissolved in dichloromethane (90 ml_) at 0°C. The mixture was st irred at r.t. for 4 h. 4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)benzene-1 ,2-diamine (7.84 g, 33.5 mmoi), dissolved in dichloromethane (60 mL) was added and the mixture was stirred at r.t. for 14 h. Water was added and the mixture was extracted with dichloromethane. The organic phase was dried (sodium sulfate) and filtered. N,N'-dipropan-2-ylcarbodiimide (7.3 mL, 47 mmol) was added. The mixture was stirred at r.t. for 14 h. Saturated ammonium chloride solution was added, the mixture was stirred for 30 minutes and was extracted with dichloromethane. Silicagel chromatography followed by trituration with methanol/water gave 10.8 g (59 % yield) of the title compound as a crude product, that was used without further purification.
LC-MS (Method 2): R, = 1.49 min; MS (ESIpos): m/z = 549 [M+H]+
Compound 23.15.01
tert-butyl 4-[(1 R or 1 S)-1 -(2-{t6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1 -carboxylate
Figure imgf000405_0001
Starting with 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzene-1 ,2-diamine (7.69 g, see Compound 01.03) and tert-butyl 4-[(1 R or 1 S)-1-(2-aminopyridin-4-yl)ethyl]piperazine-1- carboxylate, see Compound 36.05.), Compound 23.15.01 was prepared analogously to the procedure for the preparation of Compound 23.15.
Yield: 6.9 g of the 85% pure title compound.
LC-MS (Method 2): R. = 1.48 min; MS (ESIpos): m/z = 549 [M+H]+ Compound 23.16
(rac)-tert-butyl 4-[1 -(2-{[6-(pyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)ethyl]piperazine-1-carboxylate
Figure imgf000406_0001
To a stirred solution of (rac)-tert-butyl 4-[1-(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)- 1 H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1 -carboxylate (1.00 g, 1.82 mmol) and 4-bromopyrimidine hydrochloride (570 mg, 2.92 mmol) in dioxane (9 mL) and water (1.8 mL) was added sodium carbonate (773 mg, 7.29 mmol) and Pd(dppf)Cl2 . CH2CI2 (223 mg, 273 pmol). The mixture was heated to reflux for 24 h. Further 4-bromopyrimidine (180 mg) was added and the mixture was heated to reflux for 24 h. Dichloromethane was added, the mixture was dried (magnesium sulfate), filtered and the solvent was removed in vacuum. Silicagel chromatography gave 0.40 g (44 % yield) of the title compound.
LC-MS (Method 2): R, = 1.21 min; MS (ESIpos): m/z = 501 [M+H]+
Compound 23.17
(rac)-N-{4-[1 -(piperazin-1 -yl)ethyl]pyridin-2-yl}-6-(pyrimidin-4-yl)-1 H-benzimidazol-2- amine hydrochloride
Figure imgf000406_0002
Starting with (rac)-tert-butyl 4-[1 -(2-{[6-(pyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)ethyl]piperazine-1 -carboxylate (400 mg, 799 Mmol), Compound 23.17 was prepared analogously to the procedure for the preparation of Compound 01.05. Yield: 420 mg of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): R, = 0.85 min; MS (ESIpos): m/z = 401 [M+H]+
Compound 24.01
4-(2-methylpyrimidin-4-yl)-2-nitr aniline
Figure imgf000407_0001
Starting with 4-chloro-2-methylpyrimidine (1.35 g, 10.5 mmol) and 2-nitro-4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)aniline (3.04 g, 11 .5 mmol), Compound 24.01 was prepared analogously to the procedure for the preparation of Compound 02.01.
Yield: 1.85 g (78 %) of the title compound.
LC-MS (Method 2): R, = 0.87 min; MS (ESIpos): m/z = 231 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.363 (0.42), 2.647 (16.00), 7.1 14 (0.45), 7.127 (3.05), 7.150 (3.09), 7.506 (0.58), 7.774 (2.31 ), 7.788 (2.41 ), 7.818 (3.12), 8.139 (0.43), 8.145 (0.42), 8.183 (1.53), 8.188 (1.51 ), 8.205 (1.44), 8.21 1 (1.44), 8.653 (3.24), 8.667 (3.22), 8.866 (3.08), 8.871 (2.96).
Compound 24.02
4-(2-methylpyrimidin-4-yl)benzene-1,2-diamine
Figure imgf000407_0002
To a stirred solution of 4-(2-methylpyrimidin-4-yl)-2-nitroaniline (1.16 g, 5.03 mmol) in methanol (100 mL) was added palladium on carbon (10 % w/w palladium) (161 mg, 151 pmol) and the mixture was stirred at r.t. in a hydrogen atmosphere for 3 h. The mixture was filtered and the solution was concentrated in vacuum. Silicagel chromatography gave 0.61 g (100 % yield) of the title compound.
LC-MS (Method 2): Rt = 0.65 min; MS (ESIpos): m/z = 201 [M+H]+ Compound 24.03
tert-butyl 4-[(2-{[6-(2-methylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}p3
yl)methyl]piperazine-1-carboxylate
Figure imgf000408_0001
To a stirred solution of 1 H-imidazole (61.9 mg, 909 pmol) and di-1 H-imidazol-1 - ylmethanethione (810 mg, 4.54 mmol) in dichloromethane (50 mL) was added tert-butyl 4-[(2- aminopyridin-4-yl)methyl]piperazine-1-carboxylate (1.33 g, 4.54 mmol), dissolved in dichloromethane (25 mL), at 0°C. The mixture was s tirred at r.t. for 14 h. 4-(2-methylpyrimidin- 4-yl)benzene-1 ,2-diamine (910 mg, 4.54 mmol) , dissolved in dichloromethane (25 mL), was added and the mixture was stirred at r.t. for 2 h. Water was added, and the mixture was extracted with dichloromethane. The organic phase was dried (sodium sulfate) and filtered. N,N'-dipropan-2-ylcarbodiimide (330 μΙ, 2.1 mmol) was added. The mixture was stirred at r.t. for 14 h. Further N,N'-dipropan-2-ylcarbodiimide (330 μΙ, 2.1 mmol) was added and the mixture was stirred at r.t. for 14 h. Saturated ammonium chloride solution was added, the mixture was stirred for 30 minutes and was extracted with dichloromethane. Silicagel chromatography gave 509 mg (67 % yield) of the title compound as a crude product, that was used without further purification.
LC-MS (Method 2): R, = 1.22 min; MS (ESIpos): m/z = 501 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.394 (16.00), 2.344 (1.50), 2.356 (2.01 ), 2.368 (1.46), 2.523 (1.06), 2.558 (0.70), 2.663 (4.99), 3.308 (0.91 ), 3.385 (1.13), 3.395 (0.98), 3.410 (1.12), 3.500 (2.18), 6.934 (0.54), 6.946 (0.54), 7.171 (0.84), 7.922 (0.52), 8.260 (1.01 ), 8.272 (0.94), 8.638 (1.13), 8.652 (1.02). Compound 24.04
6-(2-methylpyrimidin-4-yl)-N-[4-(piperazin-1-ylm
amine hydrochloride
Starting with tert-butyl 4-[(2-{[6-(2-methylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate (504 mg, 1.01 mmol), Compound 24.04 was prepared analogously to the procedure for the preparation of Compound 01.05.
Yield: 560 mg of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): F¾ = 0.87 min; MS (ESIpos): m/z = 401 [M+H]+
Compound 24.05
tert-butyl 4-t(2-methyl-6-{[6-(2-methylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate
Figure imgf000409_0002
To a stirred solution of tert-butyl 4-[(2-methyl-6-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)-1 H-benzimidazol-2-yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate (600 mg, 1.09 mmol) and 4-chloro-2-methylpyrimidine (253 mg, 1.97 mmol) in dioxane (5 mL) and water (1.1 mL) was added sodium carbonate (348 mg, 3.28 mmol) and Pd(dppf)CI2 . CH2CI2 (134 mg, 164 μηιοΙ). The mixture was heated to reflux for 24 h. Dichloromethane was added, the mixture was dried (magnesium sulfate), filtered and the solvent was removed in vacuum. Aminophase- silicagel chromatography followed by preparative reverse phase HPLC (gradient of water and acetonitrile containing trifluoroacetic acid as additive) gave 132 mg (24 % yield) of the title compound.
LC-MS (Method 2): Rt = 1.28 min; MS (ESIpos): m/z = 515 [M+H]+
Compound 24.06
N-[6-methyl-4-(piperazin-1 -ylmethyl)pyridin-2-yl]-6-(2-methylpyrimidin
benzimidazol-2 -amine hydrochloride
Figure imgf000410_0001
Starting with tert-butyl 4-[(2-methyl-6-{[6-(2-methylpyrimidin-4-yl)- H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate (132 mg, 256 pmol), Compound 24.06 was prepared analogously to the procedure for the preparation of Compound 01.05.
Yield: 150 mg of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): R, = 0.94 min; MS (ESIpos): m/z = 415 [M+H]+
Compound 24.07
(rac)-tert-butyl 4-[1-(2-{[6-(2-methylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4' yl)ethy I] pi perazi ne-1 -carboxy late
Figure imgf000411_0001
To a stirred solution of (rac)-tert-butyl 4-[1 -(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)- 1 H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1-carboxylate (1.00 g, 1.82 mmol) and 4-bromo-2-methylpyrimidine (505 mg, 2.92 mmol) in dioxane (9 mL) and water (1.8 mL) was added sodium carbonate (773 mg, 7.29 mmol) and Pd(dppf)CI2 . CH2CI2 (223 mg, 273 μιηοΙ). The mixture was heated to reflux for 24 h. Dichloromethane was added, the mixture was dried (magnesium sulfate), filtered and the solvent was removed in vacuum. Silicagel chromatography gave 0.70 g (75 % yield) of the title compound.
LC-MS (Method 2): R, = 1.25 min; MS (ESIpos): m/z = 515 [M+H]+
Compound 24.08
(rac)-6-(2-methylpyrimidin-4-yl)-N-{4-[1 -(piperazin-1 -yl)ethyl]pyrid
benzimidazol-2 -amine hydrochloride
Figure imgf000411_0002
Starting with (rac)-tert-butyl 4-[1-(2-{[6-(2-methylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazine-1 -carboxylate (700 mg, 1.36 mmol), Compound 24.08 was prepared analogously to the procedure for the preparation of Compound 01.05. Yield: 830 mg of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): R, = 0.89 min; MS (ESIpos): m/z = 415 [M+H]+
Compound 25.01
6-(2-methoxypyrimidin-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H-benzi amine hydrochloride
Figure imgf000412_0001
Starting with tert-butyl 4-[(2-{[6-(2-methoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin- 4-yl)methyl]piperazine-1 -carboxylate (480 mg, 929 pmol), Compound 25.01 was prepared analogously to the procedure for the preparation of Compound 01.05.
Yield: 460 mg of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): Rt = 0.92 min; MS (ESIpos): m/z = 417 [M+H]+
Compound 26.01
6-(2-ethoxypyrimidin-4-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]-1 H-benzimidazol-2 amine hydrochloride
Figure imgf000412_0002
Starting with tert-butyl 4-[(2-{[6-(2-ethoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1-carboxylate (460 mg, 867 μιτιοΙ), Compound 26.01 was prepared analogously to the procedure for the preparation of Compound 01.05.
Yield: 480 mg of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): R, = 1.03 min; MS (ESIpos): m/z = 431 [M+H]+
Compound 26.02
(rac)-tert-butyl 4-[-1-(2^[6-(2-ethoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin 4-yl)ethyl]piperazine-1-carboxylate
Figure imgf000413_0001
To a stirred solution of tert-butyl (rac)-4-[1 -(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)- 1 H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1 -carboxylate (435 mg, 793 mol) and 4-chloro-2-ethoxypyrimidine (176 mg, 1.11 mmol) in dioxane (5 mL) and water (0.8 mL) was added sodium carbonate (252 mg, 2.38 mmol) and Pd(dppf)CI2 . CH2CI2 (97.1 mg, 1 19 mol). The mixture was heated to reflux for 24 h. Dichloromethane was added, the mixture was dried (magnesium sulfate), filtered and the solvent was removed in vacuum. Silicagel chromatography gave 215 mg (50 % yield) of the title compound.
LC-MS (Method 2): R, = 1.36 min; MS (ESIpos): m/z = 545 [M+H]+
Compound 26.03
(rac)-6-(2-ethoxypyrimidin-4-yl)-N-{4-[1 -(piperazin-1-yl)ethyl]pyridin-2-yl}-1 H- benzimidazol-2-amine hydrochloride
Figure imgf000414_0001
Starting with (rac)-tert-butyl 4-[1-(2-{[6-(2-ethoxypyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazine-1 -carboxylate (215 mg, 395 Mmol), Compound 26.03 was prepared analogously to the procedure for the preparation of Compound 01.05.
Yield: 370 mg of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): R, = 1.04 min; MS (ESIpos): m/z = 445 [M+H]+
Compound 27.01
tert-butyl 4-{[2-({6-[2-(trifluoromethyl)pyrimidin-4-yl]-1 H-benzimidazol-2
yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate
Figure imgf000414_0002
To a stirred solution of tert-butyl 4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate (500 mg, 936 pmol) and 4-chloro-2-(trifluoromethyl)pyrimidine (307 mg, 1.68 mmol) in dioxane (5 mL) and water (0.9 mL) was added sodium carbonate (297 mg, 2.81 mmol) and Pd(dppf)Cl2 . CH2CI2 (1 15 mg, 140 μιηοΙ). The mixture was heated to reflux for 24 h. Dichloromethane was added, the mixture was dried (magnesium sulfate), filtered and the solvent was removed in vacuum. Silicagel chromatography gave 540 mg (83 % yield) of the title compound.
LC- S (Method 2): R, = 1.40 min; MS (ESIpos): m/z = 555 [M+H]+
Compound 27.02
N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]-6-[2-(trifluoromethyl)pyrimidin
benzimidazol-2-amine hydrochloride
Figure imgf000415_0001
Starting with tert-butyl 4-{[2-({6-[2-(trifluoromethyl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate (540 mg, 974 pmol), Compound 27.02 was prepared analogously to the procedure for the preparation of Compound 01.05.
Yield: 560 mg of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): Rt = 1.08 min; MS (ESIpos): m/z = 455 [M+H]+
Compound 29.01
(rac)-tert-butyl 4- 1 -[2-({6-[6-(trifluoromethyl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate
Figure imgf000416_0001
To a stirred solution of tert-butyl (rac)-4-[1-(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)- 1 H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1 -carboxylate (1.00 g, 1.82 mmol) and 4-bromo-6-(trifluoromethyl)pyrimidine (786 mg, 3.46 mmol) in dioxane (9 mL) and water (1.8 mL) was added sodium carbonate (773 mg, 7.29 mmol) and Pd(dppf)CI2 . CH2CI2 (223 mg, 273 pmol). The mixture was heated to reflux for 24 h. Dichloromethane was added, the mixture was dried (magnesium sulfate), filtered and the solvent was removed in vacuum. Silicagel chromatography gave 330 mg (32 % yield) of the title compound.
LC-MS (Method 2): R, = 1.42 min; MS (ESIpos): m/z = 569 [M+H]+
Compound 29.02
(rac)-N-{4-[1-(piperazin-1 -yl)ethyl]pyridin-2-yl}-6-[6-(trifluoromethyl)pyrimidin-4-yl]-1 H- benzimidazol-2-amine
Figure imgf000416_0002
Starting with (rac)-tert-butyl 4-{1-[2-({6-[6-(trifluoromethyl)pyrimidin-4-yl]-1 H-benzimidazo!-2- yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate (330 mg, 580 Mmol), Compound 29.02 was prepared analogously to the procedure for the preparation of Compound 01.05. Yield: 370 mg of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): R, = 1.12 min; MS (ESIpos): m/z = 469 [M+H]+
Compound 30.01
tert-butyl 4-[(2-{[6-(6-methylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- y l)methyl] pi perazi ne-1 -carboxylate
Figure imgf000417_0001
To a stirred solution of tert-butyl 4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate (500 mg, 936 μιηοΙ) and 4-bromo-6-methylpyrimidine (291 mg, 1.68 mmol) in dioxane (5 mL) and water (0.9 mL) was added sodium carbonate (297 mg, 2.81 mmol) and Pd(dppf)C . CH2CI2 (153 mg, 187 μιηοΙ). The mixture was heated to reflux for 24 h. Dichloromethane was added, the mixture was dried (magnesium sulfate), filtered and the solvent was removed in vacuum. Aminophase-silicagel chromatography gave 480 mg (100 % yield) of the title compound as a crude product that was used without further purification.
LC-MS (Method 2): R, = 1 .20 min; MS (ESIpos): m/z = 501 [M+H]+
Compound 30.02
6-(6-methylpyrimidin-4-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]-1 H-be
amine hydrochloride
Figure imgf000418_0001
Starting with tert-butyl 4-[(2 [6-(6-methylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate (480 mg, 959 μιηοΙ), Compound 30.02 was prepared analogously to the procedure for the preparation of Compound 01.05.
Yield: 600 mg of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): R, = 0.86 min; MS (ESIpos): m/z = 401 [M+H]+
Compound 30.03
(rac)-tert-butyl 4-[1-(2-{[6-(6-methylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}py yl)ethyl] pi perazi ne-1 -carboxylate
Figure imgf000418_0002
To a stirred solution of (rac)-tert-butyl 4-[(1 -(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)- 1 H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1 -carboxylate (1.00 g, 1.82 mmol) and 4-bromo-6-methylpyrimidine (631 mg, 3.65 mmol) in dioxane (9 mL) and water (1.8 mL) was added sodium carbonate (773 mg, 7.29 mmol) and Pd(dppf)CI2 . CH2CI2 (223 mg, 273 μηηοΙ). The mixture was heated to reflux for 24 h. Dichloromethane was added, the mixture was dried (magnesium sulfate), filtered and the solvent was removed in vacuum. Aminophase- silicagel chromatography gave 0.70 g (75 % yield) of the title compound.
LC-MS (Method 2): Rt = 1.24 min; MS (ESIpos): m/z = 515 [M+H]+
Compound 30.04
(rac) 6-(6-methylpyrimidin-4-yl)-N-{4-[1-(piperazin-1 -yl)ethyl]pyrid
benzimidazol-2-amine hydrochloride
Figure imgf000419_0001
Starting with (rac)-tert-butyl 4-[1 -(2-{[6-(6-methylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazine-1-carboxylate (700 mg, 1.36 mmol), Compound 30.04 was prepared analogously to the procedure for the preparation of Compound 01.05.
Yield: 600 mg of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): R, = 0.89 min; MS (ESIpos): m/z = 415 [M+H]+
Compound 31.01
tert-butyl 4-[(2-{[6-(2,6-dimethylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1-carboxylate
Figure imgf000419_0002
Starting with tert-butyl 4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yi)-1 H-benzimidazol- 2-yl]amino}pyridin-4-yl)methyl]piperazine-1-carboxylate (500 mg, 936 pmol) and 4-chlorc~2,6- dimethylpyrimidine (267 mg, 1.87 mmol), Compound 31.01 was prepared analogously to the procedure for the preparation of Compound 02.01.
Yield: 180 mg (37 % yield) of the title compound.
LC-MS (Method 2): Rt = 1.23 min; MS (ESIpos): m/z = 515 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.395 (16.00), 2.344 (0.90), 2.357 (1.30), 2.369 (0.91 ), 2.461 (4.52), 2.615 (4.62), 3.348 (1.1 1 ), 3.500 (1.59), 5.759 (1.20), 7.900 (0.62), 7.904 (0.60), 8.256 (0.82), 8.270 (0.78).
Compound 31.02
6-(2,6-dimethylpyrimidin-4-yl)-N-[4-(pipera^
2 -amine hydrochloride
Figure imgf000420_0001
Starting with tert-butyl 4-[(2-{[6-(2,6-dimethylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazine-1-carboxylate (180 mg, 350 pmol), Compound 31.02 was prepared analogously to the procedure for the preparation of Compound 01.05.
Yield: 300 mg of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): Rt = 0.88 min; MS (ESIpos): m/z = 415 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.050 (1.02), 1.063 (2.72), 1.067 (0.66), 2.618 (14.37), 2.754 (16.00), 3.162 (6.96), 3.341 (1.31 ), 3.383 (1.12), 3.393 (1.07), 3.408 (1.39), 3.425 (2.78), 3.443 (3.83), 3.455 (2.82), 3.460 (2.44), 3.484 (0.79), 3.551 (1.21 ), 4.424 (1.10), 7.566 (2.80), 7.588 (1.03), 7.783 (2.68), 7.805 (2.74), 8.062 (2.21 ), 8.220 (2.22), 8.224 (2.16), 8.241 (1.97), 8.246 (1.88), 8.536 (2.01 ), 8.549 (1.84), 8.586 (3.18), 8.589 (3.09). Compound 32.01
tert-butyl 4-[(2-{[6-(5,6-dimethylpyrimidin-4-yl)-1 H^
y l)methyl] pi perazi ne-1 -carboxylate
Figure imgf000421_0001
Starting with tert-butyl 4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-benzimidazol- 2-yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate (500 mg, 936 pmol) and 4-chloro-5,6- dimethylpyrimidine (267 mg, 1.87 mmol), Compound 32.01 was prepared analogously to the procedure for the preparation of Compound 02.01.
Yield: 210 mg (44 %) of the title compound.
LC-MS (Method 2): Rt = 1.19 min; MS (ESIpos): m/z = 515 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1 .066 (16.00), 1 .395 (9.02), 2.519 (2.20), 3.159 (1.79), 3.172 (1.91 ), 3.939 (2.61 ).
Compound 32.02
6-(5,6-dimethylpyrimidin-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H-benzimidazol- 2-amine hydrochloride
Figure imgf000421_0002
Starting with tert-butyl 4-[(2-{[6-(5,6-dimethylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate (280 mg, 544 pmol), Compound 32.02 was prepared analogously to the procedure for the preparation of Compound 01.05. Yield: 300 mg of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): R, = 0.87 min; MS (ESIpos): m/z = 416 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.062 (16.00), 2.318 (0.97), 2.321 (1.01 ), 2.335 (5.05), 2.582 (5.48), 3.161 (8.07), 3.456 (1.17), 7.592 (0.96), 7.596 (0.87), 7.613 (1.21 ), 7.617 (1.23), 7.780 (1.05), 7.801 (0.83), 7.914 (1.09), 7.918 (1.14), 8.988 (1.86).
Compound 33.01
6-(2,5-dimethylpyrimidin-4-yl)-N 4-(piperazin-1-ylmethyl)pyridin-2-yl]-1H-benzimidazol- 2-amine hydrochloride
Figure imgf000422_0001
Starting with tert-butyl 4-[(2-{[6-(2,5-dimethylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazine-1-carboxylate (390 mg, 758 pmol), Compound 33.01 was prepared analogously to the procedure for the preparation of Compound 01.05.
Yield: 400 mg of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): Rt = 0.86 min; MS (ESIpos): m/z = 415 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.409 (1 1 .56), 2.695 (13.19), 3.057 (1.28), 3.160 (16.00), 3.468 (2.69), 5.760 (7.21 ), 7.582 (2.42), 7.726 (1.42), 7.730 (1.37), 7.747 (2.31 ), 7.750 (2.42), 7.789 (3.08), 7.81 1 (1.58), 8.049 (2.58), 8.053 (2.81 ), 8.559 (1.87), 8.572 (1.71 ), 8.760 (4.15). Compound 34.01
(rac)-tert-butyl 4-[1-(2-{[6-(6-methoxypyrimidin-4-yl)-1 H^enzimidazol-2-yl]amino}pyridin 4-yl)ethyl]piperazine-1 -carboxylate
Figure imgf000423_0001
To a stirred solution of (rac)-tert-butyl 4-[1 -(2-{[6-(4,4,5)5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)- 1 H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1 -carboxylate (1.00 g, 1.82 mmol) and 4-chloro-6-methoxypyrimidine (422 mg, 2.92 mmol) in dioxane (9 mL) and water (1.8 mL) was added sodium carbonate (773 mg, 7.29 mmol) and Pd(dppf)CI2 . CH2CI2 (223 mg, 273 pmol). The mixture was heated to reflux for 24 h. Further 4-chloro-6-methoxypyrimidine (130 mg) was added and the mixture was heated to reflux for 24 h. Dichloromethane was added, the mixture was dried (magnesium sulfate), filtered and the solvent was removed in vacuum. Silicagel chromatography gave 0.43 g (45 % yield) of the title compound.
LC-MS (Method 2): F¾ = 1.34 min; MS (ESIpos): m/z = 531 [M+H]+
Compound 34.02
(rac)-6-(6-methoxypyrimidin-4-yl)-N-{4-[1 -(piperazin-1-yl)ethyl]pyridin-2-yl}-1 H- benzimidazol-2-amine hydrochloride
Figure imgf000423_0002
Starting with (rac)-tert-butyl 4-[1 -(2-{[6-(6-methoxypyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazine-1-carboxylate (430 mg, 810 mol), Compound 34.02 was prepared analogously to the procedure for the preparation of Compound 01.05. Yield: 530 mg of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): R, = 0.97 min; MS (ESIpos): m/z = 431 [M+H]+
Compound 35.01
tert-butyl 4-[(2-{[6-(5-methoxypyrimidin-4-yl)-1H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1-carboxylate
Figure imgf000424_0001
To a stirred solution of tert-butyl 4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate (800 mg, 1.50 mmol)in dioxane (20 mL, 230 mmol) was added aqueous sodium carbonate solution (2.2 ml_, 2.0 M, 4.5 mmol), 4-chloro-5-methoxypyrimidine (335 mg, 97 % purity, 2.25 mmol) and Pd(dppf)C . CH2CI2 (183 mg, 225 pmol). The mixture was heated to 120°C in a sealed tube over night under argon atmosphere. Further 4-chloro-5-methoxypyrimidine (165 mg, 97 % purity, 1 .12 mmol) and Pd(dppf)Cl2 . CH2CI2 (122 mg, 150 pmol) were added and the mixture was stirred at 120Ό. Dichloromethane/methanol (100:1 ) was added a nd the mixture was extracted with half- saturated potassium carbonate solution. The solvent of the organic phase was removed in vacuum and silicagel chromatography gave 900 mg of the title compound as a crude product that was used for the next step without further purification.
LC-MS (Method 2): R, = 1.17 min; MS (ESIpos): m/z = 517 [M+H]+
Compound 35.02
6-(5-methoxypyrimidin-4-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]-1 H-ben
amine
Figure imgf000425_0001
To a stirred solution of crude tert-butyl 4-[(2-{[6-(5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazine-1-carboxylate (900 mg, approx. 1.05 mmol) in dichloromethane (10 mL) and methanol (1 mL) was added TFA (20 mL). The mixture was stirred at r.t. for 0.5 h. The solvent was removed in vacuum. A half-saturated solution of potassium carbonate was added and the mixture was extracted with a mixture of chloroform and methanol (5: 1 ). The organic phase was dried (sodium sulfate), filtered and the solvent was removed in vacuum. Aminophase-silicagel chromatography gave 180 mg of the title compound.
LC-MS (Method 2): Rt = 0.89 min; MS (ESIpos): m/z = 417 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.828 (0.67), 0.846 (0.50), 0.855 (0.59), 0.934 (0.96), 0.950 (1.04), 1.066 (1 1.80), 1.234 (0.54), 1.299 (8.49), 1.392 (4.25), 1.955 (1.55), 2.083 (0.70), 2.327 (1.20), 2.357 (4.27), 2.523 (1.17), 2.669 (0.42), 2.758 (4.61 ), 2.770 (6.71 ), 2.781 (5.30), 2.940 (1.91 ), 3.355 (1.29), 3.438 (2.63), 3.451 (7.61 ), 3.474 (1.16), 4.021 (16.00), 5.758 (1 1 .44), 6.899 (0.57), 6.916 (1.96), 6.930 (1.89), 7.172 (2.98), 8.228 (0.79), 8.241 (0.83), 8.253 (3.16), 8.266 (3.03), 8.631 (6.84), 8.828 (6.58).
Compound 35.03
(rac)-tert-butyl 4-[1-(2-{[6-(5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin- 4-yl)ethyl]piperazine-1 -carboxylate
Figure imgf000426_0001
To a stirred solution of (rac)-tert-butyl 4-[1 -(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)- 1 H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1 -carboxylate (1.60 g, 2.92 mmol) and 4-chloro-5-methoxypyrimidine (759 mg, 5.25 mmol) in dioxane (14 mL) and water (2.8 mL) was added sodium carbonate (1.24 g, 1 1.7 mmol) and Pd(dppf)Cl2 . CH2CI2 (357 mg, 438 pmol). The mixture was heated to reflux for 24 h. Dichloromethane was added, the mixture was dried (magnesium sulfate), filtered and the solvent was removed in vacuum. Silicagel chromatography gave 880 mg (57 % yield) of the title compound.
LC-MS (Method 2): F¾ = 1.27 min; MS (ESIpos): m/z = 531 [M+H]+
Compound 35.04
(rac)-6-(5-methoxypyrimidin-4-yl)-N-{4-[1 -(piperazin-1 -yl)ethyl]pyridin
benzimidazol-2-amine hydrochloride
Figure imgf000426_0002
Starting with (rac)-tert-butyl 4-[(1 R)-1 -(2-{[6-(5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazine-1 -carboxylate (880 mg, 1.66 mmol), Compound 35.04 was prepared analogously to the procedure for the preparation of Compound 0 .05. Yield: 900 mg of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): R, = 0.87 min; MS (ESIpos): m/z = 431 [M+H]+
Compound 36.01
4-(5-methoxypyrimidin-4-yl)-2-nitroaniline
Figure imgf000427_0001
Starting with 4-chloro-5-methoxypyrimidine (1.10 g, 98 % purity, 7.46 mmol) and (4-amino-3- nitrophenyl)boronic acid (2.44 g, 13.4 mmol), Compound 36.01 was prepared analogously to the procedure for the preparation of Compound 02.01.
Yield: 1.59 g (86 % yield) of the title compound.
LC-MS (Method 2): R, = 0.85 min; MS (ESIpos): m/z = 247 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 4.023 (16.00), 7.094 (2.83), 7.1 17 (2.85), 7.527 (0.70), 7.531 (0.82), 7.535 (0.62), 7.543 (0.71 ), 7.545 (0.96), 7.548 (0.93), 7.554 (0.78), 7.556 (0.72), 7.563 (1.1 1 ), 7.565 (0.83), 7.571 (0.89), 7.591 (0.72), 7.595 (1.34), 7.612 (1.18), 7.621 (1.23), 7.624 (1.71 ), 7.629 (0.83), 7.642 (0.84), 7.645 (0.62), 7.821 (2.69), 8.234 (1.52), 8.239 (1.49), 8.256 (1.34), 8.262 (1.44), 8.646 (5.99), 8.808 (6.57), 8.961 (2.72), 8.966 (2.76).
Compound 36.02
4-(4-amino-3-nitrophenyl)pyrimidin-5-ol
Figure imgf000427_0002
To a stirred solution of 4-(5-methoxypyrimidin-4-yl)-2-nitroaniline (1.40 g, 5.69 mmol) in DMF (21 mL) was added sodium methanethiolate (1.99 g, 28.4 mmol) and the mixture was stirred at 60° C for 3 h. A half-saturated sodium chloride sol ution was added and the mixture was extracted with chloroform / methanol (9: 1 ). The aqueous phase was concentrated in vacuum to give 15.7 g of the title compound as a crude product that was used without purification.
LC-MS (Method 1 ): Rt = 0.70 min; MS (ESIpos): m/z = 233 [M+H]+
Compound 36.03
2-nitro-4-[5-(propan-2-yloxy)pyrimidin-4-yl]aniline
Figure imgf000428_0001
To a stirred solution of 4-(4-amino-3-nitrophenyl)pyrimidin-5-ol (15.7 g, approx. 5.69 mmol) in DMA (30 ml.) was added potassium carbonate (2.36 g, 17.1 mmol) and 2-iodopropane (850 μΙ, 8.5 mmol) and the mixture was stirred at 70° C for 1 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with half-saturated sodium chloride solution, dried (sodium sulfate), filtered and the solvent was removed in vacuum. Silicagel chromatography gave 822 mg of the title compound.
LC-MS (Method 1 ): R, = 1.00 min; MS (ESIpos): m/z = 275 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.364 (14.90), 1.379 (16.00), 4.909 (0.81 ), 4.924 (1.10), 4.939 (0.81 ), 7.090 (2.41 ), 7.1 12 (2.38), 7.820 (2.06), 8.267 (1.30), 8.272 (1.33), 8.290 (1.19), 8.295 (1.25), 8.656 (4.48), 8.782 (6.98), 9.120 (2.42), 9.126 (2.45).
Compound 36.04
4-[5-(propan-2-yloxy)pyrimidin-4-yl]benzene-1,2- ■<diamine
Figure imgf000429_0001
To a stirred solution of 2-nitro-4-[5-(propan-2-yloxy)pyrimidin-4-yl]aniline (865 mg, 3.15 mmol) in ethanol (34 mL) and dichloromethane (34 mL) was added palladium on carbon (10 % w/w palladium) (336 mg) and the mixture was stirred at r.t. in a hydrogen atmosphere for 2 h. The mixture was filtered, and the solution was concentrated in vacuum to give 750 mg (88 % yield) of the title compound as crude product, that was used for the next step without purification.
LC-MS (Method 1 ): R, = 0.63 min; MS (ESIpos): m/z = 245 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.229 (1.13), 1.246 (1.1 1 ), 1.308 (16.00), 1.323 (15.97), 2.903 (0.65), 4.733 (0.90), 4.748 (1.21 ), 4.763 (0.92), 5.758 (1.01 ), 6.530 (2.76), 6.550 (2.66), 7.440 (1.46), 7.445 (1.65), 7.460 (1.23), 7.466 (1.45), 7.511 (3.05), 7.516 (2.62), 8.454 (4.48), 8.662 (7.08).
Compound 36.05
(+)-tert-butyl 4-[(1 R or 1S)-1 -(2-aminopyridin-4-yl)ethyl]piperazine-1 -carboxylate (Single Stereoisomer A)
Figure imgf000429_0002
To a stirred solution of (2R,3R)-2,3-bis(benzoyloxy)butanedioic acid (5.85 g, 16.3 mmol) in 2- propanol (200 mL) was added (rac)-tert-butyl-4-[1-(2-aminopyridin-4-yl)ethyl]piperazine-1- carboxylate (10.0 g, 32.6 mmol), dissolved in warm 2-propanol (420 mL). A clear solution formed, and after 30 minutes a precipitate started to form. The mixture was stirred at r.t. for 16 h. The precipitate was collected by filtration and was dissolved in dichloromethane / methanol (100: 1 ) and half-saturated potassium carbonate solution. The phases were separated, the organic phase was dried (sodium sulfate), filtered and the solvent was removed in vacuum to give 3.42 g of enantiomerically enriched tert-butyl 4-[(1 R or 1 S)-1 -(2-aminopyridin-4- yl)ethyl]piperazine-1-carboxylate (Optical rotation:[a]D = +17.5° from DMSO solution, c = 4.4 mg/mL; enantiomeric purity: 92.5%)
The enantiomerically enriched tert-butyl 4-[(1 R or 1 S)-1 -(2-aminopyridin-4-yl)ethyl]piperazine- 1 -carboxylate (3.40 g, 11.1 mmol) was dissolved in warm 2-propanol (130 ml_) and added to a stirred solution of (2R,3R)-2,3-bis(benzoyloxy)butanedioic acid (3.38 g, 9.43 mmol) in 2- propanol (50 ml_). A clear solution formed, and after 30 minutes a precipitate started to form. The mixture was stirred at r.t. for 72 h. The precipitate was collected by filtration and was dissolved in dichloromethane / methanol (100: 1 ) and half-saturated potassium carbonate solution. The phases were separated, the organic phase was dried (sodium sulfate), filtered and the solvent was removed in vacuum to give 3.04 g of the title compound.
Optical rotation :[a]D = +20.1 °from DMSO solution, c = 3.5 mg/mL;
Chiral HPLC (Instrument: Agilent HPLC 1260; Column : Chiralpak IA 3μ 100x4,6mm; Eluent A: acetonitrile + 0.1 Vol-% diethylamine (99%); isocratic: 100% A; Flow 1 .0 mL/min; Temperature: 25 °C; DAD 280 nm): R , = 5.34 min (99.15%); (Minor Isomer: Rt = 3.24 min (0.85%)).
LC-MS (Method 2): R, = 1.01 min; MS (ESIpos): m/z = 307 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.027 (0.93), 1.042 (0.92), 1.053 (0.51 ), 1.200 (1.79), 1.216 (1.84), 1.370 (16.00), 3.332 (3.69), 5.757 (5.64), 5.808 (1.32), 6.355 (0.91 ), 6.409 (0.54), 6.413 (0.51 ), 6.422 (0.56), 6.426 (0.52), 7.803 (0.75), 7.804 (0.73), 7.816 (0.73).
Compound 36.06
N-{4-[(1 R or 1S)-1-(piperazin-1 -yl)ethyl]pyridin-2-yl}-6-[5-(propan-2-yloxy)pyrimidin-4-yl]- I H-benzimidazol-2-amine hydrochloride
Figure imgf000430_0001
Starting with tert-butyl 4-{(1 R or 1 S)-1 -[2-({6-[5-(propan-2-yloxy)pyrimidin-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate (450 mg, 805 pmol), Compound 36.06 was prepared analogously to the procedure for the preparation of Compound 01.05.
Yield: 645 mg of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): R, = 0.98 min; MS (ESIpos): m/z = 459 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.357 (1.50), 1 .372 (16.00), 1.386 (15.28), 1.710 (2.53), 1.727 (2.57), 3.466 (0.99), 3.483 (1.08), 3.495 (1.03), 4.924 (0.98), 4.939 (1.33), 4.954 (0.99), 5.758 (4.99), 7.605 (2.21), 7.766 (2.03), 7.787 (2.15), 8.151 (1.73), 8.154 (1.68), 8.172 (1.42), 8.176 (1.51 ), 8.496 (2.63), 8.500 (2.50), 8.593 (1.65), 8.607 (1.53), 8.764 (4.88), 8.887 (6.75).
Compound 37.01
4-(1-methyl-1 H-pyrazol-4-yl)-2-nitroaniline
Figure imgf000431_0001
Starting with (4-amino-3-nitrophenyl)boronic acid (2.00 g, 11.0 mmol) and 4-bromo-l-methyl- 1 H-pyrazole (1.1 ml_, 11 mmol), Compound 37.01 was prepared analogously to the procedure for the preparation of Compound 02.01.
Yield: 1.78 g (74 % yield) of the title compound.
LC-MS (Method 2): Rt = 0.82 min; MS (ESIpos): m/z = 219 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1 .171 (0.58), 1.986 (1.13), 3.325 (16.00), 7.027 (6.54), 7.048 (6.92), 7.093 (2.33), 7.115 (2.43), 7.415 (7.31 ), 7.522 (3.25), 7.528 (1.47), 7.543 (0.68), 7.546 (0.90), 7.549 (0.86), 7.554 (0.69), 7.564 (1.07), 7.566 (0.82), 7.571 (0.75), 7.573 (0.71 ), 7.596 (1.16), 7.613 (1.10), 7.622 (1.77), 7.625 (5.38), 7.631 (4.47), 7.643 (1.13), 7.647 (3.78), 7.652 (3.56), 7.742 (1.29), 7.748 (1.30), 7.764 (1.16), 7.770 (1.23), 7.797 (9.14), 7.799 (9.90), 8.071 (6.92), 8.077 (6.71 ), 8.091 (9.29), 8.144 (2.50), 8.150 (2.42). Compound 37.02
4-(1 -methyl-1 H-pyrazol-4-yl)benzene-1 ,2-diamine
Figure imgf000432_0001
To a stirred solution of 4-(1 -methyl-1 H-pyrazol-4-yl)-2-nitroaniline (3.28 g, 15.0 mmol) in ethanol (15 mL) and dichloromethane (35 mL) was added palladium on carbon (10 % w/w palladium) (800 mg) and the mixture was stirred at r.t. in a hydrogen atmosphere for 48 h. The mixture was filtered, and the solution was concentrated in vacuum. Aminophase silicagel chromatography gave 2.17 g (77 % yield) of the title compound.
LC- S (Method 2): R, = 0.56 min; MS (ESIpos): m/z = 189 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.163 (0.68), 3.177 (0.71 ), 3.31 1 (16.00), 4.390 (5.12), 4.420 (5.20), 6.467 (4.63), 6.487 (6.97), 6.560 (3.87), 6.565 (4.03), 6.579 (2.52), 6.584 (2.80), 6.673 (6.39), 6.678 (5.99), 7.528 (8.51 ), 7.530 (8.53), 7.547 (0.68), 7.550 (0.67), 7.565 (0.81 ), 7.572 (0.61 ), 7.574 (0.57), 7.598 (0.96), 7.615 (0.81 ), 7.624 (0.98), 7.627 (1.29), 7.632 (0.66), 7.644 (0.69), 7.647 (0.52), 7.745 (7.87), 7.747 (7.47).
Compound 37.03
tert-butyl 4-[(2-{[6-(1 -methyl-1 H-pyrazol-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1-carboxylate
Figure imgf000432_0002
To a stirred solution of 1 H-imidazole (157 mg, 2.31 mmol) and di-1 H-imidazol-1- ylmethanethione (2.16 g, 95 % purity, 1 1.5 mmol) in dichloromethane (150 mL) was added tert-butyl 4-[(2-aminopyridin-4-yl)methyl]piperazine-1 -carboxylate (3.37 g, 1 1.5 mmol) , dissolved in dichloromethane (50 mL), at 0° C. The mixture was stirred at r.t. for 14 h. 4-(1- methyl-1 H-pyrazol-4-yl)benzene-1 ,2-diamine (2.17 g, 1 1.5 mmol), suspended in dichloromethane (50 ml_), was added and the mixture was stirred at r.t. for 2 h. Water was added and the mixture was extracted with dichloromethane.
The organic phase was dried (sodium sulfate) and filtered. N,N'-dipropan-2-ylcarbodiimide (5.3 mL, 34 mmol) was added and the mixture was stirred at r.t. for 14 h. Saturated ammonium chloride solution was added, the mixture was stirred for 30 minutes and the mixture was extracted with dichloromethane. The organic phase was dried (sodium sulfate) and the solvent was removed in vacuum. Silicagel chromatography followed by aminophase-silicagel chromatography gave 900 mg of the title compound as a crude product, that was used without further purification.
LC-MS (Method 2): Rt = 1.17 min; MS (ESIpos): m/z = 489 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.989 (4.82), 1.005 (5.00), 1.072 (0.41 ), 1.088 (0.42), 1.385 (5.47), 1.390 (4.18), 1.394 (16.00), 1.988 (0.57), 2.341 (1.05), 2.354 (1.52), 2.366 (1.16), 2.523 (1.79), 2.539 (0.79), 3.308 (1.10), 3.489 (1.86), 3.860 (2.88), 5.760 (0.69), 6.895 (0.54), 6.898 (0.53), 6.908 (0.59), 6.911 (0.58), 7.176 (0.70), 8.234 (0.85), 8.248 (0.81 ).
Compound 37.04
6-(1 -methyl-1 H-pyrazol-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H-benzimidazol-2- amine hydrochloride
Figure imgf000433_0001
Starting with tert-butyl 4-[(2-{[6-(1 -methyl-1 H-pyrazol-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin- 4-yl)methyl]piperazine-1 -carboxylate (900 mg, 1.84 mmol), Compound 37.04 was prepared analogously to the procedure for the preparation of Compound 01.05.
Yield: 930 mg of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): Rt = 0.86 min; MS (ESIpos): m/z = 389 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.987 (14.24), 1.004 (14.09), 2.323 (0.52), 2.327 (0.73), 2.331 (0.52), 2.523 (2.28), 2.665 (0.56), 2.669 (0.78), 2.673 (0.55), 3.162 (0.63), 3.326 (1.27), 3.564 (4.94), 3.610 (0.88), 3.627 (1.12), 3.643 (0.83), 3.892 (16.00), 4.880 (0.70), 5.760 (1.11 ), 7.524 (2.18), 7.555 (1.90), 7.559 (2.01 ), 7.576 (2.81 ), 7.580 (2.89), 7.631 (3.04), 7.653 (1.71 ), 7.753 (2.90), 7.756 (2.90), 7.861 (5.11 ), 7.863 (5.41 ), 8.157 (4.62), 8.536 (1.47), 8.549 (1.42).
Compound 38.01
4-(1-ethyl-1 H-pyrazol-4-yl)-2-nitroaniline
Figure imgf000434_0001
Starting with 4-bromo-2-nitroaniline (2.00 g, 9.22 mmol) and (1 -ethy!-1 H-pyrazol-4-yl)boronic acid (2.17 g, 95 % purity, 14.7 mmol), Compound 38.01 was prepared analogously to the procedure for the preparation of Compound 02.01.
Yield: 1.31 g (55 %) of the title compound.
LC-MS (Method 2): Rt = 0.90 min; MS (ESIpos): m/z = 233 [M+H]+
H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.369 (6.76), 1.388 (16.00), 1.406 (6.71 ), 4.093 (1.84), 4.1 1 1 (5.81 ), 4.130 (5.62), 4.147 (1.80), 7.024 (3.78), 7.046 (4.02), 7.424 (4.59), 7.640 (2.21 ), 7.645 (2.35), 7.661 (2.09), 7.667 (2.13), 7.808 (6.27), 7.810 (6.28), 8.086 (4.16), 8.091 (4.12), 8.159 (5.65), 8.161 (5.49).
Compound 38.02
4-(1 -ethyl-1 H-pyrazol-4-yl)benzene-1,2-diamine
Figure imgf000434_0002
To a stirred solution of4-(1 -ethyl-1 H-pyrazol-4-yl)-2-nitroaniline (1.30 g, 5.60 mmol) in ethanol (60 ml_) and dichloromethane (60 mL) was added palladium on carbon (10 % w/w palladium) (596 mg) and the mixture was stirred at r.t. in a hydrogen atmosphere for 2 h. The mixture was filtered and the solution was concentrated in vacuum. Aminophase-silicagel chromatography gave 1.00 g (79 % yield) of the title compound. LC-MS (Method 2): R, = 0.64 min; MS (ESIpos): m/z = 203 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.347 (7.43), 1.366 (16.00), 1.369 (2.33), 1.383 (8.05), 1.404 (1.10), 2.522 (1.43), 4.062 (2.22), 4.081 (6.84), 4.099 (6.77), 4.117 (2.44), 4.406 (5.69), 4.433 (5.86), 5.759 (0.93), 6.464 (3.89), 6.484 (5.52), 6.570 (3.00), 6.575 (3.27), 6.589 (2.16), 6.594 (2.44), 6.681 (4.96), 6.686 (5.02), 7.542 (7.65), 7.803 (7.45).
Compound 38.03
6-(1 -ethyl-1 H^yrazol-4-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]-1 H-benzimidazol-^ amine hydrochloride
Figure imgf000435_0001
Starting with tert-butyl 4-[(2-{[6-(1-ethyl-1 H-pyrazol-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate (300 mg, 597 μιηοΙ), Compound 38.03 was prepared analogously to the procedure for the preparation of Compound 01.05.
Yield: 125 mg of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): R, = 0.91 min; MS (ESIpos): m/z = 403 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.402 (6.92), 1.420 (16.00), 1 .439 (6.91 ), 2.327 (0.52), 2.523 (2.74), 2.669 (0.52), 3.338 (1.36), 3.486 (0.74), 3.564 (2.89), 4.153 (1.66), 4.171 (5.01 ), 4.189 (5.08), 4.207 (1.73), 4.417 (1.08), 4.585 (0.85), 7.533 (2.86), 7.564 (2.37), 7.568 (2.59), 7.585 (3.60), 7.589 (3.77), 7.633 (4.03), 7.654 (2.17), 7.766 (3.34), 7.770 (3.75), 7.865 (6.59), 7.867 (6.85), 8.205 (5.94), 8.534 (2.00), 8.548 (1.93). Compound 39.01
1 -(cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole
Figure imgf000436_0001
To a stirred solution of 4-(4, 4,5, 5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (8.00 g, 41.2 mmol) in DMF (130 ml_) was added potassium carbonate (17.1 g, 124 mmol) and (bromomethyl)cyclopropane (6.0 ml_, 62 mmol). The mixture was stirred at 60° C for 14 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with half-saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silicagel chromatography gave 4.95 g (48 % yield) of the title compound.
LC-MS (Method 2): Rt = 1.12 min; MS (ESIpos): m/z = 249 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.314 (0.66), 0.318 (0.59), 0.325 (0.56), 0.330 (0.65), 0.471 (0.53), 0.476 (0.61 ), 0.492 (0.62), 0.496 (0.57), 1.045 (0.78), 1.219 (1.70), 1.224 (16.00), 3.295 (1.54), 3.927 (1.24), 3.946 (1.22), 7.542 (1.07), 7.544 (1.08), 7.932 (1.09).
Compound 39.02
4-[1 -(cyclopropylmethyl)-l H-p razol-4-yl]-2-nitroaniline
Figure imgf000436_0002
To a stirred solution of 4-bromo-2-nitroaniline (2.62 g, 12.1 mmol) in 1-propanol (1 10 mL) was added potassium carbonate solution (18 mL, 2.0 M, 36 mmol), 1 -(cyclopropylmethyl)-4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (4.10 g, 95 % purity, 15.7 mmol), triphenylphosphine (158 mg, 604 pmol) and PdCI2(PPh3)2 (424 mg, 604 pmol). The mixture was heated to reflux for 2 h, the solvent was removed in vacuum. Aminophase silicagel chromatography gave a solid that was triturated with dichloromethane to give 2.61 g (84 % yield) of the title compound.
LC-MS (Method 2): Rt = 1.02 min; MS (ESIpos): m/z = 259 [M+H]+ 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.359 (2.19), 0.370 (8.88), 0.374 (7.54), 0.382 (8.21 ), 0.386 (8.43), 0.396 (3.08), 0.510 (3.12), 0.520 (7.14), 0.525 (7.44), 0.530 (3.96), 0.536 (4.01 ), 0.541 (7.72), 0.545 (7.00), 0.556 (2.35), 0.864 (2.72), 1.066 (0.76), 1.210 (0.68), 1.216 (1.04), 1.228 (2.00), 1.235 (1.86), 1.240 (1.45), 1.247 (3.09), 1.256 (1.46), 1.259 (1.73), 1.267 (1.82), 1.279 (0.90), 1.285 (0.61 ), 3.166 (1.17), 3.336 (1.85), 3.941 (16.00), 3.959 (15.90), 5.758 (2.12), 7.032 (9.58), 7.054 (9.93), 7.431 (7.13), 7.650 (6.13), 7.655 (6.01 ), 7.672 (5.41 ), 7.677 (5.69), 7.81 1 (15.49), 7.813 (15.69), 8.093 (1 1.18), 8.098(10.99), 8.177 (15.24).
Compound 39.03
4-[1 -(cyclopropylmethyl)-l H- ine
Figure imgf000437_0001
To a stirred solution of 4-[1 -(cyclopropylmethyl)- H-pyrazol-4-yl]-2-nitroaniline (2.60 g, 10.1 mmol) in ethanol ( 10 mL) and dichloromethane (1 10 mL) was added palladium on carbon (10 % w/w palladium, 1.07 g) and the mixture was stirred at r.t. in a hydrogen atmosphere for 6 h. The mixture was filtered and the solution was concentrated in vacuum. Aminophase-silicagel chromatography gave 2.25 g (98 % yield) of the title compound.
LC-MS (Method 1 ): R, = 0.61 min; MS (ESIpos): m/z = 229 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.067 (16.00), 3.917 (1.17), 3.935 (1.27), 3.941 (0.96), 5.759 (1.12), 6.502 (0.71 ), 6.521 (1.00), 6.714 (0.90), 6.719 (0.83), 7.554 (1.25), 7.556 (1.23), 7.841 (1.1 1 ), 7.843 (1.10).
Compound 39.04
6-[1 -(cyclopropylmethyl)-1 H-pyrazol-4-yl]-N-[4-(piperazin-1-ylmethyl)pyridin
benzimidazol-2 -amine hydrochloride
Figure imgf000438_0001
Starting with tert-butyl 4-{[2-({6-[1-(cyclopropylmethyl)-1 H-pyrazol-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate (355 mg, 672 pmol), Compound 39.04 was prepared analogously to the procedure for the preparation of Compound 01.05.
Yield: 320 mg of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): R, = 1.01 min; MS (ESIpos): m/z = 429 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.400 (2.31 ), 0.403 (2.02), 0.412 (2.28), 0.415 (2.18), 0.540 (1.93), 0.544 (1.84), 0.550 (1.07), 0.560 (2.08), 0.565 (1.65), 1.282 (0.86), 3.160 (7.56), 3.443 (1.44), 3.454 (1.79), 3.467 (2.51 ), 3.477 (2.63), 3.483 (2.57), 3.561 (16.00), 4.001 (3.49), 4.019 (3.50), 4.503 (1.89), 7.554 (2.34), 7.574 (1.20), 7.578 (1.18), 7.595 (1.86), 7.599 (1.99), 7.641 (3.58), 7.662 (1.51 ), 7.784 (2.36), 7.788 (2.55), 7.871 (4.39), 7.873 (4.38), 8.228 (3.94), 8.230 (3.80), 8.546 (1.82), 8.558 (1.70).
Compound 39.05
6-[1 -(cyclopropylmethyl)-1 H-pyrazol-4-yl]-N-{4-[(1 R or 1S)-1 -(piperazin-1 -yl)ethyl]pyridin- 2-yl}-1 H-benzimidazol-2-amine hydrochloride
Figure imgf000438_0002
Starting with tert-butyl 4-{(1 R or 1 S)-1 -[2-({6-[1-(cyclopropylmethyl)-1 H-pyrazol-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate (385 mg, 709 pmol), Compound 39.05 was prepared analogously to the procedure for the preparation of Compound 01.05.
Yield: 360 mg of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): Rt = 1.00 min; MS (ESIpos): m/z = 443 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.390 (1.60), 0.401 (6.25), 0.405 (5.43), 0.413 (5.95), 0.417 (6.00), 0.427 (2.20), 0.532 (2.25), 0.542 (5.29), 0.546 (5.04), 0.552 (2.83), 0.558 (2.91 ), 0.562 (5.67), 0.567 (4.38), 0.578 (1.63), 1.264 (1.48), 1.272 (1.41 ), 1.284 (2.41 ), 1.295 (1.27), 1.304 (1.41 ), 1.702 (3.96), 2.082 (1.05), 2.669 (0.84), 3.162 (8.65), 3.271 (1.50), 3.384 (1.08), 3.440 (2.01 ), 3.444 (2.16), 3.450 (2.28), 3.456 (2.74), 3.457 (2.52), 3.466 (2.73), 3.468 (2.79), 3.484 (2.52), 3.487 (2.40), 3.495 (1.99), 3.497 (2.14), 3.502 (1.68), 3.508 (1.38), 3.513 (1.29), 3.675 (0.87), 3.697 (0.90), 4.002 (9.79), 4.020 (9.75), 4.780 (1.89), 5.759 (16.00), 7.538 (5.02), 7.577 (3.15), 7.580 (3.01 ), 7.597 (5.22), 7.601 (5.52), 7.638 (8.05), 7.660 (4.93), 7.777 (6.13), 7.781 (6.70), 7.871 (1 1.32), 7.874 (11.83), 8.226 (10.39), 8.228 (10.77), 8.561 (3.52), 8.575 (3.30).
Compound 40.01
4-(1 -methyl-1 H-pyrazol-3-yl)-2-nitroaniline
H 3
Figure imgf000439_0001
Starting with 3-bromo-1 -methyl-1 H-pyrazole (2.00 g, 12.4 mmol) and 2-nitro-4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)aniline (3.44 g, 13.0 mmol), Compound 40.01 was prepared analogously to the procedure for the preparation of Compound 02.01.
Yield: 2.18 g (80% yield) of the title compound.
LC-MS (Method 2): Rt = 0.87 min; MS (ESIpos): m/z = 219 [M+H]+ Compound 40.02
4-(1-methyl-1 H-pyrazol-3-yl)benzene-1,2-diamine
H 3
Figure imgf000440_0001
To a stirred solution of 4-(1-methyl-1 H-pyrazol-3-yl)-2-nitroaniline (2.54 g, 11.6 mmol) in methanol (140 mL) and THF (70 mL) was added palladium on carbon (10 % w/w palladium) (1.24 g, 1.16 mmol) and the mixture was stirred at r.t. in a hydrogen atmosphere for 3.25 h. The mixture was filtered and the solution was concentrated in vacuum. Aminophase-silicagei chromatography gave 1.74 g (80 % yield) of the title compound.
LC-MS (Method 2): R, = 0.61 min; MS (ESIpos): m/z = 189 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.066 (3.45), 3.797 (16.00), 3.948 (0.57), 4.465 (1 .75), 4.500 (1.99), 6.337 (3.38), 6.343 (3.31 ), 6.471 (2.67), 6.490 (3.03), 6.780 (1.59), 6.785 (1.71 ), 6.800 (1.41 ), 6.804 (1.49), 6.988 (3.07), 6.993 (2.98), 7.574 (2.98), 7.580 (2.83).
Compound 40.03
tert-butyl 4-[(2-{[6-(1 -methyl-1 H-pyrazol-3-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4 yl)methyl]piperazine-1 -carboxylate
Figure imgf000440_0002
To a stirred solution of 1 H-imidazole (126 mg, 1.85 mmol) and di-1 H-imidazol-1 - ylmethanethione (1.65 g, 9.24 mmol) in dichloromethane (1 10 mL) was added tert-butyl 4-[(2- aminopyridin-4-yl)methyl]piperazine-1 -carboxylate (2.70 g, 9.24 mmol) = TH-004 = ASCB369 = , dissolved in dichloromethane (55 mL), at 0°C. The mixture was stirred at r.t. for 14 h. 4-(1 - methyl-1 H-pyrazol-3-yl)benzene-1 ,2-diamine (1.74 g, 9.24 mmol) , dissolved in dichloromethane (55 mL), was added and the mixture was stirred at r.t. for 3 h. Water was added and the mixture was extracted with dichloromethane. The organic phase was dried (sodium sulfate) and filtered. N,N'-dipropan-2-ylcarbodiimide (2.0 mL, 13 mmol) was added. The mixture was stirred at r.t. for 14 h. Further N,N'-dipropan-2-ylcarbodiimide (2.0 mL, 13 mmol) was added and the mixture was stirred at r.t. for 4 h. Further N,N'-dipropan-2- ylcarbodiimide (4.0 mL, 26 mmol) was added and the mixture was stirred at r.t. for 56 h. Saturated ammonium chloride solution was added, the mixture was stirred for 30 minutes and was extracted with dichloromethane. Aminophase silicagel chromatography gave 1.72 g of the title compound as a crude product, that was used without further purification.
LC-MS (Method 2): R, = 1.21 min; MS (ESIpos): m/z = 489 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.035 (0.59), 1.052 (1.1 1 ), 1.066 (0.47), 1.070 (0.65), 1.385 (1 1.31 ), 1.389 (7.08), 1.394 (16.00), 2.275 (0.62), 2.288 (0.89), 2.301 (0.65), 2.342 (1.10), 2.354 (1.36), 2.367 (0.97), 3.308 (2.05), 3.319 (0.93), 3.491 (1.89), 3.870 (4.92), 5.758 (0.42), 5.826 (0.77), 6.380 (0.60), 6.900 (0.51 ), 6.912 (0.50), 6.915 (0.52), 7.682 (0.80), 7.687 (0.79), 7.802 (0.49), 7.814 (0.46), 8.239 (0.77), 8.253 (0.73).
Compound 40.04
6-(1 -methyl-1 H-pyrazol-3-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H-benzimidazol-2- amine hydrochloride
Figure imgf000441_0001
Starting with tert-butyl 4-[(2-{[6-(1 -methyl-1 H-pyrazol-3-yl)-1 H-benzimidazol-2-yl]amino}pyridin- 4-yl)methyl]piperazine-1 -carboxylate (1.70 g, 3.48 mmol), Compound 40.04 was prepared analogously to the procedure for the preparation of Compound 01.05.
Yield: 1.85 g of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): R, = 0.85 min; MS (ESIpos): m/z = 389 [M+H]+ Compound 41.01
6-(1 -methyl-1 H-1 ,2,4-triazol-5-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride
Figure imgf000442_0001
Starting with tert-butyl 4-[(2-{[6-(1-methyl-1 H-1 ,2,4-triazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazine-1-carboxylate (99.0 mg, 202 pmol), Compound 41.01 was prepared analogously to the procedure for the preparation of Compound 01.05.
Yield: 111 mg of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): R, = 0.75 min; MS (ESIpos): m/z = 391 [M+H]+
Compound 42.01
ethyl 3-methylbutanimidate hydrochloride
Figure imgf000442_0002
x HCI
To 3-methylbutanenitrile (3.8 ml_, 98 % purity, 35 mmol) was added hydrochloric acid in dioxane (44 ml_, c = 4.0 M, 180 mmol) and ethanol (21 mL, 350 mmol). The mixture was stirred at room temperature overnight. The solvent was removed in vacuum, toluene was added, and the mixture was concentrated and dried under high vacuum to give 2.64 g of the title compound as a crude product that was used without purification.
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.919 (14.99), 0.936 (16.00), 0.955 (0.83), 0.972 (0.67), 1.332 (3.80), 1.349 (8.21 ), 1.366 (4.01 ), 2.016 (0.71 ), 2.033 (0.90), 2.050 (0.73), 2.472 (4.76), 2.523 (0.81 ), 3.563 (0.79), 4.394 (1.14), 4.412 (3.80), 4.429 (3.85), 4.447 (1.18). Compound 42.02
N',3-dimethylbutanimidohydrazide hydrochloride
Figure imgf000443_0001
x HCI
To a stirred solution of crude ethyl 3-methylbutanimidate hydrochloride (2.60 g, approx. 15.7 mmol)in pyridine (25 mL, 310 mmol) was added methylhydrazine (840 μΙ, 98 % purity, 16 mmol). The mixture was stirred at room temperature overnight. The solvent was removed in vacuum, the residue was triturated with dichloromethane/ hexane to give 2.32 g of the title compound as a crude product that was used without purification.
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.855 (0.55), 0.872 (0.59), 0.891 (13.71 ), 0.894 (3.91 ), 0.907 (16.00), 0.911 (4.29), 0.916 (1.17), 0.920 (1.35), 0.924 (2.25), 0.932 (1.74), 0.949 (1.59), 2.025 (0.60), 2.042 (0.76), 2.059 (0.64), 2.239 (3.53), 2.258 (2.92), 2.609 (1.04), 3.280 (0.45), 5.755 (5.30).
Compound 42.03
tert-butyl 4-({2-[(6-{[1 -methyl-2-(3-methylbutanimidoyl)hydrazinyl]carbonyl}-1 H- benzimidazol-2-yl)amino]pyridin-4-yl}methyl)piperazine-1 -carboxylate
Figure imgf000443_0002
To a stirred solution of crude 2-[(4-{[4-(tert-butoxycarbonyl)piperazin-1-yl]methyl}pyridin-2- yl)amino]-1 H-benzimidazole-6-carboxylic acid (450 mg, approx. 428 μιηοΙ) in DMA (6 mL) was added DIPEA (1.5 mL, 8.6 mmol), crude N',3-dimethylbutanimidohydrazide hydrochloride (259 mg, approx. 1.28 mmol) and PyBOP (668 mg, 1 .28 mmol). The mixture was stirred at room temperature for 3 h. A sodium bicarbonate solution was added, the mixture was stirred for 15 minutes and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate), filtered and the solvent was removed in vacuum. Aminophase-Silicagel chromatography gave 125 mg of the title compound.
LC-MS (Method 2): R, = 1.09 min; MS (ESIpos): m/z = 564 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.750 (0.81 ), 0.765 (0.85), 1.064 (0.84), 1.081 (0.89), 1.395 (16.00), 1.828 (0.78), 2.343 (0.78), 2.356 (1.28), 2.367 (1.03), 2.518 (1.23), 2.523 (0.94), 2.996 (2.11 ), 3.145 (0.41 ), 3.320 (6.69), 3.492 (1.02), 3.497 (1.01 ), 3.932 (0.76), 5.755 (4.26).
Compound 42.04
6-[1 -methyl-3-(2-methylpropyl)-1 H-1,2,4-triazol-5-yl]-N-[4-(piperazin-1-ylmethyl)pyridi yl]-1 H-benzimidazol-2-amine hydrochloride
Figure imgf000444_0001
Starting with tert-butyl 4-{[2-({6-[1 -methyl-3-(2-methylpropyl)-1 H-1 ,2,4-triazol-5-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate (26.0 mg, 47.6 pmol), Compound 42.04 was prepared analogously to the procedure for the preparation of Compound 01.05.
Yield: 26.0 mg of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): R, = 0.97 min; MS (ESIpos): m/z = 446 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.957 (15.16), 0.974 (16.00), 1.986 (0.54), 2.062 (0.74), 2.080 (0.94), 2.096 (0.75), 2.327 (0.47), 2.518 (3.54), 2.523 (2.79), 2.541 (4.32), 2.559 (3.66), 2.669 (0.50), 3.300 (0.70), 3.564 (2.68), 3.968 (15.34), 5.756 (3.02), 7.553 (1.89), 7.755 (0.76), 7.759 (0.75), 7.776 (1.72), 7.781 (1.91 ), 7.800 (2.31 ), 7.821 (0.84), 8.070 (1.97), 8.539 (0.97), 8.553 (0.96). Compound 44.01
4-bromo-1 -(cyclopropylmethyl)pyridin-2(1 H)-one
Figure imgf000445_0001
To a stirred solution of 4-bromopyridin-2(1 H)-one (3.00 g, 97 % purity, 16.7 mmol) in DMA (50 mL) was added potassium carbonate (6.93 g, 50.2 mmol) and (bromomethyl)cyclopropane (2.5 mL, 96 % purity, 25 mmol). The mixture was stirred at r.t. for 48 h. Water was added and the mixture was extracted with dichloromethane / methanol. The organic phase was washed with half-saturated sodium chloride solution, dried (sodium sulfate), filtered and the solvent was removed in vacuum. Silicagel chromatography gave 3.10 g (81 % yield) of the title compound. LC-MS (Method 2): R, = 0.88 min; MS (ESIpos): m/z = 228 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.336 (1.69), 0.348 (6.66), 0.352 (6.12), 0.361 (7.13), 0.364 (6.84), 0.374 (3.08), 0.398 (0.51 ), 0.404 (0.58), 0.41 1 (0.45), 0.423 (0.51 ), 0.440 (3.15), 0.449 (5.97), 0.454 (5.46), 0.460 (3.57), 0.465 (3.15), 0.470 (6.93), 0.475 (5.12), 0.485 (2.07), 1.139 (0.68), 1.145 (0.87), 1.158 (1.83), 1.165 (1.61 ), 1.170 (1.15), 1.177 (2.89), 1.184 (1.04), 1.186 (1.18), 1.190 (1.53), 1.196 (1.61 ), 1.198 (1.61 ), 1.208 (0.80), 1.210 (0.80), 1.216 (0.60), 2.523 (0.70), 3.695 (15.77), 3.714 (16.00), 6.450 (6.1 1 ), 6.456 (6.44), 6.468 (6.73), 6.474 (7.06), 6.704 (9.38), 6.710 (8.95), 7.716 (9.54), 7.733 (9.21 ).
Compound 44.02
1-(cyclopropylmethyl)-4-(3,4-diaminophenyl)pyridin-2(1 H)-one
Figure imgf000445_0002
To a stirred solution of 4-bromo-1-(cyclopropylmethyl)pyridin-2(1 H)-one (1.70 g, 7.45 mmol)in 1 -propanol (85 mL) was added potassium carbonate solution (1 1 mL, 2.0 M, 22 mmol), 4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzene-1 ,2-diamine (2.42 g, 90 % purity, 9.32 mmol), triphenylphosphine (82.1 mg, 745 pmol) and PdCl2(PPh3)2 (523 mg, 745 pmol). The mixture was heated to reflux for 14 h, the solvent was removed in vacuum, water was added and the mixture was extracted with ethyl acetate. The organic phase was dried (sodium sulfate), filtered and the solvent was removed in vacuum. Aminophase-silicagel chromatography gave 1.89 g (99 % yield) of the title compound.
LC-MS (Method 2): Rt = 0.73 min; MS (ESIpos): m/z = 256 [M+H]+ 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.346 (1.48), 0.358 (5.63), 0.361 (5.39), 0.370 (6.52), 0.373 (5.91 ), 0.383 (2.77), 0.406 (0.89), 0.442 (2.50), 0.451 (5.08), 0.456 (4.60), 0.462 (3.27), 0.467 (2.72), 0.471 (5.88), 0.475 (4.43), 0.487 (1.83), 1.067 (3.34), 1.168 (0.74), 1.181 (1.42), 1.183 (1.26), 1.188 (1.36), 1.193 (1.00), 1.201 (2.40), 1.206 (0.95), 1.208 (1.06), 1.213 (1.34), 1.220 (1.41 ), 1.233 (0.71 ), 2.518 (1.35), 2.523 (1.00), 3.160 (0.45), 3.173 (0.56), 3.342 (16.00), 3.687 (11.37), 3.705 (11.31 ), 3.944 (0.61 ), 4.61 1 (7.29), 4.920 (9.49), 5.759 (3.84), 6.399 (2.52), 6.401 (4.91 ), 6.406 (15.98), 6.41 1 (2.36), 6.423 (6.02), 6.428 (4.08), 6.540 (8.92), 6.561 (10.16), 6.801 (4.61 ), 6.807 (5.16), 6.821 (3.86), 6.827 (4.56), 6.889 (8.61 ), 6.894 (7.93), 7.632 (5.72), 7.634 (5.60), 7.649 (5.19), 7.651 (5.79).
Compound 44.03
tert-butyl 4-{[2-({6-[1 -(cyclopropylmethyl)-2-oxo-1 ,2-dihydropyridin-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxyiate
Figure imgf000446_0001
To a stirred solution of 1 H-imidazole (84.0 mg, 1.23 mmol) and di-1 H-imidazol-1 - ylmethanethione (1.39 g, 95 % purity, 7.40 mmol) in dichloromethane (60 mL) was added tert- butyl 4-[(2-aminopyridin-4-yl)methyl]piperazine-1-carboxylate (1.80 g, 6.17 mmol), dissolved in dichloromethane (30 mL), at 0° C. The mixture was s tirred at r.t. for 14 h. 1- (cyclopropylmethyl)-4-(3,4-diaminophenyl)pyridin-2(1 H)-one (1.89 g, 7.40 mmol), dissolved in dichloromethane (30 mL), was added and the mixture was stirred at r.t. for 2 h. Further 1 - (cyclopropylmethyl)-4-(3,4-diaminophenyl)pyridin-2(1 H)-one (88 mg) was added and the mixture was stirred at r.t. for 56 h. Water was added and the mixture was extracted with dichloromethane.
The organic phase was dried (sodium sulfate) and filtered. N,N'-dipropan-2-ylcarbodiimide (2.8 mL, 18 mmol) was added and the mixture was stirred at r.t. for 14 h. Sodium bicarbonate solution was added, the mixture was stirred for 30 minutes and the mixture was extracted with dichloromethane. The organic phase was dried (sodium sulfate) and the solvent was removed in vacuum. Aminophase-silicagel chromatography gave 2.36 g of the title compound as a crude product, that was used without further purification. LC-MS (Method 2): R, = 1.22 min; MS (ESIpos): m/z = 556 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.397 (1.13), 0.409 (1.29), 0.483 (0.93), 0.498 (1.01 ), 1.384 (4.19), 1.394 (16.00), 2.358 (2.24), 3.308 (0.94), 3.500 (2.17), 3.745 (1.35), 3.763 (1.42), 6.928 (0.63), 6.941 (0.69), 7.183 (1.16), 7.761 (0.54), 7.776 (0.56), 8.263 (0.75), 8.275 (0.78), 12.225 (0.62).
Compound 44.04
1 -(cyclopropylmethyl)-4-(2-{[4-(piperazin-1-ylmethyl)pyridin-2-yl]amino}-1 H
benzimidazol-6-yl)pyridin-2(1 H)-one hydrochloride
Figure imgf000447_0001
Starting with tert-butyl 4-{[2-({6-[1-(cyclopropylmethyl)-2-oxo-1 ,2-dihydropyridin-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate (2.36 g, 4.25 mmol), Compound 44.04 was prepared analogously to the procedure for the preparation of Compound 01.05.
Yield: 2.65 g of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): Rt = 0.93 min; MS (ESIpos): m/z = 456 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.391 (2.81 ), 0.403 (10.02), 0.407 (9.74), 0.415 (1 1.78), 0.419 (9.87), 0.428 (4.35), 0.438 (1.51 ), 0.451 (1.48), 0.457 (1.43), 0.465 (1.61 ), 0.473
(4.45) , 0.481 (9.10), 0.486 (7.57), 0.492 (5.98), 0.502 (9.64), 0.505 (7.64), 0.518 (2.56), 1.058 (0.49), 1.210 (1.12), 1.216 (1.79), 1.228 (3.12), 1.236 (2.81 ), 1.242 (2.33), 1.248 (4.19), 1.255 (2.20), 1.260 (2.53), 1.267 (2.63), 1.279 (1.48), 1.286 (0.97), 1.423 (1.35), 1.442 (3.22), 1 .461
(1.46) , 2.323 (1.05), 2.327 (1.51), 2.331 (1.10), 2.523 (9.18), 2.665 (1.10), 2.669 (1.56), 2.674 (1.07), 2.722 (1.92), 2.884 (2.35), 3.149 (0.59), 3.168 (1.41 ), 3.187 (1.41 ), 3.207 (0.79), 3.422
(10.22), 3.451 (10.63), 3.464 (13.32), 3.480 (14.65), 3.482 (14.21 ), 3.559 (16.00), 3.569 (1.35), 3.645 (0.69), 3.653 (0.79), 3.656 (0.97), 3.661 (0.79), 3.668 (0.92), 3.671 (0.97), 3.697 (0.95), 3.699 (0.89), 3.707 (0.74), 3.712 (0.84), 3.773 (14.19), 3.791 (14.24), 4.328 (1.81 ), 4.519 (7.44), 4.757 (3.14), 6.587 (6.29), 6.593 (7.11 ), 6.606 (6.26), 6.61 1 (7.26), 6.655 (0.66), 6.661 (0.84), 6.675 (13.55), 6.680 (12.19), 6.763 (0.84), 6.768 (0.77), 7.166 (4.65), 7.207 (1.33), 7.580 (10.68), 7.649 (4.50), 7.663 (4.60), 7.696 (2.58), 7.699 (2.58), 7.709 (4.04), 7.713 (3.96), 7.730 (9.71 ), 7.735 (10.12), 7.750 (14.36), 7.771 (4.88), 7.857 (2.61 ), 7.860 (2.50), 7.870 (10.91 ), 7.887 (10.30), 7.953 (1 1.02), 7.957 (11.63), 8.028 (3.42), 8.044 (4.19), 8.142 (0.51 ), 8.394 (1.43), 8.406 (1.38), 8.567 (8.20), 8.580 (7.62), 9.135 (0.92), 9.941 (4.12).
Compound 45.01
tert-butyl 4-[(2-{[6-(pyrimidin-5-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1-carboxylate
Figure imgf000448_0001
Tert-butyl 4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate (300 mg, 561 pmol) , 5-bromopyrimidine ( 16 mg, 730 pmol) and an aqueous sodium carbonate solution (700 μΙ, 2.0 , 1.4 mmol) were stirred in DME (15 ml_), sparged with argon for 2 min, Pd(dppf)CI2 . CH2CI2 (45.8 mg, 56.1 pmol) was added and the mixture was stirred at 150°C in a sealed tube for 2.5 h. The mixture was filtered through a silicone filter and concentrated under reduced pressure to give 597 mg of the title compound as a crude product that was used without further purification.
LC-MS (Method 2): R, = 1.14 min; MS (ESIpos): m/z = 487 [M+H]+
Compound 45.02
N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-6-(pyrimidin^
hydrochloride
Figure imgf000449_0001
Starting with tert-butyl 4-[(2-{[6-(pyrimidin-5-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate (597 mg, 1.23 mmol), Compound 45.02 was prepared analogously to the procedure for the preparation of Compound 01 .05.
Yield: 672 mg of the title compound as crude product were used for the next step without purification.
LC-MS (Method 2): F¾ = 0.80 min; MS (ESIpos): m/z = 387 [M+H]+
Compound 45.03
tert-butyl 4-[(2-{[6-(2-chloropyrimidin-5-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4' yl)methyl]piperazine-1 -carboxylate
Figure imgf000449_0002
tert-butyl 4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate (300 mg, 561 pmol) , 5-bromo-2- chloropyrimidine (141 mg, 730 pmol) and an aqueous sodium carbonate solution (700 μΙ, 2.0 M, 1 .4 mmol) were stirred in DME (15 ml_), sparged with argon for 2 min, Pd(dppf)CI2 . CH2CI2 (45.8 mg, 56.1 μηιοΙ) was added and the mixture was stirred at 'Ι δΟ'Ό in a sealed tube for 5 h. The mixture was filtered through a silicone filter and concentrated under reduced pressure to give 456 mg of the title compound as a crude product that was used without further purification.
LC-MS (Method 2): Rt = 1.29 min; MS (ESIpos): m/z = 521 [M+H]+
Compound 45.04
6-(2-chloropyrimidin-5-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H-benzi
amine hydrochloride salt
Figure imgf000450_0001
Starting with tert-butyl 4-[(2-{[6-(2-chloropyrimidin-5-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1-carboxylate (456 mg, 876 pmol), Compound 45.04 was prepared analogously to the procedure for the preparation of Compound 01.05.
Yield: 61 1 mg of the title compound as crude product were used for the next step without purification.
LC-MS (Method 2): R, = 0.94 min; MS (ESIpos): m/z = 421 [M+H]+
Compound 45.05
tert-butyl 4-[(2-{[6-(2-methylpyrimidin-5-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1-carboxylate
Figure imgf000451_0001
tert-butyl 4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate (300 mg, 561 pmol) , 5-bromo-2- methylpyrimidine (126 mg, 730 pmol) and an aqueous sodium carbonate solution (700 μΙ, 2.0 , 1.4 mmol) were stirred in DME (15 ml_), sparged with Ar for 2 min, Pd(dppf)Cl2 . CH2CI2 (45.8 mg, 56.1 pmol) was added and the mixture was stirred at 150Ό in a sealed tube for 5 h. The mixture was filtered through a silicone filter and concentrated under reduced pressure to give 366 mg of the title compound as a crude product that was used without further purification.
LC-MS (Method 2): R, = 1.17 min; MS (ESIpos): m/z = 501 [M+H]+
Compound 45.06
6-(2-methylpyrimidin-5-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]-1 H-benzimidazol-2- amine hydrochloride salt
Figure imgf000451_0002
Starting with tert-butyl 4-[(2-{[6-(2-methylpyrimidin-5-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate (366 mg, 731 Mmol), Compound 45.06 was prepared analogously to the procedure for the preparation of Compound 01.05. Yield: 409 mg of the title compound as crude product were used for the next step without purification.
LC-MS (Method 2): R, = 0.82 min; MS (ESIpos): m/z = 401 [M+H]+
Compound 45.07
tert-butyl 4-[(2-{[6-(2-cyclopropylpyrimidin-5-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4 yl)methyl]piperazine-1-carboxylate
Figure imgf000452_0001
tert-butyl 4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate (300 mg, 561 pmol) , 5-bromo-2- cyclopropylpyrimidine (145 mg, 730 pmol) and an aqueous sodium carbonate solution (700 μΙ, 2.0 M, 1.4 mmol) were stirred in DME (15 mL), sparged with argon for 2 min, Pd(dppf)Cl2 . CH2CI2 (45.8 mg, 56.1 μιηοΙ) was added and the mixture was stirred at 150 in a sealed tube for 5 h. The mixture was filtered through a silicone filter and concentrated under reduced pressure to give 455 mg of the title compound as a crude product that was used without further purification.
LC-MS (Method 2): Rt = 1.31 min; MS (ESIpos): m/z = 527 [M+H]+
Compound 45.08
6-(2-cyclopropylpyrimidin-5-yl)-N-[4-(piperazm^
2 -amine hydrochloride
Figure imgf000453_0001
Starting with tert-butyl 4-[(2-{[6-(2-cyclopropylpyrimidin-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate (455 mg, 863 pmol), Compound 45.08 was prepared analogously to the procedure for the preparation of Compound 01.05.
Yield: 733 mg of the title compound as crude product that was were used for the next step without purification.
LC-MS (Method 2): R, = 0.98 min; MS (ESIpos): m/z = 428 [M+H]+
Compound 45.09
tert-butyl 4-{[2-({6-[2-(methylsulfanyl)pyrimidin-5-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate
Figure imgf000453_0002
tert-butyl 4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate (300 mg, 561 μηιοΙ) , 5-bromo-2- (methylsulfanyl)pyrimidine (150 mg, 730 μιτιοΙ) and an aqueous sodium carbonate solution (700 μΙ, 2.0 M, 1.4 mmol) were stirred in DME (15 mL), sparged with argon for 2 min, Pd(dppf)CI2 . CH2CI2 (45.8 mg, 56.1 Mmol) was added and the mixture was stirred at 150Ό in a sealed tube for 2.5 h. The mixture was filtered through a silicone filter and concentrated under reduced pressure to give 564 mg of the title compound as a crude product that was used without further purification.
LC-MS (Method 2): R, = 1.33 min; MS (ESIpos): m/z = 533 [M+H]+
Compound 45.10
6-[2-(methylsulfanyl)pyrimidin-5-yl]-N-[4-(piperazin-1-ylmethyl)pyrid
benzimidazol-2-amine hydrochloride
Figure imgf000454_0001
Starting with tert-butyl 4-{[2-({6-[2-(methylsulfanyl)pyrimidin-5-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1-carboxylate (564 mg, 1.06 mmol), Compound 45.10 was prepared analogously to the procedure for the preparation of Compound 01.05.
Yield: 590 mg of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): Rt = 1.03 min; MS (ESIpos): m/z = 433 [M+H]+
Compound 46.01
6-chloro-4-iodo-3-methoxypyridazine
Figure imgf000455_0001
To a stirred solution of 2,2,6,6-tetramethylpiperidine (6.9 mL, 41 mmol) in tetrahydrofuran (200 mL, 2.5 mol), was added n-butyllithium (16 mL, c = 2.5 M in hexanes, 40 mmol) at -70Ό. 3- chloro-6-methoxypyridazine (2.90 g, 20.1 mmol) dissolved in tetrahydrofuran (150 mL) was added dropwise and the reaction mixture was stirred at -78Ό for 30 minutes. Iodine (5.30 g, 20.9 mmol) dissolved in tetrahydrofuran (50 mL) was added and the mixture was stirred at - 78Ό for 2 hours. An aqueous solution of disodium s ulfurothioate (c = 1 M; 150 mL) was added and the mixture was extracted with diethyl ether. The organic phase was dried (magnesium sulfate), filtered and the solvent was removed in vacuum. Silicagel chromatography gave 925 mg of the title compound.
LC-MS (Method 5): Rt = 2.94 min; MS (ESIpos): m/z = 271 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.495 (0.64), 2.500 (0.88), 2.505 (0.64), 3.316 (1 1.53), 3.992 (0.76), 4.049 (16.00), 8.416 (5.48).
Compound 47.01
4-bromo-5-methoxypyridazin-3(2H)-one
Figure imgf000455_0002
To a stirred suspension of 4,5-dibromopyridazin-3(2H)-one (4.00 g, 15.8 mmol) in methanol (40 mL, 990 mmol), was added potassium carbonate (4.00 g, 28.9 mmol) and the mixture was stirred at 80Ό for 67 hours. The solvent was remov ed in vacuum. Water was added to the residue and acetic acid was added until acidic pH was reached. A solid precipitated and was collected by filtration, washed with water, and dried to give 2.23 g (69 % yield) of the title compound as a crude product.
LC-MS (Method 5): Rt = 0.57 min; MS (ESIpos): m/z = 205 [M+H]+ Compound 47.02
5-methoxypyridazin-3(2H)-one
Figure imgf000456_0001
To a stirred solution of 4-bromo-5-methoxypyridazin-3(2H)-one (900 mg, 4.39 mmol) in water (20 mL) was added sodium hydroxide (180 mg, 4.50 mmol) and palladium on carbon (10 % w/w palladium) (300 mg) and the mixture was stirred at r.t. under a pressure of 2 bar of hydrogen for 2 h. The warm mixture was filtered through celite and the catalyst was washed with water. The filtrate was cooled to 0 and stir red at 0Ό for 2 hours. A solid precipitated and was collected by filtration to give 260 mg (47 % yield) of the title compound.
LC-MS (Method 5): R, = 0.31 min; MS (ESIpos): m/z = 127 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.500 (1.36), 3.328 (1 1.32), 3.779 (16.00), 6.167 (3.61 ), 6.173 (3.48), 7.657 (3.28), 7.663 (3.14), 12.613 (0.81 ).
Compound 47.03
3-chloro-5-methoxypyridazine
Figure imgf000456_0002
A suspension of 5-methoxypyridazin-3(2H)-one (250 mg, 1.98 mmol) in phosphorus oxychloride (1.5 mL, 16 mmol) was stirred at 100Ό for 10 minutes. The reaction mixture was poured into ice water and sodium carbonate was added until a basic pH-was reached. The mixture was extracted with diethyl ether, the organic phase was dried (magnesium sulfate), filtered and the solvent was removed in vacuum. The residue was crystallized from 1 ,2- dichloroethane to give 130 mg (45 % yield) of the title compound.
LC-MS (Method 5): R, = 0.85 min; MS (ESIpos): m/z = 145 [M+H]+ 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.495 (0.78), 2.499 (1.07), 2.503 (0.84), 3.317 (1 1.94), 3.944 (16.00), 7.528 (2.28), 7.534 (2.29), 8.988 (2.34), 8.994 (2.34).
Compound 49.01
2-amino-6-bromo-3-nitrophenol
Figure imgf000457_0001
To a stirred solution of 2-bromo-5-nitrophenol (10.0 g, 45.9 mmol) in D SO (150 mL) was added 1 ,1 ,1-trimethylhydrazinium iodide (10.5 g, 97 % purity, 50.5 mmol). The mixture was stirred for 90 min, then sodium 2-methylbutan-2-olate (26.6 g, 95 % purity, 229 mmol) was added. The reaction mixture was stirred at r.t. over night. Aqueous hydrochloric acid (70 mL, 4.0 M, 280 mmol) and water were added at 0Ό and th e mixture was stirred for 3 h. The reaction mixture was extracted with ethyl acetate / hexane (4 : 1 ). The organic phase was washed with saturated sodium chloride solution, filtered and the solvent was removed in vacuum, to give 10.6 g (99 % yield) of the title compound as a crude product.
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.760 (0.77), 6.617 (0.73), 6.640 (0.74), 6.752 (15.43), 6.776 (15.64), 7.175 (2.66), 7.484 (16.00), 7.507 (13.75), 7.542 (0.71 ), 7.565 (0.68), 9.998 (1.15).
Compound 49.04
3-bromo-2-(2-methylpropoxy)-6-nit
Figure imgf000457_0002
To a stirred solution of 2-amino-6-bromo-3-nitrophenol (10.6 g, 45.6 mmol) in acetonitrile (150 mL) was added potassium carbonate (12.6 g, 91.1 mmol) and 1 -bromo-2-methylpropane (20 mL, 99 % purity, 180 mmol). The mixture was stirred at 70° C for 14 h. Water was added and the mixture was extracted with ethyl acetate / hexane (3 : 1 ). The organic phase was washed with half-saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silicagel chromatography gave 10.4 g (79 % yield) of the title compound. LC-MS (Method 2): R, = 1.45 min; MS (ESIpos): m/z = 289 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.009 (1.50), 1.019 (16.00), 1 .025 (2.30), 1.036 (15.86), 2.225 (0.92), 2.241 (1.1 1 ), 2.258 (0.88), 3.655 (5.08), 3.671 (5.15), 6.854 (4.03), 6.877 (4.24), 7.063 (1.60), 7.714 (3.64), 7.738 (3.66).
Compound 49.05
2-(2-methylpropoxy)-6-nitro-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)aniline
Figure imgf000458_0001
To a stirred solution of 3-bromo-2-(2-methylpropoxy)-6-nitroaniline (5.00 g, 17.3 mmol) in dioxane (500 mL, 5.8 mol) was added potassium acetate (5.09 g, 51.9 mmol), 1 , 1 *- bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (706 mg, 865 pmol) and 4,4,4',4,,5,5,5',5'-octamethyl-2,2'-bi-1 ,3,2-dioxaborolane (13.4 g, 98 % purity, 51.9 mmol). The mixture was heated to 120° C for 14 h. The reaction mixture was filtered through celite and the solvent was removed in vacuum. Aminophase silicagel chromatography gave 4.2 g (72 % yield) of the title compound.
LC-MS (Method 1 ): Rt = 1.56 min; MS (ESIpos): m/z = 337 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.993 (4.30), 1.010 (4.68), 1.065 (0.99), 1.163 (1.66), 1.303 (16.00), 3.331 (2.01 ), 3.655 (1.27), 3.672 (1.22), 6.735 (1.00), 6.758 (0.99), 7.701 (0.92), 7.723 (0.88). Compound 49.06
3-(2-methylpropoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene-1,2-diamine
Figure imgf000459_0001
To a stirred solution of 2-(2-methylpropoxy)-6-nitro-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)aniline (4.20 g, 1 1.2 mmol) in ethanol (380 mL, 6.6 mol) was added palladium on carbon (10 % w/w palladium, 1 ,2 g) and the mixture was hydrogenated for 6 h. The mixture was filtered through celite and the solution was concentrated in vacuum. Aminophase silicagel chromatography gave 4.20 g of the title compound as crude product that was used without purification.
LC-MS (Method 1 ): R, = 1.23 min; MS (ESIpos): m/z = 307 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.986 (2.30), 1.003 (2.48), 1.066 (16.00), 1.154 (0.41 ), 1.172 (0.83), 1.190 (0.41 ), 1.230 (7.53), 1.987 (1.36), 3.335 (1.46), 3.495 (0.62), 3.51 1 (0.61 ), 3.941 (2.75), 6.268 (0.46), 6.288 (0.48), 6.721 (0.52), 6.741 (0.45).
Compound 49.07
cyclopropyl{4-[(2-{[7-(2-methylpropoxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-benzimidazol-2-yl]amino}pyridin-4-yl)methyl]piperazin-1-yl}methanone
Figure imgf000459_0002
To a stirred solution of 1 H-imidazole (78.4 mg, 1.15 mmol) and di-1 H-imidazol-1- ylmethanethione (1.30 g, 95 % purity, 6.91 mmol) in dichloromethane (80 mL) was added {4- [(2-aminopyridin-4-yl)methyl]piperazin-1-yl}(cyclopropyl)methanone (1.50 g, 5.76 mmol), dissolved in dichloromethane (20 mL) at 0° C. The m ixture was stirred at r.t. for 14 h. 3-(2- methylpropoxy)-4-(4,4,5,5-tetramethyl- ,3,2-dioxaborolan-2-yl)benzene-1 ,2-diamine (3.02 g, approx. 6.91 mmol), dissolved in dichloromethane (30 mL) was added and the mixture was stirred at r.t. for 14 h. Water was added and the mixture was extracted with dichloromethane. The organic phase was dried (sodium sulfate) and filtered. N,N'-dipropan-2-ylcarbodiimide (1.8 mL, 12 mmol) was added and the mixture was stirred at r.t. for 14 h. Saturated ammonium chloride solution was added, the mixture was stirred for 30 minutes and the mixture was extracted with dichloromethane. The organic phase was dried (sodium sulfate) and the solvent was removed in vacuum. Silicagel chromatography gave 1.90 g of the title compound as a crude product, that was used without further purification.
C-MS (Method 1 ): Rt = 1.08 min; MS (ESIpos): m/z = 575 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.678 (0.71 ), 0.697 (0.88), 0.709 (0.80), 0.716 (0.77), 0.721 (0.83), 1.021 (1.48), 1.037 (1.57), 1.153 (4.30), 1.171 (8.54), 1.189 (4.15), 1.275 (5.80), 1.289 (1.45), 1.986 (16.00), 3.334 (3.12), 3.999 (1.1 1 ), 4.016 (3.39), 4.034 (3.43), 4.052 (1.16).
Compound 50.01
3-(3-methoxypyridin-4-yl)-2-(2-methylpropoxy)-6-nitroaniline
Figure imgf000460_0001
Starting with 3-bromo-2-(2-methylpropoxy)-6-nitroaniline (1.80 g, 6.23 mmol) and (3- methoxypyridin-4-yl)boronic acid (1.20 g, 95 % purity, 7.47 mmol), Compound 50.01 was prepared analogously to the procedure for the preparation of Compound 02.01.
Yield: 1.30 g (66 %) of the title compound.
LC-MS (Method 2): R, = 1.20 min; MS (ESIpos): m/z = 318 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.577 (15.14), 0.594 (16.00), 1.171 (0.47), 1.751 (0.86), 1.768 (1.09), 1.785 (0.86), 1.986 (0.85), 2.522 (1.18), 3.213 (4.36), 3.229 (4.46), 3.331 (1.89), 3.333 (8.36), 3.818 (1.87), 5.755 (0.88), 5.758 (6.05), 6.505 (4.02), 6.527 (3.78), 7.028 (2.65), 7.254 (2.68), 7.266 (2.80), 7.810 (3.47), 7.832 (3.26), 8.279 (3.46), 8.287 (0.91 ), 8.290 (3.62), 8.495 (4.82). Compound 50.02
4-(3-methoxypyridin-4-yl)-3-(2-methylpropoxy)benzene-1 ,2-diamine
Figure imgf000461_0001
To a stirred solution of 3-(3-methoxypyridin-4-yl)-2-(2-methylpropoxy)-6-nitroaniline (1.30 g, 4.10 mmol) in ethanol (21 mL) and dichloromethane (41 mL) was added palladium on carbon (10 % w/w palladium; 436 mg) and the mixture was stirred at r.t. in a hydrogen atmosphere for 3 h. The mixture was filtered, and the solution was concentrated in vacuum. Aminophase silicagel chromatography gave 1.00 g of the title compound as crude product that was used without further purification.
LC-MS (Method 2): R, = 0.90 min; MS (ESIpos): m/z = 288 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.628 (12.69), 0.644 (12.69), 1.663 (0.65), 1.681 (0.80), 1.697 (0.62), 3.102 (3.58), 3.1 17 (3.53), 3.332 (16.00), 4.179 (2.92), 4.738 (3.17), 5.760 (0.67), 6.288 (1.87), 6.308 (3.58), 6.348 (3.18), 6.368 (1.66), 7.138 (2.28), 7.150 (2.38), 8.145 (3.09), 8.156 (2.84), 8.332 (4.23).
Compound 50.03
tert-butyl 4-t(2-{[6-(3-methoxypyridin-4-yl)-7-(2-methylpropoxy)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate
Figure imgf000461_0002
To a stirred solution of 1 H-imidazole (35.5 mg, 522 pmol) and di-1 H-imidazol-1- ylmethanethione (490 mg, 95 % purity, 2.61 mmol) in dichloromethane (25 mL) was added tert-butyl 4-[(2-aminopyridin-4-yl)methyl]piperazine-1-carboxylate (763 mg, 2.61 mmol), dissolved in dichloromethane (12 mL), at 0° C. The mixture was stirred at r.t. for 14 h. 4-(3- methoxypyridin-4-yl)-3-(2-methylpropoxy)benzene-1 ,2-diamine (1.00 g, approx. 2.61 mmol), dissolved in dichloromethane (15 mL), was added and the mixture was stirred at r.t. for 56 h. Water was added and the mixture was extracted with dichloromethane.
The organic phase was dried (sodium sulfate) and filtered. N,N'-dipropan-2-ylcarbodiimide (1.2 mL, 7.7 mmol) was added and the mixture was stirred at r.t. for 14 h. Further N,N'-dipropan-2- ylcarbodiimide (0.8 mL, 5.1 mmol) was added and the mixture was stirred at r.t. for 14 h. Sodium bicarbonate solution was added, the mixture was stirred for 30 minutes and the mixture was extracted with dichloromethane. The organic phase was dried (sodium sulfate) and the solvent was removed in vacuum. Aminophase-silicagel chromatography followed by silicagel chromatography gave 407 mg of the title compound.
LC-MS (Method 2): R, = 1.39 min; MS (ESIpos): m/z = 588 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.736 (4.14), 0.752 (4.31 ), 1.393 (16.00), 2.338 (0.95), 2.350 (1.37), 2.363 (0.98), 3.344 (1.19), 3.486 (1.50), 3.802 (4.10), 4.233 (1.29), 4.249 (1.28), 5.760 (2.85), 6.784 (0.77), 6.804 (0.81 ), 7.184 (0.78), 7.196 (0.93), 7.203 (1.54), 7.223 (0.77), 8.199 (0.87), 8.21 1 (0.84), 8.248 (0.66), 8.262 (0.61 ), 8.373 (1.38), 10.682 (0.69).
Compound 50.04
6-(3-methoxypyridin-4-yl)-7-(2-methylpropoxy)-N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]- 1 H-benzimidazol-2-amine hydrochloride
Figure imgf000462_0001
Starting with tert-butyl 4-[(2-{[6-(3-methoxypyridin-4-yl)-7-(2-methylpropoxy)-1 H-benzimidazol- 2-yl]amino}pyridin-4-yl)methyl]piperazine-1-carboxylate (407 mg, 692 pmol), Compound 50.04 was prepared analogously to the procedure for the preparation of Compound 01.05.
Yield: 474 mg of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): R, = 1.10 min; MS (ESIpos): m/z = 488 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.759 (15.96), 0.776 (16.00), 1.798 (0.51 ), 1.815 (0.99), 1.832 (1.21 ), 1.848 (0.94), 2.523 (1.01 ), 3.334 (0.82), 3.383 (0.72), 3.387 (0.68), 3.394 (0.74), 3.440 (2.22), 3.455 (1.76), 3.971 (15.15), 4.032 (1.31 ), 4.046 (1.27), 5.760 (3.82), 7.156 (1.26), 7.176 (1.38), 7.440 (2.45), 7.448 (1.55), 7.460 (2.02), 7.496 (0.65), 7.896 (2.14), 7.910 (2.13), 8.474 (1.14), 8.486 (1.09), 8.601 (2.44), 8.615 (2.26), 8.743 (4.26).
Compound 51.01
3-bromo-2-ethoxy-6-nitroaniline
Figure imgf000463_0001
To a stirred solution of 2-amino-6-bromo-3-nitrophenol (4.41 g, 18.9 mmol) in acetonitrile (130 mL) was added potassium carbonate (5.23 g, 37.8 mmol) and iodoethane (2.8 mL, 98 % purity, 34 mmol). The mixture was stirred at r.t. for 14 h. Further iodoethane (0.78 mL) was added and the mixture was stirred at r.t. for 14 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with half-saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silicagel chromatography gave 3.6 g (73 % yield) of the title compound.
LC-MS (Method 2): F¾ = 1.22 min; MS (ESIpos): m/z = 261 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.392 (7.25), 1.409 (16.00), 1.427 (7.76), 3.957 (2.27), 3.975 (7.73), 3.992 (7.46), 4.010 (2.18), 6.841 (7.10), 6.864 (7.17), 7.235 (2.90), 7.707 (6.46), 7.731 (6.55).
Compound 51.02
2-ethoxy-3-(3-methoxypyridin-4-yl)-6-nitroaniline
Figure imgf000464_0001
Starting with 3-bromo-2-ethoxy-6-nitroaniline (3.60 g, 13.5 mmol) and (3-methoxypyridin-4- yl)boronic acid (2.50 g, 15.5 mmol), Compound 51.02 was prepared analogously to the procedure for the preparation of Compound 02.01.
Yield: 2.80 g (72 %) of the title compound.
LC-MS (Method 2): R, = 1.06 min; MS (ESIpos): m/z = 290 [M+H]+
H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.953 (6.47), 0.971 (15.43), 0.988 (7.08), 1.174 (0.68), 1.987 (1.27), 3.309 (16.00), 3.507 (2.00), 3.524 (6.69), 3.542 (6.75), 3.559 (1.97), 6.512 (6.59), 6.535 (6.84), 7.135 (3.81 ), 7.277 (4.27), 7.289 (4.36), 7.543 (0.79), 7.546 (1.16), 7.548 (1.19), 7.554 (0.98), 7.557 (0.86), 7.563 (1.41 ), 7.565 (1.13), 7.571 (1.09), 7.573 (1.05), 7.593 (0.85), 7.597 (1.77), 7.604 (0.84), 7.610 (0.96), 7.613 (1.28), 7.618 (0.80), 7.623 (1.84), 7.625 (2.32), 7.630 (1.22), 7.644 (1.24), 7.647 (0.95), 7.796 (5.71 ), 7.819 (5.43), 8.292 (5.51 ), 8.303 (5.63), 8.519 (7.71 ).
Compound 51.03
3-ethoxy-4-(3-methoxypyridin-4-yl)benzene-1,2-diamine
Figure imgf000464_0002
To a stirred solution of 2-ethoxy-3-(3-methoxypyridin-4-yl)-6-nitroaniline (2.80 g, 90 % purity, 8.71 mmol)in ethanol (100 mL) and dichloromethane (100 ml_) was added palladium on carbon (10 % w/w palladium; 463 mg) and the mixture was stirred at r.t. in a hydrogen atmosphere for 14 h. The mixture was filtered through celite and the solution was concentrated in vacuum. Aminophase-silicagel chromatography gave 2.80 g of the title compound as a crude product that was used without further purification. LC-MS (Method 2): Rt = 0.72 min; MS (ESIpos): m/z = 260 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.937 (7.19), 0.954 (16.00), 0.972 (7.51 ), 3.312 (8.30), 3.393 (2.23), 3.410 (7.10), 3.427 (7.19), 3.445 (2.18), 4.232 (1.51 ), 4.723 (1.54), 5.751 (14.21 ), 6.315 (2.74), 6.335 (9.88), 6.349 (9.58), 6.369 (2.55), 7.172 (5.25), 7.184 (5.30), 7.527 (0.48), 7.543 (0.82), 7.545 (1.14), 7.548 (1.24), 7.554 (1.05), 7.556 (0.84), 7.563 (1.27), 7.565 (1.22), 7.570 (1.03), 7.572 (1.02), 7.594 (0.86), 7.598 (1.75), 7.604 (0.96), 7.613 (1.02), 7.615 (1.10), 7.618 (0.91 ), 7.625 (2.20), 7.630 (1.19), 7.644 (1.14), 8.156 (6.47), 8.168 (6.39), 8.356 (9.47).
Compound 51.04
tert-butyl 4-[(2-{[7-ethoxy-6-(3-methoxypyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin- 4-yl)methyl]piperazine-1 -carboxylate
Figure imgf000465_0001
To a stirred solution of 1 H-imidazole (81.5 mg, 1.20 mmol) and di-1 H-imidazol-1- ylmethanethione (1.12 g, 95 % purity, 5.99 mmol) in dichloromethane (40 mL) was added tert- butyl 4-[(2-aminopyridin-4-yl)methyl]piperazine-1 -carboxylate (1.75 g, 5.99 mmol) , dissolved in dichloromethane (30 mL), at 0° C. The mixture was s tirred at r.t. for 14 h. 3-ethoxy-4-(3- methoxypyridin-4-yl)benzene-1 ,2-diamine (2.22 g, 70 % purity, 5.99 mmol), dissolved in dichloromethane (40 mL), was added and the mixture was stirred at r.t. for 56 h. Water was added and the mixture was extracted with dichloromethane.
The organic phase was dried (sodium sulfate) and filtered. N,N'-dipropan-2-ylcarbodiimide (3.7 mL, 24 mmol) was added. The mixture was stirred at r.t. for 1 h. Further N,N'-dipropan-2- ylcarbodiimide (3.7 mL, 24 mmol) was added and the mixture was stirred at r.t. for 2 h. Further N,N'-dipropan-2-ylcarbodiimide (1.8 mL, 12 mmol) was added and the mixture was stirred at r.t. for 14 h. Saturated ammonium chloride solution was added, the mixture was stirred for 30 minutes and was extracted with dichloromethane. Aminophase-silicagel chromatography gave 2.00 g of the title compound as a crude product, that was used without further purification. LC-MS (Method 2): R, = 1.31 min; MS (ESIpos): m/z = 560 [M+H]+ 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.130 (1.45), 1.147 (3.18), 1.155 (3.54), 1.165 (1.67), 1.173 (7.15), 1.191 (3.59), 1.394 (16.00), 1.987 (12.79), 2.343 (0.91 ), 2.356 (1.41 ), 2.367 (1.08), 3.346 (1.25), 3.488 (1.47), 3.796 (0.72), 3.820 (4.07), 4.001 (1.03), 4.018 (3.05), 4.036 (3.02), 4.054 (0.98), 4.549 (0.87), 4.567 (0.87), 5.755 (3.87), 6.791 (0.64), 6.811 (0.69), 7.179 (0.75), 7.191 (1.38), 7.211 (0.75), 7.231 (0.63), 8.206 (0.75), 8.218 (0.71 ), 8.248 (0.77), 8.262 (0.72), 8.384 (1.23), 10.678 (0.80), 12.123 (0.70).
Compound 51.05
7-ethoxy-6-(3-methoxypyridin-4-yl)-N-[4-(piperazin-1-ylmethyl)pyridin
benzimidazol-2-amine hydrochloride
Figure imgf000466_0001
Starting with tert-butyl 4-[(2-{[7-ethoxy-6-(3-methoxypyridin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazine-1-carboxylate (2.00 g, 3.22 mmol), Compound 51.05 was prepared analogously to the procedure for the preparation of Compound 01.05.
Yield: 2.30 g of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): Rt = 0.98 min; MS (ESIpos): m/z = 460 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.078 (0.64), 1.176 (4.37), 1.193 (9.60), 1.21 1 (4.80), 2.522 (1.26), 3.049 (0.42), 3.197 (2.80), 3.223 (2.67), 3.370 (2.69), 3.384 (3.12), 3.396 (2.16), 3.692 (0.50), 3.958 (0.90), 3.967 (1.12), 3.975 (1.54), 3.980 (16.00), 4.178 (2.58), 4.275 (1.10), 4.292 (3.20), 4.310 (3.20), 4.327 (1.06), 7.171 (2.29), 7.192 (2.61 ), 7.417 (1.25), 7.434 (3.46), 7.454 (2.40), 7.546 (2.42), 7.786 (2.21 ), 7.800 (2.22), 8.442 (2.08), 8.456 (1.98), 8.509 (2.61 ), 8.523 (2.38), 8.667 (4.21 ). Compound 52.01
3-(1 -ethyl-1 H-pyrazol-4-yl)-2-(2-methylpropoxy)-6-nitroaniline
Figure imgf000467_0001
Starting with 3-bromo-2-(2-methylpropoxy)-6-nitroaniline (1.80 g, 6.23 mmol) and (1-ethyl-1 H- pyrazol-4-yl)boronic acid (1.05 g, 95 % purity, 7.16 mmol), Compound 52.01 was prepared analogously to the procedure for the preparation of Compound 02.01.
Yield: 1.21 g (64 %) of the title compound.
LC-MS (Method 2): R, = 1.27 min; MS (ESIpos): m/z = 305 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.980 (15.04), 0.990 (1.38), 0.996 (16.00), 1.390 (4.64), 1.408 (11.63), 1.427 (5.07), 2.175 (0.78), 2.192 (1.01 ), 2.209 (0.79), 2.522 (1.49), 3.391 (4.03), 3.407 (4.01 ), 4.168 (1.24), 4.185 (3.93), 4.204 (4.04), 4.222 (1.30), 6.858 (1.31 ), 6.891 (4.38), 6.913 (4.15), 7.784 (3.92), 7.807 (3.39), 7.967 (4.54), 7.969 (4.52), 8.277 (4.1 1 ), 8.279 (4.14).
Compound 52.02
4-(1 -ethyl-1H-pyrazol-4-yl)-3-( -methylpropoxy)benzene-1 ,2-diamine
Figure imgf000467_0002
To a stirred solution of 3-(1 -ethyl-1 H-pyrazol-4-yl)-2-(2-methylpropoxy)-6-nitroaniline (1.21 g, 3.98 mmol) in ethanol (20 ml.) and dichloromethane (40 mL) was added palladium on carbon (10 % w/w palladium; 423 mg) and the mixture was stirred at r.t. in a hydrogen atmosphere for 3 h. The mixture was filtered, and the solution was concentrated in vacuum. Aminophase silicagel chromatography gave 1.00 g (92 % yield)of the title compound.
LC-MS (Method 2): R, = 0.95 min; MS (ESIpos): m/z = 275 [M+H]+ 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.954 (14.62), 0.971 (16.00), 1.351 (4.90), 1.369 (12.10), 1.388 (4.87), 2.021 (0.78), 2.037 (0.95), 2.054 (0.74), 2.518 (2.78), 2.523 (1.83), 3.292 (3.77), 3.309 (3.89), 4.085 (1.42), 4.102 (7.13), 4.121 (4.47), 4.139 (1.38), 4.564 (3.70), 5.760 (7.51 ), 6.326 (2.95), 6.346 (3.44), 6.558 (3.73), 6.578 (3.17), 7.630 (4.62), 7.632 (4.66), 7.849 (4.24), 7.851 (4.01 ).
Compound 52.03
tert-butyl 4-[(2-{[6-(1 -ethyl-1 H-pyrazol-4-yl)-7-(2-methylpropoxy)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate
Figure imgf000468_0001
To a stirred solution of 1 H-imidazole (49.6 mg, 729 pmol) and di-1 H-imidazol-1 - ylmethanethione (684 mg, 95 % purity, 3.64 mmol) in dichloromethane (40 mL) was added tert-butyl 4-[(2-aminopyridin-4-yl)methyl]piperazine-1 -carboxylate (1.07 g, 3.64 mmol), dissolved in dichloromethane (20 mL), at 0° C. The mixture was stirred at r.t. for 16 h. 4-(1- ethyl-1 H-pyrazol-4-yl)-3-(2-methylpropoxy)benzene-1 ,2-diamine (1.00 g, 3.64 mmol), dissolved in dichloromethane (20 mL), was added and the mixture was stirred at r.t. for 3 h. Water was added and the mixture was extracted with dichloromethane.
The organic phase was dried (sodium sulfate) and filtered. N,N'-dipropan-2-ylcarbodiimide (1.7 mL, 1 1 mmol) was added. The mixture was stirred at r.t. for 14 h. Further N,N'-dipropan-2- ylcarbodiimide (1.7 mL, 1 1 mmol) was added and the mixture was stirred at r.t. for 5 h. Further N,N'-dipropan-2-ylcarbodiimide (1.1 mL, 7.3 mmol) was added and the mixture was stirred at r.t. for 56 h. Sodium bicarbonate solution was added, the mixture was stirred for 30 minutes and was extracted with dichloromethane. Aminophase-silicagel chromatography gave 500 mg of the title compound as a crude product, that was used without further purification.
LC-MS (Method 2): R, = 1.46 min; MS (ESIpos): m/z = 575 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.925 (2.06), 0.942 (2.14), 0.980 (4.06), 0.997 (4.21 ), 1.134 (0.74), 1.137 (0.73), 1.154 (0.65), 1.374 (1.14), 1.382 (2.45), 1.386 (4.43), 1.390 (7.33), 1.394 (16.00), 1.400 (4.28), 1.41 1 (1.46), 1.418 (1.33), 2.323 (0.59), 2.327 (0.77), 2.332 (0.99), 2.337 (1.20), 2.349 (1 .43), 2.361 (1.03), 2.523 (1.99), 2.669 (0.42), 3.308 (0.76), 3.483 (1.33), 3.496 (0.57), 4.144 (1.02), 4.149 (0.84), 4.162 (1.08), 4.167 (0.87), 4.342 (1.26), 4.359 (1.26), 7.158 (1.13), 7.167 (1.20), 7.239 (0.74), 7.772 (0.77), 7.799 (1.23), 8.016 (1.13), 8.037 (0.50), 8.228 (0.61 ), 8.241 (0.56), 10.584 (0.64).
Compound 52.04
6-(1 -ethyl-1H-pyrazol-4-yl)-7-(2-methylpropoxy)-N-[4-(piperazin-1-ylmethyl)pyrid
1 H-benzimidazol-2-amine hydrochloride
Figure imgf000469_0001
Starting with tert-butyl 4-[(2-{[6-(1-ethyl-1 H-pyrazol-4-yl)-7-(2-methylpropoxy)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate (500 mg, 870 μιτιοΙ), Compound 52.04 was prepared analogously to the procedure for the preparation of Compound
01.05.
Yield: 497 mg of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): R, = 1.17 min; MS (ESIpos): m/z = 475 [M+H]+
H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.926 (6.49), 0.942 (6.56), 0.986 (0.94), 1.003 (1.47), 1.016 (15.77), 1.033 (16.00), 1.152 (2.83), 1.168 (2.89), 1.270 (3.81 ), 1.284 (5.50), 1.299 (3.69), 1 .318 (3.06), 1.335 (3.06), 1.379 (2.98), 1.394 (5.87), 1.397 (6.71 ), 1.41 1 (10.37), 1.416 (3.81 ), 1.430 (4.73), 2.122 (0.55), 2.139 (1.06), 2.155 (1.33), 2.172 (1.15), 2.176 (0.87), 2.188 (0.67), 2.193 (0.62), 2.322 (0.60), 2.326 (0.77), 2.332 (0.58), 2.522 (4.95), 2.565 (2.99), 2.664 (0.55), 2.668 (0.71 ), 2.673 (0.51 ), 3.455 (3.51 ), 3.563 (9.69), 3.620 (0.70), 3.637 (0.90), 3.641 (1 .07), 3.659 (0.98), 3.691 (0.96), 3.708 (1.13), 3.712 (0.87), 3.729 (0.60), 3.857 (2.91 ), 3.874 (2.85), 4.144 (0.98), 4.162 (3.23), 4.181 (5.12), 4.200 (4.10), 4.218 (1.35), 4.342 (0.68), 4.362 (0.75), 4.454 (1.03), 4.842 (0.91 ), 7.124 (1.57), 7.145 (1.47), 7.404 (1.80), 7.416 (2.26), 7.426 (2.34), 7.437 (1.84), 7.513 (2.04), 7.524 (2.83), 7.546 (1.85), 7.587 (0.85), 7.827 (2.76), 7.829 (2.38), 7.876 (4.70), 7.878 (4.52), 8.105 (2.57), 8.140 (4.45), 8.517 (1.25), 8.530 (1.20), 9.810 (0.76), 10.430 (0.71 ), 10.450 (0.71 ), 10.494 (0.63), 10.515 (0.64), 13.729 (1.38). Compound 53.01
2-ethoxy-3-(1 -ethyl-1 H-pyrazol-4-yl)-6-nitroaniline
Figure imgf000470_0001
Starting with 3-bromo-2-ethoxy-6-nitroaniline (950 mg, 3.64 mmol) and (1 -ethyl-1 H-pyrazol-4- yl)boronic acid (616 mg, 95 % purity, 4.18 mmol), Compound 53.01 was prepared analogously to the procedure for the preparation of Compound 02.01.
Yield: 650 g (65 % yield) of the title compound.
LC-MS (Method 2): R, = 1 .10 min; MS (ESIpos): m/z = 277 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.364 (5.55), 1.382 (12.43), 1.393 (7.41 ), 1.400 (5.47), 1.41 1 (16.00), 1.429 (6.72), 3.692 (1.41 ), 3.709 (4.85), 3.727 (4.82), 3.745 (1.37), 4.181 (1.86), 4.200 (5.87), 4.218 (5.73), 4.236 (1.73), 6.895 (5.71 ), 6.919 (5.64), 7.140 (2.81 ), 7.767 (5.29), 7.791 (4.74), 8.006 (6.65), 8.008 (6.76), 8.325 (6.24).
Compound 53.02
3-ethoxy-4-(1 -ethyl-1 H-pyrazol- -yl)benzene-1 ,2-diamine
Figure imgf000470_0002
To a stirred solution of 2-ethoxy-3-(1 -ethyl-1 H-pyrazol-4-yl)-6-nitroaniline (650 mg, 2.35 mmol)in ethanol (100 mL) and dichloromethane (100 mL) was added palladium on carbon (10 % w/w palladium; 125 mg) and the mixture was stirred at r.t. in a hydrogen atmosphere for 3 h. The mixture was filtered, and the solution was concentrated in vacuum. Aminophase silicagel chromatography gave 0.45 g (78 % yield) of the title compound.
LC-MS (Method 2): R, = 0.76 min; MS (ESIpos): m/z = 247 [M+H]+ 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.155 (4.15), 1 .172 (8.74), 1.190 (4.39), 1.275 (4.19), 1.292 (9.82), 1.310 (4.50), 1.357 (5.58), 1.375 (12.34), 1.393 (5.82), 1.987 (16.00), 3.337 (5.56), 3.586 (1.22), 3.604 (4.13), 3.621 (4.04), 3.638 (1.18), 4.000 (1.24), 4.018 (3.74), 4.035 (3.65), 4.053 (1.16), 4.096 (1.64), 4.1 14 (5.11 ), 4.133 (4.96), 4.150 (1.60), 4.207 (4.13), 4.544 (4.34), 5.758 (2.91 ), 6.318 (3.38), 6.338 (4.01 ), 6.570 (4.27), 6.591 (3.65), 7.670 (5.55), 7.671 (5.77), 7.885 (5.69).
Compound 53.03
tert-butyl 4-[(2-{[7-ethoxy-6-(1 -ethyl-1 H-pyrazol-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate
Figure imgf000471_0001
To a stirred solution of 1 H-imidazole (24.7 mg, 363 pmol) and di-1 H-imidazol-1- ylmethanethione (340 mg, 95 % purity, 1.81 mmol) in dichloromethane (20 mL) was added tert-butyl 4-[(2-aminopyridin-4-yl)methyl]piperazine-1 -carboxylate (530 mg, 1.81 mmol) , dissolved in dichloromethane (10 mL), at 0° C. The mixture was stirred at r.t. for 14 h. 3- Ethoxy-4-(1-ethyl-1 H-pyrazol-4-yl)benzene-1 ,2-diamine (446 mg, 1.81 mmol) , dissolved in dichloromethane (10 mL), was added and the mixture was stirred at r.t. for 2 h. Water was added and the mixture was extracted with dichloromethane / methanol (20: 1 ).
The organic phase was dried (sodium sulfate) and filtered. N,N'-dipropan-2-ylcarbodiimide (700 μΙ, 4.5 mmol) was added and the mixture was stirred at r.t. for 14 h. Sodium bicarbonate solution was added, the mixture was stirred for 30 minutes and the mixture was extracted with dichloromethane. The organic phase was dried (sodium sulfate) and the solvent was removed in vacuum. The residue was triturated with ethanol, filtered and the solid was discarded. The solution was concentrated in vacuum. Silicagel chromatography followed by aminophase- silicagel chromatography gave 0.41 g of the title compound as a crude product, that was used without further purification.
LC-MS (Method 2): R, = 1.32 min; MS (ESIpos): m/z = 547 [M+H]+ 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.364 (0.70), 1.386 (16.00), 1.390 (3.24), 1.395 (5.04), 1.408 (1.13), 1.427 (0.49), 2.277 (0.89), 2.290 (1.29), 2.302 (0.98), 3.309 (2.93), 3.322 (5.25), 5.756 (0.73), 5.815 (1.12), 6.382 (0.88), 6.406 (0.54), 6.419 (0.56), 7.802 (0.71 ), 7.804 (0.66), 7.815 (0.68), 7.816 (0.69).
Compound 53.04
7-ethoxy-6-(1-ethyl-1 H-pyrazol-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyrid
benzimidazol-2-amine hydrochloride
Figure imgf000472_0001
Starting with tert-butyl 4-[(2-{[7-ethoxy-6-(1-ethyl-1 H-pyrazol-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate (400 mg, 659 pmol), Compound 53.04 was prepared analogously to the procedure for the preparation of Compound 01.05.
Yield: 0.41 g of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): Rt = 0.97 min; MS (ESIpos): m/z = 447 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.376 (6.03), 1.394 (13.61 ), 1.399 (7.64), 1.41 1 (7.18), 1.418 (16.00), 1.436 (6.58), 1.591 (0.50), 2.327 (1.51 ), 2.523 (6.71 ), 2.665 (1.18), 2.669 (1.51 ), 3.057 (1.68), 3.162 (5.88), 3.354 (8.97), 3.457 (4.19), 3.563 (3.29), 4.072 (1.41 ), 4.089 (4.07), 4.107 (4.12), 4.124 (1.86), 4.175 (2.96), 4.193 (6.53), 4.21 1 (6.33), 4.229 (2.56), 4.440 (1.18), 5.138 (0.78), 5.758 (3.01 ), 7.133 (9.07), 7.418 (2.21 ), 7.440 (2.84), 7.539 (2.61 ), 7.553 (4.30), 7.575 (3.67), 7.920 (7.08), 7.922 (6.63), 7.999 (5.53), 8.015 (5.30), 8.191 (6.41 ), 8.317 (1.86), 8.522 (1.56), 9.703 (1.51 ). Compound 54.01
3-methyl-4-(3-methyl-1 ,2,4-oxadiazol-5-yl)benzene-1 ,2-diamine
Figure imgf000473_0001
Methyl 3,4-diamino-2-methylbenzoate (PCT Int. Appl., 2009055077) (1.00 g, 5.55 mmol)N- hydroxyethanimidamide (974 mg, 95 % purity, 12.5 mmol) and caesium carbonate (1.81 g, 5.55 mmol) were solubilized in dioxane (10 mL), and the reaction was stirred for 16 hours at 1 10Έ;. N-Hydroxyethanimidamide (974 mg, 95 % purity , 12.5 mmol) and caesium carbonate (1.81 g, 5.55 mmol) were added again and the reaction was stirred for 24h additional hours. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried (silicone filter) and concentrated under reduced pressure. The residue was stirred with water at 60 . The suspension was filtered and the solid was dried under reduced pressure to give 740 mg of the title compound (62% yield).
LC-MS (Method 2): R, = 0.74 min; MS (ESIpos): m/z = 205 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.340 (16.00), 2.405 (13.00), 4.517 (2.90), 5.375 (3.38), 6.513 (2.08), 6.534 (2.19), 7.136 (2.51 ), 7.157 (2.33).
Compound 54.02
tert-butyl 4-[(2-{[7-methyl-6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazine-1-carboxylate
Figure imgf000473_0002
To a stirred solution of di-1 H-imidazol-1-ylmethanethione (314 mg, 1.76 mmol) and imidazole (20.0 mg, 294 μηιοΙ) in dichloromethane (10 mL) was added tert-butyl 4-[(2-aminopyridin-4- yl)methyl]piperazine-1-carboxylate (429 mg, 1.47 mmol) , dissolved in dichloromethane (10 mL), at 0° C. The mixture was stirred at r.t. for 1 4 h. 3-methyl-4-(3-methyl-1 ,2,4-oxadiazol-5- yl)benzene-1 ,2-diamine (300 mg, 1.47 mmol) was added and the mixture was stirred at r.t. for 4 h. Water was added and the mixture was extracted with dichloromethane.
The organic phase was dried (sodium sulfate) and filtered. N,N'-dipropan-2-ylcarbodiimide (5.0 mL, 32 mmol) was added and the mixture was stirred at r.t. for 14 h. Sodium bicarbonate solution was added, the mixture was stirred for 30 minutes and the mixture was extracted with dichloromethane. The organic phase was dried and the solvent was removed in vacuum. Aminophase-silicagel chromatography gave 480 mg of the title compound
LC-MS (Method 2): R, = 1.33 min; MS (ESIpos): m/z = 505 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.392 (4.86), 1.396 (16.00), 2.348 (0.93), 2.360 (1.42), 2.373 (1.08), 2.417 (6.35), 2.835 (4.62), 3.351 (1.21 ), 3.505 (1.44), 5.758 (4.48).
Compound 54.03
7-methyl-6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-N-[4-(piperazin-1 -ylmethyl)pyrid
benzimidazol-2-amine hydrochloride salt
Figure imgf000474_0001
Starting with tert-butyl 4-[(2-{[7-methyl-6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazine-1-carboxylate (480 mg, 951 pmol) , Compound 54.03 was prepared analogously to the procedure for the preparation of Compound 01.05.
Yield: 470 mg of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): R, = 1.00 min; MS (ESIpos): m/z = 405 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.860 (16.00), 3.162 (9.15), 3.292 (1.38), 3.455 (1.63), 3.466 (1.46), 3.485 (1.25), 3.497 (1.06), 3.563 (3.1 1 ), 3.661 (0.97), 3.664 (0.82), 3.673 (1.04), 3.697 (1.09), 3.707 (0.87), 3.71 1 (0.99), 4.354 (0.95), 7.567 (1.46), 7.638 (1.43), 7.660 (1.53), 7.949 (3.09), 7.970 (2.66), 8.485 (1.07). Compound 55.01
1 -{[(1 RS)-2,2-difluorocyclopropyl]methyl}-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)- 1 H-pyrazole
Figure imgf000475_0001
Starting with 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (757 mg, 3.90 mmoi) and 2,2-difluorocyclopropylmethyl bromide (CAS# 77613-65-1 ), Compound 55.01 was prepared analogously to the procedure for the preparation of Compound 39.01. The mixture was stirred at 80 over night.
Yield: 1.02 g (85%) of the title compound as crude product with 92 % purity that was used for the next step without purification.
LC-MS (Method 2): R, = 1.02 min; MS (ESIpos): m/z = 285 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.22 - 1.32 (m, 12H), 1.42 - 1 .57 (m, 1 H), 1.60 - 1.72 (m, 1 H), 2.15 - 2.30 (m, 1 H), 4.13 - 4.35 (m, 2H), 7.61 (s, 1 H), 7.98 (s, 1 H).
Compound 55.02
4-(1 -{[(1 RS)-2,2-difluorocyclopropyl]methyl}-1 H-pyrazol-4-yl)-2-nitroaniline
Figure imgf000475_0002
Starting with 1-{[(1 RS)-2,2-difluorocyclopropyl]methyl}-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-pyrazole (1.02 g, 3.59 mmol) compound 55.01 , Compound 55.02 was prepared analogously to the procedure for the preparation of Compound 39.02.
Yield: 577 mg (49%) of the title compound with 90 % purity.
LC-MS (Method 2): R, = 1.02 min; MS (ESIpos): m/z = 295 [M+H]+ 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.45 - 1.58 (m, 1Η), 1.61 - 1.76 (m, 1H), 2.17 - 2.31 (m, 1H), 4.13 - 4.34 (m, 2H), 7.05 (d, 1Η), 7.44 (s, 2Η), 7.66 (dd, 1Η), 7.88 (d, 1Η), 8.10 (d, 1H), 8.19 (s, 1H),
Compound 55.02.01
4-0 -{[(1R or 1S)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-2-nitroaniline
Figure imgf000476_0001
The racemic mixture of 4-(1-{[(1RS)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-2- nitroaniline compound 55.02 was separated by chiral HPLC.
Yield: 317 mg of the title compound with 97 % purity.
Chiral HPLC (Method 6): Rt = 4.75 min; > 99.9%ee
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.45 - 1.58 (m, 1H), 1.61 - 1.76 (m, 1H), 2.17 - 2.31 (m, 1H), 4.13 - 4.34 (m, 2H), 7.05 (d, 1H), 7.44 (s, 2H), 7.66 (dd, 1H), 7.88 (d, 1H), 8.10 (d, 1H), 8.19 (s, 1H).
Compound 55.02.02
4-(1-{[(1R or 1S)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-2-nitroaniline
Figure imgf000476_0002
The racemic mixture of 4-(1-{[(1RS)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-2- nitroaniline compound 55.02 was separated by chiral HPLC.
Yield: 250 mg of the title compound with 96 % purity.
Chiral HPLC (Method 6): Rt = 5.34 min; 96.2%ee 1H-NMR (400 MHz, DMSO-d6) δ [ppm] = 1.45 - 1.58 (m, 1H), 1.61 - 1.76 (m, 1H), 2.17 - 2.31 (m, 1H), 4.13 - 4.34 (m, 2H), 7.05 (d, 1H), 7.44 (s, 2H), 7.66 (dd, 1H), 7.88 (d, 1H), 8.10 (d, 1H), 8.19 (s, 1H).
Compound 55.03
4-(1 -{[(1 RS)-2,2-difluorocyclopropyl]methyl}-1 H-pyrazol-4-yl)benzene-1 ,2-diamine
Figure imgf000477_0001
Starting with 4-(1-{[(1RS)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-2-nitroaniline (570 mg, 1.94 mmol) Compound 55.02, Compound 55.03 was prepared analogously to the procedure for the preparation of Compound 39.03.
Yield: 365 mg (64%) of the title compound with 90 % purity.
LC-MS (Method 2): R, = 0.78 min; MS (ESIpos): m/z = 265 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.43 - 1.55 (m, 1H), 1.59 - 1.75 (m, 1H), 2.15 - 2.31 (m, 1H), 4.13-4.27 (m, 2H), 4.44 (brd, 4H), 6.48 (d, 1H), 6.59 (dd, 1H), 6.69 (d, 1H), 7.60 (d, 1H), 7.83 (s, 1H).
Compound 55.03.01
4-(1-{[(1R or 1S)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)benzene-1 ,2-diamine
Figure imgf000477_0002
Starting with 4-(1-{[(1R or 1S)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-2-nitroaniline (315 mg; see Compound 55.02.01), Compound 55.03.01 was prepared analogously to the procedure for the preparation of Compound 39.03.
Yield: 163 mg of the title compound with 80 % purity. LC-MS (Method 2): R, = 0.80 min; MS (ESIpos): m/z = 265 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm] = 1.43 - 1.55 (m, 1H), 1.59 - 1.75 (m, 1H), 2.15 - 2.31 (m, 1H), 4.13-4.27 (m, 2H), 4.44 (brd, 4H), 6.48 (d, 1H), 6.59 (dd, 1H), 6.69 (d, 1H), 7.60 (d, 1H), 7.83 (s, 1H).
Compound 55.03.02
4-(1 -{[(1 or 1 S)-2,2-difluorocyclopropyl]methyl}-1 H-pyrazol-4-yl)benzene-1 ,2-diamine
Figure imgf000478_0001
Starting with 4-(1-{[(1R or 1S)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-2-nitroaniline (245 mg; see Compound 55.02.02), Compound 55.03.02 was prepared analogously to the procedure for the preparation of Compound 39.03.
Yield: 143 mg of the title compound with 76 % purity.
LC-MS (Method 2): R, = 0.80 min; MS (ESIpos): m/z = 265 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm] = 1.43 - 1.55 (m, 1H), 1.59 - 1.75 (m, 1H), 2.15 - 2.31 (m, 1H), 4.13-4.27 (m, 2H), 4.44 (brd, 4H), 6.48 (d, 1H), 6.59 (dd, 1H), 6.69 (d, 1H), 7.60 (d, 1H), 7.83 (s, 1H).
Compound 55.04
6-(1 -{[(1 RS)-2,2-difluorocyclopropyl]methyl}-1 H-pyrazol-4-yl)-N-{4-[(1 R or 1S)-1 - (piperazin-1 -yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride salt
Figure imgf000479_0001
Starting with tert-butyl 4-[(1 R or 1 S)-1-(2-{[6-(1 -{[(1 RS)-2,2-difluorocyclopropyl]methyl}-1 H- pyrazol-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1 -carboxylate (360 mg, 622 μηιοΙ; Example 55.01 ), Compound 55.04 was prepared analogously to the procedure for the preparation of Compound 39.05.
Yield: 427 mg of the title compound.
LC-MS (Method 2): Rt = 1.01 min; MS (ESIpos): m/z = 479 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: ]= 1.55 (ddt, 1 H), 1.64 - 1.81 (m, 4Η), 2.21 - 2.37 (m, 1 H), 2.50 - 2.53 (m, 4H), 3.28 (br s, 2H), 3.39 - 3.53 (m, 3H), 4.23 - 4.36 (m, 2H), 7.55 (s, 1 H), 7.56 - 7.61 (m, 1 H), 7.66 (d, 2H), 7.79 (d, 1 H), 7.93 (d, 1 H), 8.23 (s, 1 H), 8.57 (d, 1 H), 9.80 (br s, 2H), 13.37 (br s, 2H). - 2 HCI not detectable.
Compound 55.04.01
6-(1 -{[(1 R or 1S)-2,2-difluorocyclopropyl]methyl}-1 H-pyrazol-4-yl)-N-{4-[(1 R or 1S)-1- (piperazin-1 -yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride
Figure imgf000479_0002
Starting with tert-butyl 4-[(1 R or 1 S)-1-(2-{[6-(1 -{[(1 R or 1 S)-2,2-difluorocyclopropyl]methyl}-1 H- pyrazol-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1 -carboxylate (70.0 mg, see Example 55.01.01 ), Compound 55.04.01 was prepared analogously to the procedure for the preparation of Compound 39.05.
Yield: 96 mg of the 78% pure title compound.
LC-MS (Method 2): Rt = 1.01 min; MS (ESIpos): m/z = 479 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm] = 1.49 - 1.60 (m, 1 H), 1.63 - 1.79 (m, 4H), 2.21 - 2.32 (m, 1 H), 3.19 - 3.54 (m, 8H), 4.20 - 4.35 (m, 3H), 7.54 (s, 1 H), 7.56 - 7.69 (m, 3H), 7.75 - 7.81 (m, 1 H), 7.88 - 7.94 (m, 1 H), 8.21 - 8.26 (m, 1 H), 8.57 (d, 1 H), 9.72 (br s, 2H), 12.83 - 13.53 (m, 3H). - 2 HCI detectable.
Compound 55.04.02
6-(1 -{[(1 R or 1S)-2,2-difluorocyclopropyl]methyl}-1 H-pyrazol-4-yl)-N-{4-[(1 R or 1S)-1 - (piperazin-1 -yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride
Figure imgf000480_0001
Starting with tert-butyl 4-[(1 R or 1 S)-1-(2-{[6-(1 -{[(1 R or 1 S)-2,2-difluorocyclopropyl]methyl}- H- pyrazol-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1 -carboxylate (80.0 mg, see Example 55.01.02), Compound 55.04.02 was prepared analogously to the procedure for the preparation of Compound 39.05.
Yield: 79 mg of the 80% pure title compound.
LC-MS (Method 2): Rt = 1.01 min; MS (ESIpos): m/z = 479 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm] = 1.49 - 1.60 (m, 1 H), 1.63 - 1.79 (m, 4H), 2.21 - 2.32 (m, 1 H), 3.16 (s, 1 H), 3.17 - 3.55 (m, 1 H), 3.19 - 3.34 (m, 2H), 3.34 - 3.54 (m, 4H), 4.20 - 4.35 (m, 3H), 7.54 (s, 1 H), 7.56 - 7.69 (m, 3H), 7.75 - 7.81 (m, 1 H), 7.88 - 7.94 (m, 1 H), 8.21 - 8.26 (m, 1 H), 8.57 (d, 1 H), 9.72 (br s, 2H), 12.83 - 13.53 (m, 3H). - 2 HCI detectable. Compound 56.01
1 -{[(1 RS,2RS)-2-methylcyclopropyl]methyl}-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)-1 H-pyrazole
Figure imgf000481_0001
Starting with (1 R,2S)-1 -(bromomethyl)-2-methylcyclopropane (2.00 g, 13.4 mmol), Compound 56.01 was prepared analogously to the procedure for the preparation of Compound 39.01. The mixture was stirred at 80Ό over night.
Yield: 890 mg (25%) of the title compound as crude product with 53 % purity that was used for the next step without purification.
LC-MS (Method 2): R, = 1.19 min; MS (ESIpos): m/z = 263.1 [M+H]+
Compound 56.02
4-(1-{[(1 RS,2RS)-2-methylcyclopropyl]methyl}-1 H-pyrazol-4-yl)-2-nitroaniline
Figure imgf000481_0002
Starting with 1 -{[(1 RS,2RS)-2-methylcyclopropyl]methyl}-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-pyrazole (890 mg, 3.39 mmol, compound 56.01 ), Compound 56.02 was prepared analogously to the procedure for the preparation of Compound 39.02.
Yield: 300 mg (30%) of the title compound with 92 % purity.
LC-MS (Method 2): R, = 1.10 min min; MS (ESIpos): m/z = 273 [M+H]+
H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.06 - 0.32 (m, H), 0.44 - 0.57 (m, 1 H), 0.68 - 0.86 (m, 1 H), 0.91 - 0.98 (m, 1 H), 0.98 - 1.14 (m, 3H), 3.84 - 4.14 (m, 2H), 7.01 - 7.09 (m, 1 H), 7.42 (s, 2H), 7.62 - 7.70 (m, 1 H), 7.78 - 7.86 (m, 1 H), 8.07 - 8.12 (m, 1 H), 8.13 - 8.20 (m, 1 H). Compound 56.03
4-(1-{[(1 S,2RS)-2-methylcyclopropyl]methyl}-1 H-pyrazol-4-yl)benzene-1 ,2-diamine
Figure imgf000482_0001
Starting with 4-(1 -{[(1 RS,2RS)-2-methylcyclopropyl]methyl}-1 H-pyrazol-4-yl)-2-nitroaniline (300 mg, 1.10 mmol, Compound 56.02), Compound 56.03 was prepared analogously to the procedure for the preparation of Compound 39.03.
Yield: 356 mg (97%) of the title compound with 73 % purity.
LC-MS (Method 2): Rt = 0.87 min; MS (ESIpos): m/z = 243 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.01 - 0.32 (m, 1 H), 0.46 - 0.55 (m, 1 H), 0.70 - 0.83 (m, 1 H), 0.89 - 0.96 (m, 1 H), 1.00 (d, 3H), 3.80 - 4.16 (m, 2H), 4.77 (br s, 4H), 6.48 - 6.54 (m, 1 H), 6.59 - 6.66 (m, 1 H), 6.68 - 6.75 (m, 1 H), 7.52 - 7.58 (m, 1 H), 7.77 - 7.86 (m, 1 H)
Compound 56.04
6-(1 -{[(1 RS,2RS)-2-methylcyclopropyl]methyl}-1H-pyrazol-4-yl)-N-{4-[(1 R or 1S)-1 - (piperazin-1-yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride salt
Figure imgf000482_0002
Starting with tert-butyl 4-[(1 R or 1 S)-1-(2-{[6-(1 -{[(1 RS,2RS)-2-methylcyclopropyl]methyl}-1 H- pyrazol-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1 -carboxylate (235 mg, 422 pmol) Example 56.01 , Compound 56.04 was prepared analogously to the procedure for the preparation of Compound 39.05.
Yield: 314 mg of the title compound.
LC-MS (Method 2): R, = 1.11 min min; MS (ESIpos): m/z = 457 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: ]= 0.132 (0.62), 0.145 (0.64), 0.288 (0.89), 0.300 (1.70), 0.312 (1.35), 0.320 (1.77), 0.332 (1.03), 0.539 (0.92), 0.550 (1.81 ), 0.561 (1.79), 0.571 (2.02), 0.582 (1.01 ), 0.734 (0.62), 0.745 (0.62), 0.755 (0.41 ), 0.807 (0.48), 0.821 (0.83), 0.832 (1.12), 0.845 (1.49), 0.849 (1.12), 0.863 (1.63), 0.881 (0.76), 0.967 (0.50), 0.979 (0.99), 0.986 (1.08), 0.991 (1.05), 0.996 (1.54), 1.013 (14.85), 1.028 (13.41 ), 1.044 (0.87), 1.130 (4.40), 1.146 (3.55), 1.231 (0.41 ), 1.277 (0.48), 1.281 (0.44), 1.295 (0.57), 1.696 (4.47), 1.712 (4.45), 2.327 (1.12), 2.331 (0.78), 2.518 (4.74), 2.523 (3.28), 2.669 (1.12), 2.674 (0.78), 2.727 (0.99), 2.887 (1.24), 3.162 (16.00), 3.202 (0.46), 3.219 (0.53), 3.288 (1.60), 3.360 (0.64), 3.371 (1.08), 3.382 (0.83), 3.387 (0.76), 3.393 (0.94), 3.456 (2.13), 3.466 (2.29), 3.468 (2.36), 3.485 (2.27), 3.487 (2.20), 3.497 (1.97), 3.595 (0.60), 3.602 (0.53), 3.613 (0.48), 3.661 (0.53), 3.665 (0.46), 3.673 (0.55), 3.675 (0.57), 3.697 (0.57), 3.699 (0.55), 3.71 1 (0.48), 3.728 (0.46), 3.948 (1.17), 3.967 (1.12), 3.983 (2.41 ), 4.001 (2.64), 4.022 (2.45), 4.040 (2.18), 4.058 (1.05), 4.075 (1.05), 4.1 18 (0.44), 4.134 (1.17), 4.154 (1.15), 4.163 (1.01 ), 4.181 (0.85), 4.702 (0.55), 5.300 (1.38), 7.544 (5.09), 7.577 (2.15), 7.581 (2.20), 7.587 (1.19), 7.598 (3.46), 7.602 (3.92), 7.608 (1.40), 7.640 (6.58), 7.661 (4.26), 7.771 (1.01 ), 7.779 (4.52), 7.783 (4.74), 7.870 (8.37), 7.871 (8.60), 7.881 (2.36), 7.883 (2.41 ), 8.194 (6.90), 8.206 (1.05), 8.217 (1.99), 8.566 (3.74), 8.579 (3.44), 9.794 (1.15), 13.357 (0.57).
Compound 57.01
2-nitro-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1 H-pyrazol-4-yl)aniline
Figure imgf000483_0001
Starting with 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 -{[2-(trimethylsilyl)ethoxy]methyl}-
1 H-pyrazole (CAS# 894807-98-8; 3.51 g, 91 % purity, 9.85 mmol), Compound 57.01 was prepared analogously to the procedure for the preparation of Compound 39.02.
Yield: 2.1 g (59%) of the title compound with 93 % purity.
LC-MS (Method 2): R, = 1.30 min min; MS (ESIpos): m/z = 335 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.07 - -0.02 (m, 9H), 0.79 - 0.88 (m, 2H), 3.50 - 3.60 (m, 2H), 5.39 (s, 2H), 7.05 (d, 1 H), 7.41 - 7.52 (m, 2H), 7.69 (dd, 1 H), 7.90 - 7.99 (m, 1 H), 8.13 (d, 1 H), 8.29 - 8.36 (m, 1 H) Compound 57.02
4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1 H-pyrazol-4-yl)benzene-1,2-diamine
Figure imgf000484_0001
Starting with 2-nitro-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1 H-pyrazol-4-yl)aniline (2.10 g, 6.28 mmol) Compound 56.01 , Compound 56.02 was prepared analogously to the procedure for the preparation of Compound 39.03.
Yield: 1.5 g (63%) of the title compound with 80 % purity.
LC-MS (Method 2): R, = 1.10 min min; MS (ESIpos): m/z = 305 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.09 - 0.00 (m, 9H), 0.76 - 0.89 (m, 2H), 3.47 - 3.59 (m, 2H), 4.45 (br d, 4H), 5.32 - 5.40 (m, 2H), 6.49 (d, 1 H), 6.62 (dd, 1 H), 6.71 (d, 1 H), 7.66 (s, 1 H), 7.94 (d, 1 H). - contains tBuOH.
Compound 57.03
tert-butyl 4-[(1 R or 1 S)-1 -(2-{[6-(1 -{[2-(trimethylsilyl)ethoxy]methyl}-1 H-pyrazol-4-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1-carboxylate
Figure imgf000484_0002
1 H-imidazole (67.1 mg, 985 pmol) and di-1 H-imidazol-1-ylmethanethione (922 mg, 5.17 mmol) were dissolved in 15 mL dichloromethane. tert-butyl 4-[(1 R or 1 S)-1-(2-aminopyridin-4- yl)ethyl]piperazine-1 -carboxylate (1.51 g, 4.93 mmol) dissolved in 15 mL dichloromethane was added. This mixture was stirred at rt for over night. 4-(1 -{[2-(trimethylsilyl)ethoxy]methyl}-1 H- pyrazol-4-yl)benzene-1 ,2-diamine (1.50 g, 4.93 mmol) compound 57.02 dissolved in 15 mL dichloromethane was added and it was stirred at rt for three hours. The reaction mixture was diluted with dichloromethane and water. The aqueous layer was extracted with dichloromethane twice. The organic layer was concentrated under reduced pressure and the residue was purified by flash chromatography to give 2.2 g of the intermediate thiourea in 76 % purity. The intermediate tert-butyl 4-{(1 R or 1 S)-1-[2-({[2-amino-4-(1-{[2- (trimethylsilyl)ethoxy]methyl}-1 H-pyrazol-4-yl)phenyl]carbamothioyl}amino)pyridin-4- yl]ethyl}piperazine-1 -carboxylate (2.19 g, 76 % purity, 2.55 mmol) was solved in 33 mL dichloromethane and N,N'-dipropan-2-ylcarbodiimide (1.2 ml, 7.6 mmol) was added. This mixture was stirred 72 h at rt. The reaction mixture was absorbed with isolute and purified by flash chromatography.
Yield: 1.39 g of the title compound with 85 % purity.
LC-MS (Method 2): R, = 1.51 min min; MS (ESIpos): m/z = 619 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.020 (1.87), -0.017 (1.41 ), -0.014 (2.68), -0.008 (16.00), 0.000 (0.76), 0.863 (0.62), 0.883 (0.77), 0.904 (0.55), 1.166 (0.45), 1.301 (1.14), 1.318 (1.01 ), 1.404 (9.35), 1.409 (2.55), 2.1 1 1 (0.96), 3.348 (0.84), 3.361 (6.54), 3.586 (0.52), 3.606 (0.64), 3.626 (0.44), 5.442 (0.86), 7.189 (0.47), 8.270 (0.61 ), 8.283 (0.57).
Compound 58.01
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 -(2,2,2-trifluoroethyl)-1 H-pyrazole
Figure imgf000485_0001
To a stirred solution of 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (2.00 g, 10.3 mmol) in DMF (20 ml) was added potassium carbonate (4.27 g, 30.9 mmol) and 2,2,2- trifluoroethyl trifluoromethanesulfonate (2.2 ml, 15 mmol). The mixture was stirred at 80° C for 14 h. Further 2,2,2-trifluoroethyl trifluoromethanesulfonate (420 μΙ, 2.9 mmol) was added and the mixture was stirred at 80° C for 1 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with half-saturated sodium chloride solution, dried (sodium sulfate), filtered and the solvent was removed in vacuum. Silicagel chromatography gave 1.76 g (62 % yield) of the title compound. H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.066 (1.33), 1.256 (16.00), 5.144 (0.85), 5.167 (0.81 ), 7.701 (1.31 ), 8.055 (1.26).
Compound 58.02
2-nitro-4-[1-(2,2,2-trifluoroethyl)-1 H-pyrazol-4-yl]aniline
Figure imgf000486_0001
To a stirred solution of 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 -(2,2,2-trifluoroethyl)- 1 H-pyrazole (1.76 g, 6.06 mmol) in 1 -propanol (42 ml) was added potassium carbonate solution (7.0 ml, 2.0 M, 14 mmol), 4-bromo-2-nitroaniline (1.01 g, 4.66 mmol), triphenylphosphine (61.1 mg, 233 pmol) and PdCI2(PPh3)2 (164 mg, 233 pmol). The mixture was heated to reflux for 2 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried (sodium sulfate), filtered and the solvent was removed in vacuum. Aminophase-silicagel chromatography gave 941 mg of the title compound.
LC-MS (Method 2): R, = 1.00 min; MS (ESIpos): m/z = 287 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.066 (0.59), 1.172 (0.65), 1.987 (1.19), 2.518 (2.95), 2.523 (2.06), 5.090 (3.14), 5.1 13 (9.09), 5.136 (8.48), 5.159 (2.55), 7.045 (9.54), 7.067 (9.88), 7.471 (12.23), 7.671 (5.50), 7.676 (5.37), 7.693 (4.69), 7.698 (5.06), 8.004 (15.43), 8.006 (16.00), 8.132 (10.24), 8.137 (10.07), 8.253 (13.82).
Compound 58.03
4-[1 -(2,2,2-trifluoroethyl)-1 H-pyrazol-4-yl]benzene-1 ,2-diamine
Figure imgf000487_0001
To a stirred solution of 2-nitro-4-[1 -(2,2,2-trifluoroethyl)-1 H-pyrazol-4-yl]aniline (921 mg, 3.22 mmol) in ethanol (34 ml) and dichloromethane (34 ml) was added palladium on carbon (10 % w/w palladium; 342 mg, 322 μπιοΙ) and the mixture was stirred at r.t. in a hydrogen atmosphere for 2.5 h. The mixture was filtered and the solution was concentrated in vacuum to give 746 mg of the title compound as a crude product that was used without purification.
LC-MS (Method 2): R, = 0.76 min; MS (ESIpos): m/z = 257 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.053 (0.76), 1.067 (0.70), 2.518 (2.53), 2.523 (1 .87), 4.831 (2.46), 5.059 (3.14), 5.082 (8.79), 5.105 (8.37), 5.128 (2.66), 5.759 (1.38), 6.524 (8.66), 6.544 (12.21 ), 6.633 (6.20), 6.637 (6.58), 6.652 (4.35), 6.657 (4.87), 6.733 (1 1.20), 6.739 (9.83), 7.733 (15.43), 7.735 (16.00), 7.913 (12.86).
Compound 58.04
tert-butyl 4-{[2-({6-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]-1H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate
Figure imgf000487_0002
To a stirred solution of 1 H-imidazole (38.7 mg, 568 μιηοΙ) and di-1 H-imidazol-1- ylmethanethione (590 mg, 90 % purity, 2.98 mmol) in dichloromethane (5 mL) was added tert- butyl 4-[(2-aminopyridin-4-yl)methyl]piperazine-1 -carboxylate (830 mg, 2.84 mmol), dissolved in dichloromethane (10 mL) at r.t. The mixture was stirred at r.t. for 14 h. 4-[1-(2,2,2- trifluoroethyl)-1 H-pyrazol-4-yl]benzene-1 ,2-diamine (750 mg, 97 % purity, 2.84 mmol), dissolved in dichloromethane (20 mL) was added and the mixture was stirred at r.t. for 14 h. Water was added and the mixture was extracted with dichloromethane. The organic phase was dried (sodium sulfate), filtered and the solvent was removed in vacuum. Silicagel chromatography gave 1.90 g of a solid that was dissolved in dichloromethane (30 ml). Ν,Ν'- dipropan-2-ylcarbodiimide (1.2 ml, 7.9 mmol) was added and the mixture was stirred for 62 h. Silicagel chromatography of the crude reaction mixture gave a solid that was triturated with ethanol to give 750 mg of the title compound as a crude product that was used for the next step without further purification.
LC-MS (Method 2): R, = 1.29 min; MS (ESIpos): m/z = 557 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.990 (2.46), 1.006 (2.45), 1.053 (0.76), 1.386 (0.89), 1.395 (16.00), 2.342 (0.88), 2.355 (1.30), 2.368 (0.92), 3.348 (1.06), 3.492 (1.67), 5.759 (0.57), 6.902 (0.50), 6.919 (0.53), 7.174 (0.68), 8.240 (0.83), 8.254 (0.8 ).
Compound 58.05
N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-6-t1 -(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]-1 H- benzimidazol-2-amine hydrochloride
Figure imgf000488_0001
Starting with tert-butyl 4-{[2-({6-[1 -(2,2,2-trifluoroethyl)-1 H-pyrazol-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate (750 mg, 1.35 mmol), Compound 58.04 was prepared analogously to the procedure for the preparation of Compound 01.05.
Yield: 850 mg of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): Rt = 0.97 min; MS (ESIneg): m/z = 457 [M-H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.985 (8.02), 1.001 (7.86), 2.518 (2.43), 2.523 (1.62), 3.160 (1 1.58), 3.388 (3.21 ), 3.404 (3.67), 3.420 (3.32), 3.455 (7.44), 3.457 (7.53), 3.465 (8.15), 3.467 (8.13), 3.483 (4.83), 3.493 (2.55), 3.495 (2.47), 3.507 (1.23), 3.609 (0.65), 3.620 (0.45), 3.625 (0.79), 3.637 (0.69), 3.642 (0.65), 3.647 (0.45), 3.654 (0.62), 3.658 (0.84), 3.662 (0.60), 3.671 (0.78), 3.673 (0.80), 3.695 (0.78), 3.697 (0.73), 3.706 (0.54), 3.709 (0.67), 4.473 (2.82), 5.171 (2.41 ), 5.194 (6.56), 5.217 (6.15), 5.240 (1.99), 7.555 (7.28), 7.599 (4.56), 7.603 (4.58), 7.619 (8.58), 7.624 (8.94), 7.666 (9.41), 7.687 (4.95), 7.815 (8.47), 7.818 (8.43), 8.046 (16.00), 8.317 (13.60), 8.543 (5.45), 8.556 (5.09), 9.940 (1.87), 13.332 (0.50).
Compound 59.01
1 -(cyclobutylmethyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole
Figure imgf000489_0001
To a stirred solution of 4-(4, 4,5, 5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (2.00 g, 10.3 mmol) in N,N-dimethylacetamide (16 ml, 170 mmol) in a microwave tube was added potassium carbonate (2.85 g, 20.6 mmol) and (bromomethyl)cyclobutane (2.30 g, 15.5 mmol). The mixture was stirred at 80° C for 14 h. Further potassium carbonate (2.85 g, 20.6 mmol) and (bromomethyl)cyclobutane (2.30 g, 5.5 mmol) was added and the mixture was stirred at 80°C for 24 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with half-saturated sodium chloride solution, dried (sodium sulfate), filtered and the solvent was removed in vacuum. Silicagel chromatography gave 1.90 g (70 % yield) of the title compound.
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.066 (1.56), 1.172 (0.85), 1.240 (16.00), 1.987 (1.36), 3.329 (2.68), 4.11 1 (1.24), 4.129 (1.23), 7.550 (1.22), 7.552 (1.23), 7.894 (1.22).
Compound 59.02
4-[1 -(cyclobutylmethyl)-l H-pyrazol-4-yl]-2-nitroaniline
Figure imgf000489_0002
To a stirred solution of 4-bromo-2-nitroaniline (1 .60 g, 7.37 mmol) in 1 -propanol (1 10 ml) was added potassium carbonate solution (1 1 ml, 2.0 M, 22 mmol), 1-(cyclobutylmethyl)-4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (1.93 g, 7.37 mmol), triphenylphosphine (96.7 mg, 369 pmol) and PdCl2(PPh3)2 (259 mg, 369 μιηοΙ). The mixture was heated to reflux for 2 h, the solvent was removed in vacuum. Aminophase silicagel chromatography gave a solid that was triturated with hexane to give 1.80 g of the title compound.
LC-MS (Method 2): R, = 1.13 min; MS (ESIpos): m/z = 272 [M+H]+
H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.743 (2.69), 1.749 (1.25), 1.762 (3.18), 1.764 (3.88), 1.771 (2.45), 1.774 (2.14), 1.779 (1.98), 1.783 (3.82), 1.788 (4.34), 1.793 (2.87), 1.798 (5.14), 1.805 (4.50), 1.810 (2.38), 1.814 (4.74), 1.820 (3.60), 1.823 (3.09), 1.830 (2.65), 1.833 (2.41 ), 1.842 (3.74), 1.845 (3.17), 1.859 (1.52), 1.863 (1.96), 1.866 (2.1 1 ), 1.881 (0.88), 1.942 (1.10), 1.946 (1.91 ), 1.949 (1.77), 1.957 (2.50), 1.963 (3.02), 1.968 (3.14), 1.969 (3.52), 1.977 (3.22), 1.982 (4.71 ), 1.991 (3.97), 1.995 (2.69), 1.998 (2.69), 2.006 (1.54), 2.010 (1.51 ), 2.518 (2.40), 2.523 (1.62), 2.717 (0.95), 2.735 (2.26), 2.755 (3.13), 2.773 (2.56), 2.792 (1.03), 4.096 (16.00), 4.1 15 (15.56), 5.758 (1.29), 7.022 (10.13), 7.044 (10.59), 7.422 (12.78), 7.636 (6.10), 7.642 (5.93), 7.659 (5.31 ), 7.664 (5.49), 7.800 (15.99), 7.803 (16.00), 8.081 (10.75), 8.087 (10.86), 8.123 (15.12), 8.125 (15.10).
Compound 59.03
4-[1 -(cyclobutylmethyl)-l H-pyrazol-4-yl]benzene-1 ,2-diamine
Figure imgf000490_0001
To a stirred solution of 4-[1-(cyclobutylmethyl)-1 H-pyrazol-4-yl]-2-nitroaniline (1.80 g, 6.61 mmol) in ethanol (200 ml) was added palladium on carbon (10 % w/w palladium; 70.3 mg, 66.1 pmol) and the mixture was stirred at r.t. in a hydrogen atmosphere for 3 h. Further palladium on carbon (10 % w/w palladium; 70.3 mg, 66.1 pmol) was added and the mixture was stirred at r.t. in a hydrogen atmosphere for 2 h. The mixture was filtered and the solution was concentrated in vacuum to give 1.55 g of the title compound as a crude product that was used without purification.
LC-MS (Method 2): Rt = 0.87 min; MS (ESIpos): m/z = 243 [M+H]+ 1H-NM (400 MHz, DMSO-d6) δ [ppm]: 1.037 (5.04), 1.055 (9.28), 1.069 (0.66), 1.072 (4.91 ), 1.715 (0.66), 1.727 (0.91 ), 1.733 (2.80), 1.739 (1.41 ), 1.745 (1.28), 1.750 (2.92), 1.752 (3.33), 1.755 (3.91 ), 1.761 (2.66), 1.765 (2.17), 1.770 (2.02), 1.775 (3.96), 1 .779 (3.84), 1.782 (2.71 ), 1.791 (4.41 ), 1.797 (3.61 ), 1.802 (2.26), 1.807 (4.24), 1.814 (3.46), 1 .816 (3.33), 1.823 (2.65), 1.834 (3.08), 1.836 (3.82), 1.839 (3.27), 1.841 (1.97), 1.853 (1.62), 1.857 (2.13), 1.859 (2.16), 1.875 (0.93), 1.880 (0.74), 1.931 (1.30), 1.934 (1.75), 1.937 (1.72), 1.945 (2.50), 1.951 (3.10), 1.956 (3.23), 1.957 (3.44), 1.965 (3.16), 1.969 (4.60), 1.980 (4.03), 1 .983 (2.65), 1.987 (2.84), 1.998 (1.66), 2.004 (0.69), 2.518 (1.15), 2.522 (0.80), 2.694 (0.94), 2.713 (2.26), 2.732 (3.15), 2.750 (2.52), 2.769 (1.04), 3.162 (2.88), 3.174 (3.00), 3.339 (4.45), 3.407 (0.42), 3.420 (0.49), 3.425 (1.22), 3.437 (1.29), 3.442 (1.26), 3.455 (1.26), 4.066 (15.07), 4.085 (15.28), 4.101 (0.80), 4. 14 (0.75), 4.348 (0.77), 4.361 (1.41 ), 4.374 (0.81 ), 4.457 (8.55), 6.467 (9.65), 6.487 (13.17), 6.568 (7.34), 6.573 (7.71 ), 6.587 (4.82), 6.592 (5.51 ), 6.679 (12.27), 6.684 (10.88), 7.535 (15.84), 7.537 (16.00), 7.762 (14.09), 7.764 (13.78).
Compound 59.04
6-[1-(cyclobutylmethyl)-1 H-pyrazol-4-yl]-N-{4-[(1 R or 1S)-1-(piperazin-1-yl)ethyl]pyridin- 2-yl}-1 H-benzimidazol-2 -amine hydrochloride
Figure imgf000492_0001
To a stirred solution of tert-butyl 4-{(1 R or 1 S)-1 -[2-({6-[1 -(cyclobutylmethyl)-1 H-pyrazol-4-yl]- 1 H-benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate (600 mg, 1.08 mmol, Example 59.01.01 ) in dichloromethane (10 ml_) and methanol (1.0 mL) was added HCI in dioxane (5.4 ml, 4.0 , 22 mmol). The mixture was stirred at room temperature for 16 h. The solvent was removed in vacuum to give 1.0 g of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): R, = 1.12 min; MS (ESIpos): m/z = 457 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.987 (16.00), 1.004 (15.59), 1.713 (1.73), 1.730 (1.85), 1.772 (0.41 ), 1.793 (0.63), 1.812 (0.96), 1.823 (1.03), 1.828 (1 .00), 1.833 (1.13), 1.840 (0.68), 1.850 (0.45), 1.859 (0.55), 1.980 (0.50), 1.988 (0.68), 1.997 (0.62), 2.009 (0.63), 2.523 (0.59), 2.784 (0.42), 3.159 (10.62), 3.330 (0.62), 3.443 (0.40), 3.454 (0.58), 3.466 (0.67), 3.483 (0.71 ), 3.495 (0.68), 3.499 (0.60), 3.506 (0.57), 3.519 (0.51 ), 3.532 (0.53), 3.596 (0.62), 3.613 (1.17), 3.629 (1.49), 3.645 (1.13), 3.661 (0.54), 4.157 (1.76), 4.175 (1.72), 5.758 (5.01 ), 7.558 (1.39), 7.566 (0.77), 7.583 (0.96), 7.587 (1.03), 7.636 (1.48), 7.657 (0.84), 7.702 (0.66), 7.712 (0.60), 7.770 (1.43), 7.772 (1.43), 7.861 (2.31 ), 8.177 (2.1 1 ), 8.568 (1.05), 8.581 (0.96), 9.937 (0.48).
Compound 59.05
tert-butyl 4-{[2-({6-[1-(cyclobutylmethyl)-1H-pyrazol-4-yl]-1H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}pjperazine-1 -carboxylate
Figure imgf000493_0001
To a stirred solution of 1 H-imidazole (23.3 mg, 342 μηιοΙ) and di-1 H-imidazol-1- ylmethanethione (356 mg, 90 % purity, 1.80 mmol) in dichloromethane (5 mL) was added tert- butyl 4-[(2-aminopyridin-4-yl)methyl]piperazine-1 -carboxylate (500 mg, 1.71 mmol), dissolved in dichloromethane (10 mL) at r.t. The mixture was stirred at r.t. for 14 h. 4-[1- (cyclobutylmethyl)-1 H-pyrazol-4-yl]benzene-1 ,2-diamine (427 mg, 1.71 mmol), dissolved in dichloromethane (10 mL) was added and the mixture was stirred at r.t. for 62 h. Silicagel chromatography of the crude reaction mixture gave 1.10 g of a solid that was dissolved in dichloromethane (20 ml). N,N'-dipropan-2-ylcarbodiimide (800 μΙ, 5.1 mmol) was added and the mixture was stirred for 14 h. Further N,N'-dipropan-2-ylcarbodiimide (300 μΙ) was added and the mixture was stirred for 24 h. Silicagel chromatography of the crude reaction mixture followed by aminophase-silicagel chromatography gave 380 mg of the title compound as a crude product that was used for the next step without further purification.
LC-MS (Method 2): R, = 1.37 min; MS (ESIpos): m/z = 543 [M+H]+
Compound 59.06
6-[1-(cyclobutylmethyl)-1 H-pyrazol-4-yl]-N-[4-(piperazin-1 -ylmethyl)pyrid
benzimidazol-2-amineydrochloride
Figure imgf000494_0001
To a stirred solution of tert-butyl 4-{[2-({6-[1-(cyclobutylmethyl)-1 H-pyrazol-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]methyl}piperazine-1-carboxylate (380 mg, 700 pmol) in dichloromethane (10 mL) and methanol (1.0 mL) was added HCI in dioxane (3.5 ml, 4.0 M, 14 mmol). The mixture was stirred at room temperature for 16 h. Further HCI in dioxane (3.5 ml, 4.0 M, 14 mmol) was added and the mixture was stirred at room temperature for 24 h. The solvent was removed in vacuum to give 500 mg of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): R, = 1.06 min; MS (ESIpos): m/z = 443 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.148 (2.30), 1.166 (5.00), 1.184 (3.02), 1.222 (1.14), 1.771 (2.88), 1.792 (4.75), 1.810 (7.18), 1.822 (7.70), 1.826 (7.55), 1.831 (8.29), 1.857 (4.09), 1.873 (1.86), 1.880 (2.43), 1.904 (1.78), 1.921 (0.40), 1.964 (2.65), 1.982 (12.44), 1.996 (4.93), 2.007 (4.61 ), 2.327 (0.87), 2.669 (0.86), 2.726 (0.45), 2.745 (1.26), 2.763 (2.47), 2.782 (3.04), 2.800 (2.42), 2.819 (1.04), 3.159 (13.82), 3.466 (14.04), 3.482 (15.56), 3.559 (1.44), 3.646 (0.60), 3.657 (1.27), 3.662 (1.01 ), 3.671 (1.43), 3.696 (1.34), 3.704 (0.91 ), 3.709 (1.14), 3.719 (0.45), 3.993 (0.74), 4.01 1 (2.06), 4.028 (2.03), 4.046 (0.67), 4.113 (1.31 ), 4.131 (1.53), 4.155 (11.97), 4.173 (11.69), 4.521 (7.06), 4.626 (1.31 ), 6.282 (0.47), 7.016 (0.52), 7.070 (0.81 ), 7.090 (0.54), 7.120 (0.81 ), 7.558 (13.27), 7.580 (6.49), 7.583 (6.79), 7.636 (12.33), 7.656 (8.40), 7.697 (1.51 ), 7.773 (10.16), 7.858 (16.00), 7.885 (1.09), 8.004 (1.29), 8.141 (1.73), 8.175 (14.34), 8.545 (6.79), 8.557 (6.31 ), 9.040 (1.26), 9.055 (1.17), 10.014 (3.54), 13.324 (0.70). Compound 60.01
tert-butyl 4-[(2-{[6-(6-chloro-5-methoxypyrimidin-4-yl)-1H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazine-1-carboxylate
Figure imgf000495_0001
To a stirred suspension of tert-butyl 4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)methyl]piperazine-1-carboxylate (7.50 g, 14.0 mmol, Compound 01.04) in 1-propanol (100 ml) was added 4,6-dichloro-5-methoxypyrimidine (7.69 g, 98 % purity, 42.1 mmol), triphenylphosphine (368 mg, 1.40 mmol), PdCI2(PPh3)2 (2.29 g, 2.81 mmol) and sodium carbonate solution (21 ml, 2.0 M, 42 mmol). The mixture was heated to reflux for 20 h. Water and a solution of potassium carbonate was added and the mixture was extracted with ethyl acetate. The organic phase was dried (sodium sulfate), filtered and the solvent was removed in vacuum. Silicagel chromatography gave a solid that was triturated with warm ethanol to give 3.0 g of the title compound.
LC-MS (Method 2): R, = 1.34 min; MS (ESIpos): m/z = 551 [M+H]+
H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.395 (16.00), 2.084 (1.04), 2.349 (0.93), 2.361 (1.30), 2.373 (0.88), 2.518 (0.68), 2.523 (0.48), 3.351 (1.04), 3.506 (1.64), 3.734 (0.76), 5.758 (0.58), 7.174 (0.40), 8.274 (0.58), 8.287 (0.55), 8.797 (0.49).
Compound 60.02
6-(6-chloro-5-methoxypyrimidin-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin
benzimidazol-2-amine hydrochloride
Figure imgf000496_0001
To a stirred solution of tert-butyl 4-[(2-{[6-(6-chloro-5-methoxypyrimidin-4-yl)-1 H-benzimidazol- 2-yl]amino}pyridin-4-yl)methyl]piperazine-1-carboxylate (300 mg, 544 pmol) in dichloromethane (10 mL) and methanol (1.0 mL) was added HCI in dioxane (1.4 ml, 4.0 M, 5.4 mmol). The mixture was stirred at room temperature for 16 h. Further HCI in dioxane (0.5 ml, 4.0 M) was added and the mixture was stirred at room temperature for 24 h. The solvent was removed in vacuum to give 315 mg of the title compound as crude product that was used for the next step without purification.
Compound 61.01
tert-butyl 4-[(2-{[6-(5-methoxy-6-methylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate
Figure imgf000496_0002
To a stirred solution of tert-butyl 4-[(2-{[6-(6-chloro-5-methoxypyrimidin-4-yl)-1 H-benzimidazol- 2-yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate (425 mg, 771 pmol) in tetrahydrofurane (50 mL) was added trimethylaluminum (770 μΙ, 2.0 M, 1.5 mmol), triphenylphosphine (20.2 mg, 77.1 pmol) and PdCl2(PPh3)2 (54.1 mg, 77.1 μιηοΙ).ΤΓΐβ mixture was heated to reflux for 2 h. Further trimethylaluminum (200 μί, 2.0 M, 0.4 mmol) was added and the mixture was heated to reflux for 0.5 h. Water and a solution of sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The organic phase was dried (sodium sulfate), filtered and the solvent was removed in vacuum. Aminophase-silicagel chromatography gave 186 mg of the title compound.
LC-MS (Method 2): R, = 1.23 min; MS (ESIpos): m/z = 531.6 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.066 (12.65), 1.137 (1.07), 1.396 (16.00), 2.349 (1.05), 2.361 (1.38), 2.373 (0.91 ), 3.353 (1.16), 3.504 (1.66), 3.939 (2.14), 5.759 (0.87), 8.266 (0.79), 8.279 (0.74), 8.799 (0.85).
Compound 61.02
6-(5-methoxy-6-methylpyrimidin-4-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]-1 H benzimidazol-2-amine hydrochloride
Figure imgf000497_0001
To a stirred solution of tert-butyl 4-[(2-{[6-(5-methoxy-6-methylpyrimidin-4-yl)-1 H-benzimidazol- 2-yl]amino}pyridin-4-yl)methyl]piperazine-1-carboxylate (180 mg, 339 pmol) in dichloromethane (10 mL) and methanol (1.0 mL) was added HCI in dioxane (3.4 ml, 4.0 M, 14 mmol). The mixture was stirred at room temperature for 64 h. The solvent was removed in vacuum to give 180 mg of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): R, = 0.90 min; MS (ESIpos): m/z = 431 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.062 (13.13), 1.233 (0.90), 1.320 (0.47), 1.542 (0.74), 2.467 (0.71 ), 2.518 (1.56), 2.523 (1.09), 2.555 (1 1.73), 3.161 (5.30), 3.408 (1.02), 3.431 (1.02), 3.440 (1.16), 3.444 (1.34), 3.455 (2.27), 3.457 (2.24), 3.466 (2.81 ), 3.468 (2.89), 3.484 (2.40), 3.486 (2.18), 3.494 (1.38), 3.497 (1.39), 3.502 (0.86), 3.507 (0.61 ), 3.513 (0.47), 3.562 (16.00), 3.660 (0.54), 3.664 (0.44), 3.672 (0.56), 3.674 (0.64), 3.697 (0.61 ), 3.699 (0.52), 3.707 (0.41 ), 3.71 1 (0.49), 3.962 (0.90), 4.487 (0.90), 5.759 (3.75), 7.381 (0.42), 7.548 (0.46), 7.587 (1.83), 7.613 (0.44), 7.630 (0.83), 7.642 (0.77), 7.673 (0.49), 7.791 (1.63), 7.813 (1.76), 8.112 (1.67), 8.1 16 (1.64), 8.133 (1.29), 8.137 (1.45), 8.459 (1.98), 8.462 (2.00), 8.560 (1.47), 8.574 (1.22), 8.893 (5.19), 9.879 (0.61 ).
Compound 62.01
tert-butyl 4-[(2-{[6-(2-chloropyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate
Figure imgf000498_0001
To a stirred solution of tert-butyl 4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)methyl]piperazine-1-carboxylate (2.00 g, 50 % purity, 1.87 mmol, Compound 01.04) in 1 ,4-dioxane (15 ml) was added 2,4-dichloropyrimidine (836 mg, 5.61 mmol), Pd(dppf)Cl2 x CH2CI2 (153 mg, 187 μητιοΙ) and sodium carbonate solution (2.8 ml, 2.0 M, 5.6 mmol). The mixture was heated to reflux for 14 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried (sodium sulfate), filtered and the solvent was removed in vacuum. Aminophase-silicagel chromatography gave 400 mg of the title compound as a crude product that was used without further purification.
LC-MS (Method 2): R, = 1.30 min; MS (ESIpos): m/z = 521 [M+H]+
Compound 62.02
6-[2-(cyclopropylmethoxy)pyrimidin-4-yl]-N-[4-(piperazin-1 -ylmethyl)pyridin
benzimidazol-2-amine hydrochloride
Figure imgf000499_0001
To a stirred solution of tert-butyl 4-{[2-({6-[2-(cyclopropylmethoxy)pyrimidin-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate (440 mg, 790 pmol) in dichloromethane (10 mL) and methanol (1.0 mL) was added HCI in dioxane (2.0 ml, 4.0 M, 7.9 mmol). The mixture was stirred at room temperature for 3 h. Further HCI in dioxane (2.0 ml, 4.0 M, 7.9 mmol) was added and the mixture was stirred at room temperature for 16 h. The solvent was removed in vacuum to give 590 mg of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): R, = 1.05 min; MS (ESIpos): m/z = 457 [M+H]+
Compound 64.01
6-[2-(cyclopropylmethoxy)-5-methoxypyrimidin-4-yl]-N-[4-(piperazin-1 -ylmethyl)pyridin- 2-yl]-1 H-benzimidazol-2-amine hydrochloride
Figure imgf000499_0002
To a stirred solution of tert-butyl 4-{[2-({6-[2-(cyclopropylmethoxy)-5-methoxypyrimidin-4-yl]- 1 H-benzimidazol-2-yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate (230 mg, 392 μητιοΙ) in dichloromethane (5.0 mL) and methanol (0.5 mL) was added HCI in dioxane (2.0 ml, 4.0 M, 7.8 mmol). The mixture was stirred at room temperature for 16 h. The solvent was removed in vacuum to give 230 mg of the title compound as crude product that was used for the next step without purification. LC-MS (Method 2): R, = 1.18 min; MS (ESIpos): m/z = 487 [M+H]+
H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.345 (0.57), 0.356 (2.25), 0.360 (1.92), 0.368 (2.14), 0.372 (2.05), 0.382 (0.71 ), 0.555 (0.69), 0.565 (1.86), 0.570 (1.81 ), 0.575 (0.90), 0.581 (0.89), 0.585 (1.94), 0.590 (1.73), 0.601 (0.58), 1.000 (0.46), 1.278 (0.50), 1.286 (0.48), 1.298 (0.84), 1.310 (0.44), 1.318 (0.46), 2.518 (1.05), 2.523 (0.75), 3.327 (0.69), 3.431 (1.86), 3.455 (1.16), 3.466 (0.79), 3.468 (0.77), 3.484 (0.54), 3.486 (0.50), 3.497 (0.43), 3.561 (2.91 ), 3.830 (1.68), 3.962 (16.00), 4.161 (4.26), 4.178 (4.27), 4.282 (0.44), 4.393 (0.51 ), 7.561 (1.97), 7.749 (1.78), 7.771 (1.85), 8.143 (1.97), 8.148 (2.01 ), 8.165 (1.48), 8.169 (1.57), 8.487 (2.20), 8.490 (2.19), 8.542 (7.61 ), 8.557 (1.14).
Compound 65.01
6-[6^cyclopropylmethoxy)-5-methoxypyrimidin^-yl]-N-[4-(piperazin-1-ylmet yl)pyridin- 2-yl]-1 H-benzimidazol-2 -amine hydrochloride
Figure imgf000500_0001
To a stirred solution of tert-butyl 4-{[2-({6-[6-(cyclopropylmethoxy)-5-methoxypyrimidin-4-yl]- 1 H-benzimidazol-2-yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate (200 mg, 341 pmol) in dichloromethane (7.5 mL) and methanol (0.75 mL) was added HCI in 2-propanol (1.7 ml, 6.0 M, 10 mmol). The mixture was stirred at room temperature for 16 h. The solvent was removed in vacuum to give 210 mg of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): Rt = 1.15 min; MS (ESIpos): m/z = 487 [M+H]+ Compound 66.01
6-(5-methyl-1,3,4-oxadiazol-2-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride
Figure imgf000501_0001
To a stirred solution of tert-butyl 4-[(2-{[6-(5-methyl-1 ,3,4-oxadiazol-2-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazine-1-carboxylate (44.7 mg, 91.1 pmol) in dichloromethane (1.0 mL) and methanol (0.1 mL) was added HCI in dioxane (1.5 ml, 6.0 mmol). The mixture was stirred at room temperature for 16 h. The solvent was removed in vacuum to give 26.0 mg of the title compound as crude product that was used for the next step without purification. LC- S (Method 2): R, = 0.78 min; MS (ESIpos): m/z = 391 [M+H]+
Compound 67.01
1 -{[(1 RS)-2,2-dimethylcyclopropyl]methyl}-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)-1 H-pyrazole
Figure imgf000501_0002
4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (587 mg), [(1 RS)-2,2- dimethylcyclopropyl]methanol (1.00 g) and polymer bound triphenylphospine (5.67 g) were dissolved in 29 mL THF and heated to 60 *C. At this temperature diisopropylazodicarboxylate (1.8 ml), dissolved in 4.8 mL toluene, was added dropwise. The mixture was stirred 1 hour at 60 Ό. The polymer was filtered off, The filter cak e was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography to provide the title compound as mixture with {1 -[(RS-2,2- dimethylcyclopropyl)methyl]-1 H-pyrazol-4-yl}boronic acid which was used without any further purification: 683 mg, 82% pure. LC-MS (Method 2): F¾ = 1.28 min; MS (ESIpos): m/z = 277 [M+H]+
Compound 67.02
4-(1-{[(1 RS)-2,2-dimethylcyclopropyl]methyl}-1 H-pyrazol-4-yl)benzene-1 ,2-diamine
Figure imgf000502_0001
Starting with 1-{[(1 RS)-2,2-dimethylcyclopropyl]methyl}-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-pyrazole (683 mg, 82 % purity; see Compound 67.01 ), Compound 67.02 was prepared analogously to the procedure for the preparation of Compound 44.02.
Yield: 153 mg of the title compound with 85 % purity.
LC-MS (Method 2): R, = 0.98 min; MS (ESIpos): m/z = 257 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.29 (t, 1 H), 0.50 (dd, 1 H), 1.05 (s, 3H), 1.06 - 1.1 1 (m, 1 H), 1.13 (s, 3H), 4.04 - 4.10 (m, 2H), 4.42 (br d, 4H), 6.48 (d, 1 H), 6.59 (dd, 1 H), 6.69 (d, 1 H), 7.55 (d, 1 H), 7.77 (d, 1 H).
Compound 67.03
6-(1 -{[(1 RS)-2,2-dimethylcyclopropyl]methyl}-1 H-pyrazol-4-yl)-N-{4-[(1 R or 1
(piperazin-1 -yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride
Figure imgf000502_0002
Starting with tert-butyl 4-[(1 R or 1 S)-1 -(2-{[6-(1-{[(1 RS)-2,2-dimethylcyclopropyl]methyl}-1 H- pyrazol-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1 -carboxylate (140 mg, see Example 67.01 ), Compound 67.03 was prepared analogously to the procedure for the preparation of Compound 39.05. Yield: 130 mg of 90% pure target compound.
LC-MS (Method 2): R, = 1.16 min; MS (ESIpos): m/z = 471 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.327 (0.60), 0.339 (1.02), 0.351 (0.65), 0.521 (0.65), 0.531 (0.67), 0.542 (0.75), 0.552 (0.63), 0.987 (0.70), 1.004 (0.75), 1.063 (16.00), 1.084 (0.45), 1.109 (0.51 ), 1.122 (0.54), 1.130 (0.56), 1.143 (0.57), 1.161 (9.81 ), 1 .548 (0.51 ), 1.683 (1.04), 2.518 (1.69), 2.522 (1.16), 2.527 (0.84), 2.685 (1.77), 2.726 (5.79), 2.887 (6.98), 3.162 (6.06), 3.456 (0.69), 3.468 (0.67), 3.485 (0.57), 4.149 (2.83), 4.167 (3.07), 4.238 (2.60), 4.385 (0.40), 5.758 (2.35), 7.530 (1.24), 7.581 (0.75), 7.585 (0.67), 7.602 (1.30), 7.605 (1.33), 7.636 (2.18), 7.657 (1.03), 7.778 (1.62), 7.882 (2.81 ), 7.949 (0.88), 8.165 (2.58), 8.560 (0.89), 8.573 (0.81 ).
Compound 68.01
1 -[(1 -methylcyclopropyl)methyl]-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- pyrazole
Figure imgf000503_0001
Starting with (l-methylcyclopropyl)methanol (1.00 g), Compound 68.01 was prepared analogously to the procedure for the preparation of Compound 67.01.
Yield: 1.24 g of the title compound in mixture with {1-[(1-methylcyclopropyl)methyl]-1 H- pyrazole-4-yl}boronic acid with 60 % purity.
LC-MS (Method 2): Rt = 1 .20 min; MS (ESIpos): m/z = 263 [M+H]+
Compound 68.02
4-{1 -[(1 -methylcyclopropyl)methyl]-1 H-pyrazol-4-yl}benzene-1 ,2-diamine
Figure imgf000504_0001
Starting with 1 -[(1-methylcyclopropyl)methyl]-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)- 1 H-pyrazole (700 mg, see Compound 68.01 ), Compound 68.02 was prepared analogously to the procedure for the preparation of Compound 44.02.
Yield: 94 mg of the title compound with 85 % purity.
LC-MS (Method 2): R, = 0.85 min; MS (ESIpos): m/z = 243 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm] = 0.30 - 0.38 (m, 2H), 0.58 - 0.64 (m, 2H), 0.96 (s, 3H), 3.91 (s, 2H), 4.44 (br s, 4H), 6.48 (d, 1 H), 6.60 (dd, 1 H), 6.70 (d, 1 H), 7.55 (d, 1 H), 7.80 (d, 1 H).
Compound 68.03
6-{1-[(1-methylcyclopropyl)methyl]-1 H-pyrazol-4-yl}-N-{4-[(1 R or S)-1 -(piperazin-1- yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride
Figure imgf000504_0002
Starting with tert-butyl 4-[(1 R or 1 S)-1-{2-[(6-{1-[(1-methylcyclopropyl)methyl]-1 H-pyrazol-4-yl}- 1 H-benzimidazol-2-yl)amino]pyridin-4-yl}ethyl]piperazine-1 -carboxylate (85.0 mg, see Example 68.01 ), Compound 68.03 was prepared analogously to the procedure for the preparation of Compound 39.05.
Yield: 86 mg of 86% pure target compound.
LC-MS (Method 2): R, = 1.13 min; MS (ESIpos): m/z = 457 [M+H]+ Ή-NMR (400 MHz, DMSO-d6) δ [ppm] = 0.34 - 0.43 (m, 2H), 0.63 - 0.72 (m, 2H), 1.00 (s, 3H), 1.68 (br s, 3H), 3.14 - 3.54 (m, 9H), 4.00 (s, 2H), 7.53 (s, 1 H), 7.58 - 7.69 (m, 3H), 7.79 (s, 1 H), 7.88 (s, 1 H), 8.21 (s, 1 H), 8.57 (d, 1 H), 9.71 (br s, 2H), 12.76 - 13.52 (m, 3H). - 2 HCI.
Compound 69.01
(1 -chlorocyclopropyl)methanol
Figure imgf000505_0001
Lithiumaluminium hydride (1.02 g) was suspended in 14 mL THF. Ethyl 1 - chlorocyclopropanecarboxylate (1.00 g; CAS-No. 1631082-82-0; corresponding carboxylic acid readily commercially available from multiple vendors), dissolved in 7 mL THF, was added dropwise to the reaction mixture under cooling with an ice bath. The mixture was stirred for 1 hour at rt. The reaction mixture was diluted with ethyl acetate and 5 mL water was added carefully. The grey slurry in the mixture was filtered off under vacuo. The clear filtrate was diluted with more water. The layers were seperated and the organic layer was extracted with ethyl acetate twice. The combined organic layers were dried using a water resistant filter and the filtrate was concentrated under reduced pressure (200 mbar) at 50 Ό to provide the 90% pure title compound: 704 mg
1H-NMR (400 MHz, DMSO-d6) δ [ppm] = 0.88 - 0.97 (m, 4H), 3.52 (d, 2H), 5.13 (t, 1 H).
Compound 69.02
1 -[(1 -chlorocyclopropyl)methyl]-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- pyrazole
Figure imgf000506_0001
Starting with (l -chlorocyclopropyl)methanol (695 mg, see Compound 69.01 ; CAS No. 154985- 94-1 ), Compound 69.02 was prepared analogously to the procedure for the preparation of Compound 67.01.
Yield: 346 mg of the title compound with 92 % purity.
LC-MS (Method 2): R, = 1.15 min; MS (ESIpos): m/z = 283 [M+H]+
Compound 69.03
4-{1 -[(1 -chlorocyclopropyl)methyl]-1 H-pyrazol-4-yl}benzene-1 ,2-diamine
Figure imgf000506_0002
Starting with 1-[(1 -chlorocyclopropyl)methyl]-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)- 1 H-pyrazole (342 mg, see Compound 69.02), Compound 69.03 was prepared analogously to the procedure for the preparation of Compound 44.02.
Yield: 71 mg of the title compound with 85 % purity.
LC-MS (Method 2): R, = 0.83 min; MS (ESIpos): m/z = 263 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm] = 1.08 - 1.15 (m, 2H), 1.19 - 1.26 (m, 2H), 4.35 (s, 2H), 4.37 - 4.70 (m, 4H), 6.49 (d, 1 H), 6.61 (dd, 1 H), 6.71 (d, 1 H), 7.61 (s, 1 H), 7.87 (s, 1 H). Compound 69.04
6-{1-[(1-chlorocyclopropyl)methyl]-1 H-pyrazol-4-yl}-N-{4-[(1 R or 1S)-1-(piperazin-1 - yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride
Figure imgf000507_0001
Starting with tert-butyl 4-[(1 R or 1 S)-1-{2-[(6-{1 -[(1-chlorocyclopropyl)methyl]-1 H-pyrazol-4-yl}- 1 H-benzimidazol-2-yl)amino]pyridin-4-yl}ethyl]piperazine-1 -carboxylate (45.0 mg, see Example 69.01 ), Compound 69.04 was prepared analogously to the procedure for the preparation of Compound 39.05.
Yield: 48 mg of 90% pure target compound.
LC-MS (Method 2): R, = 1.04 min; MS (ESIpos): m/z = 477 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm] = 1.09 - 1.18 (m, 2H), 1.24 - 1.32 (m, 2H), 1.66 (br s, 3H), 2.39 - 2.48 (m, 4H), 3.18 - 3.52 (m, 5H), 4.44 (s, 2H), 7.52 (br s, 1 H), 7.56 - 7.69 (m, 3H), 7.80 (s, 1 H), 7.94 (s, 1 H), 8.27 (s, 1 H), 8.56 (br d, 1 H), 9.62 (br s, 2H), 12.96 (br s, 1 H), 13.35 (br s, 1 H). - 1 HCI
Compound 70.01
3-chloro-4-(1 -{[(1 RS)-2,2-difluorocyclopropyl]methyl}-1 H-pyrazol-4-yl)benzene-1 ,2- diamine
Figure imgf000507_0002
Starting with 1 -{[(1 RS)-2,2-difluorocyclopropyl]methyl}-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-pyrazole (2.72 g, see Compound 55.01 ), Compound 70.01 was prepared analogously to the procedure for the preparation of Compound 44.02.
Yield: 1 .22 g of the title compound with 85 % purity.
LC-MS (Method 2): R, = 0.91 min; MS (ESIpos): m/z = 299 [M+H]+ 1H-NMR (400 MHz, DMSO-d6) δ [ppm] = 1.40 - 1.56 (m, 1H), 1.59 - 1.76 (m, 1H), 2.17 - 2.31 (m, 1H), 4.15 - 4.36 (m, 2H), 4.72 (s, 2H), 4.83 (s, 2H), 6.47 - 6.53 (m, 1H), 6.55 - 6.62 (m, 1 H), 7.61 - 7.70 (m, 1 H), 7.95 (s, 1 H).
Compound 70.02
tert-butyl 4-[(1R or 1S)-1-(2-{[7-chloro-6-(1-{[(1RS)-2,2-difluorocyclopropyl]methyl}-1H- pyrazol-4-yl)-1H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1-carboxylate
Figure imgf000508_0001
Starting with 3-chloro-4-(1-{[(1RS)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)benzene- 1,2-diamine (1.22 g, 85 % purity, see Compound 70.01), Compound 70.02 was prepared analogously to the procedure for the preparation of Example 39.02.01. The intermediate thiourea was purified by flash chromatography.
Yield: 854 mg of the 90% pure title compound.
LC-MS (Method 2): Rt = 1.41 min; MS (ESIpos): m/z = 613 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.28 (d, 3H), 1.38 (s, 9H), 1.46- 1.60 (m, 1H), 1.64- 1.80 (m, 1H), 2.22-2.44 (m, 5H), 3.25-3.33 (m, 4H), 3.40-3.50 (m, 1H), 4.19-4.39 (m, 2H), 6.95 (d, 1H), 7.08 (s, 1H), 7.19 (d, 1H), 7.45 (d, 1H), 7.83 (s, 1H), 8.15 (s, 1H), 8.27 (d, 1H), 10.96 (s, 1H), 12.31 (s, 1H).
Compound 70.03
7-chloro-6-(1 -{[(1 RS)-2,2-difluorocyclopropyl]methyl}-1 H-pyrazol-4-yl)-N-{4-[(1 R or 1S)-1■ (piperazin-1-yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride
Figure imgf000509_0001
Starting with tert-butyl 4-[(1 R or 1 S)-1 -(2-{[7-chloro-6-(1-{[(1 RS)-2,2- difluorocyclopropyl]methyl}-1 H-pyrazol-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)ethyl]piperazine-1 -carboxylate (850 mg, see Compound 70.02), Compound 70.03 was prepared analogously to the procedure for the preparation of Compound 39.05.
Yield: 795 mg of 90% pure target compound.
LC-MS (Method 2): R, = 1.13 min; MS (ESIpos): m/z = 513 [M+H]+
Compound 71.01
1-(cyclopentylmethyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole
Figure imgf000509_0002
Starting with (bromomethyl)cyclopentane (420 mg), Compound 71.01 was prepared analogously to the procedure for the preparation of Compound 39.01.
Yield: 293 mg of the title compound with 80 % purity.
LC-MS (Method 2): Rt = 1.33 min; MS (ESIpos): m/z = 277 [M+H]+ Compound 71.02
4-[1 -(cyclopentylmethyl)-l H-pyrazol-4-yl]-2-nitroaniline
Figure imgf000510_0001
Starting with 1-(cyclopentylmethyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (290 mg, see Compound 71.01 ), Compound 71.02 was prepared analogously to the procedure for the preparation of Compound 39.02.
Yield: 135 mg of the title compound with 91 % purity.
LC-MS (Method 2): R, = 1.21 min; MS (ESIpos): m/z = 287 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm] = 1.20 - 1.33 (m, 2H), 1.43 - 1.67 (m, 6H), 2.31 - 2.42 (m, 1 H), 4.00 (d, 2H), 7.03 (d, 1 H), 7.42 (s, 2H), 7.65 (dd, 1 H), 7.81 (d, 1 H), 8.09 (d, 1 H), 8.16 (s, 1 H)
Compound 71.03
4-[1 -(cyclopentylmethyl)-l H-pyrazol-4-yl]benzene-1 ,2-diamine
Figure imgf000510_0002
Starting with 4-[1-(cyclopentylmethyl)-1 H-pyrazol-4-yl]-2-nitroaniline (180 mg, see Compound 71.02), Compound 71.03 was prepared analogously to the procedure for the preparation of Compound 39.03.
Yield: 63 mg of the title compound with 62 % purity.
LC-MS (Method 2): R, = 0.96 min; MS (ESIpos): m/z = 257 [M+H]+ Compound 71.04
6-[1 -(cyclopentylmethyl)-l H-pyrazol-4-yl]-N-{4-[(1 R or 1 S)-1 -(piperazin-1 -yl)ethyl]pyridin- 2-yl}-1 H-benzimidazol-2-amine hydrochloride
Figure imgf000511_0001
Starting with tert-butyl 4-{(1 R or 1 S)-1-[2-({6-[1 -(cyclopentylmethyl)-1 H-pyrazol-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1-carboxylate (37.7 mg, see Example 71.01 ), Compound 71.04 was prepared analogously to the procedure for the preparation of Compound 39.05.
Yield: 42 mg of 90% pure target compound.
LC-MS (Method 2): R, = 1.18 min; MS (ESIpos): m/z = 471 [M+H]+
Compound 72.01
4-[1 -(propan-2-yl)-1 H-pyrazol-5-yl]benzene-1 ,2-diamine
Figure imgf000511_0002
Starting with 1-(propan-2-yl)-1 H-pyrazol-5-yl]boronic acid (570 mg), Compound 72.01 w prepared analogously to the procedure for the preparation of Compound 44.02.
Yield: 550 mg of the title compound with 90 % purity.
LC-MS (Method 2): R, = 0.75 min; MS (ESIpos): m/z = 217 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm] = 1 .33 (d, 6H), 4.50 - 4.60 (m, 1 H), 4.62 (s, 2H), 4. (s, 2H), 6.04 (d, 1 H), 6.40 (dd, 1 H), 6.53 (d, 1 H), 6.57 (d, 1 H), 7.40 (d, 1 H). Compound 72.02
N-{4-[(1 R or 1S)-1-(piperazin-1-yl)ethyl]pyridin-2-yl}-6-[1 -(propan-2-yl)-1 H-pyrazol-5-yl]- 1 H-benzimidazol-2-amine hydrochloride
Figure imgf000512_0001
Starting with tert-butyl 4-{(1 R or 1 S)-1-[2-({6-[1 -(propan-2-yl)-1 H-pyrazol-5-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate (288 mg, see Example 72.01 ), Compound 72.02 was prepared analogously to the procedure for the preparation of Compound 39.05.
Yield: 377 mg of 92% pure target compound.
LC-MS (Method 2): R, = 1.01 min; MS (ESIpos): m/z = 431 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm] = 1.40 (d, 6H), 1.57 - 1.74 (m, 3H), 3.32 - 3.54 (m, 4H), 3.63 - 3.75 (m, 1 H), 4.50 - 4.61 (m, 1 H), 6.34 (d, 1 H), 7.41 (dd, 1 H), 7.49 - 7.65 (m, 3H), 7.69 (s, 1 H), 7.78 (d, 1 H), 8.37 - 8.62 (m, 1 H), 9.29 - 9.77 (m, 2H), 13.02 - 13.28 (m, 1 H). - 4 piperazine-H not detectable.
Compound 73.01
4-(1 ,4-dimethyl-1 H-pyrazol-5-yl)benzene-1 ,2-diamine
Figure imgf000512_0002
Starting with (1 ,4-dimethyl-1 H-pyrazol-5-yl)boronic acid (434 mg), Compound 73.01 was prepared analogously to the procedure for the preparation of Compound 44.02.
Yield: 54 mg of the title compound with 90 % purity.
LC-MS (Method 2): R, = 0.68 min; MS (ESIpos): m/z = 203 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm] = 1.91 (s, 3H), 3.63 (s, 3H), 4.59 (br s, 2H), 4.69 (br s, 2H), 6.37 (dd, 1 H), 6.49 (d, 1 H), 6.58 (d, 1 H), 7.22 (s, 1 H). Compound 73.02
tert-butyl 4-[(1 R or 1S)-1 -(2-{[6-(1,4-dimethyl-1 H-pyrazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazine-1-carboxylate
Figure imgf000513_0001
Starting with 4-(1 ,4-dimethyl-1 H-pyrazol-5-yl)benzene-1 ,2-diamine (54.4 mg, see Compound 73.01 ), Compound 73.02 was prepared analogously to the procedure for the preparation of Example 39.02.01. The intermediate thiourea was purified by flash chromatography.
Yield: 29 mg of the 90% pure title compound.
LC-MS (Method 2): R, = 1.27 min; MS (ESIpos): m/z = 517 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.26 - 1.31 (m, 3H), 1.38 (s, 9H), 1.99 (s, 3H), 2.23 - 2.44 (m, 4H), 3.25 - 3.32 (m, 4H), 3.45 (q, 1 H), 3.71 (br d, 3H), 6.88 - 7.63 (m, 6H), 8.27 (d, 1 H), 10.57 - 10.73 (m, 1 H), 12.21 (br d, 1 H).
Compound 73.03
6-(1 ,4-dimethyl-1 H-pyrazol-5-yl)-N-{4-[(1 R or 1 S)-1 -(piperazin-1 -yl)ethyl]pyrid
benzimidazol-2-amine hydrochloride
Figure imgf000513_0002
Starting with tert-butyl 4-[(1 R or 1 S)-1-(2-{[6-(1 ,4-dimethyl-1 H-pyrazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazine-1-carboxylate (29.3 mg, see Compound 73.02), Compound 73.03 was prepared analogously to the procedure for the preparation of Compound 39.05.
Yield: 33 mg of 85% pure target compound.
LC-MS (Method 2): Rt = 0.95 min; MS (ESIpos): m/z = 418 [M+H]+
Compound 74.01
1 -[(1 RS)-1 -cyclopropylethyl]-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole e
Figure imgf000514_0001
Starting with (1 RS)-1-cyclopropylethanol (820 μΙ), Compound 74.01 was prepared analogously to the procedure for the preparation of Compound 67.01 .
Yield: 470 mg of the title compound with 85 % purity.
LC-MS (Method 2): Rt = 1 .18 min; MS (ESIpos): m/z = 263 [M+H]+
Compound 74.02
4-{1 -[(1 RS)-1 -cyclopropylethyl]-1 H-pyrazol-4-yl}benzene-1 ,2-diamine
Figure imgf000514_0002
Starting from 1 -[(1 RS)-1 -cyclopropylethyl]-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- pyrazole (393 mg, see Compound 74.01 ), Compound 74.02 was prepared analogously to the procedure for the preparation of Compound 44.02.
Yield: 59 mg of the title compound with 80 % purity.
LC-MS (Method 2): R, = 0.86 min; MS (ESIpos): m/z = 243 [M+H]+ 1H-NMR (400 MHz, DMSO-d6) δ [ppm] = 0.25 - 0.37 (m, 2H), 0.38 - 0.48 (m, 1 H), 0.52 - 0.62 (m, 1 H), 1.15 - 1.29 (m, 1 H), 1.49 (d, 3H), 3.59 (dq, 1 H), 4.42 (br d, 4H), 6.48 (d, 1 H), 6.59 (dd, 1 H), 6.70 (d, 1 H), 7.55 (d, 1 H), 7.86 (d, 1 H).
Compound 74.03
6-{1 -[(1 RS)-1 -cyclopropylethyl]-1 H-pyrazol-4-yl}-N-{4-[(1 R or 1 S)-1 -(piperazin-1 - yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride
Figure imgf000515_0001
Starting with tert-butyl 4-[(1 R or 1 S)-1-{2-[(6-{1-[(1 RS)-1-cyclopropylethyl]-1 H-pyrazol-4-yl}-1 H- benzimidazol-2-yl)amino]pyridin-4-yl}ethyl]piperazine-1-carboxylate (80.0 mg, see Example 74.01 ), Compound 74.03 was prepared analogously to the procedure for the preparation of Compound 39.05.
Yield: 88 mg of 95% pure target compound.
LC-MS (Method 2): R, = 1.10 min; MS (ESIpos): m/z = 457 [M+H]+
Compound 75.01
1 -(cyclobutylmethyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole
Figure imgf000515_0002
Starting with (bromomethyl)cyclobutane (870 μΙ), Compound 75.01 was prepared analogously to the procedure for the preparation of Compound 39.01.
Yield: 1.0 g of the title compound with 84 % purity. LC-MS (Method 2): R, = 1.24 min; MS (ESIpos): m/z = 263 [M+H]
Compound 75.02
3-chloro-4-[1 -(cyclobutylmethyl)-1H-pyrazol-4-yl]benzene-1 ,2-diamine
Figure imgf000516_0001
Starting with 1-(cyclobutylmethyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (1.00 g, see Compound 75.01 ), Compound 75.02 was prepared analogously to the procedure for the preparation of Compound 44.02.
Yield: 171 mg of the title compound with 86 % purity.
LC-MS (Method 2): Rt = 1.02 min; MS (ESIpos): m/z = 277 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm] = 1.68 - 1.90 (m, 4H), 1.92 - 2.04 (m, 2H), 2.69 - 2.80 (m, 1 H), 4.12 (d, 2H), 4.70 (s, 2H), 4.81 (s, 2H), 6.46 - 6.52 (m, 1 H), 6.54 - 6.60 (m, 1 H), 7.58 (s, 1 H), 7.87 (s, 1 H).
Compound 75.03
7-chloro-6-[1-(cyclobutylmethyl)-1H-pyrazol-4-yl]-N-{4-[(1R or 1S)-1-(piperazin-1- yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride
Figure imgf000516_0002
Starting with tert-butyl 4-{(1 R or 1 S)-1-[2-({7-chloro-6-[1-(cyclobutylmethyl)-1 H-pyrazol-4-yl]- 1 H-benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate (1 10 mg, see Example 75.01 ), Compound 75.03 was prepared analogously to the procedure for the preparation of Compound 39.05. Yield: 122 mg of 93% pure target compound.
LC-MS (Method 2): Rt = 1.23 min; MS (ESIpos): m/z
Compound 76.01
tert-butyl 4-[(2-{[6-(6-cyclopropylpyrimidin-4-yl)-1 H^enzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1-carboxylate
Figure imgf000517_0001
tert-Butyl 4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazine-1-carboxylate (1.00 g, see Compound 01.04), 4-chloro- 6-cyclopropylpyrimidine (868 mg), [1 ,1 '-bis(diphenylphosphino)ferrocene]palladium(ll) dichloride dichloromethane adduct (153 mg) and aqueous sodium carbonate solution (2.8 ml, 2.0 M) were dissolved in 15 ml_ dioxane and the reaction mixture was stirred at 120 overnight. The reaction mixture was treated with water and dichloromethane. The aqueous layer was extracted with dichloromethane three times, the collected organic layers were washed with water and brine, filtered through a silicone coated filter and concentrated under reduced pressure. The crude product was purified by flash chromatography.
Yield: 1.3 g of 70% pure target compound.
LC-MS (Method 2): Rt = 1.30 min; MS (ESIpos): m/z = 527 [M+H]+
Compound 76.02
6-(6 :yclopropylpyrimidin-4-yl)-N-[4-(piperazin-1-ylmethy
2 -amine hydrochloride
Figure imgf000518_0001
Starting with tert-butyl 4-[(2-{[6-(6-cyclopropylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate (1.26 g, see Compound 76.01 ), Compound 76.02 was prepared analogously to the procedure for the preparation of Compound 39.05.
Yield: 1.3 g of 81 % pure target compound.
LC-MS (Method 2): R, = 1.30 min; MS (ESIpos): m/z = 428 [M+H]+
Compound 77.01
tert-butyl 4-[(2-{[6-(6-cyanopyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin yl)methyl]piperazine-1-carboxylate
Figure imgf000518_0002
Starting with tert-butyl 4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-benzimidazol- 2-yl]amino}pyridin-4-yl)methyl]piperazine-1-carboxylate (425 mg, see Compound 01.04), Compound 77.01 was prepared analogously to the procedure for the preparation of Compound 76.01. Yield: 1 13 mg of the title compound with 36 % purity.
LC-MS (Method 2): R, = 1.27 min; MS (ESIpos): m/z
Compound 77.02
6-(2-{[4-(piperazin-1-ylmethyl)pyridin-2-yl]amino}-1 H-benzimidazol-6-yl)pyrimidine-4 carbonitrile hydrochloride
Figure imgf000519_0001
Starting with tert-butyl 4-[(2-{[6-(6-cyanopyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1-carboxylate (1 13 mg, see Compound 77.01 ), Compound 77.02 was prepared analogously to the procedure for the preparation of Compound 39.05.
Yield: 120 mg of 38% pure target compound.
LC-MS (Method 2): R, = 0.94 min; MS (ESIpos): m/z = 412 [M+H]+
Compound 78.01
tert-butyl 4-{[2-({6-[6-(propan-2-yl)pyrimidin-4-yl]-1 H-benzimidazol-2-yl}amino)pyridin-4' yl]methyl}piperazine-1 -carboxylate
Figure imgf000519_0002
Starting with tert-butyl 4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-benzimidazol- 2-yl]amino}pyridin-4-yl)methyl]piperazine-1-carboxylate (1000 mg, see Compound 01.04), Compound 78.01 was prepared analogously to the procedure for the preparation of Compound 76.01.
Yield: 240 mg of the title compound with 63 % purity.
LC-MS (Method 2): R, = 1.34 min; MS (ESIpos): m/z = 529 [M+H]+
Compound 78.02
N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-6-[6-(propan-2-yl)pyrimidin-4-yl]-1 H
benzimidazol-2-amine hydrochloride
Figure imgf000520_0001
Starting with tert-butyl 4-{[2-({6-[6-(propan-2-yl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1-carboxylate (240 mg, see Compound 78.01 ), Compound 78.02 was prepared analogously to the procedure for the preparation of Compound 39.05.
Yield: 350 mg of 70% pure target compound.
LC-MS (Method 2): R, = 1.03 min; MS (ESIpos): m/z = 429 [M+H]+
Compound 79.01
tert-butyl 4-{[2-({6-[6-(methoxymethyl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate
Figure imgf000521_0001
Starting with tert-butyl 4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-benzimidazol- 2-yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate (1000 mg, see Compound 01.04), Compound 79.01 was prepared analogously to the procedure for the preparation of Compound 76.01.
Yield: 891 mg of the title compound with 76 % purity.
LC-MS (Method 2): R, = 1.22 min; MS (ESIpos): m/z = 531 [M+H]+
Compound 79.02
6-[6-(methoxymethyl)pyrimidin-4-yl]-N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride
Figure imgf000521_0002
Starting with tert-butyl 4-{[2-({6-[6-(methoxymethyl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate (72.0 mg, see Compound 79.01 ), Compound 79.02 was prepared analogously to the procedure for the preparation of Compound 39.05. Yield: 465 mg of 61 % pure target compound.
LC-MS (Method 2): R, = 0.89 min; MS (ESIpos): m/z
Compound 80.01
tert-butyl 4-[(2-{[6-(6-chloropyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate
Figure imgf000522_0001
Starting with tert-butyl 4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-benzimidazol- 2-yl]amino}pyridin-4-yl)methyl]piperazine-1-carboxylate (3.0 g 756 mg, 22 % purity, see Compound 01.04), Compound 80.01 was prepared analogously to the procedure for the preparation of Compound 76.01.
Yield: 542 mg of the title compound as a crude product, that was used in the next step without further purification.
LC-MS (Method 2): Rt = 1.33 min; MS (ESIpos): m/z = 521 [M+H]+
Compound 80.02
6-[6-(cyclopropylmethoxy)pyrimidin-4-yl]-N-[4-(piperazin-1 -ylmethyl)pyridin
benzimidazol-2-amine hydrochloride
Figure imgf000523_0001
Starting with tert-butyl 4-{[2-({6-[6-(cyclopropylmethoxy)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1-carboxylate (310 mg, see Example 80.01 ), Compound 80.02 was prepared analogously to the procedure for the preparation of Compound 39.05.
Yield: 31 1 mg of 79% pure target compound.
LC-MS (Method 2): Rt = 1.13 min; MS (ESIpos): m/z = 457 [M+H]+
Compound 83.01
4-(6-chloro-5-methoxypyrimidin-4-yl)-2-nitroaniline
Figure imgf000523_0002
2-Nitro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)aniline (5.18 g), 4,6-dichloro-5- methoxypyrimidine (3.86 g), tetrakis(triphenylphosphane)palladium(0) (1.13 g) and aqueous sodium carbonate solution (29 ml, 2.0 M) were dissolved in 160 ml_ dioxane. The reaction mixture was stirred at eO'C for 3h. Undissolved com pouds were filtered off and washed with dichloromethane. The filtrate was concentrated under reduced pressure, treated with ethyl acetate and the undissolved precipitate was filtered off. The filtrate was concentrated under reduced pressure and purified by flash chromatography. The precipitate and the purified compound were combined.
Yield: 1.92 g of 100% pure title compound.
LC-MS (Method 2): F¾ = 1.08 min; MS (ESIpos): m/z = 281 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm] = 3.70 - 3.83 (m, 3H), 7.15 (d, 1 H), 7.94 (s, 2H), 8.20 (dd, 1 H), 8.79 (s, 1 H), 8.95 (d, 1 H).
Compound 83.02
4-(6-chloro-5-methoxypyrimidin-4-yl)benzene-1 ,2-diamine
Figure imgf000524_0001
5-(6-chloro-5-methoxypyrimidin-4-yl)-2-nitroaniline (2.03 g, see Compound 83.01 ) was dissolved in 160 mL dichloromethane and platinum on activated charcoal (1.41 g, 10 % purity) was added. The reaction vessel was evacuated and flushed with hydrogen. The mixture was stirred at room temperature for 5 h. Platinum on activated charcoal (0.70 g, 10 % purity) was added. The reaction vessel was evacuated and flushed with hydrogen. The mixture was stirred at room temperature overnight. The catalyst was carefully filtered off, washed with dichloromethane and ethanol and the combined filtrates were concentrated under reduced pressure.
Yield: 1.01 g of 87% pure title compound.
LC-MS (Method 2): Rt = 0.82 min; MS (ESIpos): m/z = 251 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm] = 3.68 (s, 3H), 4.69 (s, 2H), 5.27 (s, 2H), 6.58 (d, 1 H), 7.43 (dd, 1 H), 7.50 (d, 1 H), 8.52 - 8.70 (m, 1 H)
Compound 83.03
6-(5-methoxy-6-methylpyrimidin-4-yl)-N-{4-[(1 R or 1S)-1 -(piperazin-1-yl)ethyl]pyridin-2 yl}-1 H-benzimidazol-2-amine hydrochloride
Figure imgf000525_0001
Starting with tert-butyl 4-[(1 R or 1 S)-1 -(2-{[6-(5-methoxy-6-methylpyrimidin-4-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1 -carboxylate (630 mg, see Example 83.02), Compound 83.03 was prepared analogously to the procedure for the preparation of Compound 39.05.
Yield: 805 mg of 96% pure target compound.
LC-MS (Method 2): Rt = 0.94 min; MS (ESIpos): m/z = 446 [M+H]+
1 H-NMR (400MHz, DMSO-d6): δ [ppm] = 1 .69 (d, 3H), 2.55 (s, 3H), 3.19 - 3.52 (m, 9H), 3.59 - 3.65 (m, 3H), 7.57 (s, 1 H), 7.67 (br s, 1 H), 7.80 (d, 1 H), 8.07 - 8.18 (m, 1 H), 8.46 (d, 1 H), 8.58 (d, 1 H), 8.89 (s, 1 H), 9.72 (br s, 2H), 13.25 (br s, 2H). - 1 HCI
Compound 84.01
6-[6-(methoxymethyl)pyrimidin-4-yl]-N-{4-[(1 R or 1S)-1-(piperazin-1-yl)ethyl]pyrid 1 H-benzimidazol-2-amine hydrochloride
Figure imgf000525_0002
Starting with tert-butyl 4-{(1 R or 1 S)-1 -[2-({6-[6-(methoxymethyl)pyrimidin-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate (325 mg, see Example 84.01 ), Compound 84.01 was prepared analogously to the procedure for the preparation of Compound 39.05.
Yield: 378 mg of the title 85% pure target compound. LC-MS (Method 2): R, = 0.95 min; MS (ESIpos): m/z = 445 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.70 (br d, 3H), 3.21 - 3.53 (m, 12H), 4.60 (s, 2H),
7.57 - 7.60 (m, 1 H), 7.66 - 7.73 (m, 1 H), 7.80 (d, 1 H), 8.00 (d, 1 H), 8.24 (dd, 1 H), 8.55 (d, 1 H),
8.58 (d, 1 H), 9.20 (d, 1 H), 9.79 (br s, 2H), 13.31 (br s, 3H). - 2 HCI
Compound 85.01
4-(6-chloropyrimidin-4-yl)-2-nitroaniline
Figure imgf000526_0001
To a stirred solution of 2-nitro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)aniline (5.20 g, 97 % purity) in 1-propanol (1 10 ml) was added potassium carbonate solution (19 ml, 2.0 M), 4,6- dichloropyrimidine (3.23 g, 97 % purity), triphenylphosphine (250 mg) and PdCI2(PPh3)2 (672 mg). The mixture was heated to 90 Ό for 3 h. Water was added and a solid was collected by filtration. The solid was dissolved in acetone, filtered and the solution was concentrated in vacuum to give a solid that was triturated with ethanol to give 3.10 g of the title compound.
LC-MS (Method 2): Rt = 1.03 min; MS (ESIpos): m/z = 251 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.084 (1.18), 2.518 (2.66), 2.523 (1.73), 7.11 1 (0.53), 7.1 19 (8.72), 7.141 (8.76), 7.155 (0.53), 7.178 (0.46), 7.529 (0.43), 7.852 (0.55), 7.936 (7.61 ), 8.238 (14.54), 8.241 (16.00), 8.259 (4.08), 8.264 (4.34), 8.944 (8.80), 8.950 (9.06), 8.995 (12.27), 8.998 (1 1.92), 9.026 (0.53), 9.031 (0.55).
Compound 85.02
4-(6-chloropyrimidin-4-yl)benzene-1 ,2-diamine
Figure imgf000527_0001
To a stirred solution of 4-(6-chloropyrimidin-4-yl)-2-nitroaniline (1.00 g) in ethyl acetate (150 ml) was added platinum on carbon (389 mg, 10 % w/w platinum) and the mixture was stirred at r.t. in a hydrogen atmosphere for 2 h. The mixture was filtered and the solution was concentrated in vacuum to give 480 mg of the title compound that was used without further purification.
LC-MS (Method 2): R, = 0.76 min; MS (ESIpos): m/z = 221 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.053 (0.50), 1.153 (0.73), 1.171 (1.38), 1.189 (0.68), 1.987 (2.54), 2.518 (1.36), 2.523 (0.93), 4.016 (0.57), 4.034 (0.56), 4.689 (2.71 ), 5.332 (5.05), 6.495 (0.83), 6.515 (0.46), 6.520 (0.46), 6.564 (12.78), 6.572 (0.65), 6.585 (13.12), 6.592 (0.58), 6.674 (0.59), 6.679 (0.57), 7.363 (6.29), 7.368 (6.51 ), 7.384 (5.58), 7.389 (6.48), 7.475 (13.57), 7.480 (1 1.64), 7.849 (16.00), 7.852 (15.42), 8.828 (15.58), 8.831 (14.87).
Compound 85.03
6-[6-(cyclopropylmethoxy)pyrimidin-4-yl]-N-{4-[(1 R or 1S)-1 -(piperazin-1-yl)ethyl]pyridin- 2-yl}-1 H-benzimidazol-2 -amine hydrochloride
Figure imgf000527_0002
tert-Butyl 4-{(1 R or 1 S)-1 -[2-({6-[6-(cyclopropylmethoxy)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate (62.0 mg, see Example 85.02) was dissolved in 1.4 mL dichloromethane and 130 L methanol and cooled to 0 . At this temperature hydrochloric acid (270 μΙ, 4.0 M in dioxane) was added and this mixture was stirred under cooling for 2 hours. Thre reaction mixture was stirred under cooling for additional 2 hours and stored in the refrigerator overnight, during which it solidified to assume a jelly-like texture. The jelly-like reaction mixture was diluted with dichloromethane / isopropanol (7:3) and saturated sodium bicarbonate solution. After several minutes of shaking, the jelly got solved. The layers were seperated and the aqueous layer was extracted with dichloromethane / isopropanol (7:3) twice. The combined organic layers were concentrated under reduced pressure. The crude product was used without further purification.
Yield: 46 mg of 81 % pure target compound.
LC-MS (Method 2): R, = 1.25 min; MS (ESIpos): m/z = 471 [M+H]+
Compound 86.01
4-(1 -{[(1 RS)-2,2-difluorocyclopropyl]methyl}-1 H-pyrazol-4-yl)-3-f luorobenzene-1 ,2 diamine
Figure imgf000528_0001
Starting with 1-{[(1 RS)-2,2-difluorocyclopropyl]methyl}-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-pyrazole (2.72 g, see Compound 55.01 ), Compound 86.01 was prepared analogously to the procedure for the preparation of Compound 44.02.
Yield: 1.67 g of the title compound with 75 % purity.
LC-MS (Method 2): Rt = 0.87 min; MS (ESIpos): m/z = 283 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm] = 1.41 - 1.56 (m, 1 H), 1.59 - 1.76 (m, 1 H), 2.16 - 2.31 (m, 1 H), 4.17 - 4.31 (m, 2H), 4.43 (s, 2H), 4.79 (s, 2H), 6.29 - 6.42 (m, 1 H), 6.66 (t, 1 H), 7.72 (s, 1 H), 7.92 (d, 1 H)
Compound 86.02
6-(1 -{[(1 RS)-2,2-difluorocyclopropyl]methyl}-1 H-pyrazol-4.yl)-7-fluoro-N-{4-[(1R or 1S)-1 - (piperazin-1 -yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride
Figure imgf000529_0001
Starting with tert-butyl 4-[(1 R or 1 S)-1-(2-{[6-(1-{[(1 RS)-2,2-difluorocyclopropyl]methyl}-1 H- pyrazol-4-yl)-7-fluoro-1 H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1-carboxylate (1.50 g, see Example 86.01 ), Compound 86.02 was prepared analogously to the procedure for the preparation of Compound 39.05.
Yield: 1.7 g of 90% pure target compound.
LC-MS (Method 2): R, = 1.11 min; MS (ESIpos): m/z = 497 [M+H]+
Compound 87.01
1 -(2,2-difluoroethyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole
Figure imgf000529_0002
4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (1.00 g) was dissolved in 9.9 mL DMF and potassium carbonate (2.14 g) and 2,2-difluoroethyl trifluoromethanesulfonate (970 μΙ) were added. This mixture was stirred at 80 overn ight. The reaction mixture was diluted with ethyl acetate and water. The layers were seperated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried using a water resistant filter. The filtrate was concentrated under reduced pressure. The crude product was used without further purification.
Yield: 1.8 g of 69% pure target compound.
LC-MS (Method 2): R, = 0.82 min; MS (ESIpos): m/z = 259 [M+H]+ 1H-NMR (400 MHz, DMSO-d6) δ [ppm] = 1.25 (s, 12H), 4.64 (td, 2H), 6.17 - 6.53 (m, 1 H), 7.65 (s, 1 H), 7.99 (s, 1 H)
Compound 87.02
4-[1-(2,2-difluoroethyl)-1 H-pyrazol-4-yl]benzene-1 ,2-diamine
Figure imgf000530_0001
Starting with 1-(2,2-difluoroethyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (1.60 g, see Compound 87.01 ), Compound 87.02 was prepared analogously to the procedure for the preparation of Compound 44.02.
Yield: 421 mg of the title compound with 68 % purity.
LC-MS (Method 2): Rt = 0.68 min; MS (ESIpos): m/z = 239 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm] = 4.45 (s, 2H), 4.47 (s, 2H), 4.58 (td, 2H), 6.18 - 6.52 (m, 2H), 6.56 - 6.63 (m, 1 H), 6.69 (d, 1 H), 7.66 (s, 1 H), 7.85 (s, 1 H).
Compound 87.03
tert-butyl 4-{(1 R or 1S)-1 -[2-({6-[1-(2,2-difluoroethyl)-1 H-pyrazol-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate
Figure imgf000530_0002
Starting with 4-[1-(2,2-difluoroethyl)-1 H-pyrazol-4-yl]benzene-1 ,2-diamine (415 mg, 85 % purity; see Compound 87.02), Compound 87.03 was prepared analogously to the procedure for the preparation of Example 39.02.01. The intermediate thiourea was purified by flash chromatography.
Yield: 549 mg of the 96% pure title compound.
LC-MS (Method 2): R, = 1.28 min; MS (ESIpos): m/z = 553 [M+H]+
Compound 87.04
6-[1-(2,2-difluoroethyl)-1 H-pyrazol-4-yl]-N-{4-[(1 R or 1S)-1 -(piperazin-1 -yl)ethyl]pyridin-2- yl}-1 H-benzimidazol-2-amine hydrochloride
Figure imgf000531_0001
Starting with tert-butyl 4-{(1 R or 1 S)-1 -[2-({6-[1-(2,2-difluoroethyl)-1 H-pyrazol-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1-carboxylate (549 mg, see Compound 87.03), Compound 87.04 was prepared analogously to the procedure for the preparation of Compound 39.05.
Yield: 706 mg of the 85% pure target compound.
LC-MS (Method 2): Rt = 0.98 min; MS (ESIpos): m/z = 453 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm] = 1.70 (br d, 3H), 3.20 - 3.53 (m, 9H), 4.68 (td, 2H), 6.23 - 6.58 (m, 1 H), 7.55 (s, 2H), 7.60 (dd, 1 H), 7.64 - 7.71 (m, 2H), 7.79 (d, 1 H), 7.96 - 8.01 (m, 1 H), 8.22 - 8.27 (m, 1 H), 8.57 (d, 1 H), 9.79 (br s, 3H). - 1 HCI
Compound 88.01
4-[1 -methyl-3-(trifluoromethyl)-1 H-pyrazol-5-yl]benzene-1 ,2-diamine
Figure imgf000532_0001
Starting with 1-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1 H- pyrazole (903 mg), Compound 88.01 was prepared analogously to the procedure for the preparation of Compound 44.02.
Yield: 590 mg of the title compound with 91 % purity.
LC-MS (Method 2): R, = 0.92 min; MS (ESIpos): m/z = 257 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm] = 3.86 (s, 3H), 4.66 (s, 2H), 4.85 (s, 2H), 6.53 - 6.62 (m, 3H), 6.67 (d, 1 H).
Compound 88.02
6-[1 -methyl-3-(trifluoromethyl)-1 H-pyrazol-5-yl]-N-{4-[(1 R or 1 S)-1 -(piperazin-1 - yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride
Figure imgf000532_0002
Starting with tert-butyl 4-{(1 R or 1 S)-1-[2-({6-t1-methyl-3-(trifluoromethyl)-1 H-pyrazol-5-yl]- H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1-carboxylate (250 mg, see Example 88.01 ), Compound 88.02 was prepared analogously to the procedure for the preparation of Compound 39.05.
Yield: 201 mg of the 95% pure target compound.
LC-MS (Method 2): R, = 1.21 min; MS (ESIpos): m/z = 471 [M+H]+ 1H-NMR (400 MHz, DMSO-d6) δ [ppm] = 1.55 (br s, 3H), 3.10 - 3.48 (m, 5H), 3.53 - 3.60 (m, 4H), 3.96 (s, 3H), 6.95 (s, 1 H), 7.40 - 7.66 (m, 3H), 7.74 - 7.87 (m, 2H), 8.53 (br s, 1 H), 8.87 - 9.76 (m, 2H), 12.51 - 13.74 (m, 2H). - 1 HCI
Compound 89.01
4-(1,3-dimethyl-1 H-pyrazol-5-yl)benzene-1 ,2-diamine
Figure imgf000533_0001
Starting with (1 ,3-dimethyl-1 H-pyrazol-5-yl)boronic acid (600 mg), Compound 89.01 was prepared analogously to the procedure for the preparation of Compound 44.02.
Yield: 350 mg of the title compound with 96 % purity.
LC-MS (Method 2): R, = 0.67 min; MS (ESIpos): m/z = 203 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm] = 2.11 (s, 3H), 3.68 (s, 3H), 4.59 (s, 2H), 4.70 (s, 2H), 5.90 (s, 1 H), 6.42 - 6.50 (m, 1 H), 6.51 - 6.56 (m, 1 H), 6.59 (d, 1 H).
Compound 89.02
6-(1 ,3-dimethyl-1 H-pyrazol-5-yl)-N-{4-[(1 R or 1 S)-1 -(piperazin-1 -yl)ethyl]pyridin benzimidazol-2-amine hydrochloride
Figure imgf000533_0002
Starting with tert-butyl 4-[(1 R or 1 S)-1-(2-{[6-(1 ,3-dimethyl-1 H-pyrazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazine-1-carboxylate (190 mg, see Example 89.01 ), Compound 89.02 was prepared analogously to the procedure for the preparation of Compound 39.05. Yield: 164 mg of the 95% pure target compound.
LC-MS (Method 2): Rt = 1.01 min; MS (ESIpos): m/z = 417 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm] = 1.52 - 1.76 (m, 3H), 2.19 (s, 3H), 2.97 - 3.51 (m, 5H), 3.56 (s, 3H), 3.79 (s, 4H), 6.22 (s, 1 H), 7.42 - 7.80 (m, 5H), 8.57 (br d, 1 H), 9.54 (br s, 2H), 13.12 (br s, 2H). - 1 HCI
Compound 90.01
6-{6-[(3-methoxypropyl)amino]pyrimidin-4-yl}-N-[4-(piperazin-1 -ylmethyl)pyridin
1 H-benzimidazol-2-amine hydrochloride
Figure imgf000534_0001
Starting with tert-butyl 4-({2-[(6-{6-[(3-methoxypropyl)amino]pyrimidin-4-yl}- H-benzimidazol-2- yl)amino]pyridin-4-yl}methyl)piperazine-1-carboxylate (90.0 mg, see Example 90.01 ), Compound 90.01 was prepared analogously to the procedure for the preparation of Compound 39.05.
Yield: 86 mg of the 96% pure target compound.
LC-MS (Method 2): R, = 0.86 min; MS (ESIpos): m/z = 475 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.229 (0.85), 1.365 (1.03), 1.382 (1.10), 1.828 (2.30), 1.845 (3.42), 1.861 (2.51 ), 2.326 (1.03), 2.669 (1.03), 3.207 (1.69), 3.228 (5.14), 3.257 (16.00), 3.343 (1.73), 3.359 (2.53), 3.414 (6.28), 3.429 (7.19), 3.444 (3.65), 3.467 (1.10), 3.485 (1.14), 3.502 (1.37), 3.563 (4.65), 3.578 (2.51 ), 3.661 (0.59), 3.674 (0.64), 3.697 (0.64), 3.712 (0.57), 3.925 (0.69), 4.315 (1.01 ), 5.759 (1.25), 7.159 (6.30), 7.549 (3.31 ), 7.685 (0.61 ), 7.823 (3.72), 8.096 (2.19), 8.215 (0.50), 8.521 (1.82), 8.719 (0.53), 8.808 (3.1 1 ), 8.961 (0.41 ), 9.718 (0.73), 9.877 (0.66). Compound 91.01
6-(6-ethylpyrimidin-4-yl)-N 4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H-benzimidazol-2 amine hydrochloride
Figure imgf000535_0001
Starting with tert-butyl 4-[(2-{[6-(6-ethylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1-carboxylate (160 mg, see Example 91.01 ), Compound 91.01 was prepared analogously to the procedure for the preparation of Compound 39.05.
Yield: 169 mg of the 90% pure target compound.
LC-MS (Method 2): Rt = 0.93 min; MS (ESIpos): m/z = 416 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm] = 1.31 (t, 3H), 2.85 (q, 2H), 3.19 - 3.53 (m, 8H), 4.42 (br s, 2H), 7.57 (s, 2H), 7.79 (d, 1 H), 8.03 (s, 1 H), 8.23 (dd, 1 H), 8.51 - 8.60 (m, 2H), 9.17 (d, 1 H), 9.75 (br s, 2H), 13.18 (br s, 2H). - 1 HCI.
Compound 92.01
6-[6-(3,5-dimethyl-1 ,2-oxazol-4-yl)pyrimidin-4-yl]-N-[4-(piperazin-1-ylmethyl)pyrid 1 H-benzimidazol-2-amine hydrochloride
Figure imgf000536_0001
Starting with tert-butyl 4-{[2-({6-[6-(3,5-dimethyl-1 ,2-oxazol-4-yl)pyrimidin-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate (100 mg, see Example 92.01 ), Compound 92.01 was prepared analogously to the procedure for the preparation of Compound 39.05.
Yield: 1 10 mg of the 92% pure target compound.
LC-MS (Method 2): R, = 1.01 min; MS (ESIpos): m/z = 482 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm] = 2.53 (s, 3H), 2.74 (s, 3H), 3.16 - 3.52 (m, 8H), 4.28 - 4.51 (m, 2H), 7.54 - 7.64 (m, 2H), 7.82 (d, 1 H), 8.13 (d, 1 H), 8.28 (dd, 1 H), 8.50 - 8.61 (m, 2H), 9.31 (d, 1 H), 9.74 (br s, 2H), 12.88 - 13.64 (m, 2H). - 1 HCI
Compound 93.01
tert-butyl 4-{[2-({6-[6-(pyrrolidin-1-yl)pyrimidin-4-yl]-1 H-benzimidazol-2-yl}amino)pyridin 4-yl]methy l}pi perazi ne-1 -carboxylate
Figure imgf000536_0002
Starting with tert-butyl 4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-benzimidazol- 2-yl]amino}pyridin-4-yl)methyl]piperazine-1-carboxylate (485 mg, see Compound 01.04), Compound 93.01 was prepared analogously to the procedure for the preparation of Compound
76.01.
Yield: 106 mg of the title compound with 73 % purity.
LC-MS (Method 2): R, = 1.27 min; MS (ESIpos): m/z = 557 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm]: 0.797 (0.47), 0.814 (0.49), 0.821 (0.49), 0.904 (0.48), 1.299 (0.97), 1.386 (1.52), 1 .395 (14.74), 1.881 (0.85), 1.907 (0.45), 1.974 (0.78), 1.987 (0.74), 2.326 (0.51 ), 2.331 (0.45), 2.346 (1.03), 2.357 (1.53), 2.369 (1.09), 3.499 (2.35), 5.284 (0.47), 5.758 (16.00), 6.924 (0.57), 6.936 (0.54), 7.181 (0.90), 7.888 (0.59), 8.252 (0.92), 8.264 (0.82), 8.498 (1.40).
Compound 93.02
N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-6-[6-(pyrrolidin-1 -yl)pyrimidin-4-yl]-1 H- benzimidazol-2-amine hydrochloride
Figure imgf000537_0001
Starting with tert-butyl 4-{[2-({6-[6-(pyrrolidin-1 -yl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1-carboxylate (106 mg, see Compound 93.01 ), Compound 93.02 was prepared analogously to the procedure for the preparation of Compound 39.05.
Yield: 104 mg of the 73% pure target compound.
LC-MS (Method 2): R, = 0.96 min; MS (ESIpos): m/z = 457 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.064 (1.53), 1.144 (0.48), 1.322 (3.45), 1.907 (0.62), 1.984 (2.30), 1.991 (2.35), 2.000 (2.59), 2.016 (1.96), 2.059 (1.68), 2.073 (1.68), 2.518 (16.00), 2.523 (10.49), 3.164 (1.20), 3.345 (1.92), 3.384 (1.20), 3.457 (0.62), 3.469 (0.62), 3.487 (0.62), 3.499 (0.62), 3.606 (0.77), 3.621 (0.86), 3.636 (0.91 ), 3.677 (1.87), 3.695 (2.44), 3.713 (2.59), 3.731 (2.49), 4.147 (1.68), 5.480 (1.34), 6.963 (0.43), 7.124 (3.93), 7.487 (1.63), 7.553 (0.48), 7.581 (0.86), 7.606 (0.57), 7.657 (0.62), 7.788 (1.15), 7.809 (1.49), 7.920 (1.20), 7.942 (0.91 ), 8.191 (1.82), 8.284 (1.05), 8.493 (0.96), 8.506 (0.86), 8.720 (0.62), 8.805 (3.69).
Compound 94.01
tert-butyl 4-{[2-({6-[6-(morpholin-4-yl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1-carboxylate
Figure imgf000538_0001
Starting with tert-butyl 4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-benzimidazol- 2-yl]amino}pyridin-4-yl)methyl]piperazine-1-carboxylate (446 mg, see Compound 01.04), Compound 94.01 was prepared analogously to the procedure for the preparation of Compound 76.01.
Yield: 1 19 mg of the title compound with 77 % purity.
LC-MS (Method 4): R, = 1.20 min; MS (ESIpos): m/z = 573 [M+H]+
1 H-NMR (400MHz, DMSO-d6): δ [ppm]: 1.172 (0.52), 1.300 (1.65), 1.386 (2.45), 1.395 (16.00), 1.987 (0.92), 2.327 (0.51 ), 2.331 (0.60), 2.345 (1.31 ), 2.357 (1.66), 2.369 (1.03), 2.518 (1.90), 2.523 (1.30), 3.308 (0.42), 3.353 (1.68), 3.364 (1.19), 3.378 (0.61 ), 3.471 (0.51 ), 3.499 (1.61 ), 3.621 (0.71 ), 3.634 (0.89), 3.645 (0.83), 3.666 (0.44), 3.703 (5.60), 5.759 (2.28), 6.925 (0.40), 6.938 (0.40), 7.184 (0.83), 8.251 (0.89), 8.264 (0.72), 8.568 (1.19), 8.570 (1.22). Compound 94.02
6-[6-(morpholin-4-yl)pyrimidin-4-yl]-N-[4-(piperazin-1-ylmethyl)pyridin
benzimidazol-2 -amine hydrochloride
Figure imgf000539_0001
Starting with tert-butyl 4-{[2-({6-[6-(morpholin-4-yl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate (1 15 mg, see Compound 94.01 ), Compound 94.02 was prepared analogously to the procedure for the preparation of Compound 39.05.
Yield: 142 mg of the 78% pure target compound.
LC-MS (Method 2): R, = 0.87 min; MS (ESIpos): m/z = 470 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.064 (2.31 ), 1.322 (4.84), 2.327 (1.84), 2.669 (1.81 ), 3.163 (1.03), 3.384 (2.69), 3.564 (16.00), 3.615 (1.16), 3.754 (5.34), 3.765 (4.28), 3.936 (3.72), 4.312 (1.09), 5.760 (6.41 ), 5.800 (1.22), 6.797 (0.41 ), 6.820 (0.41 ), 7.088 (0.78), 7.353 (0.56), 7.438 (1.28), 7.460 (1.34), 7.474 (3.84), 7.517 (2.06), 7.660 (0.91 ), 7.783 (1.47), 7.806 (1.59), 7.981 (1.31 ), 8.000 (0.94), 8.253 (1.69), 8.338 (1.25), 8.499 (1.22), 8.525 (0.84), 8.810 (3.03), 9.607 (0.47).
Compound 95.01
tert-butyl 4-{[2-({6-[6-(methylsulfanyl)pyrimidin-4-yl]-1H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1-carboxylate
Figure imgf000540_0001
Starting with tert-butyl 4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-benzimidazol- 2-yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate (200 mg, see Compound 01.04), Compound 95.01 was prepared analogously to the procedure for the preparation of Compound 60.01.
Yield: 178 mg of the title compound with 48 % purity.
LC-MS (Method 4): R, = 1.32 min; MS (ESIpos): m/z = 534 [M+H]+
Compound 95.02
6-[6-(methylsulfanyl)pyrimidin-4-yl]-N-[4-(piperazin-1-ylmethyl)pyridin
benzimidazol-2-amine hydrochloride
Figure imgf000540_0002
Starting with tert-butyl 4-{[2-({6-[6-(methylsulfanyl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate (170 mg, see Compound 95.01 ), Compound 95.02 was prepared analogously to the procedure for the preparation of Compound 39.05.
Yield: 331 mg of the 33% pure target compound.
LC-MS (Method 2): R, = 1.07 min; MS (ESIpos): m/z = 433 [M+H]+ Compound 96.01
2-(6-chloropyrimidin-4-yl)propan-2-ol
Figure imgf000541_0001
Methyl magnesiumbromide (12 ml, 1.4 M in THF / toluene 1 :3) was treated with 5.5 mL THF and cooled down to -78Ό (ethanol / dry ice), methy l 6-chloropyrimidine-4-carboxylate (1.00 g), suspended in 8.5 mL THF, was added. The reaction mixture was stirred at this temperature for 2 hours. The reaction mixture was allowed to reach room temperature over night. The reaction mixture was poured into HCI (1 mol/L) and stirred for 15 minutes. Then the pH was adjusted to 7 by addition of saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted three times with ethyl acetate, the combined organic layers were washed with water and brine, filtered through a silicone coated filter and concentrated under reduced pressure. The crude product was purified by flash chromatography.
Yield: 180 mg of the 90% pure target compound.
1H-NMR (400 MHz, DMSO-d6) δ [ppm] = 1.42 (s, 6H), 5.61 (s, 1 H), 7.77 (d, 1 H), 8.98 (d, 1 H).
Compound 96.02
2-[6-(2-{[4-(piperazin-1-ylmethyl)pyridin-2-yl]amino}-1 H-benzimidazol-6-yl)pyi yl]propan-2-ol hydrochloride
Figure imgf000541_0002
Starting with tert-butyl 4-{[2-({6-[6-(2-hydroxypropan-2-yl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate (100 mg, see Example 96.01 ), Compound 96.02 was prepared analogously to the procedure for the preparation of Compound 39.05.
Yield: 122 mg of the 94% pure target compound.
LC-MS (Method 2): Rt = 0.90 min; MS (ESIpos): m/z = 445 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm] = 1.50 (s, 6H), 3.24 - 3.52 (m, 8H), 4.45 (br s, 2H), 7.53 - 7.66 (m, 2H), 7.81 (d, 1 H), 8.22 (dd, 1 H), 8.26 (d, 1 H), 8.49 - 8.60 (m, 2H), 9.18 (d, 1 H), 9.80 (br s, 2H), 13.24 (br s, 1 H). - OH not detectable
Compound 97.01
(rac)-1 -(6-chloropyrimidin-4-yl)ethanol
Figure imgf000542_0001
1-(6-chloropyrimidin-4-yl)ethanone (1.00 g) was suspended in 5 mL methanol and cooled to 0 "C with an ice bath. Then sodium borohydride (266 m g) was added portionwise, and the resulting mixture was then stirred at room temperature for 1.5 hours. Methanol was removed under reduced pressure, the residue was treated with water and the pH was adjusted to 3 by addition of aqueous HCI (1 mol/L). The aqueous layer was extracted with ethyl acetate three times, washed with water and brine, filtered through a silicone coated filter and dried under reduced pressure. The crude product was used without further purification.
Yield: 614 mg of the 99% pure target compound.
LC-MS (Method 2): Rt = 0.61 min; MS (ESIpos): m/z = 161 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm] = 1.38 (d, 3H), 4.62 - 4.78 (m, 1 H), 5.75 (d, 1 H), 7.68 (s, 1 H), 8.96 (d, 1 H). Compound 97.02
(rac)-1-[6-(2-{[4-(piperazin-1-ylmethyl)pyridin-2-yl]amm^
yl)pyrimidin-4-yl]ethanol hydrochloride
Figure imgf000543_0001
Starting with (rac)-tert-butyl 4-({2-[(6-{6-[1 -hydroxyethyl]pyrimidin-4-yl}-1 H-benzimidazol-2- yl)amino]pyridin-4-yl}methyl)piperazine-1 -carboxylate (132 mg, see Example 97.01 ), Compound 97.02 was prepared analogously to the procedure for the preparation of Compound 39.05.
Yield: 164 mg of the 32% pure target compound.
LC- S (Method 2): F¾ = 0.84 min; MS (ESIpos): m/z = 432 [M+H]+
Compound 98.01
3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene-1,2-diamine
Figure imgf000543_0002
Starting with 4-bromo-3-chlorobenzene-1 ,2-diamine (1.50 g) and 4,4, 4',4', 5,5,5', 5'-octamethyl-
2,2'-bi-1 ,3,2-dioxaborolane, Compound 98.01 was prepared analogously to the procedure for the preparation of Compound 01.04.
Yield: 650 mg of the 96% pure target compound.
LC-MS (Method 2): Rt = 1.05 min; MS (ESIpos): m/z = 269 [M+H]+ Compound 98.02
3-chloro-4-(6-methylpyrimidin-4-yl)benzene-1 ,2-diamine
2 2
Figure imgf000544_0001
Starting with 3-chloro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzene-1 ,2-diamine (540 mg) and 4-chloro-6-methylpyrimidine (775 mg), Compound 98.02 was prepared analogously to the procedure for the preparation of Compound 76.01.
Yield: 390 mg of the 86% pure target compound.
LC-MS (Method 2): R, = 0.71 min; MS (ESIpos): m/z = 235 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm] = 2.47 (s, 3H), 4.88 (s, 2H), 5.27 (s, 2H), 6.57 (d, 1 H), 6.77 (d, 1 H), 7.54 (d, 1 H), 8.99 (d, 1 H).
Compound 98.03
7-chloro-6-(6-methylpyrimidin-4-yl)-N-{4-[(1 R or 1S)-1 -(piperazin-1 -yl)ethyl]pyridin-2-yl}- 1 H-benzimidazol-2-amine hydrochloride
Figure imgf000544_0002
Starting with tert-butyl 4-[(1 R or 1 S)-1 -(2-{[7-chloro-6-(6-methylpyrimidin-4-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1 -carboxylate (245 mg, see Example 98.01 ), Compound 98.03 was prepared analogously to the procedure for the preparation of Compound 39.05.
Yield: 278 mg of the 90% pure target compound.
LC-MS (Method 2): R, = 0.95 min; MS (ESIpos): m/z = 450 [M+H]+ 1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.68 (br d, 3H), 2.56 (s, 3H), 3.14 - 3.53 (m, 5H), 4.61 (br s, 4H), 7.39 (br s, 1 H), 7.46 (d, 1 H), 7.55 (br s, 1 H), 7.61 - 7.70 (m, 1 H), 7.78 (s, 1 H), 8.49 (br d, 1 H), 9.07 - 9.20 (m, 1 H), 9.59 (br s, 2H), 1 1.25 - 13.05 (m, 1 H).
Compound 99.01
tert-butyl 4-[(1R or 1S)-1-(2-{[7-chloro-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1-carboxylate
Figure imgf000545_0001
Starting with 3-chloro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzene-1 ,2-diamine (870 mg, see Compound 98.01 ), Compound 99.01 was prepared analogously to the procedure for the preparation of Example 39.02.01. The intermediate thiourea was purified by flash chromatography.
Yield: 940 mg of the 44% pure title compound.
LC-MS (Method 2): Rt = 1.56 min; MS (ESIpos): m/z = 583 [M+H]+
Compound 99.02
tert-butyl 4-{(1 R or 1S)-1 -[2-({7-chloro-6-[6-(methoxymethyl)pyrimidin-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate
Figure imgf000545_0002
Starting with tert-butyl 4-[(1 R or 1 S)-1-(2-{[7-chloro-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1-carboxylate (200 mg, see Compound 99.01 ), Compound 99.02 was prepared analogously to the procedure for the preparation of Compound 60.01.
Yield: 1 1 1 mg of the 41 % pure target compound.
LC-MS (Method 2): R, = 1.31 min; MS (ESIpos): m/z = 580 [M+H]+
Compound 99.03
7-chloro-6-[6-(methoxymethyl)pyrimidin-4-yl]-N-{4-[(1 R or 1S)-1-(piperazin-1 - yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride
Figure imgf000546_0001
Starting with tert-butyl 4-{(1 R or 1 S)-1-[2-({7-chloro-6-[6-(methoxymethyl)pyrimidin-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1-carboxylate (105 mg, see Compound 99.02), Compound 99.03 was prepared analogously to the procedure for the preparation of Compound 39.05.
Yield: 151 mg of the 47% pure target compound.
LC-MS (Method 2): R, = 0.94 min; MS (ESIpos): m/z = 481 [M+H]+
Compound 100.01
tert-butyl 4-{(1 R or 1 S)-1-[2-({6-[6-(dimethylamino)pyrimidinT4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazine-1-carboxylate
N CH3
H3C tert-Butyl 4-[(1 R or 1 S)-1 -(2-{[6-(6-chloropyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)ethyl]piperazine-1-carboxylate (85.0 mg, see Example 85.01) was dissolved in 2 mL dioxane and N-methylmethanamine (120 μΙ, 2.0 M in THF) was added. This mixture was stirred 3 hour at 110 . N-methylmethanamine (240 μΙ, 2.0 M in THF) were added and the mixture was stirred additional 2 hours at 1 0 . The reaction mixture was concentrated under reduced pressure to provide the crude title compound which was used without further purification. Yield: 119 mg of the 87% pure target compound.
LC-MS (Method 2): R, = 1.27 min; MS (ESIpos): m/z = 544 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.29 (br d, 3H), 1.34 - 1.42 (m, 9H), 2.23 - 2.45 (m, 4H), 3.15 (s, 6H), 3.27 - 3.33 (m, 4H), 3.44 (br s, 1H), 6.95 (br d, 1H), 7.08 (s, 1H), 7.17 (s, 1H), 7.46 (brs, 1H), 7.89 (brd, 1H), 8.27 (brd, 2H), 8.53 (d, 1H), 10.72 (br s, 1H), 12.27 (brs, 1H).
Compound 100.02
6-[6-(dimethylamino)pyrimidin-4-yl]-N-{4-[(1R or 1S)-1-(piperazin-1-yl)ethyl]pyridin-2-yl}- 1 H-benzimidazol-2-amine hydrochloride
Figure imgf000547_0001
Starting with tert-butyl 4-{(1R or 1S)-1-[2-({6-[6-(dimethylamino)pyrimidin-4-yl]-1H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1-carboxylate (115 mg, see Compound 100.01 ), Compound 100.02 was prepared analogously to the procedure for the preparation of Compound 39.05.
Yield: 108 mg of the 90% pure target compound.
LC-MS (Method 2): Rt = 0.99 min; MS (ESIpos): m/z = 444 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm]: 1.225 (0.48), 1.652 (1.18), 2.518 (13.32), 3.378 (1.16), 3.416 (1.02), 3.452 (0.99), 3.464 (0.93), 3.480 (0.83), 3.492 (0.68), 3.559 (16.00), 3.656 (0.42), 3.671 (0.48), 3.695 (0.48), 3.707 (0.42), 3.991 (0.63), 4.177 (0.47), 4.198 (0.45), 7.280 (3.81 ), 7.554 (1.56), 7.810 (1.28), 7.832 (1.57), 7.961 (1.28), 7.982 (0.99), 8.219 (2.07), 8.535 (0.90), 8.547 (0.90), 8.691 (0.45), 8.805 (4.00).
Compound 107.01.01
6-[6-(dimethylamino)-5-methoxypyrimidin-4-yl]-N-[4-(piperazin-1 -ylmethyl)pyrid
1 H-benzimidazol-2-amine hydrochloride
Figure imgf000548_0001
To a stirred solution of tert-butyl 4-{[2-({6-[6-(dimethylamino)-5-methoxypyrimidin-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]methyl}piperazine-1-carboxylate (200 mg, see Example 107.01.01) in dichloromethane (8.2 ml_) and methanol (820 yL) was added HCI in dioxane (3.6 ml, 4.0 M). The mixture was stirred at room temperature for 16 h. The solvent was removed in vacuum to give 220 mg of the title compound as crude product that was used for the next step without purification.
LC-MS (Method 2): R, = 0.94 min; MS (ESIneg): m/z = 458 [M-H]- H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.023 (9.1 1 ), 1.039 (9.21 ), 2.518 (1.16), 2.523 (0.80), 3.160 (0.86), 3.384 (16.00), 3.751 (0.63), 3.766 (0.83), 3.782 (0.64), 4.410 (0.47), 5.760 (2.59), 7.577 (1.91 ), 7.749 (0.89), 7.753 (0.88), 7.771 (1.38), 7.774 (1.42), 7.829 (2.01 ), 7.851 (1.16), 8.134 (1.97), 8.533 (1.16), 8.546 (1.08), 8.659 (3.77). The compounds in the table 2 below were prepared analogously to the procedure for the preparation of Compound 107.01.01 .
Table 2:
Figure imgf000549_0001
Figure imgf000550_0001
Figure imgf000551_0001
Figure imgf000552_0001
Example 109.02.01
Figure imgf000553_0001
Example 110.01
Figure imgf000554_0001
Example 111.01
Figure imgf000555_0001
Figure imgf000556_0001
Figure imgf000557_0001
Figure imgf000558_0001
Structure
lUPAC-Name
Compound LC-MS (method): Retention time; Mass found
H-NMR
Starting material
Compound l_l C H 3
116.01
F
6-[6-(3,3-dif luoroazetidin-1 -yl)pyrimidin-4-yl]-N-{4-[(1 R or 1S)-1 - (piperazin-1 -yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride
LC-MS (Method 2): R, = 0.99 min; MS (ESIpos): m/z = 491.6 [M+H]+ Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.819 (0.45), 0.986 (15.51), 1.002 (16.00), 1.009 (2.16), 1.011 (1.38), 1.021 (0.82), 1.025 (1.91 ), 1.037 (0.70), 1.087 (1.56), 1.104 (1.58), 1.128 (1.44), 1.145 (1.56), 1.172 (0.47), 1.194 (2.37), 1.210 (2.43), 1.227 (0.86), 1.257 (5.86), 1.273 (5.96), 1.279 (3.80), 1.293 (5.88), 1.310 (5.39), 1.693 (5.26), 1.707 (5.27), 1.740 (3.91 ), 1.749 (2.02), 1.777 (3.41 ), 1.976 (1.71 ), 2.131 (0.86), 2.518 (3.85), 2.523 (2.39), 2.669 (1.03), 2.673 (0.70), 3.096 (0.84), 3.107 (0.86), 3.114 (0.88), 3.125 (0.88), 3.133 (0.43), 3.143 (0.43), 3.160 (0.90), 3.218 (0.88), 3.276 (2.02), 3.288 (2.10), 3.371 (1.27), 3.403 (1.46), 3.449 (2.90), 3.455 (3.46), 3.465 (3.60), 3.467 (3.64), 3.483 (3.62), 3.485 (3.54), 3.495 (2.96), 3.507 (1.97), 3.578 (1.05), 3.585 (1.17), 3.594 (1.25), 3.601 (0.97), 3.609 (1.48), 3.625 (1.64), 3.641 (1.30), 3.649 (0.66), 3.660 (1.13), 3.664 (0.88), 3.672 (1.15), 3.674 (1.23), 3.696 (1.13), 3.698 (1.05), 3.706 (0.78), 3.710 (0.95), 3.715 (0.53), 3.722 (0.51 ), 3.726 (0.53), 4.105 (0.62), 4.247 (0.72), 4.283 (0.41 ), 4.466 (0.78), 4.496 (1.44), 4.525 (0.78), 4.738 (5.45), 4.768 (10.18), 4.798 (5.08), 7.211 (10.02), 7.591 (5.45), 7.691 (1.77), 7.813 (4.98), 7.834 (5.53), 8.059 (3.87), 8.064 (3.91 ), 8.081 (3.17), 8.085 (3.27), 8.343 (5.88), 8.565 (3.74), 8.578 (3.52), 8.822 (9.89), 9.879 (1.38).
Example 116.01
Figure imgf000560_0001
Example 117.01 Structure
lUPAC-Name
Compound LC-MS (method): Retention time; Mass found
1H-NMR
Starting material
Compound H C H 3
118.01
6-[6-(morpholin-4-yl)pyrimidin-4-yl]-N-{4-[(1 R or 1S)-1-(piperazin-1 - yl)ethyl]pyridin-2-yl}-1H-benzimidazol-2-amine hydrochloride
LC-MS (Method 2): Rt = 0.92 min; MS (ESIpos): m/z = 485.6 [M+H]+ Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.829 (0.64), 0.850 (0.64), 0.856 (0.85), 0.987 (4.69), 1 .004 (4.65), 1.064 (0.81 ), 1.179 (0.43), 1.230 (2.01 ), 1.655 (3.58), 2.518 (8.53), 2.523 (6.06), 3.046 (1.24), 3.058 (2.13), 3.069 (2.86), 3.081 (2.22), 3.093 (1.37), 3.221 (1.54), 3.418 (2.94), 3.441 (2.90), 3.457 (3.33), 3.469 (3.37), 3.485 (2.94), 3.498 (2.52), 3.509 (1.62), 3.627 (0.94), 3.650 (1.07), 3.661 (1.62), 3.666 (1.37), 3.676 (1.83), 3.698 (1.92), 3.708 (1.54), 3.712 (1.83), 3.744 (10.28), 3.755 (16.00), 3.764 (14.38), 3.789 (3.71 ), 3.946 (11.78), 4.182 (0.47), 4.203 (0.55), 4.628 (0.60), 7.483 (11.48), 7.552 (5.03), 7.575 (1 .28), 7.749 (0.55), 7.798 (5.12), 7.819 (5.76), 7.990 (4.22), 8.009 (3.46), 8.258 (6.66), 8.536 (2.94), 8.817 (13.01 ), 9.257 (0.60), 9.709 (0.85), 12.904 (0.47).
Example 118.01
Figure imgf000562_0001
Example 119.01 Compound 120.01
4-[1-(cyclopropylmethyl)-3,5-dimethyl-1 H-pyrazol-4-yl]benzene-1 ,2-diamine
Figure imgf000563_0001
4-Bromobenzene-1 ,2-diamine (388 mg), 1 -(cyclopropylmethyl)-3,5-dimethyl-4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (1.05 g, 60 % purity) and tetrakis(triphenylphosphine)palladium(0) (120 mg) were added to K2CO3 (3.1 ml, 2.0 M) and 1 - propanol (39 ml). The mixture was stirred under inert atmosphere for 2h at 120Ό. The mixture was then filtered (silicone filter) and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica gel to give 1 10 mg of the title compound.
1 H-NMR (400MHz, DMSO-d6): δ [ppm]= 0.29 - 0.35 (m, 2H), 0.45 - 0.51 (m, 2H), 1.17 (br t, 1 H), 2.06 (s, 3H), 2.16 (s, 3H), 3.83 (d, 2H), 4.41 (br d, 4H), 6.25 (dd, 1 H), 6.41 (d, 1 H), 6.52 (d, 1 H).
Compound 120.02
tert-butyl 4-[(1 R or 1S)-1 -{2-[({2-amino-4-[1 -(cyclopropylmethyl)-3,5-dimethyl-1 H-pyrazol- 4-yl]phenyl}carbamothioyl)amino]pyridin-4-yl}ethyl]piperazine-1 -carboxylate
Figure imgf000563_0002
Imidazole (5.84 mg, 85.8 pmol) and TCDI (91.8 mg) were solubilised in dichloromethane (5.6 ml) under argon. The solution was cooled to CC and tert-butyl 4-[(1 R or 1S)-1 -(2- aminopyridin-4-yl)ethyl]piperazine-1 -carboxylate (131 mg) was added. The mixture was allowed to warm up to rt overnight. 4-[1 -(cyclopropylmethyl)-3,5-dimethyl-1 H-pyrazol-4- yl]benzene-1 ,2-diamine (110 mg) was added and the mixture was stirred for 4h at rt. The reaction mixture was diluted with water and extracted three times with DCM. The combined organic phases were dried (silicone filter) and concentrated under reduced pressure. The crude material was used without further purification.
Compound 120.03
6-[1 -(cyclopropylmethyl)-3,5-dimethyl-1 H-pyrazol-4-yl]-N-{4-[(1 R or 1 S)-1 -(piperazin-1 - yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride
Figure imgf000564_0001
tert-butyl 4-{(1 R or 1 S)-1 -[2-({6-[1 -(cyclopropylmethyl)-3,5-dimethyl-1 H-pyrazol-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate (55.0 mg; see Example 120.01 ) was dissolved in a mixture of dichloromethane (950 μΙ) and methanol (480 μΙ) , HQ in dioxane (240 μΙ, 4.0 M) was added and the mixture stirred for overnight at rt. The mixture was concentrated under reduced pressure and the crude residue (56 mg) was used without further purification.
LC-MS (Method 2): Rt = 1.05 min; MS (ESIpos): m/z = 471 [M+H]+
Compound 121.01
4-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-3-fluorobenzene-1 ,2-diamine
Figure imgf000564_0002
4-Bromo-3-fluorobenzene-1 ,2-diamine (500 mg), 1 -(cyclopropylmethyl)-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (666 mg), triphenyl phosphine (32.0 mg) and bis(triphenylphosphine)palladium(ll) dichloride (85.6 mg) were added to aqueous K2C03 (3.7 ml, 2.0 M) and 1 -propanol (10 ml). The mixture was stirred under argon for 2h at 120Ό. The reaction mixture was diluted with DCM and water. The aqueous phase was extracted three times with DCM. The organic phase was washed sequentially with water and brine. The organic phase was then dried (silicone filter) and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica gel to give 445 mg of the title compound.
LC-MS (Method 2): Rt = 0.84 min; MS (ESIpos): m/z = 247 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm]= 0.33 - 0.40 (m, 2H), 0.46 - 0.55 (m, 2H), 1.17 - 1.29 (m, 1 H), 3.96 (d, 2H), 4.42 (s, 2H), 4.76 (s, 2H), 6.35 (dd, 1 H), 6.65 (t, 1 H), 7.65 (s, 1 H), 7.91 (d, 1 H).
Compound 121.02
tert-butyl 4-[(1 R or 1S)-1 -{2-[({2-amino-4-[1 -(cyclopropylmethyl)-1 H-pyrazol-4-yl]-3- fluorophenyl}carbamothioyl)amino]pyridin-4-yl}ethyl]piperazine-1 -carboxylate
Figure imgf000565_0001
Imidazole (24.6 mg) and TCDI (386 mg) were solubilised in dichloromethane (15 ml) under argon. The solution was cooled to 0Ό and tert-buty l 4-[(1 R or 1 S)-1 -(2-aminopyridin-4- yl)ethyl]piperazine-1 -carboxylate (554 mg; see Compound 36.05) was added. The mixture was allowed to warm up to rt overnight. 4-[1 -(cyclopropylmethyl)-1 H-pyrazol-4-yl]-3-fluorobenzene- 1 ,2-diamine (445 mg) was added and the mixture was stirred for 4h at rt. The mixture was diluted with water and extracted three times with DCM. The combined organic phases were dried (silicone filter) and concentrated under reduced pressure. The crude title compound (1.3 g) was used without further purification.
LC-MS (Method 2): Rt = 1.39 min; MS (ESIpos): m/z = 595 [M+H]+ Compound 121.03
6-[1 -(cyclopropylmethyl)-1 H-pyrazol-4-yl]-7-fluoro-N-{4-[(1 R or 1S)-1-(piperazin-1 - yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride
Figure imgf000566_0001
tert-Butyl 4-{(1 R or 1 S)-1-[2-({6-[1 -(cyclopropylmethyl)-1 H-pyrazol-4-yl]-7-fluoro-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1-carboxylate (708 mg; see Example 121.02) was solubilised in dichloromethane (7.2 ml) and HCI in dioxane (1.8 ml, 4.0 M) was added. The mixture was stirred overnight at rt. The mixture was concentrated under reduced pressure and the crude residue (730 mg) was used without further purification.
LC-MS (method 2): R, = 1.05 min; MS (ESIpos): m/z = 461 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.388 (0.72), 0.399 (2.74), 0.403 (2.39), 0.411 (2.69), 0.414 (2.57), 0.424 (0.94), 0.526 (0.98), 0.536 (2.32), 0.541 (2.17), 0.546 (1.29), 0.556 (2.44), 0.560 (2.00), 0.572 (0.69), 1.269 (0.64), 1.277 (0.61 ), 1.289 (1.00), 1.296 (0.46), 1.301 (0.56), 1.308 (0.57), 1.686 (2.56), 1.701 (2.34), 2.518 (1.28), 2.522 (0.81 ), 3.160 (16.00), 3.331 (0.55), 3.467 (1.48), 4.031 (4.29), 4.049 (4.19), 4.655 (0.48), 7.476 (1.62), 7.498 (2.05), 7.565 (2.05), 7.592 (1.38), 7.608 (1.61 ), 7.612 (1.43), 7.629 (1.59), 7.922 (3.44), 8.238 (2.69), 8.241 (2.54), 8.524 (1.15), 8.536 (1.07), 9.831 (0.68).
Compound 122.01
3-chloro-4-[1 -(cyclopropylmethyl)-1 H-pyrazol-4-yl]benzene-1,2-diamine
Figure imgf000567_0001
4-Bromo-3-chlorobenzene-1 ,2-diamine (500 mg), 1 -(cyclopropylmethyl)-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (616 mg), triphenylphosphine (29.6 mg) and bis(triphenylphosphine)palladium(ll) dichloride (79.2 mg) were added to aqueous K2CO3 (3.4 ml, 2.0 M) and 1 -propanol (10 ml) . The mixture was stirred under argon for 2h at 120Ό. The reaction mixture was then diluted with DCM and water and the aqueous phase was extracted three times with DCM. The organic phase was sequentially washed with water and brine, dried (silicone filter) and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica gel to give 441 mg of the title compound.
LC-MS (Method 2): Rt = 0.90 min; MS (ESIpos): m/z = 263 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm]= 0.35 - 0.39 (m, 2H), 0.50 - 0.55 (m, 1 H), 1.20 - 1.29 (m, 1 H), 3.96 (d, 2H), 4.71 (s, 2H), 4.81 (s, 2H), 6.48 - 6.52 (m, 1 H), 6.58 (d, H), 7.59 (d, 1 H), 7.92 (d, 1 H).
Compound 122.02
tert-butyl 4-[(1 R or 1S)-1-{2-[({2-amino-3-chloro-4-[1-(cyclopropylmethyl)-1 H-pyrazol-4- yl]phenyl}carbamothioyl)amino]pyridin-4-yl}ethyl]piperazine-1-carboxylate
Figure imgf000567_0002
Imidazole (22.9 mg) and TCDI (359 mg) were solubilised in dichloromethane (15 ml) under argon. The solution was cooled to CC and tert-buty l 4-[(1 R or 1 S)-1-(2-aminopyridin-4- yl)ethyl]piperazine-1 -carboxylate (514 mg) was added. The mixture was allowed to warm up to rt overnight. 3-chloro-4-[1 -(cyclopropylmethyl)-1 H-pyrazol-4-yl]benzene-1 ,2-diamine (441 mg) was added and the mixture was stirred for 4h at rt. The mixture was diluted with water and extracted three times with DCM. The combined organic phases were dried (silicone filter) and concentrated under reduced pressure. The crude mixture (1 g) was used without further purification.
Compound 122.03
7-chloro-6-[1-(cyclopropylmethyl)-1 H-pyrazol-4-yl]-N-{4-[(1 R or 1 S)-1 -(piperazin-1 - yl )eth y I] pyri d i n-2-yl}- 1 H-benzimidazol-2-amine hydrochloride
Figure imgf000568_0001
tert-butyl 4-{(1 R or 1 S)-1-[2-({7-chloro-6-[1 -(cyclopropylmethyl)-1 H-pyrazol-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1-carboxylate (534 mg; see Example 122.01 ) was solubilsed in dichloromethane (5.3 ml) and HCI in dioxane (1.3 ml, 4.0 M) was added. The mixture was stirred overnight at rt and then concentrated under reduced pressure. The crude mixture was used without further purification.
LC-MS (method 2): R, = 1.08 min; MS (ESIpos): m/z = 477 [M+H]+
Compound 123.01
4-(1 -methyl-1 H-pyrazol-5-yl)benzene-1 ,2-diamine
Figure imgf000568_0002
4-Bromobenzene-1 ,2-diamine (300 mg), 1 -methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)-1 H-pyrazole (667 mg) and the bis(triphenylphosphine)palladium(ll) dichloride (113 mg) were solubilised in 1 ,2-dimethoxyethane (10 ml) and aqueous K2CO3 (1.8 ml, 2.0 M) was added. The reaction was stirred for 10min under microwave radiation at 130Ό. The reaction mixture was filtered (silicone filter) and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica gel to give 125 mg (99 % purity) of the title compound.
LC-MS (Method 2): R, = 0.60 min; MS (ESIpos): m/z = 189 [M+H]+
H-NMR (500MHz, DMSO-d6): d [ppm]= 3.77 (s, 3H), 4.60 (s, 2H), 4.72 (s, 2H), 6.13 (d, 1 H), 6.50 - 6.53 (m, 1 H), 6.57 (d, 1 H), 6.63 (d, 1 H), 7.35 (d, 1 H).
Compound 123.02
tert-butyl 4-{(1 R or 1S)-1-[2-({[2-amino-4-(1 -methyl-1 H-pyrazol-5- yl)phenyl]carbamothioyl}amino)pyridin-4-yl]ethyl}piperazine-1-carboxylate
Figure imgf000569_0001
Imidazole (9.04 mg) and TCDI (142 mg) were solubilised in dichloromethane (2.0 ml) under argon. The solution was cooled to 0^ and tert-buty l 4-[(1 R or 1 S)-1-(2-aminopyridin-4- yl)ethyl]piperazine-1 -carboxylate (203 mg; see Compound 36.05) was added. The mixture was allowed to warm up to rt overnight. 4-(1 -methyl-1 H-pyrazol-5-yl)benzene-1 ,2-diamine (125 mg) was added and the mixture was stirred for 4h at rt. The mixture was diluted with water and extracted three with DCM. The combined organic phases were dried (silicone filter) and concentrated under reduced pressure. The crude title compound was used without further purification.
LC-MS (Method 2): Rt = 1.24 min; MS (ESIpos): m/z = 537 [M+H]+
Compound 123.03
6-(1 -methyl-1 H^yrazol-5-yl)-N-{4-[(^ ^
benzimidazol-2 -amine hydrochloride
Figure imgf000570_0001
tert-butyl 4-[(1 R or 1 S)-1-(2-{[6-(1-methyl-1 H-pyrazol-5-yl)-1 H-benzim^
4-yl)ethyl]piperazine-1-carboxylate (191 mg; see Example 123.01 ) was solubilsed in dichloromethane (2.2 ml) and HCI in dioxane (550 μΙ, 4.0 M) was added. The mixture was stirred overnight at rt. The mixture was concentrated under reduced pressure and used without further purification.
LC-MS (method 2): Rt = 0.90 min; MS (ESIpos): m/z = 403 [M+H]+
Compound 124.01
(rac)-4-{1 -[tetrahydro-2H-pyran-2-yl]-1 H-pyrazol-5-yl}benzene-1 ,2-diamine
Figure imgf000570_0002
4-Bromobenzene-1 ,2-diamine (300 mg), (rac)-1-[tetrahydro-2H-pyran-2-yl]-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (892 mg) and the bis(triphenylphosphine)palladium(ll) dichloride (1 13 mg) were solubilised in 1 ,2- dimethoxyethane (3.0 ml) and aqueous K2CO3 (1.8 ml, 2.0 M) was added. The reaction was stirred for 10 min under microwave radiation at 130Ό. The reaction mixture was filtered (silicone filter) and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica gel to give 139 mg (90 % purity) of the title compound. 1H-NMR (400MHz, DMSO-d6): d [ppm]= 1.46 - 1.62 (m, 3H), 1.66 - 1.75 (m, 1 H), 1.89 - 1.97 (m, 1 H), 2.30 - 2.42 (m, 1 H), 3.47 - 3.57 (m, 1 H), 3.93 - 4.06 (m, 1 H), 4.62 (s, 2H), 4.75 (s, 2H), 5.18 (dd, 1 H), 6.16 (d, 1 H), 6.50 - 6.60 (m, 2H), 6.64 (d, 1 H), 7.44 (d, 1 H).
Compound 124.02
(rac)-tert-butyl 4-[(2-{[(2-amino-5-{1 -[tetrahydro-2H-pyran-2-yl]-1 H-pyrazol-5- yl}phenyl)carbamothioyl]amino}pyridin-4-yl)methyl]piperazine-1-carboxylate
Figure imgf000571_0001
Imidazole (6.85 mg) was added to TCDI (108 mg) and solubilized in dichloromethane (4.0 ml) at O D under argon. tert-Butyl 4-[(2-aminopyridin-4 -yl)methyl]piperazine-1 -carboxylate (147 mg; see Compound 01.02) (solubilized in 4ml DCM) was added and the reaction was stirred at rt overnight. (rac)-4-{1 -[tetrahydro-2H-pyran-2-yl]-1 H-pyrazol-5-yl}benzene-1 ,2-diamine (130 mg, 503 pmol) (in 2ml DCM) was then added to the mixture and the reaction was stirred for 4h at rt. The reaction mixture was diluted with water and extracted three times with DCM. The organic layer was filtered (silicone filter) and concentrated under reduced pressure. The crude material was used without further purification.
LC-MS (Method 2): R, = 1 .30 min; MS (ESIneg): m/z = 591 [M-H]-
Compound 124.03
(rac)-tert-butyl 4-({2-[(6-{1-[tetrahydro-2H-pyran-2-yl]-1 H-pyrazol-5-yl}-1 H-benzimidazol- 2-yl)amino]pyridin-4-yl}methyl)piperazine-1-carboxylate
Figure imgf000572_0001
N,N'-dipropan-2-ylcarbodiimide (1.0 ml) was added to (rac)-tert-butyl 4-[(2-{[(2-amino-5-{1 - [tetrahydro-2H-pyran-2-yl]-1 H-pyrazol-5-yl}phenyl)carbamothioyl]amino}pyridin-4- yl)methyl]piperazine-1-carboxylate (100 mg) in dichloromethane (4 ml) under argon and the reaction was stirred overnight at rt. The mixture was diluted with sat. NaHCC>3 and extracted three times with DCM. The organic phase was dried (MgSC ), filtered and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica gel to give 34.7 mg (84 % purity) of the title compound.
LC-MS (Method 2): R, = 1.30 min; MS (ESIneg): m/z = 557 [M-H]-
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.989 (0.59), 1.005 (0.60), 1.389 (1 1.36), 1.395 (16.00), 1.412 (0.85), 2.322 (1.17), 2.326 (1.29), 2.331 (1.28), 2.336 (1.14), 2.347 (1.47), 2.359 (1.41 ), 2.372 (0.99), 2.518 (2.33), 2.522 (1.54), 2.668 (0.71 ), 3.501 (2.08), 7.541 (0.79), 8.263 (0.83), 8.276 (0.79).
Compound 124.04
N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-6-(1 H-pyrazol-5-yl)-1 H-benzimidazol-2-amine hydrochloride
Figure imgf000572_0002
(rac)-tert-Butyl 4-({2-[(6-{1-[tetrahydro-2H-pyran-2-yl]-1 H-pyrazol-5-yl}-1 H-benzimidazol-2- yl)amino]pyridin-4-yl}methyl)piperazine-1 -carboxylate (33.0 mg; see Compound 124.03) was solubilised in a mixture of dichloromethane (950 μΙ) /methanol (950 μΙ) and HCI in dioxane (1.4 ml, 4.0 M) was added. The mixture was stirred for 3h at rt and concentrated under reduced pressure. The crude material was used without further purification.
LC-MS (Method 2): R, = 0.81 min; MS (ESIneg): m/z = 373 [M-H]-
Compound 125.01
(2-amino-5-bromopyridin-4-yl)methanol
Figure imgf000573_0001
Methyl 2-amino-5-bromopyridine-4-carboxylate (500 mg) was solubilised in THF (10 ml, 120 mmol) and the mixture was cooled to CC. DIBAL in h exane (9.7 ml, 1.0 M) was added dropwise. The mixture stirred overnight at rt. The reaction mixture was diluted carefully with 2- propanol and water. The mixture stirred 24h at rt, the precipitate was filtered, stirred twice in EtOAc and filtered each time. The filtrate was concentrated under reduced pressure and dried under reduced pressure. The crude product was used without further purification.
LC-MS (Method 2): Rt = 0.57 min; MS (ESIpos): m/z = 203 [M+H]+
Compound 125.02
5-bromo-4-(bromomethyl)pyridin-2-amine hydrobromide (1 :1)
Figure imgf000573_0002
(2-Amino-5-bromopyridin-4-yl)methanol (436 mg) was stirred in aqueous HBr (5.0 ml, 48 % purity) 72h at 120 . The reaction mixture was then concentrated under reduced pressure and used without further purification. Compound 125.03
tert-butyl 4-[(2-amino-5-bromopyridin-4-yl)methyl]piperazine-1 -carboxylate
Figure imgf000574_0001
5-Bromo-4-(bromomethyl)pyridin-2-amine hydrobromide (1 : 1 ) (630 mg, 80 % purity), tert-butyl piperazine-1-carboxylate (460 mg) and K2CO3 (1.00 g) were solubilised in DMF (10 ml) . The mixture was stirred overnight at 50 . The reaction mixture was diluted with EtOAc and washed with half cone. NaCI solution. The organic layer was dried (MgSO.*) filtered and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica gel to give 80.0 mg of the title compound.
LC-MS (Method 2): R, = 1.18 min; MS (ESIpos): m/z = 371 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.40 (s, 9H), 2.38 (t, 4H), 3.31 - 3.36 (m, 4H), 3.38 (s, 2H), 6.10 (s, 2H), 6.62 (s, 1 H), 7.93 (s, 1 H).
Compound 125.04
tert-butyl 4-{[2-({[2-amino-4-(3-methyl-1 ,2,4-oxadiazol-5-yl)phenyl]carbamothioyl}amino)- 5-bromopyridin-4-yl]methyl}piperazine-1 -carboxylate
Figure imgf000574_0002
Imidazole (5.13 mg) and TCDI (80.6 mg) were solubilised in dry dichioromethane (2.5 ml) under argon. The solution was cooled to 0*C and tert-butyl 4-[(2-amino-5-bromopyridin-4- yl)methyl]piperazine-1 -carboxylate (140 mg), solubilised in dry dichioromethane (2.5 ml), was added. The mixture was stirred at rt overnight. 4-(3-methyl-1 ,2,4-oxadiazol-5-yl)benzene-1 ,2- diamine (71.7 mg; see Compound 16.20) was then added to the mixture and it was stirred overnight at rt. The reaction mixture was diluted with water and extracted three times with DCM. The organic phase was dried (silicone filter) and concentrated under reduced pressure. The crude was used without further purification
LC-MS (Method 2): R, = 1.18 min; MS (ESIpos): m/z = 603 [M+H]+ Compound 125.05
N-[5-bromo-4-(piperazin-1-ylmethyl)pyridin-2-yl]-6-(3-methyl-1,2,4-oxadiazol-5-yl)-1 H- benzimidazol-2-amine hydrochloride
Figure imgf000575_0001
Tert-Butyl 4-[(5-bromo-2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate (90.0 mg; see Example 125.01 ) was solubilised in dichloromethane (1.6 ml) and HCI in dioxane (160 μΙ, 4.0 ) was added. The mixture was stirred at rt overnight. The reaction was concentrated under reduced pressure and the crude residue (90 mg) was used without further purification.
LC-MS (Method 2): Rt = 1.05 min; MS (ESIpos): m/z = 469 [M+H]+
Compound 126.01
tert-butyl 4-[(2-{[6-(hydrazinylcarbonyl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1-carboxylate
Figure imgf000575_0002
2-[(4-{[4-(tert-Butoxycarbonyl)piperazin-1 -yl]methyl}pyridin-2-yl)amino]- H-benzimidazole-6- carboxylic acid (500 mg, 50 % purity; see compound 16.05), hydrazine in THF (2.2 ml, 1.0 M), K2CO3 (382 mg) and HATU (630 mg) were dissolved in DMF. The mixture stirred overnight at rt. Hydrazine in THF (2.2 ml, 1.0 M) and HATU (630 mg) were added again and the mixture stirred overnight at rt. The reaction mixture was diluted with water and stirred 24h at rt. The precipitate was filtered, washed with water and dried overnight at 60Ό. The product was used without further purification.
LC-MS (Method 2): Rt = 0.97 min; MS (ESIpos): m/z = 467 [M+H]+ 1H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.39 (s, 9H), 2.36 (br d, 4H), 3.35 (br s, 4H), 3.50 (s, 2H), 4.42 (br s, 2H), 6.93 (br d, 1H), 7.17 (br s, 1H), 7.28 - 7.51 (m, 1H), 7.52 - 7.59 (m, 1H), 7.82 - 8.02 (m, 1H), 8.26 (d, 1H), 9.52 - 9.63 (m, 1H), 10.67 - 10.79 (m, 1H), 12.19 - 12.35 (m, 1H).
Compound 126.02
tert-butyl 4-({2-[(6-{[2-(cyclobutylacetyl)hydrazinyl]carbonyl}-1H-benzimidazol-2- yl)amino]pyridin-4-yl}methyl)piperazine-1 -carboxylate
Figure imgf000576_0001
tert-Butyl 4-[(2-{[6-(hydrazinylcarbonyl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1-carboxylate (75.0 mg), cyclobutylacetic acid (55.0 mg), K2C03 (133 mg) and HATU (183 mg) were dissolved in DMF (3.8 ml). The mixture stirred overnight at rt. Water was added and the mixture stirred for 1 h at rt and then filtered. The crude mixture was purified without work up by preparative HPLC to give 7 mg of the title compound.
LC-MS (Method 2): Rt = 1.07 min; MS (ESIpos): m/z = 563 [M+H]+
H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.40 (s, 9H), 1.69 - 1.87 (m, 4H), 2.01 - 2.11 (m, 2H), 2.30 (d, 2H), 2.36 (br t, 4H), 2.59 - 2.66 (m, 1H), 3.35 (br s, 4H), 3.50 (s, 2H), 6.94 (br s, 1H), 7.17 (brd, 1H), 7.31 -7.55 (m, 1H), 7.61 (brdd, 1H), 7.89 - 8.03 (m, 1H), 8.27 (d, 1H), 9.72 (s, 1H), 10.08 (brd, 1H), 10.74 (brs, 1H), 12.29 (brs, 1H).
Compound 126.03
6-[5-(cyclobutylmethyl)-1 ,3,4-oxadiazol-2-yl]-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine
Figure imgf000577_0001
tert-Butyl 4-({2-[(6-{[2-(cyclobutylacetyl)hydrazinyl]carbonyl}-1 H-benzimidazol-2- yl)amino]pyridin-4-yl}methyl)piperazine-1-carboxylate (7.00 mg, 80 % purity) was dissoved in SOCI2 (1 10 μΙ) and the mixture stirred overnight at 50Ό . The reaction mixture was concentrated under reduced pressure and the crude title compound (6 mg) was used without further purification.
Compound 127.01
6-chloro-N-(cyclopropylmethyl)-N-methylpyrimidin-4-amine
Figure imgf000577_0002
4,6-Dichloropyrimidine (300 mg), 1 -cyclopropyl-N-methylmethanamine hydrochloride (1 :1 ) (257 mg) and K2CO3 (306 mg) were stirred in dioxane 1 ,4-dioxane (4.0 ml) overnight at 1 10Ό. The mixture diluted in water and EtOAc. The aqueous phase was extracted two times with EtOAc. The organic phase was then dried (silicone filter) and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica gel to give 158 mg (95 % purity) of the title compound.
LC-MS (method 2): Rt = 1.08 min; MS (ESIpos): m/z = 199 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ ppm 0.23 - 0.33 (m, 2 H) 0.39 - 0.49 (m, 2 H) 0.98 - 1.08 (m, 1 H) 3.07 (br s, 3 H) 3.35 - 3.59 (m, 2 H) 6.76 (br s, 1 H) 8.30 (s, 1 H) Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.259 (2.95), 0.270 (1 1.68), 0.273 (10.68), 0.282 (12.22), 0.285 (1 1.46), 0.295 (4.07), 0.320 (0.41 ), 0.427 (2.85), 0.438 (7.41 ), 0.441 (7.66), 0.447 (4.61 ), 0.457 (8.07), 0.472 (2.34), 0.978 (0.51 ), 0.991 (1.05), 0.995 (1.34), 1.002 (0.83), 1.007 (2.68), 1.010 (2.49), 1.015 (2.49), 1.019 (1.88), 1.027 (4.44), 1.035 (1.85), 1.040 (2.34), 1.045 (2.44), 1.047 (2.34), 1.052 (0.78), 1.057 (1.15), 1.059 (1.15), 1.064 (0.95), 1.077 (0.41 ), 2.518 (5.37), 2.523 (3.80), 3.069 (10.66), 3.469 (2.27), 6.761 (1.29), 8.300 (16.00).
Compound 128.01
6-bromo-N-(cyclopropylmethyl)pyrimidin-4-amine
Figure imgf000578_0001
4,6-dibromopyrimidine (300 mg) and 1 -cyclopropylmethanamine (130 μΙ) were stirred in dioxane 1 ,4-dioxane (6.0 ml) for 2h at 1 10Ό. The m ixture was then concentrated under reduced pressure. The crude was solubilised in DCM and water was added. The aqueous phase was extracted two times with EtOAc. The organic phase was dried (silicone filter) and concentrated under reduced pressure. The crude was used without further purification.
LC-MS (Method 2): Rt = 0.99 min; MS (ESIpos): m/z = 228 [M+H]+
Compound 129.01
6-bromo-N,N-dimethylpyrimidin-4-amine
Figure imgf000578_0002
4,6-Dibromopyrimidine (300 mg) and N-methylmethanamine in THF (760 μΙ, 2.0 M) were stirred in dioxane 1 ,4-dioxane (6.0 ml) overnight at 1 10Ό. The mixture was then concentrated under reduced pressure and the crude mixture was purified by flash chromatography on silica gel to give 1 16 mg of the title compound.
1 H-NMR (400MHz, DMSO-d6): δ [ppm]= 3.00 - 3.14 (m, 6H), 6.86 - 6.93 (m, 1 H), 8.21 - 8.28 (m, 1 H). The following compounds shown in table 3, below, were prepared according to the general procedure :
The corresponding Boc protected amine (see Examples 130.01. to 162.01., tables 14 and 15, or as specified below for the respective Compound) (1 eq.) was solubilized in a mixture of DCM and MeOH (generally 2:1 ) and 4N HCI in dioxane (5 eq.) was added slowly. The reaction was stirred between 2 and 48 hours at rt and then concentrated. The crude mixture was used without further purification.
Table 3:
Figure imgf000579_0001
Figure imgf000580_0001
Figure imgf000581_0001
LC-MS (Method 2): Rt = 0.97 min; MS (ESIpos): m/z = 404 [M+H]+
Figure imgf000582_0001
Figure imgf000583_0001
Figure imgf000584_0001
Figure imgf000585_0001
Figure imgf000586_0001
Figure imgf000587_0001
Figure imgf000588_0001
LC-MS (Method 2): Rt = 1 .19 min; MS (ESIneg): m/z = 523 [M-H]"
Figure imgf000589_0001
LC-MS (Method 2): Rt = 1.02 min; MS (ESIneg): m/z = 429 [M-H]"
Figure imgf000590_0001
Compound 169.01
1 ,1 -difluoro-3-(iodomethyl)cyclobutane
Figure imgf000590_0002
To a stirred solution of (3,3-difluorocyclobutyl)methanol (3.41 g) in THF (60 ml) was added triphenylphosphine (8.79 g) and imidazole (2.85 g). The mixture was cooled to 0Ό and iodine (8.50 g) was added. The mixture was stirred at r.t. for 16 h. An aqueous solution of disodium sulfurothioate (c = 1 M; 50 mL) was added and the reaction mixture was stirred for 5 minutes. The phases were separated and the aqueous phase was extracted with diethyl ether. The combined organic phases were washed with aqueous ammonium chloride solution, dried (sodium sulfate), filtered and the solvent was carefully removed in vacuum (750 mBar, 45 Ό) to give 6.48 g of the title compound as a crude product that was used for the next step without purification.
The Compounds in the following table 4 were synthesised according to the preparations, and from starting materials (SM), as specified for the respective Compounds in their table entries below.
Table 4:
Figure imgf000592_0001
Figure imgf000593_0001
Synthesis in analogy to the preparation of Compound 39.01
Figure imgf000594_0001
Figure imgf000595_0001
Figure imgf000596_0001
Synthesis in analogy to the preparation of Compound 39.02
Figure imgf000597_0001
Figure imgf000598_0001
Figure imgf000599_0001
Figure imgf000600_0001
Synthesis in analogy to the preparation of Compound 60.01
Figure imgf000601_0001
Synthesis in analogy to the preparation of Compound 60.01
The Compounds in the table 5 below were prepared analogously to the proced preparation of Compound 107.01.01 .
Table 5:
Figure imgf000602_0001
Figure imgf000603_0001
SM: Example 165.01
Figure imgf000604_0001
SM: Example 166.01
Figure imgf000605_0001
Figure imgf000606_0001
Figure imgf000607_0001
Figure imgf000608_0001
Figure imgf000609_0001
SM: Example 171.01
Figure imgf000610_0001
Figure imgf000611_0001
SM: Example 173.01
Compound 174.01.01
4-[6-(difluoromethyl)pyrimidin-4-yl]benzene-1,2- di iamine
Figure imgf000612_0001
4-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzene-1 ,2-diamine (500 mg, see Compound 01.03), 4-chloro-6-(difluoromethyl)pyrimidine (387 mg; for a preparation see e.g. WO2011/045353)), tetrakis(triphenylphosphine)palladium(0) (123 mg, 107 μηιοΙ) were solubilised in 1 ,4-dioxane (17 ml) and aqueous K2CO3 solution (3.2 ml, 2.0 ) was added. The reaction mixture was stirred at 8CC for 3h. The re action mixture was then filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel to give 468 mg (73 % purity) of the title compound.
LC-MS (Method 2): R, = 0.75 min; MS (ESIpos): m/z = 237 [M+H]+
H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.066 (7.55), 1.156 (0.56), 1.227 (16.00), 1.241 (3.30), 1.281 (1.02), 2.518 (1.67), 2.523 (1.16), 3.159 (1 1.42), 3.172 (11.15), 3.939 (1.16), 4.084 (0.85), 4.097 (2.57), 4.1 10 (2.57), 4.123 (0.82), 4.374 (0.49), 4.725 (3.86), 4.821 (1.04), 5.333 (4.96), 5.758 (0.50), 6.444 (0.98), 6.463 (1.06), 6.586 (4.1 1 ), 6.607 (4.04), 6.748 (0.59), 6.752 (0.63), 6.768 (0.52), 6.771 (0.55), 6.791 (1.97), 6.874 (1.05), 6.877 (1.01 ), 6.927 (4.03), 7.063 (1.67), 7.403 (2.01 ), 7.408 (2.16), 7.424 (1.83), 7.429 (2.08), 7.510 (4.12), 7.516 (3.83), 7.915 (3.85), 9.105 (3.82).
Compound 174.01.02
tert-butyl 4-[(1 R or 1S)-1 -{2-[({2-amino-4-[6-(difluoromethyl)pyrimidin-4- yl]phenyl}carbamothioyl)amino]pyridin-4-yl}ethyl]piperazine-1-carboxylate
Figure imgf000612_0002
Imidazole (26.5 mg), TCDI (405 mg, 90 % purity) and tert-butyl 4-[(1 R or 1 S)-1-(2- aminopyridin-4-yl)ethyl]piperazine-1 -carboxylate (597 mg, see Compound 36.05) were combined in dichloromethane (9 ml) and the reaction mixture was stirred at 0Ό for 30 minutes. Then the mixture was stored in a refrigerator overnight. The mixture was stirred at room temperature for 2 additional hours and additional portions of imidazole (26.5 mg) and TCDI (405 mg, 90 % purity) were added. The reaction mixture was stirred at room temperature for 2 hours. 4-[6-(Difluoromethyl)pyrimidin-4-yl]benzene-1 ,2-diamine (460 mg), solubilised in dichloromethane (9 ml), was added and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with DCM. The organic phase was washed with water and brine and then dried (silicone filter) and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel to give 601 mg of the title compound.
LC-MS (Method 2): Rt = 1.33 min; MS (ESIpos): m/z = 585 [M+H]+
Compound 175.01.01
4-(2-chlorothiophen-3-yl)benzene-1 ,2-diamine
Figure imgf000613_0001
4-Bromobenzene-1 ,2-diamine (600 mg), (2-chlorothiophen-3-yl)boronic acid (1.04 g) and bis(triphenylphosphine)palladium(ll) dichloride (1 13 mg) were solubilised in 1 ,2- dimethoxyethane (20 ml) and an aqueous solution of K2C03 (4.8 ml, 2.0 M) was added. The reaction mixture was stirred for 10 min under microwave irradiation at 130 . The mixture was filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel to give 250 mg of the title compound.
LC-MS (Method 2): Rt = 1.01 min; MS (ESIpos): m/z = 225 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm]= 4.54 - 4.68 (m, 4H), 6.55 (d, 1 H), 6.62 - 6.66 (m, 1 H), 6.78 (d, 1 H), 7.06 (d, 1 H), 7.43 (d, 1 H). Compound 175.01.02
tert-butyl 4-{[2-({[4-amino-6-(2-chlorothiophen-3-yl)pyridin-3- yl]carbamothioyl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate
Figure imgf000614_0001
Imidazole (15.1 mg) and TCDI (238 mg) were solubilised in dichloromethane (9.1 ml) under inert atmosphere. The solution was cooled to 0Ό an d a solution of tert-butyl 4-[(2- aminopyridin-4-yl)methyl]piperazine-1 -carboxylate (325 mg, see Compound 01.02) in dichloromethane (9.1 ml) was added. The mixture was stored overnight in the refrigerator, after which 4-(2-chlorothiophen-3-yl)benzene-1 ,2-diamine (250 mg, 1.11 mmol) was added and the mixture was stirred for 5h at rt. The mixture was diluted with water and extracted with DCM. The combined organic phases were dried over a silicone filter and concentrated under reduced pressure. The crude title compound was used without further purification.
Compound 179.01.01
5,6-dichloro-N,N-dimethylpyrimidin-4-amine
Figure imgf000614_0002
4,5,6-Trichloropyrimidine (500 mg), a solution of N-methylmethanamine in THF (1.5 ml, 2.0 M) and solid potassium carbonate (414 mg) were stirred in dioxane overnight at 1 10 . The mixture was then diluted with water and extracted with DCM. The organic layer was dried over a silicone filter and concentrated under reduced pressure. The crude title compound (493 mg) was used without further purification
LC-MS (Method 2): R, = 1.05 min; MS (ESIpos): m/z = 192 [M+H]+ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.518 (0.95), 2.523 (0.68), 3.017 (5.70), 3.191 (16.00),.303 (1.46).
The following Compounds shown in table 6, below, were prepared according to the following general procedure :
The corresponding Boc protected amine (see Examples 174.01 to 199.01 , tables 20 and 21 ) (1 eq.) was solubilized in a mixture of DCM and MeOH (generally 2:1 ) and 4N HCI in dioxane (5 eq.) was added slowly. The reaction was stirred between 2 and 48 hours at rt and then concentrated. The crude mixture was used without further purification.
Table 6:
Figure imgf000616_0001
Figure imgf000617_0001
LC-MS (Method 2): Rt = 1 .14 min; MS (ESIpos): m/z = 444 [M-H]+
Figure imgf000618_0001
Figure imgf000619_0001
Figure imgf000620_0001
Figure imgf000621_0001
Figure imgf000623_0001
EXPERIMENTAL SECTION - DESCRIPTION OF EXAMPLES
Example 01.01
tert-butyl 4-[(2-{[6-(2-methylpyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1-carboxylate
Figure imgf000624_0001
To a stirred solution of 4-bromo-2-methylpyridine (225 mg, 1.31 mmol) and tert-butyl 4-[(2-{[6- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1-carboxylate (500 mg, 936 pmol) in dioxane (4.5 mL) and water (910 μΙ) was added sodium carbonate (297 mg, 2.81 mmol) and Pd(dppf)CI2 . CH2CI2 (115 mg, 140 pmol). The mixture was heated to reflux for 19 h. Dichloromethane was added, the mixture was filtered and the solvent was removed in vacuum. Aminophase-silicagel chromatography followed by preparative reverse phase HPLC (gradient of water and acetonitrile containing ammonia as additive) gave 21.0 mg (4 % yield) of the title compound.
LC-MS (Method 2): Rt = 1.24 min; MS (ESIpos): m/z = 500 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.395 (16.00), 2.359 (2.40), 2.525 (9.91 ), 3.501 (2.39), 7.181 (1.30), 8.260 (0.95), 8.273 (0.95).
Example 01.02
cyclopropyI{4-[(2-{t6-(2-methylpyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1-yl}methanone
Figure imgf000624_0002
To a stirred solution of crude 6-(2-methylpyridin-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]- 1 H-benzimidazol-2-amine hydrochloride (81.0 mg, approx. 186 pmol) in DMF (4 ml_) was added sodium bicarbonate (93.6 mg, 1.11 mmol), cyclopropanecarboxylic acid (24.0 mg, 279 pmol) and HATU (106 mg, 279 pmol). The mixture was stirred at room temperature for 16 h. Water was added, the mixture was stirred for 15 minutes and the mixture was extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Preparative reverse phase HPLC (gradient of water and acetonitrile containing ammonia as additive) gave 19 mg of the title compound.
LC-MS (Method 4): Rt = 1 .01 min; MS (ESIpos): m/z = 468 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.678 (1.22), 0.685 (2.83), 0.691 (1.78), 0.698 (1.46), 0.705 (3.54), 0.709 (2.98), 0.713 (3.28), 0.721 (3.07), 0.726 (3.50), 0.733 (1.59), 1.949 (0.64), 1.956 (0.71 ), 1.969 (1.20), 1.981 (0.69), 2.323 (0.97), 2.327 (1.39), 2.332 (1.09), 2.366 (1.35), 2.446 (1.31 ), 2.518 (7.34), 2.526 (16.00), 2.539 (1.63), 2.665 (0.90), 2.669 (1.31 ), 2.673 (0.92), 3.525 (5.51 ), 3.710 (1.24), 6.946 (1.27), 6.959 (1.31 ), 7.202 (2.60), 7.457 (0.92), 8.271 (2.47), 8.284 (2.34), 8.439 (0.99).
Example 01.03
3,3,3-trifluoro-1 -{4-[(2-{[6-(2-methylpyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}propan-1 -one
Figure imgf000625_0001
Starting with crude 6-(2-methylpyridin-4-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (81.0 mg, approx. 186 pmol) and 3,3,3-trifluoropropanoic acid (35.7 mg, 279 pmol), Example 01.03 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 33.0 mg of the title compound.
LC-MS (Method 2): Rt = 1 .05 min; MS (ESIpos): m/z = 510 [M+H]+ 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.322 (0.95), 2.327 (1.44), 2.332 (1.06), 2.370 (1.25), 2.383 (1.89), 2.395 (1.44), 2.41 1 (1.23), 2.425 (1.75), 2.437 (1.51 ), 2.518 (8.20), 2.525 (16.00), 2.539 (1.80), 2.665 (0.99), 2.669 (1.44), 2.673 (1.04), 3.472 (1.54), 3.484 (1.58), 3.510 (1.84), 3.526 (5.15), 3.613 (0.73), 3.640 (2.03), 3.667 (1.89), 4.050 (2.34), 6.936 (1.06), 6.949 (1.1 1 ), 7.197 (2.10), 7.457 (0.90), 8.267 (2.10), 8.281 (2.03), 8.439 (0.90).
Example 01.04
2-cyclopropyl-1 -{4-[(2-{[6-(2-methylpyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4 yl)methyl]piperazin-1-yl}ethanone
Figure imgf000626_0001
Starting with crude 6-(2-methylpyridin-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (81.0 mg, approx. 186 pmol) and cyclopropylacetic acid (27.9 mg, 279 μηιοΙ), Example 01.04 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 10.0 mg of the title compound.
LC-MS (Method 4): Rt = 1.05 min; MS (ESIpos): m/z = 482 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.000 (0.93), 0.01 1 (3.08), 0.014 (2.78), 0.023 (3.17), 0.026 (2.88), 0.037 (1.07), 0.330 (1.15), 0.340 (2.73), 0.344 (2.82), 0.350 (1.53), 0.355 (1.38), 0.360 (2.93), 0.364 (2.77), 0.375 (1.11 ), 0.854 (1.02), 2.154 (4.93), 2.171 (4.75), 2.238 (0.86), 2.242 (1.22), 2.247 (0.93), 2.277 (2.02), 2.290 (1.82), 2.310 (2.02), 2.434 (5.35), 2.441 (16.00), 2.580 (0.80), 2.584 (1.13), 2.589 (0.80), 3.372 (1.98), 3.383 (1.80), 3.407 (1 .97), 3.426 (5.59), 6.852 (1.26), 6.865 (1.31 ), 7.109 (2.69), 7.370 (0.96), 8.181 (2.51 ), 8.194 (2.44), 8.356 (0.98). Example 01.05
cyclobutyl{4-[(2-{[6-(2-methylpyridin-4-yl)-1H^enzimidazol-2-yl]amino}pyridin-4 yl)methyl]piperazin-1-yl}methanone
Figure imgf000627_0001
Starting with crude 6-(2-methylpyridin-4-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (81.0 mg, approx. 186 pmol) and cyclobutanecarboxylic acid (27.9 mg, 279 pmol), Example 01.05 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 31.0 mg of the title compound.
LC-MS (Method 4): R, = 1.08 min; MS (ESIpos): m/z = 482 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.862 (1.09), 1.884 (0.84), 1.889 (0.82), 2.052 (1.21 ), 2.061 (0.94), 2.075 (1.43), 2.083 (1.14), 2.100 (0.93), 2.106 (0.84), 2.123 (1.62), 2.128 (1.12), 2.145 (1.75), 2.169 (0.84), 2.174 (0.91 ), 2.322 (0.91 ), 2.327 (1.41 ), 2.332 (1.50), 2.337 (1.96), 2.352 (3.28), 2.518 (6.90), 2.525 (16.00), 2.539 (1.87), 2.665 (0.73), 2.669 (1.05), 2.673 (0.75), 3.305 (1.05), 3.473 (1.75), 3.485 (1.66), 3.500 (4.99), 6.930 (1.27), 6.944 (1.28), 7.188 (2.49), 8.262 (2.23), 8.275 (2.24), 8.438 (1.18), 8.451 (1.18).
Example 02.01
tert-butyl 4-[(2-{[6-(2-methoxypyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate
Figure imgf000628_0001
To a stirred solution of 1 H-imidazole (83.8 mg, 1.23 mmol) and di-1 H-imidazol-1 - ylmethanethione (1.58 g, 90 % purity, 8.00 mmol) in dichloromethane (50 mL) was added tert-butyl 4-[(2-aminopyridin-4-yl)methyl]piperazine-1 -carboxylate (1.80 g, 6.16 mmol) dissolved in dichloromethane (50 mL) at 0° C. The m ixture was stirred at r.t. for 14 h. 4-(2- methoxypyridin-4-yl)benzene-1 ,2-diamine (1.78 g, 97 % purity, 8.00 mmol) dissolved in dichloromethane (27 mL) was added and the mixture was stirred at r.t. for 2 h. Water was added and the mixture was extracted with dichloromethane. The organic phase was dried (sodium sulfate) and filtered. N,N'-dipropan-2-ylcarbodiimide (1.33 mL, 8.8 mmol) was added. The mixture was stirred at r.t. for 14 h. Further N,N'-dipropan-2-ylcarbodiimide (0.47 mL, 3.1 mmol) was added and the mixture was stirred at r.t. for 14 h. Saturated ammonium chloride solution was added, the mixture was stirred for 30 minutes and was extracted with dichloromethane. Aminophase-silicagel chromatography gave 585 mg of the title compound. LC-MS (Method 2): R, = 1.33 min; MS (ESIpos): m/z = 516 [M+H]+
H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.390 (1.33), 1.396 (16.00), 2.347 (0.86), 2.360 (1.27), 2.372 (0.94), 3.321 (7.45), 3.501 (1.68), 3.894 (5.54), 5.756 (0.92), 7.194 (0.84), 8.177 (0.60), 8.190 (0.57), 8.261 (0.75), 8.273 (0.74).
Example 02.02
cyclopropyl{4-[(2-{[6-(2-methoxypyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1-yl}methanone
Figure imgf000629_0001
To a stirred solution of 6-(2-methoxypyridin-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (100 mg, 221 μιηοΙ) in DMF (8 mL) was added potassium carbonate (153 mg, 1.1 1 mmol), cyclopropanecarboxylic acid (57.1 mg, 664 μιηοΙ) and HATU (252 mg, 664 μηιοΙ). The mixture was stirred at room temperature for 16 h. Water was added, the mixture was stirred for 15 minutes and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Aminophase-silicagel chromatography gave a solid that was triturated with dichloromethane to give 73.0 mg (61 % yield) of the title compound.
LC-MS (Method 2): R, = 1.10 min; MS (ESIpos): m/z = 484 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.677 (1.07), 0.685 (2.44), 0.691 (1.47), 0.698 (1.20), 0.705 (2.94), 0.710 (2.22), 0.716 (2.52), 0.723 (2.46), 0.728 (2.97), 0.735 (1.36), 1.940 (0.61 ), 1.948 (0.65), 1.960 (1.10), 1.972 (0.61 ), 1.979 (0.56), 2.370 (1.02), 2.444 (1.02), 2.523 (1.00), 3.525 (5.78), 3.712 (0.90), 3.896 (16.00), 6.942 (1.34), 6.945 (1.41 ), 6.958 (1.42), 7.065 (0.72), 7.218 (2.61 ), 8.177 (2.02), 8.191 (1.93), 8.270 (2.35), 8.283 (2.26).
Example 02.03
3,3,3-trifluoro-1 -{4-[(2-{[6-(2-methoxypyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyri^ yl)methyl]piperazin-1-yl}propan-1 -one
Figure imgf000630_0001
Starting with 6-(2-methoxypyridin-4-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (100.0 mg, 221 μιτιοΙ) and 3,3,3-trifluoropropanoic acid (85.0 mg, 664 pmol) Example 02.03. was prepared analogously to the procedure for the preparation of Example 02.02.
Yield: 50.0 mg (39 %) of the title compound.
LC-MS (Method 2): R, = 1.14 min; MS (ESIpos): m/z = 526 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.375 (1.20), 2.388 (1.81 ), 2.400 (1.37), 2.415 (1.32), 2.523 (1.07), 3.463 (1.28), 3.477 (1.77), 3.487 (1.46), 3.499 (1.44), 3.513 (1.80), 3.528 (5.65), 3.601 (0.93), 3.628 (2.68), 3.656 (2.52), 3.683 (0.79), 3.896 (16.00), 6.935 (1.30), 6.948 (1.36), 6.951 (1.36), 7.213 (2.45), 8.178 (1.79), 8.191 (1.73), 8.268 (2.24), 8.282 (2.14).
Example 02.04
cyclobutyl{4-[(2-{[6-(2-met oxypyridin-4-yl)-1H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone
Figure imgf000630_0002
Starting with 6-(2-methoxypyridin-4-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (100 mg, 221 pmol) and cyclobutanecarboxylic acid (66.5 mg, 664 pmol) Example 02.04. was prepared analogously to the procedure for the preparation of Example 02.02.
Yield: 86.0 mg (70 %) of the title compound.
LC- S (Method 2): f¾ = 1.17 min; MS (ESIpos): m/z = 498 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.737 (0.74), 1.841 (0.61 ), 1.862 (1.19), 1.885 (0.92), 1 .889 (0.90), 1.912 (0.55), 2.045 (0.76), 2.054 (1.31 ), 2.063 (0.96), 2.069 (0.95), 2.076 (1.50), 2.085 (1.15), 2.100 (0.83), 2.104 (0.91 ), 2.126 (1.72), 2.131 (1.16), 2.147 (1.83), 2.152 (1.44), 2.171 (0.86), 2.177 (0.96), 2.354 (4.04), 2.366 (2.89), 2.523 (0.83), 3.301 (1.52), 3.308 (16.00), 3.322 (2.50), 3.341 (2.57), 3.474 (1.87), 3.487 (1.59), 3.499 (6.14), 6.925 (1.60), 6.928 (1.58), 6.938 (1.63), 6.941 (1.61 ), 7.062 (0.76), 7.204 (2.97), 7.309 (0.71 ), 7.465 (0.70), 8.177 (2.26), 8.190 (2.15), 8.261 (2.63), 8.274 (2.52).
Example 02.05
2-cyclopropyl-1 -{4-[(2-{[6-(2-methoxypyridin-4-yl)-1 H^enzimidazol-2-yl]amino}pyridin yl)methyl]piperazin-1-yl}ethanone
Figure imgf000631_0001
Starting with 6-(2-methoxypyridin-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (100 mg, 221 pmol) and cyclopropylacetic acid (66.5 mg, 664 μιηοΙ) Example 02.05. was prepared analogously to the procedure for the preparation of Example 02.02.
Yield: 69.0 mg (56 %) of the title compound.
LC-MS (Method 2): Rt = 1.14 min; MS (ESIpos): m/z = 498 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.000 (0.73), 0.01 1 (2.69), 0.014 (2.40), 0.023 (2.71 ), 0.026 (2.45), 0.037 (0.85), 0.329 (0.90), 0.339 (2.35), 0.343 (2.41 ), 0.349 (1.18), 0.354 (1.12), 0.359 (2.44), 0.364 (2.34), 0.374 (0.84), 0.855 (0.84), 2.151 (4.45), 2.168 (4.38), 2.279 (1.83), 2.291 (1.78), 2.309 (1.84), 2.436 (0.85), 3.370 (1.75), 3.404 (1.78), 3.425 (5.75), 3.809 (16.00), 6.846 (1.46), 6.859 (1.51 ), 6.976 (0.77), 7.123 (2.67), 7.222 (0.66), 7.379 (0.68), 8.090 (2.07), 8.104 (1.97), 8.177 (2.42), 8.191 (2.31 ).
Example 03.01
cyclopropyl{4-[(2-{[6-(5-fluoro-2-methoxypyridin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1-yl}methanone
Figure imgf000632_0001
Starting with crude 6-(5-fluoro-2-methoxypyridin-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]- 1 H-benzimidazol-2-amine hydrochloride (150 mg, approx. 239 μιτιοΙ) and cyclopropanecarboxylic acid (30 μΙ, 95 % purity, 360 pmol) Example 03.01 . was prepared analogously to the procedure for the preparation of Example 16.01.02.
Yield: 60.0 mg of the title compound.
LC-MS (Method 2): R, = 1.18 min; MS (ESIpos): m/z = 502 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.676 (1.05), 0.683 (2.38), 0.689 (1.42), 0.696 (1.18), 0.703 (2.86), 0.709 (2.14), 0.714 (2.45), 0.721 (2.40), 0.726 (2.85), 0.733 (1.30), 1.028 (0.98), 1.044 (1.01 ), 1.961 (1.06), 3.523 (5.42), 3.879 (16.00), 6.944 (1.46), 6.947 (1.39), 6.957 (1.54), 6.959 (1.56), 7.200 (2.45), 8.205 (2.04), 8.21 1 (1.91 ), 8.270 (2.36), 8.283 (2.22).
Example 03.02
3,3,3-trifluoro-1 -{4-[(2-{[6-(5-fluoro-2-methoxypyridin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1-yl}propan-1 -one
Figure imgf000633_0001
Starting with crude 6-(5-fluoro-2-methoxypyridin-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]- 1 H-benzimidazol-2-amine hydrochloride (150 mg, approx. 239 pmol) and 3,3,3- trifluoropropanoic acid (32 pi, 360 pmol) Example 03.02. was prepared analogously to the procedure for the preparation of Example 16.01.02.
Yield: 30.0 mg of the title compound.
LC-MS (Method 2): Rt = 1.21 min; MS (ESIpos): m/z = 544 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.856 (0.76), 1.028 (1.39), 1.044 (1.44), 2.371 (1.33), 2.384 (2.03), 2.397 (1.53), 2.413 (1.49), 2.425 (1.97), 2.437 (1.43), 3.461 (1.47), 3.473 (1.98), 3.485 (1.64), 3.496 (1.61 ), 3.51 1 (2.06), 3.526 (5.91 ), 3.606 (0.95), 3.633 (2.72), 3.661 (2.55), 3.879 (16.00), 6.937 (1.47), 6.940 (1.53), 6.953 (1.58), 7.196 (2.70), 8.205 (1.96), 8.21 1 (1.84), 8.269 (2.46), 8.282 (2.33).
Example 03.03
cyclobutyl{4-[(2-{[6-(5-fluoro-2-methoxypyridin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1-yl}methanone
Figure imgf000633_0002
Starting with 6-(5-fluoro-2-methoxypyridin-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine (100 mg, 231 pmol)and cyclobutanecarboxylic acid (34 μΙ, 98 % purity, 350 pmol) Example 03.03. was prepared analogously to the procedure for the preparation of Example 16.01.02.
Yield: 60.0 mg of the title compound.
LC-MS (Method 2): R, = 1.25 min; MS (ESIpos): m/z = 516 [M+H]+
H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.831 (1.05), 0.858 (1.79), 0.936 (0.93), 0.953 (0.94), 1.239 (1.12), 1.396 (1.84), 1.728 (1.02), 1.863 (1.15), 2.054 (1.23), 2.076 (1.41 ), 2.085 (1.18), 2.126 (1.59), 2.147 (1.68), 2.177 (0.91 ), 2.355 (3.84), 2.539 (4.86), 2.730 (5.68), 2.889 (6.74), 3.323 (2.68), 3.342 (2.54), 3.474 (1.83), 3.501 (5.83), 3.879 (16.00), 5.752 (1 .24), 6.928 (1.49), 6.944 (1.58), 7.192 (2.44), 7.952 (0.90), 8.201 (2.14), 8.208 (2.06), 8.261 (2.55), 8.275 (2.46).
Example 03.04
2-cyclopropyl-1 -{4-[(2-{[6-(5-fluoro-2-methoxypyridin-4-yl)-1 H-benzimidazol-2
yl]amino}pyridin-4-yl)methyl]piperazin-1-yl}ethanone
Figure imgf000634_0001
Starting with 6-(5-fluoro-2-methoxypyridin-4-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine (100 mg, 231 pmol)and cyclopropylacetic acid (33 μΙ, 97 % purity, 350 pmol) Example 03.04. was prepared analogously to the procedure for the preparation of Example 16.01.02.
Yield: 60.0 mg of the title compound.
LC-MS (Method 2): Rt = 1.21 min; MS (ESIpos): m/z = 516 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.01 1 (2.48), 0.014 (2.36), 0.023 (2.63), 0.027 (2.39), 0.037 (0.84), 0.330 (0.81 ), 0.339 (2.14), 0.343 (2.28), 0.350 (1.10), 0.354 (1.05), 0.360 (2.32), 0.364 (2.27), 0.374 (0.81 ), 0.744 (1.35), 0.766 (1.05), 0.771 (2.20), 0.850 (1.44), 0.855 (0.86), 0.866 (1.56), 1.152 (1.33), 1.310 (1.98), 2.152 (4.27), 2.168 (4.16), 2.279 (1.90), 2.309 (1.99), 3.425 (5.80), 3.793 (16.00), 5.665 (0.69), 6.848 (1.50), 6.864 (1.60), 7.1 1 1 (2.58), 8. 15 (2.21 ), 8.121 (2.10), 8.179 (2.49), 8.192 (2.37). Example 04.01
tert-butyl 4-[(2-{[6-(3-methoxypyridin-4-yl)-1 H-benzimidazol-2-yl]amino}py
yl)methyl]piperazine-1 -carboxylate
Figure imgf000635_0001
To a stirred solution of N-[4-(chloromethyl)pyridin-2-yl]-6-(3-methoxypyridin-4-yl)-1 H- benzimidazol-2-amine (870 mg, 2.38 mmol) in DMF (20 mL) was added potassium carbonate (1.64 g, 1 1.9 mmol) and tert-butyl piperazine-1 -carboxylate (685 mg, 97 % purity, 3.57 mmol). The mixture was stirred at r.t. for 14 h. Water was added, and a solid precipitated and was collected by filtration. Ethyl acetate / methanol (1 :1 ) was added to the solid and the mixture was stirred for 15 minutes. Solids were removed by filtration, and the solution was concentrated in vacuum. Silicagel chromatography gave 800 mg (59 % yield) of the title compound.
LC-MS (Method 2): R, = 1.25 min; MS (ESIpos): m/z = 516 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.039 (1.85), 1.056 (4.16), 1.074 (2.09), 1.396 (16.00), 2.349 (0.92), 2.361 (1.36), 2.374 (0.98), 2.730 (2.27), 2.889 (2.88), 3.312 (7.39), 3.427 (0.85), 3.439 (0.91 ), 3.444 (0.91 ), 3.457 (0.91 ), 3.499 (1.84), 3.905 (4.57), 4.320 (0.59), 4.332 (1.12), 4.346 (0.55), 6.913 (0.54), 6.916 (0.54), 6.926 (0.55), 6.930 (0.55), 7.189 (0.68), 7.357 (0.76), 7.369 (0.80), 8.248 (1.27), 8.254 (0.96), 8.260 (1.22), 8.268 (0.86), 8.434 (1.93).
Example 04.02
3,3,3-trifluoro-1 -{4-[(2-{[6-(3-methoxypyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyri yl)methyl]piperazin-1-yl}propan-1 -one
Figure imgf000636_0001
Starting with crude 6-(3-methoxypyridin-4-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]-1 H- berizimidazol-2-amine hydrochloride (100 mg, approx. 191 pmol)and 3,3,3-trifluoropropanoic acid (26 μΙ, 98 % purity, 290 pmol) Example 04.02. was prepared analogously to the procedure for the preparation of Example 16.01.02.
Yield: 50.0 mg of the title compound.
LC-MS (Method 2): R, = 1.07 min; MS (ESIpos): m/z = 526 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm]= 2.40 (dt, 4H), 3.43 - 3.55 (m, 6H), 3.63 (q, 2H), 3.90 (s, 3H), 6.92 (d, 1 H), 7.15 - 7.85 (m, 5H), 8.19 - 8.30 (m, 2H), 8.42 (s, 1 H), 10.63 (br s, 1 H), 12.15 (br s, 1 H).
Example 04.03
cyclopropyl{4-[(2-{[6-(3-methoxypyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4' yl)methyl]piperazin-1-yl}methanone
Figure imgf000636_0002
Starting with crude 6-(3-methoxypyridin-4-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (100 mg, approx. 191 pmol)and cyclopropanecarboxylic acid (24 μΙ, 95 % purity, 290 pmol) Example 04.03. was prepared analogously to the procedure for the preparation of Example 16.01.02. Yield: 60.0 mg of the title compound.
LC-MS (Method 2): R, = 1.03 min; MS (ESIneg): m/z = 482 [M-H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.685 (1.1 1 ), 0.690 (0.81 ), 0.698 (0.66), 0.705 (1.33), 0.710 (1.10), 0.717 (1.25), 0.723 (1.24), 0.729 (1.40), 0.735 (0.72), 1.396 (16.00), 3.523 (2.74), 3.907 (5.91 ), 5.752 (2.33), 6.935 (0.73), 6.949 (0.74), 7.207 (1.16), 7.358 (1.03), 7.370 (1.08), 8.249 (1.28), 8.261 (1.65), 8.278 (1.02), 8.435 (2.20).
Example 04.04
cyclobutyl{4-[(2-{[6-(3-methoxypyridin-4-yl)-1H-benzimidazol-2-yl]amino}pyridin-4 yl)methyl]piperazin-1-yl}methanone
Figure imgf000637_0001
Starting with crude 6-(3-methoxypyridin-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (100 mg, approx. 191 μιτιοΙ) and cyclobutanecarboxylic acid (28 μΙ, 97 % purity, 290 μιηοΙ) Example 04.04. was prepared analogously to the procedure for the preparation of Example 16.01.02.
Yield: 40.0 mg of the title compound.
LC-MS (Method 2): Rt = 1.09 min; MS (ESIpos): m/z = 498 [M+H]+
1 H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.66 - 1.78 (m, 1 H), 1.80 - 1.95 (m, 1 H), 1.99 - 2.21 (m, 4H), 2.29 - 2.41 (m, 4H), 3.32 (br d, 3H), 3.42 - 3.53 (m, 4H), 3.84 - 3.94 (m, 3H), 6.91 (d, 1 H), 7.12 - 7.81 (m, 5H), 8.25 (dd, 2H), 8.42 (s, 1 H), 10.62 (br s, 1 H), 12.16 (br s, 1 H).
Example 04.05
2-cyclopropyl-1-{4-[(2-{[6-(3-methoxypyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin yl)methyl]piperazin-1-yl}ethanone
Figure imgf000638_0001
Starting with crude 6-(3-methoxypyridin-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (100 mg, approx. 191 pmol)and cyclopropylacetic acid (26 μΙ, 98 % purity, 290 pmol) Example 04.05. was prepared analogously to the procedure for the preparation of Example 16.01.02.
Yield: 40.0 mg of the title compound.
LC-MS (Method 2): R, = 1.07 min; MS (ESIpos): m/z = 498 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm]= 0.09 (q, 2H), 0.37 - 0.47 (m, 2H), 0.90 - 0.96 (m, 1 H), 2.24 (d, 2H), 2.32 - 2.43 (m, 4H), 3.39 - 3.62 (m, 6H), 3.90 (s, 3H), 6.92 (d, 1 H), 7.15 - 7.30 (m, 2H), 7.32 - 7.84 (m, 3H), 8.18 - 8.32 (m, 2H), 8.42 (s, 1 H), 10.63 (br s, 1 H), 12.15 (br s, 1 H).
Example 04.06
1 -{4-[(2-{[6-(3-methoxypyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}-2,2-dimethylpropan-1 -one
Figure imgf000638_0002
Starting with crude 6-(3-methoxypyridin-4-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (80.0 mg, approx. 152 μmol)and 2,2-dimethylpropanoic acid (26 μΙ, 230 μιηοΙ) Example 04.06. was prepared analogously to the procedure for the preparation of Example 16.01.02. Yield: 23.0 mg of the title compound.
LC-MS (Method 2): R, = 1.13 min; MS (ESIpos): m/z = 500 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.184 (16.00), 2.373 (0.92), 2.385 (1.40), 2.397 (0.98), 3.497 (2.02), 3.572 (1.14), 3.906 (3.59), 6.926 (0.61 ), 6.929 (0.59), 6.939 (0.59), 6.942 (0.58), 7.358 (0.63), 7.370 (0.67), 8.248 (1.17), 8.260 (1.99), 8.273 (0.88), 8.435 (1.89).
The Example compounds in the following table 7 were synthesized in analogy to the preparation of Example 1 17.02, followed by purification by preparative reverse phase HPLC or silicagel chromatography.
Table 7:
Figure imgf000640_0001
Figure imgf000641_0001
Figure imgf000642_0001
Example 05.01
3,3,3-trifluoro-1-(4-{[2-({6-[3-(2,2,2-trifluoroethoxy)pyridin-4-yl]-1H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1-yl)propan-1 -one
Figure imgf000643_0001
To a stirred solution of crude N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-6-[3-(2,2,2- trifluoroethoxy)pyridin-4-yl]-1 H-benzimidazol-2-amine hydrochloride (159 mg, approx. 229 pmol) in DMF (5 mL) was added sodium bicarbonate (115 mg, 1.37 mmol), 3,3,3- trifluoropropanoic acid (31 μΙ, 98 % purity, 340 pmol) and HATU (130 mg, 343 pmol). The mixture was stirred at room temperature for 16 h. Water was added, the mixture was stirred for 15 minutes and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silicagel chromatography gave a solid that was triturated with a mixture of dichloromethane and hexane to give 43 mg of the title compound.
LC-MS (Method 2): R, = 1.13 min; MS (ESIpos): m/z = 594 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm]= 2.41 (dt, 4H), 3.42 - 3.56 (m, 6H), 3.66 (q, 2H), 4.91 (q, 2H), 6.90 - 6.98 (m, 1 H), 7.14 - 7.58 (m, 4H), 7.67 (br s, 1 H), 8.28 (d, 1 H), 8.35 (d, 1 H), 8.52 (s, 1 H), 12.20 (br s, 1 H), 12.64 - 13.71 (m, 1 H).
Example 06.01
3,3,3-trifluoro-l -(4-{[2-({6-[3-(propan-2-yloxy)pyridin-4-yl]-1H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1 -yl)propan-1 -one
Figure imgf000644_0001
Starting with crude N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-6-[3-(propan-2-yloxy)pyridin-4-yl]- 1 H-benzimidazol-2-amine hydrochloride (1 10 mg, approx. 141 mol)and 3,3,3- trifluoropropanoic acid (54.0 mg, 422 pmol) Example 06.01. was prepared analogously to the procedure for the preparation of Example 02.02.
Yield: 35.0 mg of the title compound.
LC-MS (Method 2): Rt = 1.13 min; MS (ES+): m/z = 554 [M+1]
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.227 (16.00), 1.242 (15.73), 2.323 (0.69), 2.327 (0.94), 2.331 (0.71 ), 2.373 (3.11 ), 2.386 (4.75), 2.398 (3.61 ), 2.414 (3.40), 2.427 (4.67), 2.439 (3.31 ), 2.518 (3.60), 2.523 (2.54), 2.540 (1.57), 2.665 (0.67), 2.669 (0.92), 2.673 (0.67), 3.462 (3.42), 3.476 (4.71 ), 3.487 (3.91 ), 3.499 (3.82), 3.512 (5.03), 3.525 (15.50), 3.606 (2.34), 3.634 (6.70), 3.661 (6.28), 3.688 (2.02), 4.575 (1.1 1 ), 4.590 (2.83), 4.605 (3.87), 4.621 (2.86), 4.636 (1.12), 5.756 (9.43), 6.924 (3.82), 6.927 (3.70), 6.937 (3.75), 6.940 (3.88), 7.202 (6.21 ), 7.303 (1.19), 7.370 (2.14), 7.787 (0.87), 8.222 (8.15), 8.234 (7.52), 8.270 (5.42), 8.283 (5.13), 8.398 (12.48), 10.647 (1.53), 12.147 (3.07).
Example 06.02
cyclopropyl(4-{[2-({6-[3-(propan-2-yloxy)pyridin-4-yl]-1 H-benzimidazol-2
yl}amino)pyridin-4-yl]methyl}piperazin-1-yl)methanone
Figure imgf000645_0001
Starting with crude N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]-6-[3-(propan-2-yloxy)pyridin-4-yl]- 1 H-benzimidazol-2-amine hydrochloride (1 10 mg, approx. 141 pmol)and cyclopropanecarboxylic acid (36.3 mg, 422 pmol) Example 06.02. was prepared analogously to the procedure for the preparation of Example 02.02.
Yield: 35.0 mg of the title compound.
LC-MS (Method 2): Rt = 1.10 min; MS (ES+): m/z = 512 [M+H]
1H-NMR (400MHz, DMSO-d6): δ [ppm]= 0.63 - 0.77 (m, 4H), 1.24 (br d, 6H), 1.91 - 2.02 (m, 1 H), 2.30 - 2.47 (m, 4H), 3.42 - 3.80 (m, 6H), 4.61 (dt, 1 H), 6.95 (d, 1 H), 7.22 (s, 1 H), 7.25 - 7.85 (m, 4H), 8.24 (d, 1 H), 8.29 (d, 1 H), 8.40 (s, 1 H), 10.66 (br s, 1 H), 12.16 (br s, 1 H).
Example 06.03
2-cyclopropyl-1 -(4-{[2-({6-[3-(propan-2-yloxy)pyridin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1 -yl)ethanone
Figure imgf000645_0002
Starting with crude N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]-6-[3-(propan-2-yloxy)pyridin-4-yl]- 1 H-benzimidazol-2-amine hydrochloride (1 10 mg, approx. 141 prnol) and cyclopropylacetic acid (42.2 mg, 422 μηιοΙ) Example 06.03. was prepared analogously to the procedure for the preparation of Example 02.02.
Yield: 21.0 mg of the title compound.
LC-MS (Method 2): R, = 1.13 min; MS (ES+): m/z = 526 [M+H]
1H-NMR (400MHz, DMSO-d6): δ [ppm]= 0.06 - 0.15 (m, 2H), 0.39 - 0.49 (m, 2H), 0.88 - 1.01 (m, 1 H), 1.24 (br d, 6H), 2.25 (d, 2H), 2.33 - 2.45 (m, 4H), 3.41 - 3.57 (m, 6H), 4.61 (dt, 1 H), 6.94 (dd, 1 H), 7.21 (s, 1 H), 7.25 - 7.86 (m, 4H), 8.23 (d, 1 H), 8.28 (d, 1 H), 8.40 (s, 1 H), 10.65 (br s, 1 H), 12.15 (s, 1 H).
Example 07.01
cyclopropyl{4-[(2-{[6-(5-methoxy-2-methylpyridin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}methanone
Figure imgf000646_0001
To a stirred solution of 6-(5-methoxy-2-methylpyridin-4-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2- yl]-1 H-benzimidazol-2-amine (65.0 mg, 151 pmol) in dichloromethane (1.0 mL, 16 mmol) was added triethylamine (50 μΙ, 360 mol) and cyclopropanecarbonyl chloride (17 μΙ, 190 pmol). The mixture was stirred at r.t. for 1 h. A saturated sodium bicarbonate solution was added and the mixture was extracted with dichloromethane. The organic phase was dried (magnesium sulfate) and the solvent was removed in vacuum. Silicagel chromatography gave a solid that was triturated with diethylether to give 40 mg (53 % yield) of the title compound.
LC-MS (Method 5): Rt = 2.21 min; MS (ESIpos): m/z = 498 [M+H]+
1H-NMR (400 MHz, DMSO-d6): δ fppm] = 0.59-0.82 (m, 4H), 1.95 (m, 1 H), 2.37 (m, 2H), 2.45 (m, 5H), 3.52(m, 4H), 3.70 (m, 2H), 3.85 (s, 3H), 6.94 (m, 1 H), 7.18-7.33 (m, 3H), 7.45 (m, 1 H), 7.66 (s, 1 H), 8.27 (m, 1 H), 10.70 (s, 1 H), 12.10 (s, 1 H).
13C-NMR (101 MHz, DMSO-d6): δ [ppm] = 6.9, 10.2, 23.1 , 41.5, 44.8, 52.4, 53.0, 56.4, 60.6, 1 10.5, 1 16.5, 121.6, 123.7, 127.4, 133.9, 138.2, 146.9, 149.4, 150.2, 150.4, 150.5, 153.6, 170.9. Example 07.02
3,3,3-trifluoro-1 -{4-[(2-{[6-(5-methoxy-2-methylpyridin^-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1-yl}propan-1 -one
Figure imgf000647_0001
Starting with crude 6-(5-methoxy-2-methylpyridin-4-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]- 1 H-benzimidazol-2-amine hydrochloride (180 mg, approx. 309 pmol) and 3,3,3- trifluoropropanoic acid (35 μΙ, 400 pmol) Example 07.02. was prepared analogously to the procedure for the preparation of Example 16.01.02.
Yield: 100.0 mg of the title compound.
LC-MS (Method 2): R, = 1.07 min; MS (ESIpos): m/z = 540 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm]= 2.35 - 2.48 (m, 7H), 3.43 - 3.57 (m, 6H), 3.65 (q, 2H), 3.86 (s, 3H), 6.94 (d, 1 H), 7.09 - 7.89 (m, 5H), 8.20 - 8.35 (m, 2H), 10.66 (br s, 1 H), 12.17 (br s, 1 H).
Example 07.03
cyclobutyl{4-[(2-{[6-(5-methoxy-2-methylpyridin-4-yl)-1 H-benzimidazol-2
yl]amino}pyridin-4-yl)methyl]piperazin-1-yl}methanone
Figure imgf000648_0001
To a stirred solution of 6-(5-methoxy-2-methylpyridin-4-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2- yl]-1 H-benzimidazol-2-amine (100 mg, 233 pmol) in tetrahydrofurane (1.0 mL). was added triethylamine (100 μΙ, 720 pmol) and cyclobutanecarbonyl chloride (35 μΙ, 310 μmol). The mixture was stirred at r.t. for 1 h. A saturated sodium bicarbonate solution was added and the mixture was extracted with dichloromethane. The organic phase was dried (magnesium sulfate) and the solvent was removed in vacuum. Silicagel chromatography gave 62 mg (52 % yield) of the title compound.
LC-MS (Method 5): R, = 2.33 min; MS (ESIpos): m/z = 512 [M+H]+
1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 1.72 (m, 1 H), 1.87 (m, 1 H), 1.98-2.22 (m, 4H), 2.34 (m, 4H), 2.45 (s, 3H), 3.48 (m, 4H), 3.85 (s, 3H), 7.12-7.33 (m, 3H), 7.33-7.90 (m, 2H), 8.22- 8.34 (m, 2H), 10.66 (s, 1 H), 12.17 (s, 1 H).
13C-NMR (101 MHz, DMSO-d6): δ [ppm] = 17.3, 23.1 , 24.5, 36.2, 41.1 , 44.3, 52.4, 52.9, 56.4, 60.6, 1 10.4, 116.4, 123.6, 134.0, 138.1 , 146.9, 149.4, 150.4, 153.6, 171.9.
Example 07.04
2-cyclopropyl-1 -{4-[(2-{[6-(5-methoxy-2-methylpyridin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1-yl}ethanone
Figure imgf000649_0001
To a stirred solution of 6-(5-methoxy-2-methylpyridin-4-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2- yl]-1 H-benzimidazol-2-amine (100 mg, 233 pmol) in tetrahydrofurane (1.0 mL). was added triethylamine (100 μΙ, 720 pmol) and cyclopropylacetyl chloride (45 μΙ, 440 μιηοΙ). The mixture was stirred at r.t. for 1 h. A saturated sodium bicarbonate solution was added and the mixture was extracted with dichloromethane. The organic phase was dried (magnesium sulfate) and the solvent was removed in vacuum. Silicagel chromatography gave a solid that was triturated with pentane to give 65 mg (55 % yield) of the title compound
LC-MS (Method 5): R, = 2.30 min; MS (ESIpos): m/z = 512 [M+H]+
1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 0.10 (m, 2H), 0.44 (m, 2H), 0.94 (m, 1 H), 2.24 (d, 2H), 2.37 (m, 4H), 2.45 (s 3H), 3.45 (m, 2H), 3.50 (m, 4H), 3.85 (s, 3H), 6.92 (m, 1 H), 7.09- 7.32 (m, 3H), 7.32-7.88 (m, 2H), 8.17-8.31 (m, 2H), 10.66 (s, 1 H), 12.16 (s, 1 H).
13C-NMR (101 MHz, DMSO-d6): δ [ppm] = 4.2, 7.2, 23.1 , 37.3, 40.9, 45.0, 52.3, 53.0, 56.4, 60.6, 1 10.4, 1 16.4, 123.6, 134.0, 138.1 , 146.9, 149.4, 150.3, 150.41 , 150.43, 153.6, 170.2.
Example 08.01
4-{2 (4-{[4-(cyclopropylcarbonyl)piperazin-1 -yl]methyl}pyridin-2-yl)amino]-1 H- benzimidazol-6-yl}-5-methoxy-N,N-dimethylpyridine-2-carboxamide
Figure imgf000650_0001
To a stirred solution of 4-bromo-5-methoxy-N,N-dimethylpyridine-2-carboxamide (206 mg, 796 μιτιοΙ) and cyclopropyl{4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-benzimidazol- 2-yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}methanone (200 mg, 398 pmol) in dioxane (2.5 mL) and water (500 μΙ) was added sodium carbonate (173 mg, 1.63 mmol) and Pd(dppf)CI2 . CH2CI2 (65.0 mg, 79.6 pmol). The mixture was heated to reflux for 16 h. Methanol was added, the mixture was filtered and the solvent was removed in vacuum. Silicagel chromatography gave 130 mg (57 % yield) of the title compound.
LC-MS (Method 5): Rt = 2.67 min; MS (ESIpos): m/z = 555 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.675 (1.04), 0.682 (2.25), 0.688 (1.57), 0.695 (1.21 ), 0.702 (2.75), 0.708 (1.68), 0.710 (1.61 ), 0.716 (2.35), 0.723 (2.39), 0.728 (2.89), 0.735 (1.48), 1.089 (0.51 ), 1.934 (0.60), 1.941 (0.65), 1.945 (0.51 ), 1.953 (1.05), 1.959 (0.57), 1.965 (0.63), 1.972 (0.58), 2.373 (0.97), 2.443 (0.97), 2.490 (1.79), 2.495 (3.91 ), 2.500 (5.61 ), 2.505 (4.18), 2.509 (2.05), 3.019 (8.33), 3.078 (9.10), 3.309 (16.00), 3.521 (5.24), 3.701 (0.85), 3.970 (12.24), 6.933 (1.42), 6.936 (1.45), 6.946 (1.45), 6.950 (1.47), 7.208 (2.35), 7.278 (0.51 ), 7.297 (0.57), 7.562 (6.03), 7.567 (0.70), 8.262 (2.17), 8.277 (2.12), 8.416 (5.24), 10.663 (0.61 ).
Example 09.01
1-{4-[(2-{[6-(5-ethoxy-2-methylpyridin-4-yl)-1H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1-yl}-3,3,3-trifluoropropan-1-one
Figure imgf000651_0001
To a stirred solution of 6-(5-ethoxy-2-methylpyridin-4-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2- yl]-1 H-benzimidazol-2-amine (80.0 mg, 180 pmol) in dichloromethane (1.0 mL) was added triethylamine (200 μΙ, 1.4 mmol) and 3,3,3-trifluoropropanoyl chloride (46 μΙ, 450 μιηοΙ). The mixture was stirred at r.t. for 0.5 h. A saturated sodium bicarbonate solution was added and the mixture was extracted with dichloromethane. The organic phase was dried (magnesium sulfate) and the solvent was removed in vacuum. Silicagel chromatography gave 23 mg (23 % yield) of the title compound.
LC-MS (Method 5): R, = 2.50 min; MS (ESIpos): m/z = 554 [M+H]+
H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.089 (0.47), 1.175 (0.68), 1.193 (0.46), 1.232 (0.95), 1.270 (3.65), 1.288 (7.67), 1.306 (4.05), 1.355 (0.43), 2.393 (2.80), 2.404 (2.38), 2.435 (3.69), 2.446 (16.00), 2.495 (9.42), 2.499 (1 1.12), 2.502 (8.84), 3.306 (14.41 ), 3.373 (1.00), 3.390 (1.51 ), 3.477 (3.06), 3.512 (3.28), 3.531 (7.20), 3.596 (1.20), 3.623 (3.28), 3.651 (3.20), 3.678 (1.08), 4.079 (1.38), 4.096 (4.1 1 ), 4.1 13 (4.09), 4.131 (1.32), 5.747 (1.42), 6.928 (2.04), 6.942 (2.08), 7.205 (3.50), 7.242 (4.75), 7.287 (1.55), 7.308 (1.94), 7.442 (1.38), 7.461 (1.10), 7.694 (1.44), 8.249 (5.15), 8.266 (2.72), 8.279 (2.50).
Example 09.02
cyclopropyl{4-[(2-{[6-(5-ethoxy-2-methylpyridin-4-yl)-1 H-benzimidazol-2
yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}methanone
Figure imgf000652_0001
Starting with 6-(5-ethoxy-2-methylpyridin-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine (80.0 mg, 180 μιηοΙ) and cyclopropanecarbonyl chloride (21 μΙ, 230 μmol), Example 09.02 was prepared analogously to the procedure for the preparation of Example 09.01.
Yield: 54.0 mg (56 %)of the title compound.
LC-MS (Method 5): Rt = 2.37 min; MS (ESIpos): m/z = 512 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.444 (1.86), 2.490 (0.86), 2.495 (1.97), 2.500 (2.80), 2.505 (1.97), 2.509 (0.86), 3.302 (16.00), 8.245 (0.54).
Example 09.03
2-cyclopropyl-1 -{4-[(2-{[6-(5-ethoxy-2-methylpyridin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1-yl}ethanone
Figure imgf000652_0002
To a stirred solution of 6-(5-ethoxy-2-methylpyridin-4-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2- yl]-1 H-benzimidazol-2-amine (80.0 mg, 180 pmol) in dichloromethane (1.0 mL) was added triethylamine (200 μΙ, 1.4 mmol) and cyclopropylacetyl chloride (27.8 mg, 234 pmol) The mixture was stirred at r.t. for 0.5 h. Further cyclopropylacetyl chloride (10 mg, 80 μιτιοΙ) was added and the mixture was stirred at r.t. for 0.5 h. A saturated sodium bicarbonate solution was added and the mixture was extracted with dichloromethane. The organic phase was dried (sodium sulfate) and the solvent was removed in vacuum. Silicagel chromatography gave 65.0 mg (69 % yield) of the title compound.
LC-MS (Method 5): Rt = 2.50 min; MS (ESIpos): m/z = 526 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.011 (1.54), 0.013 (1.62), 0.025 (1.73), 0.036 (0.52), 0.329 (0.44), 0.338 (1.28), 0.343 (1.40), 0.348 (0.77), 0.353 (0.73), 0.358 (1.41 ), 0.363 (1.49), 0.374 (0.48), 0.855 (0.51 ), 1.182 (1.46), 1.200 (2.82), 1.216 (1.51 ), 2.148 (2.73), 2.166 (2.68), 2.278 (1.61 ), 2.292 (1.77), 2.307 (1.64), 2.357 (8.76), 2.410 (1.78), 2.414 (2.31 ), 2.419 (1.76), 3.232 (16.00), 3.367 (1.54), 3.418 (4.57), 3.988 (0.78), 4.005 (2.30), 4.022 (2.23), 4.039 (0.70), 5.663 (0.89), 6.834 (1.15), 6.847 (1.16), 7.1 18 (2.10), 7.145 (1.58), 7.215 (0.52), 8.158 (3.14), 8.172 (1.66), 8.185 (1.51 ), 10.551 (0.47), 12.052 (0.50).
Example 09.04
cyclobutyl{4-[(2-{[6-(5-ethoxy-2-methylpyridin-4-yl)-1 H^enzimidazol-2-yl]amino}pyridin 4-yl)methyl]piperazin-1-yl}methanone
Figure imgf000653_0001
Starting with 6-(5-ethoxy-2-methylpyridin-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine (80.0 mg, 180 pmol) and cyclobutanecarbonyl chloride (27 μΙ, 230 pmol), Example 09.04 was prepared analogously to the procedure for the preparation of Example 09.01
Yield: 71.0 mg (75 %).
LC-MS (Method 5): Rt = 2.53 min; MS (ESIpos): m/z = 526 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.267 (1.48), 1.284 (2.78), 1.301 (1.63), 1.71 1 (0.45), 1.735 (0.56), 1.858 (0.66), 1.880 (0.67), 1.903 (0.41 ), 2.051 (1.03), 2.072 (1.23), 2.101 (0.84), 2.123 (1.25), 2.146 (1.40), 2.169 (0.82), 2.349 (3.71 ), 2.443 (6.82), 2.495 (2.34), 2.499 (2.58), 3.272 (0.47), 3.314 (16.00), 3.331 (3.28), 3.490 (4.38), 4.072 (0.74), 4.090 (1.93), 4.108 (1.86), 4.124 (0.67), 6.910 (1.20), 6.922 (1.16), 7.198 (2.03), 7.229 (1.66), 7.299 (0.65), 8.243 (2.55), 8.253 (1.57), 8.266 (1.31 ), 12.130 (0.48).
Example 10.01
cyclopropyl{4-[(2-{[6-(2-methoxy-3-methylpyridin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}methanone
Figure imgf000654_0001
Starting with cyclopropyl{4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)methyl]piperazin-1-yl}methanone (200 mg, 398 pmol)and 4-iodo-2-methoxy-3-methylpyridine (130 mg, 522 pmol), Example 10.01 was prepared analogously to the procedure for the preparation of Example 08.01.
Yield: 125 mg (62 %) of the title compound.
LC-MS (Method 5): Rt = 2.96 min; MS (ESIpos): m/z = 498 [M+H]+
H-NMR (400 MHz, DMSO-d6): δ [ppm] = 0.70 (m, 4H), 1.94 (m, 1 H), 2.13 (s, 3H), 2.40 (m, 4H), 3.51 (m, 4H), 3.69 (s, 2H), 3.92 (s, 3H), 6.83-6.97 (m, 2H), 6.94 (s, 1 H), 7.21 (s, 1 H), 7.26-7.68 (m, 2H), 8.01 (d, 1 H), 8.27 (d, 1 H), 10.66 (s, 1 H), 12.17 (s, 1 H). 13C-NMR (101 MHz, DMSO-d6): δ [ppm] = 6.9, 10.2, 12.9, 41.6, 44.8, 52.4, 53.1 , 53.3, 60.6, 1 10.4, 1 16.4, 1 18.7, 142.9, 146.9, 149.4, 150.3, 153.6, 162.2, 170.9.
Example 11.01
cyclopropyl(4-{[2-({6-[3-methyl-2-(propan-2-yloxy)pyridin-4-yl]-1 H-benzimidazol-2 yl}amino)pyridin-4-yl]methyl}piperazin-1 -yl)methanone
Figure imgf000655_0001
Starting with cyclopropyl{4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- benzimidazoI-2-yl]amino}pyridin-4-yl)methyl]piperazin-1-yl}methanone (150 mg, 299 pmol)and 4-iodo-3-methyl-2-(propan-2-yloxy)pyridine (200 mg, 722 μιηοΙ) Example 1 1.01 was prepared analogously to the procedure for the preparation of Example 08.01.
Yield: 72 mg (46 %) of the title compound.
LC-MS (Method 5): Rt = 3.26 min; MS (ESIpos): m/z = 526 [M+H]+
1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 0.71 (m, 4H), 1.33 (d, 6H), 1.94 (m, 1 H), 2.10 (s, 3H), 2.40 (m, 4H), 3.51 (s, 4H), 3.69 (s, 2H), 5.31 (quin, 1 H), 6.84 (d, 1 H), 6.93 (d, 1 H), 7.01 (s, 1 H), 7.22 (s, 1 H), 7.26-7.72 (m, 2H), 7.98 (d, 1 H), 8.27 (d, 1 H), 10.66 (s, 1 H), 12.17 (s, 1 H).
13C-NMR (101 MHz, DMSO-d6): δ [ppm] = 6.9, 10.2, 13.0, 22.1 , 41 .6, 44.8, 52.4, 53.1 , 60.6, 67.4, 110.4, 1 16.4, 1 17.2, 118.2, 143.0, 146.9, 149.4, 150.3, 151.8, 153.6, 161.5, 170.9.
Example 12.01
tert-butyl 4-[(2-{[6-(6-methylpyridin-2-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate
Figure imgf000656_0001
Starting with tert-butyl 4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-benzimidazol- 2-yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate (500 mg, 936 pmol) and 2-bromo-6- methylpyridine (225 mg, 1 .31 mmol), Example 12.01 was prepared analogously to the procedure for the preparation of Example 01 .01.
Yield: 3.20 mg (1 %) of the title compound.
LC-MS (Method 4): R, = 1 .34 min; MS (ESIpos): m/z = 500 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.395 (16.00), 2.358 (1.24), 2.537 (5.24), 3.335 (10.1 1 ), 8.250 (0.85), 8.264 (0.87).
Example 12.02
cyclopropyl{4-[(2-{[6-(6-methylpyridin-2-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone
Figure imgf000656_0002
Starting with crude 6-(6-methylpyridin-2-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (190 mg, approx. 218 pmol) and cyclopropanecarboxylic acid (28.1 mg, 327 pmol), Example 12.02 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 7.00 mg of the title compound.
LC-MS (Method 4): R, = 1.12 min; MS (ESIpos): m/z = 468 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.679 (1.12), 0.686 (2.60), 0.691 (1.55), 0.698 (1.20), 0.705 (3.15), 0.710 (2.60), 0.715 (2.83), 0.722 (2.58), 0.727 (3.09), 0.734 (1.37), 1.968 (1.12), 2.322 (1.26), 2.327 (1.75), 2.332 (1.29), 2.365 (1.20), 2.518 (7.04), 2.523 (4.67), 2.538 (16.00), 2.665 (1.20), 2.669 (1.69), 2.674 (1.14), 3.523 (5.84), 3.708 (1.12), 6.935 (1.32), 6.951 (1.35), 7.1 15 (1.26), 7.136 (1.32), 7.193 (2.20), 7.721 (1.12), 8.260 (2.75), 8.273 (2.43), 10.680 (1.55).
Example 12.03
2-cyclopropyl-1 -{4-[(2-{[6-(6-methylpyridin-2-yl)-1 H-benzimidazol-2-yl]amino}pyridin yl)methyl]piperazin-1-yl}ethanone
Figure imgf000657_0001
Starting with crude 6-(6-methylpyridin-2-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (190 mg, approx. 218 pmol) and cyclopropylacetic acid (32.7 mg, 327 pmol), Example 12.03 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 23.0 mg of the title compound.
LC-MS (Method 2): Rt = 1.16 min; MS (ESIpos): m/z = 500 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.01 1 (0.96), 0.000 (3.41 ), 0.012 (3.56), 0.026 (1.10), 0.319 (1.03), 0.329 (2.70), 0.333 (2.81 ), 0.339 (1.72), 0.349 (2.99), 0.353 (2.84), 0.364 (1.07), 0.843 (1.05), 0.871 (1.10), 0.893 (1.97), 0.909 (2.22), 1.01 1 (15.89), 2.004 (0.87), 2.143 (4.55), 2.159 (4.41 ), 2.231 (1.33), 2.297 (2.95), 2.427 (7.88), 2.441 (16.00), 2.573 (1.14), 3.360 (2.76), 3.412 (6.84), 4.098 (1.42), 6.832 (1.71 ), 6.845 (1.71 ), 7.019 (1.46), 7.040 (1.56), 7.089 (3.00), 7.622 (1.58), 7.690 (1.17), 8.159 (2.97), 8.172 (2.76).
Example 13.01
tert-butyl 4-[(2-{[6-(6-methoxypyridin-3-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4' yl)methyl] pi perazine-1 -carboxylate
Figure imgf000658_0001
To a stirred solution of 1 H-imidazole (31.6 mg, 465 pmol) and di-1 H-imidazol-1- ylmethanethione (436 mg, 95 % purity, 2.32 mmol) in dichloromethane (20 mL) was added tert-butyl 4-[(2-aminopyridin-4-yl)methyl]piperazine-1 -carboxylate (679 mg, 2.32 mmol) dissolved in dichloromethane (10 mL) at 0° C. The m ixture was stirred at r.t. for 14 h. 4-(6- methoxypyridin-3-yl)benzene-1 ,2-diamine (500 mg, 2.32 mmol) , dissolved in dichloromethane (10 mL) was added and the mixture was stirred at r.t. for 65 h. Water was added and the mixture was extracted with dichloromethane. The organic phase was dried (sodium sulfate) and filtered. N,N'-dipropan-2-ylcarbodiimide (720 μΙ, 4.7 mmol) was added. The mixture was stirred at r.t. for 14 h. Sodium bicarbonate solution was added and the mixture was extracted with dichloromethane. Silicagel chromatography followed by aminophase-silicagel chromatography gave 180 mg of the title compound.
LC-MS (Method 2): R, = 1.36 min; MS (ESIpos): m/z = 516 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.394 (16.00), 2.356 (1.33), 3.495 (1.72), 3.892 (8.10), 7.184 (0.91 ), 8.253 (0.83), 8.267 (0.81 ). Example 13.02
cyclopropyl{4-[(2-{[6-(6-methoxypyridin-3-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4' yl)methyl]piperazin-1-yl}methanone
Figure imgf000659_0001
Starting with 6-(6-methoxypyridin-3-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (45.0 mg, 90 % purity, 89.6 pmol) and cydopropanecarboxylic acid (1 1 μΙ, 130 pmol) Example 13.02. was prepared analogously to the procedure for the preparation of Example 16.01.02.
Yield: 20.0 mg (42 %) of the title compound.
LC-MS (Method 2): R, = 1.12 min; MS (ESIpos): m/z = 484 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.684 (2.14), 0.689 (1.34), 0.696 (1.07), 0.703 (2.58), 0.708 (2.25), 0.713 (2.36), 0.720 (2.21 ), 0.726 (2.54), 0.733 (1.19), 1.966 (0.92), 3.520 (4.95), 3.708 (1.1 1 ), 3.893 (16.00), 6.930 (1.35), 6.933 (1.38), 6.943 (1.35), 6.946 (1.37), 7.202 (2.29), 8.263 (2.10), 8.277 (2.00), 10.649 (1.63).
Example 13.03
3,3,3 rifluoro-1 -{4-[(2-{[6-(6-methoxypyridin-3-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1-yl}propan-1 -one
Figure imgf000659_0002
Starting with 6-(6-methoxypyridin-3-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (1 10 mg, 90 % purity, 219 pmol) and 3,3,3- trifluoropropanoic acid (29 μΙ, 330 pmol) Example 13.03. was prepared analogously to the procedure for the preparation of Example 16.01.02.
Yield: 27.0 mg (21 %) of the title compound.
LC-MS (Method 1 ): R. = 0.84 min; MS (ESIpos): m/z = 526 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.335 (16.00), 3.639 (1.58), 3.667 (1.48), 3.893 (12.15), 7.198 (1.44), 8.262 (1.48), 8.276 (1.40), 10.647 (1 .1 1 ).
Example 14.01
cyclobutyl{4-[(2-{[6-(4-methoxypyridin-3-yl)-1H^enzimidazol-2-yl]amino}py
yl)methyl]piperazin-1 -yl}methanone
Figure imgf000660_0001
Starting with crude 6-(4-methoxypyridin-3-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (101 mg, approx. 167 pmol) cyclobutanecarboxylic acid (25.2 mg, 251 pmol), Example 14.01 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 30 mg of the title compound.
LC-MS (Method 2): R, = 1.04 min; MS (ESIpos): m/z = 498 [M+H]+
1H-NMR (400 MHz, CHLOROFORM-d) δ [ppm]: 1.147 (0.84), 1.163 (0.83), 1.260 (1.55), 1.814 (0.98), 1.840 (2.06), 1.853 (1.91 ), 1.864 (2.70), 1.874 (1.82), 1.891 (1.91 ), 1.897 (1.16), 1.914 (2.38), 1.935 (4.04), 1.941 (1.71 ), 1.957 (2.98), 1.962 (2.68), 1.979 (1.50), 1.984 (1.80), 2.007 (0.95), 2.038 (0.48), 2.081 (1.45), 2.090 (1.66), 2.097 (1.55), 2.102 (2.64), 2.1 12 (4.35), 2.121 (3.05), 2.127 (2.98), 2.133 (4.55), 2.142 (3.27), 2.155 (1.89), 2.164 (1.47), 2.178 (0.46), 2.240 (0.49), 2.281 (5.27), 2.287 (6.09), 2.298 (11.36), 2.304 (13.23), 2.309 (13.78), 2.325 (9.16), 2.333 (5.73), 2.349 (3.31 ), 2.356 (3.86), 2.373 (1.02), 2.378 (1.40), 2.627 (4.15), 3.173 (0.82), 3.196 (2.93), 3.216 (4.35), 3.240 (5.88), 3.255 (6.54), 3.266 (4.60), 3.417 (16.00), 3.532 (5.49), 3.919 (10.64), 6.918 (5.81 ), 6.921 (6.38), 6.931 (7.87), 6.934 (7.59), 6.942 (3.75), 7.006 (0.75), 7.130 (7.90), 7.360 (2.14), 7.379 (2.45), 7.528 (1.23), 7.668 (1.26), 8.281 (7.19), 8.295 (6.97), 8.473 (1.74), 8.539 (8.43).
Example 14.02
2-cyclopropyl-1 -{4-[(2-{[6-(4-methoxypyridin-3-yl)-1 H-benzimidazol-2-yl]amino}pyridin yl)methyl]piperazin-1-yl}ethanone
Figure imgf000661_0001
Starting with crude 6-(4-methoxypyridin-3-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (40.0 mg) and cyclopropylacetic acid (7.75 mg, 77.4 pmol), Example 14.02 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 3 mg of the title compound.
LC-MS (Method 2): R, = 1.01 min; MS (ESIpos): m/z = 498 [M+H]+
1H-NMR (400 MHz, CHLOROFORM-d) δ [ppm]: 0.078 (0.60), 0.103 (0.66), 0.155 (2.41 ), 0.167 (10.14), 0.181 (10.63), 0.193 (3.07), 0.545 (2.76), 0.556 (7.64), 0.559 (8.27), 0.565 (4.74), 0.572 (4.54), 0.577 (8.59), 0.580 (8.45), 0.592 (2.84), 0.888 (1.15), 1.004 (1.21 ), 1.016 (2.04), 1.024 (2.07), 1.036 (3.10), 1.049 (2.07), 1.053 (2.07), 1.261 (7.73), 1.293 (1.87), 1.612 (3.76), 1.896 (0.98), 2.178 (1.55), 2.252 (14.99), 2.269 (15.20), 2.286 (1.41 ), 2.360 (1 1.78), 2.371 (1 1.63), 3.397 (6.75), 3.454 (16.00), 3.526 (0.98), 3.589 (6.00), 3.930 (8.01 ), 6.944 (8.50), 6.955 (6.41 ), 7.006 (1.78), 7.093 (6.61 ), 7.286 (2.38), 7.364 (1.78), 7.529 (2.59), 7.641 (2.10), 7.749 (1.49), 8.290 (5.92), 8.303 (6.03), 8.485 (2.15), 8.536 (7.24), 12.328 (0.49). Example 14.03
cyclopropyl{4-[(2-{[6-(4-methoxypyridin-3-yl)-1 H^enzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1-yl}methanone
Figure imgf000662_0001
Starting with crude 6-(4-methoxypyridin-3-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (101 mg) and cyclopropanecarboxylic acid (21.6 mg, 251 μηιοΙ), Example 14.03 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 21 mg of the title compound.
LC-MS (Method 2): R, = 0.98 min; MS (ESIpos): m/z = 484 [M+H]+
1H-NMR (400 MHz, CHLOROFORM-d) δ [ppm]: 0.746 (1.86), 0.756 (5.53), 0.763 (6.34), 0.773 (4.36), 0.776 (6.18), 0.784 (6.51 ), 0.792 (2.67), 0.974 (2.40), 0.982 (6.58), 0.989 (6.81 ), 0.994 (7.59), 1.001 (6.74), 1.01 1 (2.38), 1.261 (0.94), 1.678 (2.02), 1 .690 (3.15), 1.698 (3.52), 1.709 (4.93), 1.721 (3.41 ), 1.729 (3.06), 1.741 (1.98), 2.179 (0.94), 2.315 (4.10), 2.375 (4.16), 3.425 (9.1 1 ), 3.430 (9.34), 3.577 (5.39), 3.848 (0.46), 3.893 (14.78), 3.938 (16.00), 6.914 (2.71 ), 6.931 (6.28), 6.939 (4.44), 6.944 (5.66), 6.946 (5.68), 6.953 (3.46), 7.006 (0.79), 7.131 (3.51 ), 7.153 (3.52), 7.282 (1.36), 7.289 (0.89), 7.334 (1.73), 7.338 (1.74), 7.354 (2.05), 7.358 (2.14), 7.386 (1.77), 7.390 (1.78), 7.406 (1.92), 7.410 (1.94), 7.518 (2.87), 7.528 (1.18), 7.538 (2.39), 7.646 (3.47), 7.649 (3.55), 7.709 (2.58), 7.730 (2.30), 7.774 (3.42), 8.286 (3.04), 8.294 (3.55), 8.298 (3.49), 8.306 (3.01 ), 8.458 (2.87), 8.472 (2.95), 8.490 (3.29), 8.505 (3.00), 8.549 (1 1.23), 12.369 (1.31 ).
Example 15.01
3,3,3-trifluoro-1 -{4-[(2-{[6-(2-methoxypyridin-3-yl)-1 H-benzimidazol-2-yl]amino}pyridi yl)methyl]piperazin-1-yl}propan-1 -one
Figure imgf000663_0001
Starting with crude 6-(2-methoxypyridin-3-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (64.0 mg) and 3,3,3-trifluoropropanoic acid (21.4 mg, 167 pmol), Example 15.01 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 7 mg of the title compound.
LC-MS (Method 2): R, = 1.16 min; MS (ESIpos): m/z = 526 [M+H]+
1H-NMR (400 MHz, CHLOROFORM-d) δ [ppm]: 0.078 (0.71 ), 0.103 (0.68), 0.136 (1.07), 0.865 (0.84), 0.889 (0.97), 1.148 (0.94), 1.164 (0.94), 1.263 (6.56), 1.385 (1.10), 1.610 (1.29), 2.236 (0.71 ), 2.254 (0.68), 2.380 (8.05), 2.627 (2.04), 2.638 (0.65), 2.653 (0.94), 3.179 (2.72), 3.205 (7.89), 3.230 (7.76), 3.255 (2.72), 3.369 (4.53), 3.452 (7.14), 3.592 (4.33), 3.988 (10.67), 4.034 (16.00), 6.909 (3.36), 6.923 (3.56), 6.981 (1.13), 6.993 (1.36), 6.999 (1.45), 7.006 (3.26), 7.020 (1.84), 7.026 (1.78), 7.039 (1.65), 7.083 (3.81 ), 7.286 (1.58), 7.386 (1.49), 7.402 (2.52), 7.421 (1.68), 7.494 (2.39), 7.514 (1.71 ), 7.529 (2.07), 7.661 (1.78), 7.682 (1.97), 7.687 (3.91 ), 7.692 (3.88), 7.706 (3.46), 7.710 (3.52), 7.722 (3.26), 7.792 (2.20), 8.141 (1.33), 8.145 (1.42), 8.153 (1.42), 8.158 (1.42), 8.172 (1.87), 8.176 (1.91 ), 8.184 (2.00), 8.189 (1.84), 8.290 (3.01 ), 8.295 (3.04), 8.303 (3.04), 8.309 (2.55), 12.295 (0.97).
Example 15.02
2-cyclopropyl-1-{4-[(2-{[6-(2-methoxypyridin-3-y
yl)methyl]piperazin-1-yl}ethanone
Figure imgf000664_0001
Starting with crude 6-(2-methoxypyridin-3-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (69.0 mg) and cyclopropylacetic acid (18.1 mg, 180 pmol), Example 15.02 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 8 mg of the title compound.
LC-MS (Method 2): R, = 1.15 min; MS (ESIpos): m/z = 498 [M+H]+
1H-NMR (400 MHz, CHLOROFORM-d) δ [ppm]: 0.102 (0.65), 0.148 (1.90), 0.161 (7.69), 0.175 (7.97), 0.187 (2.30), 0.539 (2.21 ), 0.549 (5.88), 0.553 (6.04), 0.559 (3.21 ), 0.565 (3.42), 0.570 (6.57), 0.573 (6.19), 0.585 (2.21 ), 0.888 (0.56), 0.996 (0.93), 1.009 (1 .53), 1.029 (2.18), 1.045 (1.53), 1.055 (1.31 ), 1.074 (1.62), 1.092 (0.81 ), 1.252 (1.03), 1.261 (3.05), 1.385 (1.37), 1 .692 (1.56), 2.038 (0.40), 2.180 (0.65), 2.240 (9.99), 2.257 (9.74), 2.366 (8.65), 2.627 (0.62), 2.653 (0.47), 3.380 (4.39), 3.445 (7.25), 3.592 (4.33), 3.988 (10.15), 4.033 (16.00), 6.923 (3.74), 6.937 (4.08), 6.977 (1.03), 6.994 (1.49), 7.006 (3.95), 7.017 (1.96), 7.022 (1.87), 7.035 (1.62), 7.088 (4.08), 7.283 (2.30), 7.384 (1.43), 7.400 (2.74), 7.416 (2.21 ), 7.487 (2.05), 7.507 (1.49), 7.528 (2.05), 7.669 (1.99), 7.689 (5.04), 7.707 (4.14), 7.712 (5.20), 7.785 (2.37), 8.147 (1.43), 8.160 (1.62), 8.168 (2.18), 8.172 (2.15), 8.180 (2.02), 8.184 (1.90), 8.285 (3.89), 8.298 (3.89), 12.308 (0.93). Example 15.03
cyclopropyl{4-[(2-{[6-(2-methoxypyridin-3-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4' yl)methyl]piperazin-1 -yl}methanone
Figure imgf000665_0001
Starting with cyclopropyl{4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)methyl]piperazin-1-yl}methanone (98.0 mg, 195 pmol) and 3-iodo-2-methoxypyridine (55.0 mg, 234 pmol), Example 15.03 was prepared analogously to the procedure for the preparation of Example 01.01.
Yield: 25 mg (27 %) of the title compound.
LC-MS (Method 2): R, = 1.12 min; MS (ESIpos): m/z = 484 [M+H]+
1H-NMR (400 MHz, CHLOROFORM-d) δ [ppm]: 0.103 (0.41 ), 0.733 (2.96), 0.743 (8.63), 0.751 (9.56), 0.759 (6.48), 0.763 (8.81 ), 0.770 (9.50), 0.779 (3.48), 0.796 (0.49), 0.817 (0.55), 0.850 (0.77), 0.889 (0.63), 0.931 (0.43), 0.969 (3.87), 0.978 (10.63), 0.981 (7.92), 0.985 (10.21 ), 0.989 (1 1.20), 0.996 (9.58), 1.006 (3.20), 1.261 (3.48), 1.293 (0.83), 1.341 (0.51), 1.665 (1.82), 1.677 (3.26), 1.685 (3.77), 1.688 (2.90), 1.697 (5.73), 1.705 (2.73), 1.708 (3.32), 1.717 (2.90), 1.728 (1.52), 2.182 (0.53), 2.368 (7.13), 3.447 (16.00), 3.589 (11.71 ), 3.995 (5.02), 4.030 (7.62), 4.261 (0.61 ), 4.266 (0.63), 4.725 (0.57), 4.730 (0.59), 6.936 (6.44), 6.949 (6.18), 7.006 (3.56), 7.1 13 (0.75), 7.138 (10.67), 7.255 (1.26), 7.402 (3.69), 7.422 (4.31 ), 7.475 (0.63), 7.478 (0.75), 7.498 (1.36), 7.528 (1.72), 7.567 (0.61 ), 7.570 (0.65), 7.587 (0.61 ), 7.597 (0.65), 7.601 (0.71 ), 7.618 (0.57), 7.690 (6.83), 7.695 (6.93), 7.709 (6.99), 7.713 (6.97), 7.791 (1.48), 8.165 (3.65), 8.279 (0.93), 8.291 (9.15), 8.304 (8.36), 12.351 (0.75). Example 16.01.01
tert-butyl 4-[(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4 yl)methyl]piperazine-1-carboxylate
Figure imgf000666_0001
A mixture of tert-butyl 4-({2-[(6-{[(ethanimidoylamino)oxy]carbonyl}-1 H-benzimidazol-2- yl)amino]pyridin-4-yl}methyl)piperazine-1 -carboxylate (30.0 mg, 59.0 pmol) and sodium acetate (5.32 mg, 64.9 μηιοΙ) in 1-propanol (1.5 mL) and water (750 μΙ) was heated to 120° C in a microwave oven for 2 h. The solvent was removed in vacuum. Silicagel chromatography gave 21.0 mg (65 % yield) of the title compound.
LC-MS (Method 1 ): Rt = 0.87 min; MS (ESIpos): m/z = 491 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.396 (16.00), 2.349 (1.01 ), 2.361 (1.47), 2.373 (1.07), 2.398 (5.1 1 ), 3.319 (8.20), 3.510 (1.82), 5.755 (0.73), 7.181 (0.87), 8.284 (0.56), 8.297 (0.53).
Example 16.01.02
3,3,3-trifluoro-1 -{4-[(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}propan-1 -one
Figure imgf000666_0002
To a stirred solution of crude 6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-N-[4-(piperazin-1 - ylmethyl)pyridin-2-yl]-1 H-benzimidazol-2-amine hydrochloride (3.55 g, approx. 7.65 mmol) in DMA (50 mL) was added DIPEA (8.0 ml_, 46 mmol), 3,3,3-trifluoropropanoic acid (1.0 ml_, 98 % purity, 11 mmol) and PyBOP (5.97 g, 1 1.5 mmol). The mixture was stirred at room temperature for 1 h. Water was added, the mixture was stirred for 15 minutes and the mixture was extracted with dichloromethane and methanol (10:1 mixture). The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Aminophase-silicagel chromatography gave a solid that was triturated with dichloromethane/hexane (1 :1 ) to give 2.98 g of the title compound.
LC-MS (Method 2): R, = 1.07 min; MS (ESIpos): m/z = 501 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm]= 2.34 - 2.46 (m, 7H), 3.55 (s, 1 H), 3.61 (s, 1 H), 3.63 (s, 1 H), 3.63 - 3.70 (m, 2H), 6.97 (d, 1 H), 7.20 (s, 1 H), 7.38 - 7.87 (m, 2H), 7.89 - 8.38 (m, 2H), 10.89 (br s, 1 H), 12.46 (br s, 1 H).
Example 16.01.03
2-cyclopropyl-1 -{4-[(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yI)methyl]piperazin-1 -yl}ethanone
Figure imgf000667_0001
To a stirred solution of crude 6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-N-[4-(piperazin-1- ylmethyl)pyridin-2-yl]-1 H-benzimidazol-2-amine hydrochloride (70.0 mg, approx. 164 Mmol) in DMF (2 mL) was added DIPEA (140 μΙ, 820 pmol), T3P (170 pi, 50 % in DMF, 300 μηηοΙ) and cyclopropylacetic acid (28.5 mg, 98 % purity, 279 pmol). The mixture was stirred at r.t. for 14 h. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate), filtered and the solvent was removed in vacuum. Aminophase-silicagel chromatography gave a solid that was triturated with dichloromethane/hexane to give 22 mg of the title compound.
LC-MS (Method 2): Rt = 1.08 min; MS (ESIpos): m/z = 473 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.000 (0.67), 0.01 1 (2.35), 0.014 (2.15), 0.023 (2.39), 0.026 (2.27), 0.037 (0.82), 0.330 (0.86), 0.340 (2.10), 0.343 (2.18), 0.350 (1.13), 0.354 (1.02), 0.360 (2.28), 0.364 (2.15), 0.374 (0.85), 0.855 (0.77), 2.152 (4.09), 2.169 (3.96), 2.279 (1.57), 2.292 (1.57), 2.302 (1.79), 2.31 1 (16.00), 2.436 (0.85), 3.371 (1.52), 3.382 (1.41 ), 3.393 (1.37), 3.406 (1.51 ), 3.433 (4.88), 6.877 (1.10), 6.893 (1.16), 7.109 (2.32), 7.701 (0.68), 8.201 (1.61 ), 8.215 (1.57).
Example 16.01.04
cyclopropyl{4-[(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H^enzimidazol-2-yl]amino}pyridin 4-yl)methyl]piperazin-1-yl}methanone
Figure imgf000668_0001
To a stirred solution of crude 6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-N-[4-(piperazin-1- ylmethyl)pyridin-2-yl]-1 H-benzimidazol-2-amine hydrochloride (70.0 mg, approx. 164 pmol) in DMF (2 mL) was added DIPEA (140 μΙ, 820 μιτιοΙ), T3P (170 μΙ, 50 % in DMF, 300 μηιοΙ) and cyclopropanecarboxylic acid (23 μΙ, 98 % purity, 280 μιηοΙ). The mixture was stirred at r.t. for 14 h. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate), filtered and the solvent was removed in vacuum. Aminophase-silicagel chromatography gave 36.0 mg of the title compound.
LC-MS (Method 2): R, = 1.05 min; MS (ESIpos): m/z = 459 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.678 (0.95), 0.685 (2.22), 0.691 (1.38), 0.698 (1.07), 0.705 (2.77), 0.710 (2.13), 0.717 (2.35), 0.723 (2.34), 0.728 (2.82), 0.735 (1.29), 1.941 (0.56), 1.948 (0.59), 1.960 (1.02), 1.972 (0.57), 1.980 (0.53), 2.370 (0.93), 2.389 (1.07), 2.399 (16.00), 2.447 (0.93), 2.523 (0.85), 3.503 (0.85), 3.534 (5.20), 3.704 (0.82), 6.973 (1.14), 6.986 (1.18), 7.204 (2.30), 7.790 (0.73), 8.294 (1.71 ), 8.307 (1.62). Example 16.01.05
cyc!obutyl{4-[(2-{[6-(3-methyl-1,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2-yl]amino}pyridin- 4-yl)methyl]piperazin-1-yl}methanone
Figure imgf000669_0001
To a stirred solution of crude 6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-N-[4-(piperazin-1- ylmethyl)pyridin-2-yl]-1 H-benzimidazol-2-amine hydrochloride (70.0 mg, approx. 164 pmol) in DMF (2 mL) was added DIPEA (140 μΙ, 820 pmol), T3P (170 μΙ, 50 % in DMF, 300 μιηοΙ) and cyclobutanecarboxylic acid (28.5 mg, 98 % purity, 279 pmol).The mixture was stirred at r.t. for 14 h. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate), filtered and the solvent was removed in vacuum. Aminophase-silicagel chromatography gave 33.0 mg of the title compound.
LC-MS (Method 2): R, = 1.1 1 min; MS (ESIpos): m/z = 473 [M+H]+
1 H-NMPv (400 MHz, DMSO-d6) δ [ppm]: 1.842 (0.50), 1.863 (0.98), 1.886 (0.73), 1.890 (0.74), 2.055 (1.04), 2.064 (0.77), 2.071 (0.74), 2.076 (1.19), 2.080 (0.92), 2.086 (0.94), 2.126 (1.39), 2.131 (0.92), 2.148 (1.54), 2.153 (1.16), 2.155 (1.02), 2.172 (0.71 ), 2.177 (0.78), 2.356 (3.13), 2.367 (2.36), 2.398 (16.00), 2.523 (0.90), 3.325 (2.38), 3.343 (2.20), 3.476 (1.49), 3.509 (5.00), 6.957 (1.14), 6.970 (1.21 ), 7.192 (2.34), 7.787 (0.80), 8.285 (1.78), 8.298 (1.72).
Example 16.01.06
2,2-dimethyl-1 -{4-[(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1-yl}propan-1 -one
Figure imgf000670_0001
Starting with crude 6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]- 1 H-benzimidazol-2-amine hydrochloride (140 mg, approx. 328 pmol)and 2,2- dimethylpropanoic acid (57 μΙ, 490 μηηοΙ) Example 16.01.06 was prepared analogously to the procedure for the preparation of Example 16.01.02.
Yield: 160.0 mg of the title compound.
LC-MS (Method 2): Rt = 1.16 min; MS (ESIpos): m/z = 475 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.184 (16.00), 2.374 (0.94), 2.386 (1.48), 2.399 (7.16), 3.509 (1.97), 3.574 (1.10), 7.196 (0.87), 8.289 (0.73), 8.302 (0.70).
Example 16.02.01
tert-butyl (2R,5S)-2,5-dimethyl-4-[(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol- 2-yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate
Figure imgf000670_0002
A mixture of tert-butyl (2R,5S)-4-({2-[(6-{[(ethanimidoylamino)oxy]carbonyl}-1 H-benzimidazol- 2-yl)amino]pyridin-4-yl}methyl)-2,5-dimethylpiperazine-1 -carboxylate (496 mg, 924 μιηοΙ) and sodium acetate (83.4 mg, 1.02 mmol) in 1-propanol (24 mL, 310 mmol) and water (12 mL) was heated to 100°C in a microwave oven for 48 h. The solvent was removed in vacuum. Silicagel chromatography gave 374 mg (70 % yield) of the title compound.
LC-MS (Method 2): Rt = 1.40 min; MS (ESIpos): m/z = 519 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.921 (1.85), 0.937 (1 .91 ), 1.229 (1.95), 1.246 (1.99), 1.400 (16.00), 2.396 (5.59), 5.757 (3.66).
Example 16.02.02
1 -{(2R,5S)-2,5-dimethyl-4-[(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1H-benzimidazol-2- yl]amino}pyridin-4-yl)rnethyl]piperazin-1-yl}-3,3,3-trifluoropropan-1-one
Figure imgf000671_0001
Starting with crude N-(4-{[(2S,5R)-2,5-dimethylpiperazin-1-yl]methyl}pyridin-2-yl)-6-(3-methyl- 1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2-amine hydrochloride (100 mg, approx. 177 μιτιοΙ) and 3,3,3-trifluoropropanoic acid (68.0 mg, 531 pmol) Example 16.02.02 was prepared analogously to the procedure for the preparation of Example 02.02.
Yield: 43.0 mg of the title compound.
LC-MS (Method 2): Rt = 1.19 min; MS (ESIpos): m/z = 529 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.868 (1.35), 0.884 (1.43), 0.964 (1.44), 0.980 (1.39), 1.230 (1.42), 1.248 (1.42), 1.352 (1.36), 1.369 (1.29), 2.398 (16.00), 3.441 (1.1 1 ), 3.478 (1.71 ), 3.530 (1.32), 3.664 (1.71 ), 3.703 (1.23), 6.991 (1.29), 7.290 (3.06), 7.488 (0.91 ), 8.233 (1.29), 8.283 (1.46), 8.297 (1.02), 12.440 (1.79). Example 16.02.03
2-cyclopropyl-1 -{(2R,5S)-2,5-dimethyl-4-[(2-{[6-(3-methyl-1,2,4-oxadiazol-5-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)methyl]piperazin-1-yl}ethanone
Figure imgf000672_0001
Starting with crude N-(4-{[(2S,5R)-2,5-dimethylpiperazin-1-yl]methyl}pyridin-2-yl)-6-(3-methyl- 1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2-amine hydrochloride (90.0 mg, approx. 159 pmol) and cyclopropylacetic acid (47.9 mg, 478 pmol) Example 16.02.03 was prepared analogously to the procedure for the preparation of Example 02.02.
Yield: 48.0 mg of the title compound.
LC-MS (Method 2): R, = 1.20 min; MS (ESIpos): m/z = 501 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.1 13 (1.72), 0.433 (2.12), 0.437 (2.09), 0.453 (2.29), 0.457 (2.12), 0.934 (1.35), 0.950 (1.43), 2.123 (0.91 ), 2.140 (0.87), 2.161 (1.46), 2.178 (1.51 ), 2.207 (1.31 ), 2.233 (1.55), 2.397 (16.00), 3.427 (1.39), 3.466 (1.95), 3.656 (1.72), 3.695 (1.33), 6.988 (1.15), 7.286 (2.71 ), 8.231 (1.01 ), 8.281 (1.27), 12.444 (1.85).
Example 16.02.04
cyclopropyl{(2R,5S)-2,5-dimethyl-4-[(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)methyl]piperazin-1-yl}methanone
Figure imgf000673_0001
Starting with crude N-(4-{[(2S,5R)-2,5-dimethylpiperazin-1-yl]methyl}pyridin-2-yl)-6-(3-methyl- 1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2-amine hydrochloride (100 mg, approx. 177 pmol)and cyclopropanecarboxylic acid (45.7 mg, 531 μηιοΙ) Example 16.02.04 was prepared analogously to the procedure for the preparation of Example 02.02.
Yield: 56.0 mg of the title compound.
LC-MS (Method 2): R, = 1.16 min; MS (ESIpos): m/z = 487 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.687 (1.49), 0.706 (1.59), 0.721 (2.06), 0.732 (2.15), 2.398 (16.00), 2.518 (1.85), 3.489 (1.22), 3.664 (1.54), 3.702 (1.14), 6.994 (1.07), 7.007 (1.10), 7.297 (2.29), 8.282 (1.44), 8.294 (1.38).
Example 16.02.05
cyclobutyl{(2R)5S)-2,5-dimethyl-4-[(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)methyl]pi erazin-1 -yl}methanone
Figure imgf000673_0002
Starting with crude N-(4-{[(2S,5R)-2,5-dimethylpiperazin-1-yl]methyl}pyridin-2-yl)-6-(3-methyl- 1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2-amine hydrochloride (90.0 mg, approx. 159 pmol)and cyclobutanecarboxylic acid (47.9 mg, 478 μητιοΙ) Example 16.02.05 was prepared analogously to the procedure for the preparation of Example 02.02.
Yield: 34.0 mg of the title compound.
LC-MS (Method 2): Rt = 1.23 min; MS (ESIpos): m/z = 501 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.913 (1.23), 1.208 (1.18), 2.196 (1.27), 2.224 (1.33), 2.397 (16.00), 3.418 (1.16), 3.456 (1.51 ), 6.978 (1.17), 6.991 (1.18), 7.286 (1.93), 8.273 (1.69), 8.285 (1.60).
Example 16.03.01
tert-butyl (3R)-3-methyl-4-[(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazine-1-carboxylate
Figure imgf000674_0001
A mixture of tert-butyl (3R)-4-({2-[(6-{[(ethanimidoylamino)oxy]carbonyl}-1 H-benzimidazol-2- yl)amino]pyridin-4-yl}methyl)-3-methylpiperazine-1 -carboxylate (510 mg, 976 pmol) and sodium acetate (88.1 mg, 1.07 mmol) in 1-propanol (20 mL, 270 mmol) and water (10 mL) was heated to 100° C in a microwave oven for 40 h. The solvent was removed in vacuum. Aminophase-silicagel chromatography gave 310 mg (57 % yield) of the title compound.
LC-MS (Method 2): R, = 1.33 min; MS (ESIpos): m/z = 505 [M+H]+
1H-NMR (400MHz, DMSC-d6): δ [ppm]= 0.98 - 1.06 (m, 3H), 1.39 (s, 9H), 2.08 - 2.15 (m, 1 H), 2.39 (s, 7H), 2.45 (br s, 1 H), 2.56 - 2.64 (m, 1 H), 3.06 - 3.16 (m, 1 H), 3.45 - 3.64 (m, 2H), 3.88 (br d, 1 H), 6.96 (d, 1 H), 7.20 (s, 1 H), 7.51 (br s, 1 H), 7.79 (br d, 1 H), 7.90 - 8.41 (m, 2H), 10.84 (br s, 1 H), 12.45 (br s, 1 H). Example 16.03.02
3,3,3-trifluoro-1 -{(3R)-3-methyl-4-[(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol- 2-yl]amino}pyridin-4-yl)methyl]piperazin-1-yl}propan-1-one
Figure imgf000675_0001
To a stirred solution of crude 6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-N-(4-{[(2R)-2-methylpiperazin- 1 -yl]methyl}pyridin-2-yl)-1 H-benzimidazol-2-amine hydrochloride (75.0 mg, approx. 143 pmol) in DMF (5 mL) was added potassium carbonate (98.8 mg, 715 pmol) , 3,3,3-trifluoropropanoic acid (54.9 mg, 429 μιτιοΙ) and HATU (163 mg, 429 pmol). The mixture was stirred at r.t. for 2 h. A solution of sodium bicarbonate was added, the mixture was stirred for 15 minutes and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate), filtered and the solvent was removed in vacuum. Aminophase-silicagel chromatography gave a solid that was triturated with dichloromethane / hexane to give 52.0 mg of the title compound.
LC-MS (Method 1 ): R, = 0.78 min; MS (ESIpos): m/z = 515 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.042 (2.76), 1.058 (2.92), 1.070 (2.86), 1.086 (2.79), 2.398 (16.00), 3.621 (1.41 ), 3.649 (1.28), 6.976 (1.35), 6.989 (1.35), 7.213 (2.17), 8.281 (1.84), 8.294 (1.74).
Example 16.03.03
2-cyclopropyl-1 -{(3R)-3-methyl-4-[(2-{[6-(3-methy!-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol- 2-yl]amino}pyridin-4-yl)methyl]piperazin-1-yl}ethanone
Figure imgf000676_0001
To a stirred solution of crude 6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-N-(4-{[(2R)-2-methylpiperazin- 1 -yl]methyl}pyridin-2-yl)-1 H-benzimidazol-2 -amine hydrochloride (75.0 mg, approx. 143 pmol) in DMF (5 mL) was added potassium carbonate (98.8 mg, 715 μιτιοΙ), cyclopropylacetic acid (42.9 mg, 429 pmol) and HATU (163 mg, 429 pmol). The mixture was stirred at r.t. for 2 h. A solution of sodium bicarbonate was added, the mixture was stirred for 15 minutes and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate), filtered and the solvent was removed in vacuum. Aminophase-silicagel chromatography gave a solid that was triturated with dichloromethane / hexane to give 40.0 mg of the title compound.
LC-MS (Method 2): F¾ = 1.12 min; MS (ESIpos): m/z = 487 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.090 (1.09), 0.094 (1 .19), 0.103 (1.90), 0.1 1 1 (1.28), 0.423 (1.10), 0.427 (1.18), 0.438 (1.19), 0.442 (1.29), 1.038 (2.00), 1.055 (3.82), 1.071 (2.12), 2.228 (1.40), 2.245 (1.58), 2.256 (1.18), 2.397 (16.00), 2.518 (1.67), 2.523 (1.27), 3.254 (1.34), 3.291 (1.49), 6.974 (1.08), 6.989 (1.09), 7.201 (1.92), 8.279 (1.60), 8.292 (1.49).
Example 16.03.04
cyclopropyl{(3R)-3-methyl-4-[(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yi)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1-yl}methanone
Figure imgf000677_0001
To a stirred solution of crude 6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-N-(4-{[(2R)-2-methylpiperazin- 1 -yl]methyl}pyridin-2-yl)-1 H-benzimidazol-2-amine hydrochloride (75.0 mg, approx. 143 pmol) in DMF (5 mL) was added potassium carbonate (98.8 mg, 715 μητιοΙ), cyclopropanecarboxylic acid (36.9 mg, 429 pmol) and HATU (163 mg, 429 pmol). The mixture was stirred at r.t. for 14 h. A solution of sodium bicarbonate was added, the mixture was stirred for 15 minutes and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate), filtered and the solvent was removed in vacuum. Aminophase-silicagel chromatography gave a solid that was triturated with dichloromethane / hexane to give 55.0 mg of the title compound.
LC-MS (Method 2): R, = 1.09 min; MS (ESIpos): m/z = 473 [M+H]+
H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.683 (1.85), 0.703 (2.40), 0.722 (2.00), 1.078 (1.22), 2.399 (16.00), 6.984 (1.26), 6.999 (1.25), 7.218 (2.49), 8.283 (1 .70), 8.296 (1.64).
Example 16.03.05
cyclobutyl{(3R)-3-methyl-4-[(2-{[6-(3-methyl-1,2,4-oxadiazol-5-yl)-1H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}methanone
Figure imgf000678_0001
To a stirred solution of crude 6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-N-(4-{[(2R)-2-methylpiperazin- 1-yl]methyl}pyridin-2-yl)-1 H-benzimidazol-2-amine hydrochloride (75.0 mg, approx. 143 μιτιοΙ) in DMF (5 mL) was added potassium carbonate (98.8 mg, 715 μιηοΙ), cyclobutanecarboxylic acid (42.9 mg, 429 pmol) and HATU (163 mg, 429 pmol). The mixture was stirred at r.t. for 2 h. A solution of sodium bicarbonate was added, the mixture was stirred for 15 minutes and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate), filtered and the solvent was removed in vacuum. Aminophase-silicagel chromatography gave a solid that was triturated with dichloromethane / hexane to give 51.0 mg of the title compound.
LC-MS (Method 2): R, = 1.15 min; MS (ESIpos): m/z = 487 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.027 (2.71 ), 1.039 (3.40), 1.043 (3.55), 1.055 (2.68), 2.063 (1.27), 2.071 (1.35), 2.397 (16.00), 2.518 (1.61 ), 2.523 (1.18), 3.283 (1.13), 6.969 (1.08), 6.982 (1.10), 7.193 (2.18), 8.276 (1.41 ), 8.289 (1.34).
Example 16.04.01
tert-butyl 3,3-dimethyl-4-[(2-{[6-(3-methyl-1,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazine-1-carboxylate
Figure imgf000678_0002
To a stirred solution of 1 H-imidazole (65.9 mg, 967 μιηοΙ) and di-1 H-imidazol-1- ylmethanethione (907 mg, 95 % purity, 4.84 mmol) in dichloromethane (20 ml_) was added tert-butyl 4-[(2-aminopyridin-4-yl)methyl]-3,3-dimethylpiperazine-1-carboxylate (1.55 g, 4.84 mmol) , dissolved in dichloromethane (10 ml_) at 0° C. The mixture was stirred at r.t. for 14 h. 4-(3-methyl-1 ,2,4-oxadiazol-5-yl)benzene-1 ,2-diamine (920 mg, 4.84 mmol) , dissolved in dichloromethane (10 mL) was added and the mixture was stirred at r.t. for 14 h. Water was added and the mixture was extracted with dichloromethane / methanol (100:1 ). The organic phase was dried (sodium sulfate), filtered and the solvent was removed in vaccuum. The residue was dissolved in dichloromethane (60 mL) and N,N'-dipropan-2-ylcarbodiimide (1.9 mL, 12 mmol) was added. The mixture was stirred at r.t. for 56 h. Sodium carbonate solution was added he mixture was extracted with dichloromethane / methanol (100:1 ) and the solvent was removed in vacuum. The residue was triturated with a mixture of ethanol and hexane to give 1.1 g of the title compound.
LC-MS (Method 2): Rt = 1.41 min; MS (ESIpos): m/z = 519 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.045 (8.53), 1.402 (16.00), 2.347 (0.68), 2.396 (5.52), 3.173 (0.79), 3.51 1 (1.27), 8.253 (0.76), 8.267 (0.73).
Example 16.04.02
1-{3,3-dimethyl-4-[(2-{[6-(3-methyl-1,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1-yl}-3,3,3-trifluoropropan-1-one
Figure imgf000679_0001
Starting with crude N-{4-[(2,2-dimethylpiperazin-1 -yl)methyl]pyridin-2-yl}-6-(3-methyl-1 ,2,4- oxadiazol-5-yl)-1 H-benzimidazol-2-amine hydrochloride (200 mg, approx. 330 μηιοΙ) and 3,3,3- trifluoropropanoic acid (44 μΙ, 490 pmol) Example 16.04.02 was prepared analogously to the procedure for the preparation of Example 16.01.02.
Yield: 130.0 mg of the title compound.
LC-MS (Method 2): R, = 1.19 min; MS (ESIpos): m/z = 529 [M+H]+ Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.044 (13.97), 1.080 (12.82), 2.355 (0.83), 2.368 (1.33), 2.382 (1.15), 2.397 (16.00), 2.414 (1.48), 2.427 (0.96), 3.306 (2.51 ), 3.425 (0.90), 3.439 (1.29), 3.452 (1.23), 3.470 (0.97), 3.516 (2.63), 3.526 (2.79), 3.561 (0.56), 3.589 (1.42), 3.616 (1.35), 3.633 (0.71 ), 3.661 (1.75), 3.688 (1.64), 3.716 (0.51 ), 6.998 (1.29), 7.010 (1.18), 7.222 (1.51 ), 7.472 (0.56), 7.492 (0.64), 7.797 (0.83), 7.818 (0.59), 8.233 (0.98), 8.271 (1.37), 8.284 (1.16), 10.897 (0.60), 12.475 (1.40).
Example 16.04.03
2-cyclopropyl-1 -{3,3-dimethyl-4-[(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol- 2-yl]amino}pyridin-4-yl)methyl]piperazin-1-yl}ethanone
Figure imgf000680_0001
Starting with crude N-{4-[(2,2-dimethylpiperazin-1 -yl)methyl]pyridin-2-yl}-6-(3-methyl-1 ,2,4- oxadiazol-5-yl)-1 H-benzimidazol-2-amine hydrochloride (120 mg, approx. 198 pmol)and cyclopropylacetic acid (29 μΙ, 95 % purity, 300 pmol) Example 16.04.03 was prepared analogously to the procedure for the preparation of Example 16.0 .02.
Yield: 90.0 mg of the title compound.
LC-MS (Method 2): R, = 1.19 min; MS (ESIpos): m/z = 501 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.097 (1.64), 0.1 10 (2.84), 0.1 19 (1.86), 0.417 (0.96), 0.427 (2.63), 0.431 (2.70), 0.437 (1.44), 0.442 (1.39), 0.447 (2.81 ), 0.452 (2.70), 0.462 (0.91 ), 1.033 (10.16), 1.059 (10.62), 2.228 (1.97), 2.245 (2.30), 2.251 (2.39), 2.268 (1.89), 2.323 (0.98), 2.335 (1.28), 2.392 (16.00), 3.257 (2.18), 3.305 (1.48), 3.331 (10.35), 3.414 (1.18), 6.989 (1.35), 7.001 (1.31 ), 7.222 (1.73), 8.262 (1.48), 8.275 (1.37), 12.473 (1.50). Example 16.04.04
cyclopropyl{3,3-dimethyl-4-[(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1-yl}methanone
Figure imgf000681_0001
Starting with crude N 4-[(2,2-dimethylpiperazin-1 -yl)methyl]pyridin-2-yl}-6-(3-methyl-1 ,2,4- oxadiazol-5-yl)-1 H-benzimidazol-2-amine hydrochloride (200 mg, approx. 330 pmol)and cyclopropanecarboxylic acid (41 μΙ, 95 % purity, 490 μιηοΙ) Example 16.04.04 was prepared analogously to the procedure for the preparation of Example 16.01.02.
Yield: 120.0 mg of the title compound.
LC-MS (Method 2): R, = 1.17 min; MS (ESIpos): m/z = 487 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.679 (1.19), 0.686 (2.31 ), 0.692 (1.75), 0.700 (1.32), 0.707 (2.72), 0.712 (1.56), 0.719 (1.67), 0.724 (1.97), 0.730 (2.27), 0.735 (2.39), 0.742 (1.28), 1.025 (2.67), 1.095 (5.12), 2.323 (0.84), 2.327 (1.01 ), 2.331 (0.96), 2.397 (14.05), 3.337 (16.00), 7.003 (1.10), 7.015 (1.04), 7.230 (1.76), 8.271 (1.12), 8.283 (1.01 ), 12.482 (1.19).
Example 16.04.05
cyclobutyl{3,3-dimethyl-4-[(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1-yl}methanone
Figure imgf000681_0002
Starting with crude N-{4-[(2,2-dimethylpiperazin-1 -yl)methyl]pyridin-2-yl}-6-(3-methyl-1 ,2,4- oxadiazol-5-yl)-1 H-benzimidazol-2 -amine hydrochloride (120 mg, approx. 198 pmol)and cyciobutanecarboxylic acid (30 μΙ, 95 % purity, 300 pmol) Example 16.04.05 was prepared analogously to the procedure for the preparation of Example 16.01.02.
Yield: 70.0 mg of the title compound.
LC-MS (Method 2): R, = 1.23 min; MS (ESIpos): m/z = 501 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.025 (12.38), 1.048 (11.54), 2.055 (1.45), 2.064 (1.00), 2.074 (2.75), 2.078 (1.66), 2.085 (1.15), 2.140 (1.77), 2.145 (1.25), 2.161 (1.91 ), 2.168 (1.53), 2.185 (0.93), 2.190 (1.08), 2.327 (1.87), 2.341 (1.76), 2.397 (16.00), 3.152 (2.19), 3.285 (2.16), 3.504 (3.52), 6.989 (1.16), 7.221 (1.91 ), 8.230 (0.99), 8.266 (1.30), 8.278 (1.02), 12.475 (1.47).
Example 16.05.01
(rac)-tert-butyl 4-[1-(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazine-1-carboxylate
Figure imgf000682_0001
To a stirred solution of 1 H-imidazole (52.5 mg, 772 pmol) and di-1 H-imidazol-1 - ylmethanethione (917 mg, 90 % purity, 4.63 mmol) in dichloromethane (30 mL) was added (rac)-tert-butyl 4-[1-(2-aminopyridin-4-yl)ethyl]piperazine-1 -carboxylate (1.18 g, 3.86 mmol), dissolved in dichloromethane (30 mL) at 0° C. The m ixture was stirred at r.t. for 14 h. 4-(3- methyl-1 ,2,4-oxadiazol-5-yl)benzene-1 ,2-diamine (908 mg, 97 % purity, 4.63 mmol), dissolved in dichloromethane (15 mL) was added and the mixture was stirred at r.t. for 2 h. Water was added and the mixture was extracted with dichloromethane. The organic phase was dried (sodium sulfate) and filtered. N,N'-dipropan-2-ylcarbodiimide (0.87 mL, 5.4 mmol) was added. The mixture was stirred at r.t. for 4 h. Further N,N'-dipropan-2-ylcarbodiimide (0.43 mL, 2.7 mmol) was added and the mixture was stirred at r.t. for 56 h. Saturated sodium chloride solution was added, the mixture was stirred for 30 minutes and was extracted with dichloromethane, dried (sodium sulfate) and the solvent was removed in vacuum. Aminophase-silicagel chromatography followed by silicagel chromatography gave a solid that was triturated with ethanol to give 980 mg of the title compound. LC-MS (Method 2): R, = 1.32 min; MS (ESipos): m/z = 505 [M+H]+
1 H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.156 (0.68), 1.170 (1.63), 1.185 (0.75), 1.278 (1.86), 1.292 (1.83), 1.369 (3.94), 1.375 (16.00), 1.986 (2.85), 2.397 (5.60), 3.333 (5.91), 4.032 (0.64), 5.758 (1.40), 7.164 (0.91 ).
Example 16.05.02
(rac)-3,3,3-trifluoro-1 -{4-[1 -(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}propan-1 -one
Figure imgf000683_0001
To a stirred solution of crude (rac)-6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-N-{4-[1 -(piperazin-1 - yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride (1.20 g, approx. 2.39 mmol) in DMF (30 ml_) was added sodium bicarbonate (1.20 g, 14.3 mmol), 3,3,3-trifluoropropanoic acid (380 pi, 4.3 mmol) and HATU (2.00 g, 5.25 mmol). The mixture was stirred at room temperature for 3 h. Water was added, the mixture was stirred for 15 minutes and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Aminophase- silicagel chromatography followed by silicagel chromatography gave 760 mg of the title compound.
LC-MS (Method 2): R, = 1.10 min; MS (ESipos): m/z = 515 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.31 (d, 3H), 2.29 - 2.48 (m, 7H), 3.40 - 3.54 (m, 5H), 3.63 (q, 2H), 7.00 (br d, 1 H), 7.18 (s, 1 H), 7.37 - 8.40 (m, 4H), 10.91 (br s, 1 H), 12.49 (br s, 1 H). Example 16.05.03
(rac)-cyclopropyl{4-[1 -(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}methanone
Figure imgf000684_0001
Starting with crude (rac)-6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-N-{4-[(1 -(piperazin-1-yl)ethyl]pyridin- 2-yl}-1 H-benzimidazol-2-amine hydrochloride (255 mg, approx. 406 pmol)and cyclopropanecarboxylic acid (105 mg, 1.22 mmol) Example 16.05.03 was prepared analogously to the procedure for the preparation of Example 02.02.
Yield: 139.0 mg of the title compound.
LC-MS (Method 2): Rt = 1.07 min; MS (ESIpos): m/z = 473 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm]= 0.60 - 0.75 (m, 4H), 1.31 (d, 3H), 1.85 - 2.00 (m, 1 H), 2.41 (s, 7H), 3.48 (br d, 3H), 3.68 (br s, 2H), 6.94 - 7.07 (m, 1 H), 7.19 (s, 1 H), 7.38 - 8.38 (m, 4H), 10.91 (br s, 1 H), 12.49 (br s, 1 H).
Example 16.06.01. A
tert-butyl 4-[(1 R or 1S)-1 -(2-{[6-(3-methyl-1,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazine-1-carboxylate (single stereoisomer A)
Figure imgf000684_0002
To a stirred solution of 1 H-imidazole (33.6 mg, 493 pmol) and di-1 H-imidazol-1- ylmethanethione (523 mg, 2.94 mmol) in dichloromethane (30 mL) was added tert-butyl 4-[(1 R or 1 S)-1-(2-aminopyridin-4-yl)ethyl]piperazine-1 -carboxylate (750 mg, 2.45 mmol) , dissolved in dichloromethane (30 mL) at 0° C. The mixture was stirred at r.t. for 14 h. Further di-1 H- imidazol-1 -ylmethanethione (260 mg) dissolved in dichloromethane (15 mL) was added and the mixture was stirred for 4 h. 4-(3-methyl-1 ,2,4-oxadiazol-5-yl)benzene-1 ,2-diamine (605 mg, 3.18 mmol), dissolved in dichloromethane (15 mL) was added and the mixture was stirred at r.t. for 14 h. Dioxane (40 mL) and N,N'-dipropan-2-ylcarbodiimide (760 μΙ, 4.9 mmol) was added and the mixture was heated to reflux for 4 h. Water was added, the mixture was stirred for 30 minutes and the mixture was extracted with dichloromethane, dried (sodium sulfate) and the solvent was removed in vacuum. Silicagel chromatography followed by aminophase- silicagel chromatography gave 220 mg of the title compound.
Optical rotation [a]D +28.81[from solution in D SO, c = 6.0 mg/mL)
LC-MS (Method 2): R, = 1.29 min; MS (ESIpos): m/z = 505 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.153 (1.19), 1.171 (2.41 ), 1.189 (1.18), 1.277 (1.68), 1.294 (1.69), 1.370 (1.72), 1.375 (16.00), 1.986 (4.01 ), 2.398 (4.43), 3.333 (8.90), 4.016 (0.90), 4.034 (0.89), 7.160 (0.95).
Example 16.06.02.A
3,3,3-trifluoro-1 -{4-[(1 R or 1S)-1 -(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}propan-1-one (single stereoisomer A)
Figure imgf000685_0001
Example 16.06.02.B
3,3,3-trifluoro-1 -{4-[(1 S or 1 R)-1 -(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}propan-1 -one (single stereoisomer B)
Figure imgf000686_0001
750 mg of (rac)-3,3,3-trifluoro-1 -{4-[(1 -(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol- 2-yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}propan-1 -one was separated into the single stereoisomers (Example 16.6.2. A and Example 16.6.2.B) via preparative, chiral HPLC.
Instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241 , Labcol Vario 4000,
Column: Chiralpak I A 5μ 250x30mm;
Eluent A: tert.-butyl methyl ether; Eluent B: ethanol; isocratic: 90%A+10%B;
Flow: 40.0 mL/min;
Solution:750 mg / 7.8 mL dichloromethane/methanol 1 :1
Injection: 13 x 0.6 mL
Detection: UV 325 nm
Figure imgf000686_0002
Example 16.06.02. A
LC- S (Method 2): R, = 1.13 min; MS (ESIpos): m/z = 515 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.31 (d, 3H), 2.29 - 2.47 (m, 7H), 3.40 - 3.54 (m, 5H), 3.63 (q, 2H), 7.00 (br d, 1 H), 7.18 (s, 1 H), 7.44 - 7.87 (m, 2H), 7.97 - 8.27 (m, 1 H), 8.31 (br d, 1 H), 10.74 - 11.05 (m, 1 H), 12.48 (br s, 1 H).
Example 16.06.02.B
LC-MS (Method 2): R, = 1.13 min; MS (ESIpos): m/z = 515 [M+H]+
Example 16.06.03. A
cyclopropyl{4-[(1R or 1S)-1 -(2-{[6-(3-methyl-1,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}methanone (single stereoisomer A)
Figure imgf000687_0001
Starting with crude 6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-N-{4-[(1 R or 1 S)-1-(piperazin-1 - yl)ethylJpyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride (single stereoisomer A) (100 mg, approx. 198 μιηοΙ) and cyclopropanecarboxylic acid (23 μΙ, 300 pmol), Example 16.06.03.A was prepared analogously to the procedure for the preparation of Example 05.01.
Yield: 70.0 mg of the title compound.
Optical rotation [a]D +47.2c(DMSO) (from solution in DMSO, c = 6.0 mg/mL )
LC-MS (Method 2): R, = 1.07 min; MS (ESIpos): m/z = 473 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.656 (1.40), 0.663 (3.18), 0.669 (2.03), 0.675 (1.67), 0.682 (3.92), 0.687 (3.54), 0.691 (3.80), 0.698 (3.30), 0.703 (3.74), 0.710 (1.79), 0.81 1 (1.03), 0.828 (1.72), 0.833 (0.78), 0.837 (0.95), 0.847 (1.05), 0.855 (1.93), 0.933 (0.92), 0.950 (0.96), 1.233 (1.40), 1.293 (6.16), 1.310 (6.16), 1.915 (0.75), 1.922 (0.85), 1.935 (1.35), 1.947 (0.80), 1.954 (0.73), 2.327 (0.87), 2.398 (16.00), 2.523 (1.30), 2.619 (0.67), 3.462 (2.74), 3.478 (2.68), 3.673 (1.63), 5.760 (0.78), 6.994 (1.39), 7.175 (3.19), 7.495 (0.84), 7.799 (0.96), 8.236 (1.28), 8.303 (1.51 ), 12.474 (1.58).
The Example compounds in the following table 8 were synthesized in analogy to the preparation of Example 1 17.02, followed by purification by preparative reverse phase HPLC or silicagel chromatography.
Table 8:
Figure imgf000689_0001
Structure
lUPAC-Name
Example LC-MS (method): Retention time; Mass found
1 H-NMR
Starting materials (SM):
Example H ^ H 3
16.06.05
C H 3
((1 RS)-2,2-difluorocyclopropyl){4-[(1 R or 1 S)-1 -(2-{[6-(3-methyl-1 ,2,4- oxadiazol-5-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazin- 1 -yl}methanone
LC-MS (Method 2): R, = 1.12 min; MS (ESIneg): m/z = 507 [M-H]"
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.295 (5.02), 1.31 (5.05), 1.793 (0.46), 1.810 (0.52), 1.822 (0.53), 1.840 (0.52), 1.853 (0.49), 1.859 (0.56), 1.873 (0.67), 1.892 (0.62), 1.905 (0.40), 2.306 (0.47), 2.323 (0.70), 2.327 (0.76), 2.332 (0.80), 2.361 (0.87), 2.371 (0.73), 2.398 (16.00), 2.442 (1.05), 2.449 (1.00), 2.518 (1.27), 2.523 (0.92), 3.074 (0.43), 3.095 (0.48), 3.103 (0.55), 3.109 (0.56), 3.122 (0.49), 3.129 (0.59), 3.137 (0.49), 3.157 (0.41 ), 3.482 (1.06), 3.490 (1.32), 3.498 (1.35), 3.506 (1.49), 3.516 (1.23), 3.523 (1.22), 3.539 (0.78), 3.547 (0.69), 3.562 (0.82), 3.572 (0.64), 3.618 (0.61 ), 3.634 (0.54), 6.991 (0.98), 7.003 (0.91 ), 7.180 (2.15), 7.475 (0.43), 7.495 (0.49), 7.798 (0.67), 7.818 (0.46), 8.235 (0.75), 8.301 (1.09), 8.313 (0.98), 10.910 (0.47), 12.477 (0.98).
SM: Compound 16.07 and (1 RS)-2,2-difluorocyclopropanecarboxylic acid
Structure
lUPAC-Name
Example LC-MS (method): Retention time; Mass found
1 H-NMR
Starting materials (SM):
Example C H
16.06.06
C H 3
2-hydroxy-2-methyl-1 -{4-[(1 R or 1 S)-1 -(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5- yl)-1 H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}propan- 1-one
LC-MS (Method 2): R, = 1.02 min; MS (ESIneg): m/z = 489 [M-H]"
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.278 (16.00), 1.287 (3.46), 1.304 (2.87), 2.322 (0.53), 2.327 (0.46), 2.336 (0.67), 2.350 (0.75), 2.397 (10.66), 3.432 (0.81 ), 3.449 (0.82), 5.365 (2.64), 6.974 (0.81 ), 6.976 (0.82), 6.987 (0.82), 6.989 (0.82), 7.168 (1.53), 7.785 (0.60), 7.807 (0.51 ), 8.291 (1.29), 8.304 (1.21 ).
SM: Compound 16.07 and 2-hydroxy-2-methylpropanoic acid
Example 17.01
tert-butyl 4-[(2-{[6-(3-cyclopropyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2
yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate
Figure imgf000692_0001
A mixture of tert-butyl 4-[(2-{[6-({[(cyclopropylcarbonoimidoyl)amino] oxy}carbonyl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate (7.50 g, 14.0 mmol) and sodium acetate (1.27 g, 15.4 mmol) in 1 -propanol (330 mL) and water (170 mL) was heated to 100° C for 72 h. The mixture was concentrated in va cuum, a half-saturated solution of sodium bicarbonate was added and the mixture was extracted with dichloromethane / methanol (9:1 ). The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate), filtered and the solvent was removed in vacuum. Aminophase-silicagel chromatography gave 6.40 g (88 % yield) of the title compound.
LC-MS (Method 2): R, = 1.41 min; MS (ESIpos): m/z = 517 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.986 (0.62), 0.992 (0.68), 0.997 (0.63), 1.004 (0.69), 1.054 (0.62), 1.085 (0.60), 1.106 (0.67), 1.395 (16.00), 2.162 (0.45), 2.346 (0.86), 2.359 (1.29), 2.371 (0.95), 2.518 (1.44), 2.523 (1.03), 3.347 (1.37), 3.360 (0.90), 3.507 (1.66), 5.755 (0.47), 8.271 (0.74), 8.284 (0.73).
Example 17.02
1 -{4-[(2- [6-(3-cyclopropyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1-yl}-3,3,3-trifluoropropan-1-one
Figure imgf000693_0001
To a stirred solution of crude 6-(3-cyclopropyl-1 ,2,4-oxadiazol-5-yl)-N-[4-(piperazin-1- ylmethyl)pyridin-2-yl]-1 H-benzimidazol-2-amine hydrochloride (100 mg, approx. 221 pmol) in DMF (2 mL) was added DIPEA (190 μΙ, 1.1 mmol), T3P (230 μΙ, 50 % in DMF, 400 pmol) and 3,3,3-trifluoropropanoic acid (34 μΙ, 98 % purity, 380 pmol). The mixture was stirred at r.t. for 14 h. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate), filtered and the solvent was removed in vacuum. Aminophase-silicagel chromatography gave 19.0 mg of the title compound.
LC-MS (Method 1 ): R, = 0.92 min; MS (ESIpos): m/z = 527 [M+H]+
1H-NMR (300MHz, DMSO-d6): δ [ppm]= 0.94 - 1.14 (m, 4H), 2.09 - 2.21 (m, 1 H), 2.32 - 2.45 (m, 4H), 3.40 - 3.56 (m, 6H), 3.64 (q, 2H), 6.96 (br d, 1 H), 7.17 (s, 1 H), 7.36 - 8.35 (m, 4H), 10.92 (br s, 1 H), 12.47 (br s, 1 H).
Example 17.03
2-cyclopropyl-1 -{4-[(2-{[6-(3-cyclopropyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1-yl}ethanone
Figure imgf000694_0001
Starting with crude 6-(3-cyclopropyl-1 ,2,4-oxadiazol-5-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2- yl]-1 H-benzimidazol-2-amine hydrochloride (310 mg, approx. 548 pmol)and cyclopropylacetic acid (74 μΙ, 98 % purity, 820 pmol) Example 17.03. was prepared analogously to the procedure for the preparation of Example 16.01.02.
Yield: 150.0 mg of the title compound.
LC-MS (Method 2): R, = 1.21 min; MS (ESIpos): m/z = 499 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.000 (2.04), 0.01 1 (7.50), 0.014 (6.93), 0.023 (7.67), 0.026 (7.29), 0.037 (2.48), 0.330 (2.56), 0.340 (6.58), 0.344 (6.76), 0.350 (3.41 ), 0.354 (3.1 1 ), 0.360 (7.06), 0.364 (6.77), 0.374 (2.48), 0.818 (0.62), 0.822 (0.79), 0.835 (1.46), 0.838 (1.50), 0.842 (1.44), 0.847 (1.20), 0.854 (2.45), 0.859 (1.39), 0.862 (1.23), 0.867 (1.43), 0.871 (1.52), 0.874 (1.41 ), 0.890 (2.04), 0.902 (7.07), 0.908 (6.74), 0.914 (6.44), 0.920 (8.15), 0.928 (2.70), 0.939 (1.62), 0.954 (0.64), 0.975 (0.46), 0.991 (2.41 ), 0.999 (6.10), 1.006 (4.83), 1.01 1 (4.04), 1.020 (6.74), 1.027 (5.07), 1.039 (1.83), 2.044 (1.17), 2.056 (2.22), 2.064 (2.59), 2.077 (4.54), 2.089 (2.40), 2.097 (2.69), 2.109 (1.14), 2.151 (12.69), 2.168 (12.24), 2.237 (0.59), 2.241 (0.81 ), 2.247 (0.78), 2.278 (5.47), 2.296 (5.74), 2.309 (6.09), 2.437 (1.58), 2.579 (0.43), 2.584 (0.56), 2.589 (0.42), 3.370 (5.03), 3.380 (4.54), 3.405 (5.07), 3.430 (16.00), 6.363 (0.47), 6.608 (0.48), 6.878 (3.57), 6.890 (3.69), 7.100 (9.00), 7.393 (1.16), 7.571 (0.50), 7.668 (2.20), 7.888 (0.63), 8.130 (1.65), 8.192 (6.66), 8.205 (6.46), 10.81 1 (1.46), 12.377 (4.51 ).
Example 17.04
1 -{4-[(2-{[6-(3-cyclopropyl-1 ,2,4-oxadiazol-5-yl)-1H-benzimidazol-2-yl]amino}pyridin-4 yl)methyl]piperazin-1-yl}but-3-en-1 -one
Figure imgf000695_0001
Starting with crude 6-(3-cyclopropyl-1 ,2,4-oxadiazol-5-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2- yl]-1 H-benzimidazol-2-amine hydrochloride (80.0 mg, approx. 141 pmol)and but-3-enoic acid (19 μΙ, 97 % purity, 210 pmol) Example 17.04. was prepared analogously to the procedure for the preparation of Example 16.01.02.
Yield: 60.0 mg of the title compound.
LC-MS (Method 2): R, = 1.18 min; MS (ESIpos): m/z = 485 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.975 (1.61 ), 0.987 (5.70), 0.993 (6.21 ), 0.998 (5.70), 1.000 (5.29), 1.004 (6.04), 1.013 (2.47), 1.042 (0.52), 1.077 (2.30), 1.086 (5.84), 1.092 (4.43), 1.097 (3.74), 1.107 (6.32), 1.1 13 (4.77), 1.125 (1.75), 1.818 (0.65), 1.822 (0.65), 1.835 (0.62), 1.839 (0.62), 1.955 (0.48), 2.131 (1.13), 2.143 (2.16), 2.151 (2.44), 2.155 (1.34), 2.163 (4.26), 2.172 (1.55), 2.175 (2.20), 2.184 (2.06), 2.196 (0.96), 2.318 (0.48), 2.323 (0.96), 2.327 (1.34), 2.332 (1.06), 2.337 (0.86), 2.349 (3.36), 2.361 (5.25), 2.375 (4.19), 2.392 (4.33), 2.404 (5.42), 2.416 (3.67), 2.518 (3.43), 2.523 (2.33), 2.665 (0.86), 2.669 (1.13), 2.674 (0.79), 2.782 (0.45), 2.942 (0.69), 3.133 (5.25), 3.137 (9.13), 3.141 (5.42), 3.150 (5.53), 3.153 (9.13), 3.157 (5.15), 3.472 (8.52), 3.482 (8.34), 3.519 (16.00), 5.069 (5.53), 5.073 (11.64), 5.076 (5.60), 5.093 (1.30), 5.097 (3.33), 5.101 (5.32), 5.105 (2.33), 5.109 (2.20), 5.113 (5.29), 5.1 18 (3.91 ), 5.122 (1.20), 5.826 (1.34), 5.843 (3.12), 5.850 (0.72), 5.854 (0.86), 5.859 (1.37), 5.867 (2.13), 5.871 (2.06), 5.883 (2.13), 5.888 (2.23), 5.895 (1.17), 5.899 (0.65), 5.904 (0.86), 5.911 (2.44), 5.928 (1.03), 6.965 (3.78), 6.978 (3.71 ), 7.187 (7.35), 7.483 (0.69), 7.750 (2.44), 7.769 (1.99), 8.210 (0.76), 8.278 (6.94), 8.292 (6.49), 10.894 (1.10), 12.473 (2.20). Example 17.05
cyclopropyl{4-[(2-{[6-(3-cyclopropyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}methanone
Figure imgf000696_0001
Starting with crude 6-(3-cyclopropyl-1 ,2,4-oxadiazol-5-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2- yl]-1 H-benzimidazol-2-amine hydrochloride (6.10 g, approx. 13.5 mmol)and cyclopropanecarboxylic acid (2.7 mL, 98 % purity, 34 mmol) Example 17.05. was prepared analogously to the procedure for the preparation of Example 02.02.
Yield: 5.12 g of the title compound.
LC-MS (Method 2): R, = 1.15 min; MS (ESIpos): m/z = 485 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm]= 0.63 - 0.79 (m, 4H), 0.97 - 1.03 (m, 2H), 1.07 - 1.14 (m, 2H), 1.89 - 2.03 (m, 1 H), 2.1 1 - 2.22 (m, 1 H), 2.32 - 2.48 (m, 4H), 3.43 - 3.59 (m, 4H), 3.71 (br s, 2H), 6.99 (d, 1 H), 7.20 (s, 1 H), 7.33 - 8.39 (m, 4H), 10.91 (br s, 1 H), 12.49 (br s, 1 H).
Example 17.06
cyclobutyl{4-[(2-{[6-(3-cyclopropyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1-yl}methanone
Figure imgf000696_0002
To a stirred solution of crude 6-(3-cyclopropyl-1 ,2,4-oxadiazol-5-yl)-N-[4-(piperazin-1 - ylmethyl)pyridin-2-yl]-1 H-benzimidazol-2-amine hydrochloride (100 mg, approx. 221 pmol) in DMF (2 mL) was added DIPEA (190 μΙ, 1.1 mmol), T3P (230 μΙ, 50 % in DMF, 400 pmol) and cyclobutanecarboxylic acid (34 μΙ, 98 % purity, 380 pmol). The mixture was stirred at r.t. for 2 h. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate), filtered and the solvent was removed in vacuum. Aminophase-silicagel chromatography gave 68.0 mg of the title compound.
LC-MS (Method 1 ): F¾ = 0.89 min; MS (ESIpos): m/z = 499 [M+H]+
1 H-NMR (400MHz, DMSO-d6): δ [ppm]= 0.94 - 1.02 (m, 2H), 1 .05 - 1.14 (m, 2H), 1.65 - 1.78 (m, 1 H), 1.80 - 1.93 (m, 1 H), 2.00 - 2.20 (m, 5H), 2.34 (br s, 4H), 3.33 (br s, 3H), 3.41 - 3.53 (m, 4H), 6.95 (br d, 1 H), 7.17 (s, 1 H), 7.34 - 8.35 (m, 4H), 10.86 (br s, 1 H), 12.45 (br s, 1 H).
Example 17.07
N-(4-{[4-(2-chlorophenyl)piperazin-1-yl]methyl}pyridin-2-yl)-6-(3-cyclopropyl-1 ,2,4- oxadiazol-5-yl)-1 H-benzimidazol-2-amine
Figure imgf000697_0001
A mixture of N-[({2-[(4-{[4-(2-chlorophenyl)piperazin-1-yl]methyl}pyridin-2-yl)amino]-1 H- benzimidazol-6-yl}carbonyl)oxy]cyclopropanecarboximidamide (160 mg, 294 μητιοΙ) and sodium acetate (26.5 mg, 323 pmol) in 1 -propanol (7.0 mL), water (3.5 mL) and DMA (700 μΙ) was heated to 100° C 30 h. The mixture was cooled to r. t. and a white solid precipitated. Filtration gave 1 10 mg (64 % yield) of the title compound.
LC-MS (Method 2): R, = 1.49 min; MS (ESIpos): m/z = 527.5 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.976 (1.51 ), 0.987 (5.57), 0.994 (6.21 ), 0.999 (5.89), 1.006 (5.87), 1.014 (2.39), 1.040 (0.65), 1.061 (0.43), 1.077 (2.29), 1.085 (5.83), 1.092 (4.50), 1.097 (3.78), 1.106 (6.35), 1.1 12 (4.78), 1 .124 (1.74), 2.130 (1.06), 2.142 (2.03), 2.150 (2.32), 2.163 (3.94), 2.174 (2.13), 2.183 (1.91 ), 2.195 (0.89), 2.322 (0.49), 2.327 (0.66), 2.331 (0.50), 2.523 (1.85), 2.599 (7.95), 2.659 (0.49), 2.664 (0.69), 2.669 (0.84), 2.674 (0.61 ), 3.022 (9.56), 3.575 (16.00), 6.992 (3.44), 7.005 (3.51 ), 7.015 (3.07), 7.020 (2.89), 7.035 (4.83), 7.039 (4.86), 7.054 (3.32), 7.057 (3.38), 7.158 (4.02), 7.162 (4.09), 7.178 (5.89), 7.182 (5.18), 7.213 (7.67), 7.278 (3.26), 7.283 (3.50), 7.297 (4.15), 7.301 (4.58), 7.317 (2.23), 7.321 (2.25), 7.388 (6.45), 7.392 (6.1 1 ), 7.407 (5.86), 7.41 1 (5.42), 7.481 (1.05), 7.756 (2.05), 7.774 (1.54), 7.975 (0.54), 8.219 (1.45), 8.291 (6.52), 8.305 (6.21 ), 10.910 (1.28), 12.476 (3.81 ).
Example 18.01
3,3,3-trifluoro-1 -(4-{[2-({6-[3-(2-methyl propyl )-1 ,2,4-oxadiazol-5-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1 -yl)propan-1 -one
Figure imgf000698_0001
Starting with crude 6-[3-(2-methylpropyl)-1 ,2,4-oxadiazol-5-yl]-N-[4-(piperazin-1- ylmethyl)pyridin-2-yl]-1 H-benzimidazol-2-amine hydrochloride (139 mg, approx. 296 μιηοΙ)3Γ^ 3,3,3-trifluoropropanoic acid (55 μΙ, 98 % purity, 590 μηιοΙ) Example 18.01. was prepared analogously to the procedure for the preparation of Example 02.02.
Yield: 40.0 mg of the title compound.
LC-MS (Method 2): R, = 1.33 min; MS (ESIpos): m/z = 543 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.974 (15.10), 0.991 (16.00), 2.1 12 (0.86), 2.130 (1.07), 2.146 (0.84), 2.327 (0.47), 2.373 (1.22), 2.386 (1.82), 2.398 (1.37), 2.414 (1.34), 2.427
(1.80) , 2.438 (1.32), 2.523 (0.96), 2.624 (4.30), 2.642 (3.99), 2.669 (0.50), 3.461 (1.30), 3.474
(1.81 ) , 3.486 (1.46), 3.497 (1.43), 3.51 1 (1.76), 3.522 (1.48), 3.535 (4.95), 3.606 (0.90), 3.634 (2.58), 3.661 (2.42), 3.688 (0.76), 6.968 (1.14), 6.982 (1.16), 7.195 (2.16), 7.794 (0.65), 8.289
(1.85), 8.302 (1.72), 12.471 (0.78).
Example 18.02
cyclopropyl(4-{[2-({6-[3-(2-methylpropyl)-1 ,2,4-oxadiazol-5-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1 -yl)methanone
Figure imgf000699_0001
A mixture of N-[({2-[(4-{[4-(cyclopropylcarbonyl)piperazin-1 -yl]methyl}pyridin-2-yl)amino]-1 H- benzimidazol-6-yl}carbonyl)oxy]-3-methylbutanimidamide (125 mg, 241 μιηοΙ) and sodium acetate (21.7 mg, 265 mol) in 1-propanol (6 mL) and water (3 mL) was heated to 100° C for 120 h. The solvent was removed in vacuum. Silicagel chromatography gave 95.0 mg (71 % yield) of the title compound.
LC-MS (Method 2): R, = 1.29 min; MS (ESIpos): m/z = 501 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.679 (1.01 ), 0.686 (2.41 ), 0.692 (1.49), 0.699 (1.15), 0.706 (2.84), 0.7 1 (2.46), 0.717 (2.59), 0.723 (2.46), 0.729 (2.88), 0.735 (1.33), 0.976 (15.35), 0.993 (16.00), 1.943 (0.59), 1.949 (0.63), 1.962 (1.04), 1.974 (0.61 ), 1.981 (0.59), 2.1 14 (0.83), 2.131 (1.08), 2.148 (0.86), 2.327 (0.59), 2.375 (1.04), 2.447 (1.06), 2.523 (1.76), 2.625 (4.28), 2.642 (4.01 ), 2.669 (0.56), 3.501 (0.97), 3.535 (5.50), 3.705 (0.95), 6.976 (1.28), 6.989 (1.31 ), 7.209 (2.19), 7.793 (0.86), 7.813 (0.70), 8.290 (2.03), 8.303 (1.94).
Example 19.01
{4-[(2-{[6-(3-cyclopentyl-1,2,4-oxadiazol-5-yl)-1H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1-yl}(cyclopropyl)methanone
Figure imgf000700_0001
A mixture of N-[({2-[(4-{[4-(cyclopropylcarbonyl)piperazin-1 -yl]methyl}pyridin-2-yl)amino]-1 H- benzimidazol-6-yl}carbonyl)oxy]cyclopentanecarboximidamide (135 mg, 254 μιτιοΙ) and sodium acetate (23.0 mg, 280 pmol) in 1 -propanol (6.5 mL) and water (3.2 mL) was heated to 100° C for 16 h. The solvent was removed in vacuum. Silicagel chromatography gave 90.0 mg (62 % yield) of the title compound.
LC-MS (Method 2): R, = 1.33 min; MS (ESIpos): m/z = 513 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.666 (0.99), 0.678 (3.12), 0.685 (7 47), 0 690 (4 50),
0 .698 (3.50), 0.704 (8.91 ), 0.709 (7.62), 0.714 (8.08), 0.721 (7.47), 0.726 (8 76), 0 733 (3 81 ),
0 746 (0.91 ), 1.229 (0.76), 1.637 (0.46), 1.652 (0.99), 1.656 (1.52), 1.659 (2 13), 1 662 (1 98),
1 666 (2.21 ), 1.675 (2.97), 1.679 (3.43), 1.686 (2.97), 1.694 (3.28), 1.699 (2 90), 1 704 (1 52),
1 718 (1.30), 1.722 (1.52), 1.728 (1.60), 1.733 (1.52), 1.746 (1.83), 1.755 (2 74), 1 758 (2 44),
1 762 (1.98), 1.765 (2.51 ), 1.769 (2.97), 1.773 (3.35), 1.777 (2.51 ), 1.790 (4 50), 1 805 (3 20),
1 814 (2.51 ), 1.821 (2.82), 1.826 (2.51 ), 1.831 (2.06), 1.840 (3.50), 1.845 (2 59), 1 852 (1 52),
1 859 (2.59), 1.865 (1.07), 1.875 (0.84), 1.932 (0.84), 1.945 (1.83), 1.952 (1 98), 1 956 (1 45),
1 964 (3.28), 1.970 (1.60), 1.976 (1.83), 1.983 (1.75), 1.995 (0.91 ), 2.010 (0 91 ), 2 019 (1 68),
2 025 (2.21 ), 2.029 (2.13), 2.034 (2.44), 2.040 (3.96), 2.043 (3.05), 2.054 (1 90), 2 060 (3 43),
2 068 (2.36), 2.077 (0.91 ), 2.085 (0.84), 2.092 (0.91 ), 2.317 (0.76), 2.322 (1 60), 2 326 (2 21 ),
2 331 (1.83), 2.336 (1.22), 2.366 (3.20), 2.444 (3.35), 2.518 (5.87), 2.522 (3 96), 2 659 (0 69),
2 664 (1.45), 2.668 (1.98), 2.673 (1.37), 2.678 (0.61 ), 3.227 (1.14), 3.247 (3 35), 3 252 (0 76),
3 266 (4.50), 3.280 (1.14), 3.285 (3.05), 3.294 (1.60), 3.499 (3.12), 3.533 (16 00), 3 705 (3 05),
5 755 (1.30), 6.972 (3.66), 6.985 (3.73), 7.204 (5.33), 7.489 (0.61 ), 7.783 (2 59), 7 804 (2 21 ),
8 239 (0.61 ), 8.284 (6.78), 8.297 (6.32), 10.891 (0.91 ), 12.481 (1.45). Example 20.01
(4-{[2-({6-[3-(butan-2-yl)-1,2,4-oxadiazol-5-yl]-1H-benzimidazol-2-yl}amino)pyridin-4- yl]methyl}piperazin-1-yl)(cyclopropyl)methanone
Figure imgf000701_0001
A mixture of N-[({2-[(4-{[4-(cyclopropylcarbonyl)piperazin-1 -yl]methyl}pyridin-2-yl)amino]-1 H- benzimidazol-6-yl}carbonyl)oxy]-2-methylbutanimidamide (190 mg, 366 μΓηοΙ) and sodium acetate (33.1 mg, 403 pmol) in 1-propanol (10 mL) and water (5 ml_) was heated to 100°C for 16 h. The solvent was removed in vacuum. Silicagel chromatography gave 100 mg (49 % yield) of the title compound.
LC-MS (Method 2): R, = 1.29 min; MS (ESIpos): m/z = 501 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.664 (0.63), 0.676 (1.80), 0.683 (4.30), 0.689 (2.67), 0.696 (2.06), 0.703 (5.19), 0.709 (4.07), 0.714 (4.44), 0.721 (4.37), 0.726 (5.18), 0.733 (2.36), 0.745 (0.60), 0.866 (6.49), 0.885 (15.58), 0.904 (7.13), 1.295 (16.00), 1.312 (15.80), 1.631 (0.67), 1.647 (1.17), 1.650 (0.86), 1.665 (2.00), 1.681 (1.44), 1.683 (1 .59), 1.699 (1.12), 1.741 (1.29), 1.759 (2.06), 1.774 (1.12), 1.778 (1.46), 1.793 (1.22), 1.812 (0.73), 1.942 (1.07), 1.949 (1.12), 1.953 (0.85), 1.961 (1.90), 1.967 (0.90), 1.973 (1.07), 1.980 (0.97), 2.366 (1.89), 2.446 (1.93), 2.899 (1.14), 2.917 (1.93), 2.933 (1.85), 2.951 (1.03), 3.501 (1.81 ), 3.531 (9.32), 3.704 (1.75), 6.974 (2.03), 6.987 (2.06), 7.194 (4.52), 7.797 (1.17), 7.818 (0.96), 8.287 (3.94), 8.299 (3.70), 12.480 (1.56).
Example 21.01
{4-[(2-{[6-(3-benzyl-1,2,4-oxadiazol-5-yl)-1H^enzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1-yl}(cyclopropyl)methanone
Figure imgf000702_0001
A mixture of N-[({2-[(4-{[4-(cyclopropylcarbonyl)piperazin-1 -yl]methyl}pyridin-2-yl)amino]-1 H- benzimidazol-6-yl}carbonyl)oxy]-2-phenylethanimidamide (235 mg, 425 pmol) and sodium acetate (38.4 mg, 468 mol) in 1 -propanol (1 1 mL) and water (5.5 mL) was heated to 100° C for 70 h. The solvent was removed in vacuum. Silicagel chromatography gave a solid that was triturated with a mixture of ethanol and water (1 : 1 ) to give 25.0 mg (10 % yield) of the title compound.
LC-MS (Method 2): F¾ = 1.28 min; MS (ESIpos): m/z = 535 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.665 (0.79), 0.676 (2.49), 0.684 (5.84), 0.689 (3.72), 0.697 (2.96), 0.704 (6.98), 0.708 (6.19), 0.713 (6.46), 0.721 (5.97), 0.725 (6.90), 0.732 (3.20), 0.745 (0.74), 1.232 (0.86), 1.931 (0.67), 1.944 (1.38), 1.950 (1.55), 1.963 (2.47), 1.975 (1.45), 1.982 (1.33), 1.994 (0.57), 2.323 (1.38), 2.327 (1.90), 2.331 (1.60), 2.337 (1.26), 2.365 (2.81 ), 2.445 (2.98), 2.523 (4.24), 2.660 (0.57), 2.665 (1.16), 2.669 (1.58), 2.673 (1.16), 2.678 (0.59), 3.495 (2.66), 3.530 (12.77), 3.702 (2.61 ), 4.146 (15.53), 6.972 (3.03), 6.984 (3.06), 7.201 (3.77), 7.250 (0.64), 7.255 (1.21 ), 7.259 (0.84), 7.265 (0.99), 7.271 (2.88), 7.278 (1.41 ), 7.283 (1.31 ), 7.288 (2.49), 7.293 (1.63), 7.332 (2.86), 7.338 (1.75), 7.348 (2.84), 7.352 (8.55), 7.370 (16.00), 7.375 (1 1.19), 7.391 (2.74), 7.396 (1.75), 7.474 (0.57), 7.769 (2.22), 7.790 (1.82), 8.228 (0.54), 8.280 (4.93), 8.294 (4.71 ), 10.896 (0.69), 12.473 (1.65).
Example 22.01
N-(4-{[4-(2-chlorophenyl)piperazin-1 -yl]methyl}pyridin-2-yl)-6-(5-cyclopropyl-1 ,2,4' oxadiazol-3-yl)-1 H-benzimidazol-2-amine
Figure imgf000703_0001
A mixture of 2-[(4-{[4-(2-chlorophenyl)piperazin-1 -yl]methyl}pyridin-2-yl)amino]-N'- [(cyclopropylcarbonyl)oxy]-1 H-benzimidazole-6-carboximidamide (160 mg, 294 pmol) and sodium acetate (26.5 mg, 323 pmol) in 1 -propanol (10 mL), water (4 mL) and DMA (1.0 mL) was heated to 100° C 14 h. Water was added and the mixture was extracted with dichloromethane/methanol (20:1 ). The organic phase was dried (sodium sulfate), filtered and the solvent was removed in vacuum. Silicagel chromatography gave a solid that was triturated with a mixture of warm ethanol and ethyl acetate (3:1 ) to give 70 mg (37 % yield) of the title compound.
LC-MS (Method 2): Rt = 1.51 min; MS (ESIpos): m/z = 527 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.167 (0.71 ), 1.179 (2.54), 1.186 (3.28), 1.191 (2.72), 1.198 (2.94), 1.206 (1.22), 1.254 (1.18), 1.263 (2.73), 1.271 (2.08), 1.275 (2.03), 1.284 (3.38), 1.291 (2.07), 1.304 (0.74), 2.350 (0.54), 2.362 (1.04), 2.370 (1.15), 2.382 (1.95), 2.391 (0.84), 2.394 (1.09), 2.403 (0.98), 2.595 (3.90), 3.019 (4.71 ), 3.313 (16.00), 6.969 (2.14), 6.982 (2.15), 7.013 (1.23), 7.017 (1.31 ), 7.033 (2.30), 7.036 (2.27), 7.051 (1.54), 7.055 (1.54), 7.154 (1.97), 7.158 (1.98), 7.174 (2.79), 7.178 (2.46), 7.207 (4.19), 7.274 (1.60), 7.278 (1.70), 7.293 (2.00), 7.297 (2.20), 7.313 (1.06), 7.317 (1.09), 7.386 (2.97), 7.389 (2.93), 7.406 (2.98), 7.410 (2.76), 7.683 (0.83), 8.276 (3.51 ), 8.288 (3.36), 10.789 (1.70), 12.362 (0.92).
Example 22.02
N-(4-{[4-(2-chlorophenyl)piperazin-1 -yl]methyl}pyridin-2-yl)-6-[5-(2,2-dimethylpropyl)- 1 ,2,4-oxadiazol-3-yl]-1 H-benzimidazol-2-amine
Figure imgf000704_0001
A mixture of 2-[(4-{[4-(2-chlorophenyl)piperazin-1 -yl]methyl}pyridin-2-yl)amino]-N'-[(3,3- dimethylbutanoyl)oxy]-1 H-benzimidazole-6-carboximidamide (130 mg, 226 pmol) and sodium acetate (20.4 mg, 249 pmol) in 1-propanol (8 mL), water (3 mL) and DMA (770 μΙ) was heated to 100° C 14 h. Water was added and the mixture was extracted with dichloromethane/methanol (20:1 ). The organic phase was dried (sodium sulfate), filtered and the solvent was removed in vacuum. Silicagel chromatography gave a solid that was triturated with warm ethyl acetate to give 80 mg (64 % yield) of the title compound.
LC-MS (Method 2): R, = 1.65 min; MS (ESIpos): m/z = 557 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.059 (16.00), 2.904 (3.28), 3.024 (1.35), 3.572 (2.30), 6.975 (0.61 ), 6.988 (0.62), 7.021 (0.42), 7.036 (0.67), 7.039 (0.71 ), 7.055 (0.49), 7.058 (0.51 ), 7.160 (0.59), 7.164 (0.61 ), 7.180 (0.85), 7.184 (0.77), 7.209 (1.23), 7.279 (0.50), 7.283 (0.53), 7.298 (0.59), 7.302 (0.66), 7.389 (0.91 ), 7.393 (0.89), 7.409 (0.91 ), 7.413 (0.83), 8.279 (1.03), 8.293 (1.00), 10.787 (0.59).
Example 23.01.01
2-cyclopropyl-1-{4-[(2-{[6-(pyrimidin-4-yl)-1H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1-yl}ethanone
Figure imgf000705_0001
Starting with crude N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]-6-(pyrimidin-4-yl)-1 H-benzimidazol- 2-amine hydrochloride (144 mg) and cydopropylacetic acid (25.6 mg, 255 prnol), Example 23.01.01 was prepared analogously to the procedure for the preparation of Example 01.02. Yield: 12.0 mg of the title compound.
LC-MS (Method 2): , = 0.96 min; MS (ESIpos): m/z = 469 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.01 (2.89), 0.014 (2.74), 0.023 (2.95), 0.026 (2.84), 0.037 (1.04), 0.330 (1.02), 0.340 (2.57), 0.345 (2.69), 0.350 (1.49), 0.355 (1.34), 0.360 (2.74), 0.365 (2.65), 0.375 (1.04), 0.854 (0.98), 1.022 (16.00), 2.154 (4.65), 2.171 (4.52), 2.242 (1.38), 2.247 (1.08), 2.279 (2.12), 2.291 (1.99), 2.31 1 (2.19), 2.434 (7.87), 2.438 (5.62), 2.584 (1.27), 2.608 (1.72), 3.373 (2.10), 3.407 (2.08), 3.431 (5.71 ), 4.1 10 (1.36), 6.864 (1.34), 6.877 (1.38), 7.1 18 (2.48), 8.189 (2.27), 8.202 (2.21 ), 8.668 (3.44), 8.682 (3.25), 9.080 (3.06), 9.083 (3.23).
Example 23.01.02
cyclopropyl{4-[(2-{[6-(pyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1-yl}methanone
Figure imgf000706_0001
Starting with crude N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-6-(pyrimidin-4-yl)-1 H-benzimidazol- 2-amine hydrochloride (144 mg) and cyclopropanecarboxylic acid (22.0 mg, 255 μιηοΙ), Example 23.01.02 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 30.0 mg of the title compound.
LC-MS (Method 2): Rt = 0.93 min; MS (ESIpos): m/z = 455 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.686 (2.19), 0.691 (1.38), 0.706 (2.81 ), 0.710 (2.27), 0.714 (2.50), 0.722 (2.31 ), 0.726 (2.65), 0.733 (1.19), 1.107 (16.00), 2.323 (1.69), 2.327 (2.42), 2.332 (1.77), 2.518 (13.54), 2.523 (9.46), 2.665 (1.65), 2.669 (2.31 ), 2.674 (1.65), 3.530 (4.00), 4.194 (1.50), 7.200 (1.65), 8.754 (2.58), 8.768 (2.42), 9.167 (1.69).
Example 23.02.01
3,3,3-trifluoro-1 -{4-[(2-methyl-6-{[6-(pyri
4-yl)methyl]piperazin-1-yl}propan-1 -one
Figure imgf000706_0002
Starting with N-[6-methyl-4-(piperazin-1-ylmethyl)pyridin-2-yl]-6-(pyrimidin-4-yl)-1 H- benzimidazol-2-amine (68.0 mg, 170 pmol) and 3,3,3-trifluoropropanoic acid (32.6 mg, 255 μητιοΙ), Example 23.02.01 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 33.0 mg (34 %) of the title compound.
LC-MS (Method 4): Rt = 1.04 min; MS (ESIpos): m/z = 51 1 [M+H]+
1 H-NMR (400 MHz, CHLOROFORM-d) δ [ppm]: 1.260 (0.99), 2.397 (2.13), 2.410 (2.53), 2.423 (1.87), 2.632 (16.00), 3.157 (1.05), 3.183 (3.12), 3.208 (3.02), 3.233 (0.95), 3.373 (1.58), 3.433 (2.72), 3.478 (5.58), 3.573 (1.43), 6.796 (1.09), 6.808 (1.65), 6.897 (2.03), 7.681 (0.99), 7.701 (1.12), 7.783 (1.86), 7.786 (1.75), 7.797 (1.91 ), 7.800 (1.71 ), 7.956 (1.01 ), 7.960 (1.19), 7.977 (0.81 ), 7.981 (0.82), 8.345 (1.73), 8.349 (1.68), 8.737 (0.83), 8.745 (1.85), 8.751 (0.94), 8.759 (1.68), 9.243 (1.22), 9.251 (2.33), 9.254 (2.10).
Example 23.02.02
cyclopropyl{4-[(2-methyl-6-{[6-(pyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin yl)methyl]piperazin-1-yl}methanone
Figure imgf000707_0001
Starting with N-[6-methyl-4-(piperazin-1 -ylmethyl)pyridin-2-yl]-6-(pyrimidin-4-yl)-1 H- benzimidazol-2-amine (68.0 mg, 170 pmol) and cyclopropanecarboxylic acid (21.9 mg, 255 μηηοΙ), Example 23.02.02 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 33.0 mg (37 %) of the title compound.
LC-MS (Method 4): R, = 1.00 min; MS (ESIpos): m/z = 469 [M+H]+
1H-NMR (400 MHz, CHLOROFORM-d) δ [ppm]: 0.725 (2.01 ), 0.732 (2.27), 0.745 (2.17), 0.752 (2.30), 0.762 (0.85), 0.944 (0.81 ), 0.953 (2.28), 0.961 (2.27), 0.965 (2.61 ), 0.972 (2.35), 1.630 (3.34), 1.648 (1.70), 1.656 (1.31 ), 1.660 (1.18), 1.667 (1.42), 1.671 (1.04), 1.679 (0.92), 2.383 (1.40), 2.443 (1.40), 2.632 (16.00), 3.476 (5.52), 3.595 (1.69), 6.816 (1.34), 6.830 (2.48), 6.934 (3.02), 7.561 (1.07), 7.582 (1.18), 7.699 (1.60), 7.720 (1.84), 7.782 (0.83), 7.785 (1.03), 7.788 (1.65), 7.791 (1.65), 7.795 (1.00), 7.799 (1.08), 7.801 (1.69), 7.805 (1.62), 7.941 (0.78), 7.946 (0.77), 7.958 (1.49), 7.962 (2.05), 7.967 (0.80), 7.979 (1.25), 7.983 (1.26), 8.351 (2.33), 8.355 (2.27), 8.426 (1.03), 8.727 (1.42), 8.739 (2.97), 8.752 (2.54), 9.240 (1.53), 9.243 (1.64), 9.248 (2.89), 9.251 (2.93), 12.629 (1.28).
Example 23.03.01
cyclopropyl(4-{[2-{[6-(pyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}-6- (trifluoromethyl)pyridin-4-yl]methyl}piperazin-1 -yl)methanone
Figure imgf000708_0001
Starting with cyclopropyl(4-{[2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- benzimidazol-2-yl]amino}-6-(trifluoromethyl)pyridin-4-yl]methyl}piperazin-1 -yl)methanone (169 mg, 297 μιηοΙ) and 4-bromopyrimidine hydrochloride (1 :1 ) (104 mg, 535 pmol), Example 23.03.01 was prepared analogously to the procedure for the preparation of Example 01.01. Yield: 9.00 mg (6 %) of the title compound.
LC-MS (Method 2): R, = 1.09 min; MS (ESIpos): m/z = 523 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.682 (2.62), 0.702 (3.08), 0.715 (2.62), 0.722 (2.62), 0.727 (3.08), 0.734 (1.54), 1.230 (0.92), 1.972 (1.08), 2.318 (1.54), 2.323 (3.54), 2.327 (4.92), 2.332 (3.54), 2.337 (1.38), 2.410 (1.38), 2.518 (16.00), 2.523 (1 1.85), 2.660 (1.54), 2.665 (3.54), 2.669 (5.08), 2.673 (3.38), 2.679 (1.54), 3.523 (1.38), 3.634 (4.92), 3.732 (1.23), 7.219 (1.38), 7.982 (1.23), 8.180 (1.38), 8.540 (3.69), 8.640 (1.54), 8.654 (1.38), 9.075 (2.46).
Example 23.04.01
(rac)-cyclobutyl{4-[1-(2-{[6-(pyrimidin-4-yl)-1H-benzimidazol-2-yl]amino}pyridin-4' yl)ethyl]piperazin-1-yl}methanone
Figure imgf000709_0001
Starting with (rac)-N-{4-[(1 -(piperazin-1 -yl)ethyl]pyridin-2-yl}-6-(pyrimidin-4-yl)-1 H- benzimidazol-2-amine (210 mg, 524 pmol) and cyclobutanecarboxylic acid (78.7 mg, 787 μιηοΙ), Example 23.04.01 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 30.0 mg (1 1 %) of the title compound.
LC-MS (Method 2): R, = 1.07 min; MS (ESIpos): m/z = 483 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.276 (3.36), 1.293 (3.26), 1.844 (0.78), 2.031 (0.98), 2.052 (1.13), 2.061 (0.94), 2.099 (1.13), 2.121 (1.1 1 ), 2.430 (1.18), 3.275 (1.16), 3.294 (1.93), 3.307 (1.71 ), 3.318 (1.78), 3.336 (16.00), 3.429 (1.39), 3.445 (1.58), 7.173 (1.78), 8.274 (1.18), 8.286 (1.09), 8.753 (2.06), 8.766 (1.91 ), 9.167 (1.57).
Example 23.04.02
(rac)-cyclopropyl{4-[1 -(2-{[6-(pyrimidin-4-yl)-1H-benzimidazol-2-yl]amino}pyridin-4- yl)ethyl]piperazin-1-yl}methanone
Figure imgf000710_0001
Starting with (rac)-N 4-[(1 -(piperazin-1-yl)ethyl]pyridin-2-yl}-6-(pyrimidin-4-yl)-1 H- benzimidazol-2-amine (210 mg, 524 pmol) and cyclopropanecarboxylic acid (67.7 mg, 787 μιηοΙ), Example 23.04.02 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 33.5 mg (13 %) of the title compound.
LC-MS (Method 4): R, = 0.97 min; MS (ESIpos): m/z = 469 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.656 (4.11 ), 0.663 (8.74), 0.669 (6.30), 0.676 (5.23), 0.683 (10.92), 0.691 (10.79), 0.699 (9.15), 0.703 (10.07), 0.710 (4.93), 1.295 (15.98), 1.312 (16.00), 1.917 (2.10), 1.924 (2.36), 1.936 (3.58), 1.948 (2.14), 1.955 (1.91 ), 2.326 (2.74), 2.397 (3.32), 2.668 (1.13), 3.455 (6.73), 3.471 (8.23), 3.674 (4.60), 6.970 (3.83), 6.983 (3.92), 7.187 (9.13), 7.454 (1.31 ), 7.953 (2.94), 7.974 (3.25), 8.227 (1.29), 8.282 (6.17), 8.295 (5.93), 8.407 (1.95), 8.753 (8.97), 8.766 (8.48), 9.167 (8.65), 10.792 (1.22), 12.358 (1.84).
Example 23.04.03
(rac)-3,3,3-trifluoro-1 -{4-[1 -(2-{[6-(pyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)ethyl]piperazin-1 -yl}propan-1 -one
Figure imgf000711_0001
Starting with crude (rac)-N-{4-[1 -(piperazin-1 -yl)ethyl]pyridin-2-yl}-6-(pyrimidin-4-yi)-1 H- benzimidazol-2-amine hydrochloride (212 mg) and 3,3,3-trifluoropropanoic acid (66.2 mg, 517 μηιοΙ), Example 23.04.03 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 63 mg of the title compound.
LC-MS (Method 2): R, = 1.02 min; MS (ESIpos): m/z = 51 1 [M+H]+
1H-NMR (400 MHz, CHLOROFORM-d) δ [ppm]: 1.260 (1.92), 1.330 (15.82), 1.346 (16.00), 1.640 (3.19), 2.339 (4.95), 2.384 (2.75), 2.422 (2.52), 3.128 (3.35), 3.153 (9.73), 3.178 (9.41 ), 3.203 (3.24), 3.297 (6.15), 3.354 (1.46), 3.373 (3.82), 3.390 (3.75), 3.404 (2.03), 3.492 (3.63), 6.933 (2.82), 6.947 (5.43), 6.962 (3.93), 6.964 (3.75), 7.006 (1.1 1 ), 7.090 (10.52), 7.529 (1.25), 7.573 (4.09), 7.594 (4.60), 7.708 (4.97), 7.729 (5.60), 7.770 (4.21 ), 7.774 (4.53), 7.780 (4.14), 7.784 (6.91 ), 7.787 (5.09), 7.794 (3.56), 7.797 (2.98), 7.925 (2.94), 7.929 (2.96), 7.945 (2.50), 7.950 (2.61 ), 7.997 (3.98), 8.002 (3.86), 8.018 (3.40), 8.023 (3.40), 8.306 (4.62), 8.314 (8.62), 8.318 (15.56), 8.332 (5.73), 8.467 (4.72), 8.471 (4.60), 8.736 (5.02), 8.748 (9.69), 8.762 (6.68), 9.230 (5.71 ), 9.234 (5.64), 9.254 (8.12), 9.257 (7.79), 12.512 (2.96).
Example 23.05.01. A
cyclopropyl{4-[(1 R or 1S)-1 -(2-{[6-(pyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)ethyl]piperazin-1-yl}methanone (single stereoisomer A)
Figure imgf000712_0001
Example 23.05.01. B
cyclopropyl{4-[(1S or 1 R)-1 -(2-{[6-(pyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)ethyl]piperazin-1 -yl}methanone (single stereoisomer B)
Figure imgf000712_0002
30 mg of (rac)-cyclopropyl{4-[1 -(2-{[6-(pyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)ethyl]piperazin-1-yl}methanone was separated into the single stereoisomers (Example 23.05.01. A and Example 23.05.01 .B) via preparative, chiral HPLC.
Instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241 , Labcol Vario 4000;
Column: IB 5μ 250x30mm;
Eluent A: hexane + 0.2 Vol-% diethylamine (99%); Eluent B: ethanol; isocratic: 70%A+30%B;
Flow 30 mL/min;
Solution: 30 mg / 2 mL ethanol
Injection: 4 x 0.5 mL
Detection: DAD @ 325 nm Retention time in
purity in % yield Optical rotation [a]o min
Example - 36.8° (from solution 23.05.01.A 9.5 - 11.0 > 99% 8 mg in DMSO, c = 2.7
Stereoisomer A mg/mL)
Example +27.1 ° (from solution 23.05.01. B 1 1.2 - 13.5 94% 8 mg in DMSO, c = 2.6
Stereoisomer B mg/mL)
Example 23.05.01. A
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.658 (3.31 ), 0.666 (7.60), 0.671 (4.94), 0.685 (10.02), 0.692 (9.53), 0.700 (7.95), 0.704 (8.84), 0.71 1 (4.25), 1.107 (16.00), 1.231 (6.32), 1.298 (14.67), 1.314 (14.52), 1.919 (1.88), 1.926 (2.07), 1.938 (3.21 ), 1.951 (1.98), 1.957 (1.83), 2.323 (3.60), 2.327 (4.25), 2.331 (3.41 ), 2.399 (2.91 ), 2.523 (9.93), 2.665 (2.22), 2.669 (2.96), 2.673 (2.22), 3.458 (5.68), 3.474 (6.81 ), 3.678 (3.75), 4.191 (1.48), 6.975 (3.16), 7.184 (7.46), 7.433 (1.53), 7.453 (1.63), 7.619 (1.04), 7.958 (2.62), 7.980 (3.01 ), 8.091 (1.14), 8.225 (1.68), 8.283 (4.35), 8.296 (4.15), 8.407 (2.52), 8.753 (7.90), 8.767 (7.56), 9.166 (6.62), 10.789 (1.98), 12.306 (1.73), 12.344 (2.57).
Example 23.05.01. B
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.646 (0.67), 0.658 (2.13), 0.666 (5.1 1 ), 0.671 (3.17), 0.678 (2.57), 0.685 (6.60), 0.692 (6.27), 0.700 (5.07), 0.704 (5.82), 0.71 1 (2.69), 0.851 (0.78), 1.107 (16.00), 1.146 (0.63), 1.195 (0.71 ), 1.212 (0.90), 1.232 (4.25), 1.256 (1.04), 1.259 (1.08), 1.277 (0.97), 1.298 (10.14), 1.315 (9.85), 1.348 (0.63), 1.907 (0.63), 1.920 (1.23), 1.926 (1.38), 1.939 (2.16), 1.945 (1.12), 1.951 (1.31 ), 1.958 (1.19), 1.970 (0.63), 2.318 (1.79), 2.323 (2.54), 2.327 (3.10), 2.331 (2.39), 2.337 (1.38), 2.399 (1.86), 2.523 (5.15), 2.659 (0.71 ), 2.665 (1.60), 2.669 (2.20), 2.673 (1.60), 2.678 (0.75), 3.443 (1.38), 3.458 (3.80), 3.475 (4.44), 3.504 (1.08), 3.51 1 (0.86), 3.678 (2.39), 4.191 (1.53), 6.977 (2.05), 7.185 (5.07), 7.433 (0.97), 7.454 (1.04), 7.619 (0.71 ), 7.958 (1.72), 7.980 (1.90), 7.995 (1.12), 8.102 (0.71 ), 8.225 (1.12), 8.283 (2.98), 8.296 (2.80), 8.407 (1.68), 8.753 (5.74), 8.767 (5.30), 9.166 (4.44), 10.744 (0.75), 10.790 (1.12), 12.307 (0.97), 12.345 (1.45). Example 23.05.02.A
3,3,3-trifluoro-1 -{4-[(1 R or 1 S)-1 -(2-{[6-(pyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}propan-1-one (single stereoisomer A)
Figure imgf000714_0001
Example 23.05.02.B
3,3,3-trifluoro-1-{4-[(1S or 1 R)-1 -(2-{[6-(pyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}propan-1-one (single stereoisomer B)
Figure imgf000714_0002
63 mg of (rac)-3,3,3-trifluoro-1 -{4-[1 -(2-{[6-(pyri
4-yl)ethyl]piperazin-1 -yl}propan-1-one was separated into the single stereoisomers (Example
23.05.02.A and Example 23.05.02. B) via preparative, chiral HPLC.
Instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241 , Labcol Vario 4000,
Column: Chiralpak ID 5μ 250x30mm;
Eluent A: ethanol + 0.1 Vol-% diethylamine (99%); Eluent B: tert.butylmethyl ether; isocratic:
20%A+80%B;
Flow: 50.0 mL/min;
Solution:54 mg / 4.5 mL ethanol
Injection: 2 x 2.25 mL
Detection: UV 325 nm Retention time in
purity in % yield Optical rotation [a]o min
Example + 10.0°
23.05.02.A
(from solution in
5.6 - 7.4 99.8% 23 mg
Stereoisomer A DMSO, c = 2.4 mg/mL)
Example -35.6°
23.05.02.B
(from solution in
8.0 - 10.0 99.0% 23 mg
Stereoisomer B DMSO, c = 2.6 mg/mL)
Example 23.05.02.A
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.107 (16.00), 1.295 (8.58), 1.312 (8.66), 2.323 (1.97), 2.327 (2.69), 2.332 (2.61 ), 2.431 (2.31 ), 2.523 (8.19), 2.540 (4.38), 2.665 (1.14), 2.669 (1.57), 2.674 (1.14), 3.438 (4.60), 3.476 (4.75), 3.492 (4.30), 3.582 (1.82), 3.610 (5.10), 3.637 (4.88), 3.665 (1.64), 4.195 (1.12), 6.965 (2.49), 6.977 (2.56), 7.178 (5.05), 7.951 (1.97), 7.973 (2.09), 8.283 (4.13), 8.296 (3.98), 8.754 (6.32), 8.768 (6.12), 9.166 (5.72), 9.169 (5.95).
Example 23.05.02.B
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.107 (16.00), 1 .295 (7.48), 1.31 1 (7.66), 2.323 (1.64), 2.327 (2.19), 2.332 (2.21 ), 2.431 (2.23), 2.523 (6.97), 2.540 (4.44), 2.669 (1.06), 3.354 (2.07), 3.438 (4.05), 3.475 (4.14), 3.582 (1.56), 3.610 (4.47), 3.637 (4.23), 3.664 (1.36), 4.194 (1.06), 6.964 (2.39), 6.978 (2.40), 7.178 (4.60), 7.951 (2.00), 7.974 (2.00), 8.283 (3.80), 8.296 (3.64), 8.754 (5.64), 8.768 (5.30), 9.166 (5.36), 9.169 (5.48).
Example 23.05.03.A
cyclobutyl{4-[(1 R or 1S)-1 -(2-{[6-(pyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)ethyl]piperazin-1 -yl}methanone (single stereoisomer A)
Figure imgf000716_0001
Example 23.05.03.B
cyclobutyl{4-[(1 S or 1 R)-1 -(2-{[6-(pyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)ethyl]piperazin-1 -yl}methanone (single stereoisomer B)
Figure imgf000716_0002
30 mg of (rac)- cyclobutyl{4-[1 -(2-{[6-(pyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)ethyl]piperazin-1-yl}methanone was separated into the single stereoisomers (Example 23.05.03.A and Example 23.05.03.B) via preparative, chiral HPLC.
Instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241 , Labcol Vario 4000,
Column: Chiralpak IB 5μ 250x30mm;
Eluent A: hexane + 0.2 Vol-% diethylamine (99%); Eluent B: ethanol; isocratic: 70%A+30%B; Flow: 30.0 mL/min;
Solution:30 mg / 2.0 mL ethanol
Injection: 4 x 0.5 mL
Detection: UV 325 nm Retention time in
purity in % yield Optical rotation [ min
Example - 36.1 °
23.05.03.A
(from solution in
8.5 - 10.0 >99.0% 10 mg
Stereoisomer A DMSO, c = 3.0 mg/mL)
Example +35.6°
23.05.03.B
(from solution in
10.2 - 12.5 97.5% 9 mg
Stereoisomer B DMSO, c = 2.8 mg/mL)
Example 23.05.03.A
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.108 (16.00), 1.231 (2.47), 1.279 (7.41 ), 1.296 (7.52), 1.847 (1.63), 1.873 (1.29), 2.033 ( .94), 2.055 (2.20), 2.064 (1.71 ), 2.077 (1.56), 2.084 (1.52), 2.101 (2.36), 2.123 (2.43), 2.151 (1.29), 2.285 (1.67), 2.299 (1.90), 2.323 (2.32), 2.327 (2.70), 2.331 (1.86), 2.523 (5.09), 2.665 (1.56), 2.669 (2.13), 2.674 (1.48), 3.277 (1.75), 3.297 (4.03), 3.309 (3.84), 3.432 (2.74), 3.449 (3.46), 4.191 (1.56), 6.960 (1.56), 7.173 (4.03), 7.978 (1.48), 8.275 (2.36), 8.287 (2.24), 8.406 (1.25), 8.753 (4.60), 8.767 (4.37), 9.166 (3.76), 12.340 (1.29).
Example 23.05.03.B
H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.851 (0.99), 0.967 (0.52), 1.107 (16.00), 1.135 (1.04), 1 .154 (1.25), 1.172 (0.78), 1.231 (4.99), 1.259 (2.03), 1.279 (14.39), 1.295 (14.70), 1.347 (0.94), 1.694 (1.66), 1.719 (2.13), 1.742 (1.04), 1.825 (1.61 ), 1.846 (3.17), 1.868 (2.49), 1.873 (2.49), 1.896 (1.61 ), 1.918 (0.73), 2.033 (3.74), 2.041 (2.81 ), 2.054 (4.36), 2.064 (3.38), 2.078 (3.06), 2.084 (2.44), 2.101 (4.62), 2.123 (4.88), 2.152 (2.55), 2.175 (0.83), 2.284 (3.32), 2.297 (3.74), 2.312 (3.48), 2.323 (3.79), 2.327 (4.16), 2.331 (2.91 ), 2.364 (2.29), 2.403 (2.75), 2.523 (7.48), 2.665 (2.18), 2.669 (2.96), 2.673 (2.18), 2.678 (1.09), 3.256 (0.88), 3.276 (3.38), 3.297 (7.95), 3.308 (7.43), 3.432 (5.51 ), 3.449 (6.86), 3.504 (0.94), 3.5 1 (0.78), 4.191 (1.45), 6.958 (3.12), 6.969 (3.12), 7.172 (8.00), 7.431 (1.14), 7.453 (1.30), 7.619 (0.83), 7.955 (2.39), 7.978 (2.70), 8.101 (0.99), 8.224 (1.35), 8.275 (4.94), 8.287 (4.78), 8.407 (2.03), 8.753 (8.62), 8.767 (8.26), 9.166 (7.79), 10.785 (1.71 ), 12.301 (1.45), 12.340 (2.29). Example 24.01.01
3,3,34rifluoro-1-{4-[(2-{[6-(2-methylpyrimidin-4-yl)-1H-benzimidazol-2-yl]amino}pyrid yl)methyl]piperazin-1-yl}propan-1 -one
Figure imgf000718_0001
Starting with crude 6-(2-methylpyrimidin-4-yl)-N-[4-(piperazin-1 -ylrnethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (140 mg, approx. 252 pmol) and 3,3,3-trifluoropropanoic acid (48.3 mg, 377 pmol), Example 24.01.01 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 31 mg of the title compound.
LC-MS (Method 4): F¾ = 1.00 min; MS (ESIpos): m/z = 51 1 [M+H]+
1H-NMR (400 MHz, CHLOROFORM-d) δ [ppm]: 0.077 (0.53), 0.102 (1.32), 0.180 (1.82), 1.466 (8.21 ), 2.404 (3.20), 2.416 (3.53), 2.438 (1.94), 2.81 1 (16.00), 3.160 (1.38), 3.185 (3.91 ), 3.210 (3.84), 3.235 (1.32), 3.366 (1.68), 3.381 (2.08), 3.390 (1.57), 3.427 (1.17), 3.439 (1.77), 3.516 (6.44), 3.589 (1.87), 6.974 (1.83), 6.984 (1.75), 6.987 (1.73), 7.006 (0.50), 7.137 (3.18), 7.529 (0.46), 7.548 (2.47), 7.562 (2.54), 7.642 (0.70), 7.969 (1.63), 7.972 (1.65), 7.989 (1.48), 7.993 (1.51 ), 8.310 (3.01 ), 8.323 (3.03), 8.335 (3.05), 8.339 (2.97), 8.650 (3.38), 8.664 (3.20).
Example 24.01.02
cyclobutyl{4-[(2-{[6-(2-methylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4^ yl)methyl]piperazin-1-yl}methanone
Figure imgf000719_0001
Starting with crude 6-(2-methylpyrimidin-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (140 mg, approx. 252 pmol) and cyclobutanecarboxylic acid (37.8 mg, 377 μιτιοΙ), Example 24.01.02 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 60 mg of the title compound.
LC-MS (Method 4): R. = 1.03 min; MS (ESIpos): m/z = 483 [M+H]+
1H-NMR (400 MHz, CHLOROFORM-d) δ [ppm]: 0.077 (0.40), 0.102 (1.02), 0.180 (1.38), 1.831 (0.78), 1.855 (1.07), 1.878 (0.80), 1.900 (0.99), 1.922 (1.63), 1.943 (1.22), 1.949 (1.08), 1.966 (0.70), 1.971 (0.76), 1.993 (0.45), 2.062 (0.70), 2.071 (0.77), 2.092 (1.79), 2.101 (1.32), 2.1 13 (1.83), 2.123 (1.41 ), 2.137 (0.87), 2.144 (0.77), 2.265 (0.84), 2.271 (0.71 ), 2.287 (1.95), 2.293 (1.49), 2.309 (2.35), 2.318 (2.18), 2.339 (4.11 ), 2.350 (3.69), 2.362 (3.44), 2.374 (2.07), 2.812 (16.00), 3.164 (1.10), 3.185 (1.62), 3.207 (1 .08), 3.249 (1.74), 3.261 (2.31 ), 3.273 (1.67), 3.485 (6.73), 3.542 (2.04), 6.978 (1.87), 6.981 (1.85), 6.994 (1.89), 7.006 (0.49), 7.140 (3.18), 7.529 (0.42), 7.549 (2.39), 7.562 (2.48), 7.641 (0.68), 7.971 (1.32), 7.988 (1.18), 8.298 (3.03), 8.31 1 (2.98), 8.336 (2.71 ), 8.647 (3.18), 8.661 (3.1 1 ).
Example 24.01.03
cyclopropyl{4-[(2-{[6-(2-methylpyrimidin-4-yl)-1 ^
yl)methyl]piperazin-1-yl}methanone
Figure imgf000720_0001
Starting with crude 6-(2-methylpyrimidin-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (140 mg, approx. 252 pmol) and cyclopropanecarboxylic acid (32.5 mg, 377 pmol), Example 24.01.03 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 71 mg of the title compound.
LC-MS (Method 4): R, = 0.97 min; MS (ESIneg): m/z = 467 [M-H]+
1H-NMR (400 MHz, CHLOROFORM-d) δ [ppm]: 0.102 (0.74), 0.180 (1.00), 0.717 (0.85), 0.727 (2.38), 0.734 (2.65), 0.744 (1.83), 0.747 (2.57), 0.755 (2.84), 0.764 (1.16), 0.948 (1.04), 0.957 (2.89), 0.964 (2.83), 0.969 (3.06), 0.976 (2.74), 0.986 (1.04), 1.466 (1.06), 1.639 (0.49), 1.651 (0.85), 1.658 (0.97), 1.670 (1.59), 1.682 (0.91 ), 1.691 (0.82), 2.383 (1.84), 2.435 (1.87), 2.812 (16.00), 3.509 (7.01 ), 3.539 (1.02), 3.591 (2.30), 6.988 (1.88), 6.991 (1.85), 7.001 (1.93), 7.005 (1.93), 7.152 (3.31 ), 7.553 (2.54), 7.567 (2.58), 7.644 (0.58), 7.969 (1.73), 7.973 (1.72), 7.989 (1.52), 7.994 (1.56), 8.306 (3.13), 8.319 (3.08), 8.342 (3.41 ), 8.345 (3.37), 8.643 (3.27), 8.657 (3.12).
Example 24.01.04
2-cyclopropyl-1 -{4-[(2-{[6-(2-methylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin yl)methyl]piperazin-1 -yl}ethanone
Figure imgf000721_0001
Starting with crude 6-(2-methylpyrimidin^-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (140 mg, approx. 252 pmol) and cyclopropylacetic acid (37.8 mg, 377 pmol), Example 24.01.04 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 81 mg of the title compound.
LC-MS (Method 4): R, = 1.00 min; MS (ESIpos): m/z = 483 [M+H]+
1H-NMR (400 MHz, CHLOROFORM-d) δ [ppm]: 0.127 (1.18), 0.139 (4.30), 0.142 (3.48), 0.151 (3.83), 0.154 (4.24), 0.166 (1.49), 0.180 (0.51 ), 0.183 (0.50), 0.522 (1.44), 0.533 (3.27), 0.536 (3.52), 0.542 (1.92), 0.548 (1.95), 0.551 (2.40), 0.553 (3.71 ), 0.556 (3.60), 0.568 (1.53), 0.577 (0.47), 0.963 (0.45), 0.975 (0.76), 0.979 (0.78), 0.983 (0.74), 0.988 (0.65), 0.995 (1.27), 0.999 (0.70), 1.003 (0.65), 1.007 (0.76), 1.012 (0.78), 1.015 (0.72), 1.041 (0.61 ), 1.060 (1.11 ), 1.079 (0.52), 2.204 (6.67), 2.221 (6.57), 2.263 (0.73), 2.280 (0.70), 2.373 (5.17), 2.456 (0.58), 2.81 1 (16.00), 3.335 (1.87), 3.346 (2.51 ), 3.494 (8.02), 3.545 (2.48), 6.962 (2.23), 6.965 (2.22), 6.978 (2.27), 7.007 (0.41 ), 7.151 (4.02), 7.554 (3.31 ), 7.567 (3.40), 7.960 (2.58), 7.965 (2.60), 7.981 (2.27), 7.985 (2.37), 8.303 (4.01 ), 8.316 (3.93), 8.341 (3.78), 8.344 (3.77), 8.643 (3.58), 8.656 (3.45).
Example 24.02.01
cyclopropyl{4-[(2-methyl-6-{[6-(2-methylpyrimidin-4-yl)-1 H-benzimidazol-2
yl]amino}pyridin-4-yl)methyl]piperazin-1-yl}methanone
Figure imgf000722_0001
Starting with N-[6-methyl-4-(piperazin-1 -ylmethyl)pyridin-2-yl]-6-(2-methylpyrimidin-4-yl)-1 H- benzimidazol-2-amine (75.0 mg, 181 pmol) and cyclopropanecarboxylic acid (23.4 mg, 271 μιτιοΙ), Example 24.02.01 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 30.0 mg (32 %) of the title compound.
LC-MS (Method 4): R, = 1.03 min; MS (ESIpos): m/z = 483 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.676 (1.26), 0.683 (2.91 ), 0.689 (1.83), 0.696 (1.47), 0.703 (3.59), 0.707 (3.09), 0.712 (3.33), 0.719 (2.93), 0.724 (3.46), 0.731 (1.57), 1.945 (0.71 ), 1.964 (1.26), 2.323 (1.41 ), 2.327 (2.04), 2.331 (1.83), 2.337 (1.41 ), 2.349 (1.39), 2.432 (1.47), 2.518 (7.54), 2.523 (5.05), 2.539 (2.28), 2.549 (2.30), 2.573 (5.16), 2.659 (1.49), 2.667 (16.00), 2.673 (2.57), 3.472 (6.36), 3.704 (1.31 ), 6.805 (2.44), 7.015 (1.39), 7.41 1 (0.97), 7.432 (1.05), 7.797 (0.94), 7.81 1 (1.00), 7.924 (0.92), 7.945 (0.92), 8.483 (1.34), 8.641 (3.35), 8.655 (3.25), 10.726 (1.05).
Example 24.02.02
3,3,3-trifluoro-1-{4-[(2-methyl-6-{[6-(2-methylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}propan-1 -one
Figure imgf000723_0001
Starting with N-[6-methyl-4-(piperazin-1-ylmethyl)pyridin-2-yl]-6-(2-methylpyrimidin-4-yl)-1 H- benzimidazol-2-amine (75.0 mg, 181 pmol) and 3,3,3-trifluoropropanoic acid (34.8 mg, 271 μιτιοΙ), Example 24.02.02 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 30.0 mg (29 %) of the title compound.
LC-MS (Method 4): Rt = 1.07 min; MS (ESIpos): m/z = 525 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.323 (1.29), 2.327 (1 .77), 2.331 (1.29), 2.357 (1.48), 2.369 (2.17), 2.382 (1.64), 2.409 (2.09), 2.518 (7.60), 2.523 (4.99), 2.540 (1.64), 2.546 (2.38), 2.571 (5.10), 2.667 (16.00), 2.674 (2.22), 3.474 (7.16), 3.502 (1.98), 3.608 (0.92), 3.635 (2.59), 3.662 (2.46), 3.690 (0.77), 4.045 (1.21 ), 6.796 (2.30), 7.010 (1.35), 7.410 (0.95), 7.432 (1.03), 7.797 (0.95), 7.8 1 (1.00), 7.924 (0.92), 7.945 (0.92), 8.480 (1.40), 8.641 (3.51 ), 8.655 (3.17), 10.724 (1.19), 12.094 (1.08).
Example 24.03.01
cyclopropyl(4-{[2-{[6-(2-methylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]
(trifluoromethyl)pyridin-4-yl]methyl}piperazin-1 -yl)methanone
Figure imgf000724_0001
To a stirred solution of 4-chloro-2-methylpyrimidine (81 .1 mg, 631 pmol), and cyclopropyl(4-{[2- {[6-(4,4,5,5-tetramet yl-1 ,3,2-dioxaborolan-2-yl)-1 H-benzimidazol-2-yl]amino}-6- (trifluoromethyl)pyridin-4-yl]methyl}piperazin-1 -yl)met anone (200 mg, 351 pmol) in Dioxane (1.7 mL) and water (340 μΙ) was added sodium carbonate (1 1 1 mg, 1.05 mmol) and Pd(dppf)CI2 . CH2CI2 (42.9 mg, 52.6 pmol). The mixture was heated to reflux for 19 h. Dichloromethane was added, the mixture was filtered and, the solvent was removed in vacuum. Preparative reverse phase HPLC (gradient of water and acetonitrile containing ammonia as additive) gave 20.0 mg (10 % yield) of the title compound.
LC-MS (Method 2): F¾ = 1.16 min; MS (ESIpos): m/z = 537 [M+H]+
1H-NMR (400 MHz, CHLOROFORM-d) δ [ppm]: 0.725 (4.36), 0.951 (5.34), 1.261 (1.93), 1.284 (6.51 ), 1.648 (2.1 1 ), 2.388 (3.45), 2.793 (3.68), 2.845 (16.00), 3.560 (7.24), 7.582 (2.62), 7.985 (1.62), 8.348 (0.99), 8.675 (3.91 ), 8.688 (3.75), 1 1.977 (2.41 ).
Example 24.04.01
(rac)-cyclopropyl{4-[1 -(2-{[6-(2-methylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}methanone
Figure imgf000725_0001
Starting with 6-(2-methylpyrimidin-4-yl)-N-{4-[(1 R)-1-(piperazin-1-yl)ethyl]pyridin-2-yl}-1 H- benzimidazol-2-amine (207 mg, 499 μιτιοΙ) and cyclopropanecarboxylic acid (64.5 mg, 749 μιτιοΙ), Example 24.04.01 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 53.0 mg (22 %) of the title compound.
LC-MS (Method 4): R, = 1.01 min; MS (ESIpos): m/z = 483 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.656 (1.22), 0.664 (2.91 ), 0.669 (1.82), 0.676 (1.42), 0.683 (3.51 ), 0.687 (3.01 ), 0.691 (3.35), 0.698 (2.83), 0.704 (3.29), 0.711 (1.55), 1.296 (5.42), 1.312 (5.54), 1.936 (1.21 ), 2.083 (0.77), 2.327 (0.91 ), 2.665 (16.00), 3.453 (2.09), 3.469 (2.63), 3.676 (1.35), 6.966 (1.55), 6.980 (1.59), 7.196 (1.71 ), 7.920 (1.57), 7.924 (1.67), 7.941 (1.45), 7.945 (1.50), 8.271 (2.87), 8.284 (2.76), 8.639 (3.72), 8.653 (3.53).
Example 24.04.02
(rac)-cyclobutyl{4-[1 -(2-{[6-(2-methylpyrimidin-4-yl)-1 H^enzimidazol-2-yl]amino}pyridin 4-yl)ethyl]piperazin-1-yl}methanone
Figure imgf000726_0001
Starting with 6-(2-methylpyrimidin-4-yl)-N-{4-[(1 R)-1-(piperazin-1 -yl)ethyl]pyridin-2-yl}-1 H- benzimidazol-2-amine (207 mg, 499 μιτιοΙ) and cyclobutanecarboxylic acid (75.0 mg, 749 μηιοΙ), Example 24.04.02 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 56.5 mg (22 %) of the title compound.
LC-MS (Method 4): R, = 1.08 min; MS (ESIpos): m/z = 497 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.274 (5.70), 1 .291 (5.90), 1.843 (1.23), 1.865 (0.93), 1.870 (0.97), 2.029 (1.44), 2.038 (1.07), 2.051 (1.67), 2.060 (1.29), 2.075 (1.12), 2.081 (0.96), 2.099 (1.80), 2.120 (1.86), 2.150 (0.97), 2.279 (1.27), 2.293 (1.44), 2.307 (1.40), 2.397 (1.03), 2.665 (16.00), 3.271 (1.23), 3.293 (2.89), 3.304 (2.46), 3.314 (2.50), 3.424 (2.30), 3.442 (2.95), 6.950 (1.33), 6.963 (1.36), 7.167 (1.66), 7.922 (1.32), 7.943 (1.22), 8.264 (2.98), 8.277 (2.83), 8.639 (4.06), 8.653 (3.78).
Example 24.04.03
(rac)-3,3,3-trifluoro-H4-[1-(2-{[6-(2-methylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}propan-1 -one
Figure imgf000727_0001
Starting with 6-(2-methylpyrimidin-4-yl)-N-{4-[(1 R)-1 -(piperazin-1 -yl)ethyl]pyridin-2-yl}-1 H- benzimidazol-2-amine (207 mg, 499 μιηοΙ) and 3,3,3-trifluoropropanoic acid (95.9 mg, 749 pmol), Example 24.04.03 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 1 15 mg (41 %) of the title compound.
LC-MS (Method 4): R, = 1.05 min; MS (ESIpos): m/z = 525 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.293 (5.27), 1.309 (5.41 ), 2.327 (1.20), 2.343 (1.21 ), 2.366 (0.97), 2.417 (1.27), 2.429 (1.45), 2.665 (16.00), 3.424 (1.41 ), 3.436 (2.49), 3.449 (1.67), 3.470 (2.84), 3.487 (2.83), 3.580 (0.95), 3.608 (2.71 ), 3.635 (2.57), 3.662 (0.90), 6.960 (1.47), 6.973 (1.50), 7.174 (2.46), 7.922 (1.56), 7.926 (1.63), 7.943 (1.43), 7.947 (1.47), 8.272 (2.73), 8.285 (2.58), 8.640 (3.83), 8.654 (3.63).
Example 24.04.04
(rac)-2-cyclopropyl-1 -{4-[1 -(2-{[6-(2-methylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}ethanone
Figure imgf000728_0001
Starting with (rac)-6-(2-methylpyrimidin-4-yl)-N-{4-[1 -(piperazin-1 -yl)ethyl]pyridin-2-yl}-1 H- benzimidazol-2-amine (207 mg, 499 pmol) and cyclopropylacetic acid (75.0 mg, 749 pmol), Example 24.04.04 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 40.4 mg (16 %) of the title compound.
LC-MS (Method 4): R, = 1.05 min; MS (ESIpos): m/z = 497 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.000 (0.93), 0.01 1 (3.18), 0.014 (2.97), 0.023 (3.21 ), 0.026 (3.07), 0.037 (1.01 ), 0.331 (1.07), 0.341 (2.69), 0.345 (2.83), 0.351 (1.42), 0.356 (1.36), 0.361 (2.93), 0.365 (2.82), 0.376 (1.02), 0.851 (1.04), 1.220 (5.74), 1.237 (5.79), 2.145 (5.05), 2.162 (4.94), 2.262 (1.81 ), 2.266 (1.58), 2.338 (1.68), 2.457 (1.95), 2.599 (16.00), 3.358 (2.86), 3.375 (2.97), 3.392 (3.10), 6.895 (1.23), 7.108 (1.56), 7.858 (1.19), 7.878 (1.05), 8.202 (2.97), 8.216 (2.85), 8.353 (1.01 ), 8.575 (4.14), 8.589 (3.90).
Example 24.05.01. A
3,3,3-trifluoro-l -{4-[(1 R or 1 S)-1 -(2-{[6-(2-methylpyrimidin-4-yl)-1 H-benzimidazol-2 - yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}propan-1-one (single stereoisomer A)
Figure imgf000729_0001
Example 24.05.01. B
3,3,3-trifluoro-1 -{4-[(1 S or 1 R)-1 -(2-{[6-(2-methylpyrimidin-4-yl)-1 H-benzimidazol-2 - yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}propan-1 -one (single stereoisomer B)
Figure imgf000729_0002
110 mg of (rac)-3,3,3-trifluoro-1-{4-[1-(2-{[6-(2-methylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}propan-1-one was separated into the single stereoisomers (Example 24.05.01. A and Example 23.05.01. B) via preparative, chirai HPLC. Instrument: Sepiatec: Prep SFC100,
Column: Chiralpak IC 5μ 250x30mm;
Eluent A C02, Eluent B: methanol + 0.4 Vol-% diethylamine (99%); isocratic: 53%B;
Flow 100.0 mL/min;
Temperature: 4CC;
Backpressure: 150bar;
Solution: 1 10 mg / 2 mL dichloromethane/methanol 1 :1
Injection: 9 x 0.25 mL Detection: MWD @ 254nm
Figure imgf000730_0001
Example 24.05.01. A
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.107 (12.79), 1.133 (0.93), 1.143 (0.81 ), 1.151 (1.79), 1.161 (1.09), 1.169 (0.89), 1.293 (5.46), 1.309 (5.51 ), 2.250 (1.99), 2.323 (1.04), 2.327 (1.52), 2.332 (1.39), 2.337 (1.23), 2.417 (1.33), 2.429 (1.52), 2.523 (1.58), 2.665 (16.00), 2.673 (1.39), 3.437 (2.72), 3.447 (2.03), 3.470 (2.92), 3.487 (2.98), 3.503 (1.02), 3.582 (1.04), 3.609 (2.87), 3.637 (2.70), 3.664 (0.87), 6.958 (1.31 ), 6.972 (1.34), 7.182 (1.82), 7.925 (1.31 ), 7.946 (1.16), 8.271 (2.85), 8.285 (2.71 ), 8.640 (3.90), 8.654 (3.57).
Example 24.05.01. B
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.966 (0.53), 1.107 (14.94), 1.143 (0.62), 1.293 (6.06), 1.309 (6.15), 2.318 (0.98), 2.323 (1.39), 2.327 (2.01 ), 2.332 (1.82), 2.337 (1.51 ), 2.344 (1.46), 2.366 (1.18), 2.417 (1.58), 2.429 (1.84), 2.442 (1.32), 2.458 (1.18), 2.523 (2.99), 2.665 (16.00), 2.673 (1.99), 3.424 (1.72), 3.437 (3.02), 3.449 (2.01 ), 3.470 (3.26), 3.487 (3.36), 3.503 (1.29), 3.582 (1.13), 3.609 (3.16), 3.637 (2.99), 3.664 (0.94), 4.194 (1.29), 6.965 (1.37), 7.167 (1.87), 7.414 (0.76), 7.435 (0.79), 7.771 (0.79), 7.785 (0.82), 7.925 (1.22), 7.946 (1.08), 8.203 (0.69), 8.272 (3.09), 8.285 (2.94), 8.421 (1.24), 8.641 (4.26), 8.654 (3.86), 10.787 (0.91 ), 12.368 (0.98). Example 24.05.02.A
cyclobutyl{4-[(1 R or 1 S)-1 -(2-{[6-(2-methylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}methanone (single stereoisomer A)
Figure imgf000731_0001
Example 24.05.02.B
cyclobutyl{4-[(1S or 1 R)-1 -(2-{[6-(2-methylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}methanone (single stereoisomer B)
Figure imgf000731_0002
61.9 mg of (rac)-cyclobutyl{4-[1 -(2-{[6-(2-methylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}methanone was separated into the single stereoisomers (Example 24.05.02.A and Example 23.05.02. B) via preparative, chiral HPLC. Instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241 , Labcol Vario 4000,
Column: Chiralpak IB 5μ 250x30mm;
Eluent A: hexane + 0.2 Vol-% diethylamine (99%); Eluent B: ethanol; isocratic: 70%A+30%B; Flow 30.0 mL/min;
Solution: 61 mg / 2.5 mL ethanol
Injection: 5 x 0.5 mL
Detection: UV @ 325 nm Retention time in
purity in % yield Optical rotation [a]D min
Example - 38.5°
24.05.02.A
(from solution in
10.1 - 12.0 >99.0% 25 mg
Stereoisomer A DMSO, c = 2.6 mg/mL)
Example + 26.7°
24.05.02.B
(from solution in
12.1 - 14.9 93.7% 27 mg
Stereoisomer B DMSO, c = 2.6 mg/mL)
Example 24.05.02.A
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.107 (12.20), 1.232 (1.31 ), 1.277 (5.97), 1.294 (6.07), 1.846 (1.28), 1.873 (0.98), 2.032 (1.48), 2.054 (1.74), 2.063 (1.31 ), 2.076 (1.18), 2.100 (1.80), 2.122 (1.90), 2.152 (0.95), 2.282 (1.34), 2.297 (1.51 ), 2.323 (1.38), 2.327 (1.44), 2.331 (0.98), 2.393 (1.08), 2.523 (2.79), 2.665 (16.00), 2.673 (1.77), 3.276 (1.31 ), 3.296 (3.15), 3.308 (3.05), 3.319 (3.93), 3.428 (2.36), 3.445 (2.92), 4.193 (1.21 ), 6.957 (1.28), 7.162 (1.54), 7.924 (1.08), 7.945 (0.95), 8.264 (3.02), 8.278 (2.89), 8.418 (1.15), 8.641 (4.26), 8.654 (4.00), 12.364 (1.1 1 ).
Example 24.05.02.B
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.107 (8.76), 1.231 (1.53), 1.258 (0.70), 1.276 (6.00), 1.293 (6.28), 1.693 (0.76), 1.719 (0.93), 1.824 (0.67), 1.845 (1.26), 1.872 (1.15), 1.895 (0.71 ), 2.031 (1.66), 2.040 (1.31 ), 2.053 (1.92), 2.062 (1.57), 2.078 (1.38), 2.083 (1.15), 2.100 (2.01 ), 2.121 (2.05), 2.151 (1.16), 2.283 (1.51 ), 2.296 (1.74), 2.310 (1.63), 2.322 (1.24), 2.326 (1.19), 2.362 (1.08), 2.377 (1.08), 2.399 (1.32), 2.522 (2.92), 2.665 (16.00), 3.275 (1.42), 3.296 (3.52), 3.307 (3.28), 3.317 (3.85), 3.410 (0.80), 3.428 (2.53), 3.445 (3.27), 4.192 (0.93), 6.953 (1.53), 6.965 (1.58), 7.164 (1.90), 7.414 (0.55), 7.434 (0.62), 7.783 (0.71 ), 7.925 (1.47), 7.945 (1.32), 8.264 (2.95), 8.278 (2.89), 8.421 (0.94), 8.640 (3.66), 8.653 (3.42), 10.773 (0.76), 12.283 (0.54), 12.365 (0.99). Example 24.05.03.A
2-cyclopropyl-1 -{4-[(1R or 1S)-1-(2-{[6-(2-methylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}ethanone (single stereoisomer A)
Figure imgf000733_0001
Example 24.05.03.B
2-cyclopropyl-1-{4-[(1S or 1R)-1-(2-{[6-(2-methylpyrimidrn-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}ethanone (single stereoisomer B)
Figure imgf000733_0002
72 mg of (rac)-2-cyclopropyl-1-{4-[1-(2-{[6-(2-methylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}ethanone was separated into the single stereoisomers (Example 24.05.03.A and Example 23.05.03. B) via preparative, chiral HPLC.
Instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241 , Labcol Vario 4000,
Column: Chiralpak IC 5μ 250x30mm;
Eluent A: methanol + 0.1 Vol-% diethylamine (99%); Eluent B: ethanol; isocratic: 50%A+50%B; Flow 50.0 mL/min;
Solution: 72 mg / 4.0 mL dichloromethane/methanol 1 :1
Injection: 4 x 1.0 mL
Detection: UV @ 325 nm Retention time in
purity in % yield Optical rotation [a]D min
Example + 42.2°
24.05.03.A
(from solution in
10.5 - 1 1.5 >99.0% 34 mg
Stereoisomer A DMSO, c = 2.8 mg/mL)
Example - 40.1 °
24.05.03.B
(from solution in
1 1.5 - 12.5 95.0% 24 mg
Stereoisomer B DMSO, c = 3.0 mg/mL)
Example 24.05.03.A
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.000 (0.89), 0.01 1 (3.1 1 ), 0.014 (2.93), 0.023 (3.20), 0.026 (3.02), 0.037 (1.07), 0.331 (1.07), 0.341 (2.76), 0.345 (2.84), 0.352 (1.42), 0.356 (1.42), 0.362 (2.93), 0.366 (2.84), 0.376 (1.07), 0.830 (0.98), 0.846 (0.98), 0.851 (1.16), 1.042 (8.00), 1.165 (0.89), 1.220 (5.69), 1.237 (5.78), 1.982 (1.42), 2.145 (5.16), 2.162 (4.98), 2.183 (0.89), 2.253 (1.42), 2.257 (1.87), 2.262 (2.22), 2.267 (1.87), 2.271 (1.16), 2.338 (1.60), 2.353 (1.42), 2.367 (1.07), 2.453 (5.16), 2.458 (3.29), 2.584 (0.80), 2.600 (16.00), 2.608 (1.87), 3.346 (1.69), 3.358 (3.02), 3.375 (2.93), 3.392 (3.02), 3.405 (1.87), 3.450 (1.51 ), 3.756 (1.24), 4.134 (0.71 ), 6.898 (1.24), 7.099 (1.51 ), 7.347 (0.71 ), 7.369 (0.80), 7.705 (0.80), 7.719 (0.80), 7.860 (1.07), 7.882 (0.89), 8.204 (2.93), 8.216 (2.76), 8.353 (1.16), 8.576 (4.62), 8.589 (4.18), 10.716 (0.89), 12.304 (0.98).
Example 24.05.03.B
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.000 (0.85), 0.0 1 (3.08), 0.014 (2.83), 0.023 (3.18), 0.026 (2.95), 0.037 (1.05), 0.331 (1.03), 0.341 (2.72), 0.345 (2.80), 0.351 (1.46), 0.356 (1.34), 0.361 (2.88), 0.366 (2.77), 0.376 (1.00), 0.830 (0.67), 0.834 (0.67), 0.838 (0.64), 0.851 (1.05), 0.862 (0.57), 0.867 (0.62), 0.871 (0.54), 0.901 (0.62), 1.042 (3.78), 1.078 (0.46), 1.165 (0.95), 1.220 (5.57), 1.236 (5.62), 2.144 (4.91 ), 2.161 (4.83), 2.183 (0.69), 2.253 (1.18), 2.257 (1.34), 2.262 (1.54), 2.267 (1.31 ), 2.279 (0.85), 2.337 (1.59), 2.351 (1.44), 2.365 (1.03), 2.458 (2.05), 2.600 (16.00), 2.608 (1.39), 3.358 (2.88), 3.374 (2.98), 3.391 (3.08), 6.895 (1.21 ), 6.905 (1.18), 7.102 (1.62), 7.349 (0.54), 7.369 (0.62), 7.719 (0.64), 7.858 (1.16), 7.879 (1.03), 8.203 (2.95), 8.216 (2.77), 8.353 (0.95), 8.575 (4.24), 8.589 (4.03), 10.717 (0.69), 12.308 (0.74). Example 24.05.04.A
cyclopropyl{4-[(1 R or 1S)-1 -(2-{[6-(2-methylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}methanone (single stereoisomer A)
Figure imgf000735_0001
Example 24.05.04.B
cyclopropyl{4-[(1S or 1 R)-1-(2-{t6-(2-methylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}methanone (single stereoisomer B)
Figure imgf000735_0002
49.6 mg of (rac)-cyclopropyl{4-[1-(2-{[6-(2-methylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}methanone was separated into the single stereoisomers (Example 24.05.04.A and Example 23.05.04. B) via preparative, chiral HPLC.
Instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241 , Labcol Vario 4000,
Column: Chiralpak IB 5μ 250x30mm;
Eluent A: hexane + 0.2 Vol-% diethylamine (99%); Eluent B: ethanol; isocratic: 80%A+20%B;
Flow 30.0 mL/min;
Solution: 49 mg / 2.5 mL ethanol
Injection: 5 x 0.5 mL
Detection: UV @ 325 nm Retention time in
purity in % yield Optical rotation [a]o min
Example - 43.7°
24.05.04.A (from solution in
10.8 - 12.3 >99.0% 18 mg
Stereoisomer A DMSO, c = 3.0 mg/mL)
Example + 45.3°
24.05.04.B
(from solution in
12.5 - 14.9 95.9% 16 mg
Stereoisomer B DMSO, c = 2.8 mg/mL)
Example 24.05.04.A
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.664 (3.07), 0.684 (3.95), 0.691 (3.88), 0.698 (3.14), 0.703 (3.51 ), 0.710 (1.66), 1.106 (8.08), 1.228 (1.06), 1.295 (5.73), 1.312 (5.73), 1.917 (0.74), 1 .937 (1.29), 2.326 (1.09), 2.394 (1.1 1 ), 2.462 (1.22), 2.522 (2.05), 2.665 (16.00), 3.304 (1.04), 3.326 (2.42), 3.377 (0.83), 3.382 (0.74), 3.454 (2.24), 3.469 (2.82), 3.677 (1.57), 4.198 (0.85), 6.968 (1.45), 6.980 (1.45), 7.175 (2.03), 7.925 (1.41 ), 7.944 (1.27), 8.273 (2.91 ), 8.286 (2.77), 8.640 (3.74), 8.654 (3.53).
Example 24.05.04.B
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.657 (1.37), 0.665 (3.23), 0.670 (2.11 ), 0.677 (1.69), 0.684 (4.20), 0.691 (4.03), 0.699 (3.26), 0.703 (3.69), 0.71 1 (1.66), 0.966 (0.51 ), 1.107 (10.23), 1.143 (0.40), 1.149 (0.40), 1.230 (0.89), 1.258 (0.69), 1.295 (6.09), 1.312 (6.03), 1.919 (0.74), 1.926 (0.86), 1.938 (1.31 ), 1.950 (0.80), 1.957 (0.69), 2.322 (1.29), 2.327 (1.46), 2.332 (1.1 1 ), 2.397 (1.20), 2.523 (2.83), 2.665 (16.00), 3.454 (2.43), 3.470 (3.09), 3.677 (1.63), 4.197 (1.06), 6.970 (1.31 ), 7.172 (1.74), 7.414 (0.69), 7.435 (0.74), 7.772 (0.74), 7.785 (0.77), 7.925 (1.20), 7.946 (1.06), 8.202 (0.63), 8.273 (3.09), 8.286 (2.91 ), 8.420 (1.17), 8.640 (4.1 1 ), 8.654 (3.83), 10.739 (0.49), 10.785 (0.91 ), 12.290 (0.60), 12.373 (1.11 ). Example 25.01.01
tert-butyl 4-[(2-{[6-(2-methoxypyrimidin-4-yl)-1 H^enzimidazol-2-yl]amino}pyridin-4 yl)methyl]piperazine-1-carboxylate
Figure imgf000737_0001
Starting with tert-butyl 4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-benzimidazol- 2-yl]amino}pyridin-4-yl)methyl]piperazine-1-carboxylate (500 mg, 936 μιηοΙ) and 4-bromo-2- methoxypyrimidine (248 mg, 1.31 mmol), Example 25.01.01 was prepared analogously to the procedure for the preparation of Example 01.01.
Yield: 19.0 mg (4 %) of the title compound.
LC-MS (Method 2): R, = 1.25 min; MS (ESIpos): m/z = 517 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.396 (16.00), 2.360 (1.40), 2.372 (1.01 ), 2.523 (2.96), 3.349 (1.41 ), 3.506 (1.68), 4.006 (2.25), 8.561 (1.33), 8.575 (1.21 ).
Example 25.01.02
cyclobutyl{4-[(2-{[6-(2-methoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4 yl)methyl]piperazin-1 -yl}methanone
Figure imgf000737_0002
Starting with crude 6-(2-methoxypyrimidin-4-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (1 15 mg) and cyclobutanecarboxylic acid (38.1 mg, 381 μιηοΙ), Example 25.01.02 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 2.50 mg of the title compound.
LC-MS (Method 4): Rt = 1.08 min; MS (ESIpos): m/z = 499 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.230 (0.96), 1.734 (1.42), 1.840 (0.92), 1.862 (1.82), 1.884 (1.63), 1.912 (1.02), 2.052 (2.56), 2.074 (3.02), 2.100 (2.44), 2.123 (3.39), 2.144 (3.36), 2.173 (1.82), 2.323 (2.16), 2.327 (2.99), 2.332 (3.05), 2.355 (6.10), 2.523 (10.76), 2.539 (3.39), 2.665 (1.39), 2.669 (1.88), 2.673 (1.45), 3.169 (1.1 1 ), 3.304 (2.71 ), 3.477 (3.73), 3.506 (7.00), 3.896 (0.83), 3.955 (1.02), 3.973 (1.26), 4.003 (16.00), 6.548 (0.65), 6.943 (1.88), 6.955 (2.03), 7.189 (3.08), 7.617 (0.92), 7.937 (1.66), 7.955 (1.57), 8.271 (2.47), 8.284 (2.47), 8.561 (4.47), 8.574 (4.32).
Example 25.01.03
2-cyclopropyl-1 -{4-[(2-{[6-(2-methoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin- 4-yl)methyl]piperazin-1-yl}ethanone
Figure imgf000738_0001
Starting with crude 6-(2-methoxypyrimidin-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (1 15 mg) and cyclopropylacetic acid (38.1 mg, 381 pmol), Example 25.01.03 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 15.0 mg of the title compound.
LC-MS (Method 4): Rt = 1 .05 min; MS (ESIpos): m/z = 499 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.000 (1.65), 0.01 1 (5.58), 0.014 (5.26), 0.023 (5.66), 0.027 (5.23), 0.037 (2.05), 0.331 (2.05), 0.340 (4.93), 0.345 (5.38), 0.351 (2.75), 0.355 (2.65), 0.361 (5.38), 0.365 (5.23), 0.376 (2.13), 0.834 (1.10), 0.838 (1.10), 0.842 (1.08), 0.847 (0.88), 0.854 (1.90), 0.858 (1.00), 0.862 (0.88), 0.867 (1.03), 0.871 (1.08), 0.874 (1.03), 2.154 (8.99), 2.171 (8.91 ), 2.239 (1.15), 2.243 (1.68), 2.248 (1.33), 2.253 (0.90), 2.279 (3.76), 2.291 (3.46), 2.311 (3.81 ), 2.434 (8.39), 2.439 (5.93), 2.455 (1.28), 2.581 (1.08), 2.585 (1.55), 2.589 (1.13), 3.372 (3.71 ), 3.384 (3.36), 3.407 (3.68), 3.431 (10.17), 3.920 (16.00), 6.868 (1.90), 7.109 (3.08), 7.334 (0.88), 7.356 (0.98), 7.526 (1.40), 7.853 (1.60), 7.873 (1.43), 8.125 (0.80), 8.192 (2.23), 8.204 (2.15), 8.325 (1.48), 8.477 (8.36), 8.491 (7.46), 10.731 (0.90), 12.218 (0.88), 12.260 (1.53).
Example 25.01.04
3,3,3-trifluoro-1 -{4-[(2-{[6-(2-methoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino
4-yl)methyl]piperazin-1-yl}propan-1 -one
Figure imgf000739_0001
Starting with crude 6-(2-methoxypyrimidin-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (1 15 mg) and 3,3,3-trifluoropropanoic acid (48.8 mg, 381 pmol), Example 25.01.04 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 30.0 mg of the title compound.
LC-MS (Method 4): R, = 1.05 min; MS (ESIpos): m/z = 527 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.075 (4.09), 2.322 (1.23), 2.327 (1.83), 2.332 (1.35), 2.336 (0.66), 2.371 (2.58), 2.383 (4.06), 2.396 (3.02), 2.425 (3.75), 2.437 (3.06), 2.518 (10.58), 2.523 (7.72), 2.539 (2.02), 2.665 (1.29), 2.669 (1.86), 2.673 (1.35), 3.473 (3.50), 3.484 (3.24), 3.510 (3.91 ), 3.530 (10.90), 3.613 (1 .67), 3.640 (4.79), 3.667 (4.54), 3.695 (1.45), 4.005 (16.00), 4.050 (3.15), 6.953 (1.98), 7.196 (3.40), 7.419 (0.98), 7.441 (1.07), 7.610 (1.57), 7.937 (1.67), 7.958 (1.45), 8.209 (0.94), 8.278 (2.27), 8.290 (2.14), 8.409 (1.64), 8.561 (8.79), 8.575 (8.16), 10.817 (1.07), 12.342 (1.29). Example 25.01.05
cyclopropyl{4-[(2-{[6-(2-methoxypyrimidin-4-yl)-1 H^enzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone
Figure imgf000740_0001
Starting with crude 6-(2-methoxypyrimidin-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (1 15 mg) and cyclopropanecarboxylic acid (32.8 mg, 381 pmol), Example 25.01.05 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 27.0 mg of the title compound.
LC-MS (Method 4): R, = 1.01 min; MS (ESIpos): m/z = 485 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.665 (0.77), 0.677 (2.26), 0.684 (5.32), 0.690 (3.32), 0.697 (2.64), 0.704 (6.64), 0.708 (5.56), 0.713 (5.96), 0.720 (5.63), 0.726 (6.46), 0.733 (3.03), 0.745 (0.81 ), 1.948 (1.25), 1.955 (1.32), 1.967 (2.29), 1.973 (1.08), 1.979 (1.30), 1.986 (1.19), 2.323 (1.08), 2.327 (1.54), 2.332 (1.30), 2.337 (0.92), 2.366 (2.46), 2.447 (2.51 ), 2.518 (7.78), 2.523 (5.67), 2.539 (3.19), 2.665 (0.95), 2.669 (1.36), 2.673 (0.97), 3.510 (2.57), 3.528 (10.70), 3.709 (2.42), 3.950 (0.84), 4.004 (16.00), 6.959 (1.85), 7.202 (3.05), 7.420 (0.84), 7.441 (0.95), 7.61 1 (1.36), 7.938 (1.60), 7.958 (1.47), 8.21 1 (0.79), 8.279 (2.29), 8.292 (2.20), 8.41 1 (1.41 ), 8.561 (8.92), 8.575 (8.04), 10.821 (0.79), 12.305 (0.81 ), 12.347 (1.41 ).
Example 25.02.01
cyclopropyl(4-{[2-{[6-(2-methoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}-6- (trifluoromethyl)pyridin-4-yl]methyl}piperazin-1 -yl)methanone
Figure imgf000741_0001
Starting with cyclopropyl(4-{[2-{[6-(4,4,5,5-tetrame
benzimidazol-2-yl]amino}-6-(trifluoromethyl)pyridin-4-yl]methyl}piperazin-1 -yl)methanon (200 mg, 351 μιηοΙ) and 4-bromo-2-methoxypyrimidine (1 19 mg, 631 pmol), Example 25.02.01 was prepared analogously to the procedure for the preparation of Example 24.03.01.
Yield: 33.0 mg (15 %) of the title compound.
LC-MS (Method 4): R, = 1.18 min; MS (ESIpos): m/z = 553 [M+H]+
1 H-NMR (400 MHz, CHLOROFORM-d) δ [ppm]: 0.738 (2.47), 0.951 (2.97), 1.622 (1.97), 2.397 (1.97), 3.565 (4.59), 4.083 (1.72), 4.147 (16.00), 4.263 (0.69), 7.006 (0.87), 7.292 (1.72), 7.428 (1.37), 7.529 (1.14), 7.571 (0.95), 7.601 (0.94), 8.560 (3.36), 8.573 (3.20), 11.967 (2.47).
Example 26.01.01
tert-butyl 4-[(2-{[6-(2-ethoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1-carboxylate
Figure imgf000741_0002
Starting with tert-butyl 4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-benzimidazol- 2-yl]amino}pyridin-4-yl)methyl]piperazine-1-carboxylate (500 mg, 936 μιηοΙ) and 4-chloro-2- ethoxypyrimidine (267 mg, 1 .68 mmol), Example 26.01.01 was prepared analogously to the procedure for the preparation of Example 01 .01.
Yield: 16.5 mg (3 %) of the title compound.
LC-MS (Method 4): R, = 1.31 min; MS (ESIpos): m/z = 531 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.377 (0.99), 1.396 (16.00), 1.412 (1.1 1 ), 2.360 (1.23), 2.518 (1.68), 3.506 (1.45), 8.545 (1.22), 8.558 (1.1 1 ).
Example 26.01.02
cyclopropyl{4-[(2-{[6-(2-ethoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4 yl)methyl]piperazin-1-yl}methanone
Figure imgf000742_0001
Starting with crude 6-(2-ethoxypyrimidin-4-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride ( 20 mg) and cyclopropanecarboxylic acid (26.5 mg, 308 pmol), Example 26.01.02 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 28.0 mg of the title compound.
LC-MS (Method 4): R, = 1.09 min; MS (ESIpos): m/z = 499 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.667 (0.93), 0.678 (2.78), 0.686 (6.61 ), 0.691 (3.92), 0.698 (3.26), 0.705 (8.15), 0.710 (6.83), 0.715 (7.23), 0.722 (6.74), 0.727 (7.67), 0.734 (3.44), 1.244 (1.10), 1.377 (7.54), 1.395 (16.00), 1.412 (7.67), 1.948 (1.54), 1.955 (1.63), 1.968 (2.78), 1.980 (1.54), 1.987 (1.41 ), 2.322 (2.07), 2.327 (2.87), 2.332 (2.12), 2.336 (1.37), 2.365 (3.00), 2.444 (2.95), 2.518 (1 1.1 1 ), 2.523 (7.36), 2.660 (0.79), 2.665 (1.85), 2.669 (2.64), 2.674 (1.85), 2.679 (0.84), 3.529 (13.18), 3.709 (2.82), 4.448 (3.88), 4.466 (3.79), 6.962 (2.34), 7.204 (3.39), 7.437 (1.28), 7.599 (1.90), 7.923 (1.72), 8.194 (1.15), 8.282 (2.56), 8.399 (1.98), 8.545 (10.27), 8.559 (9.26), 10.811 (1.19), 12.334 (1.23). Example 26.01.03
1 -{4-[(2-{[6-(2-ethoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1-yl}-3,3,3-trifluoropropan-1-one
Figure imgf000743_0001
Starting with crude 6-(2-ethoxypyrimidin-4-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (120 mg) and 3,3,3-trifluoropropanoic acid (39.5 mg, 308 ymol), Example 26.01.03 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 26.7 mg of the title compound.
LC-MS (Method 4): R, = 1.12 min; MS (ESIpos): m/z = 541 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.244 (0.91 ), 1.377 (7.64), 1.395 (16.00), 1.412 (7.76), 2.322 (1.70), 2.327 (2.34), 2.332 (1.66), 2.336 (0.83), 2.372 (3.21 ), 2.385 (4.91 ), 2.396 (3.68), 2.426 (4.67), 2.518 (10.10), 2.523 (6.69), 2.660 (0.71 ), 2.665 (1.66), 2.669 (2.34), 2.674 (1.62), 2.679 (0.75), 3.473 (4.44), 3.485 (3.96), 3.510 (4.75), 3.530 (13.19), 3.611 (2.18), 3.638 (6.26), 3.666 (5.86), 3.693 (1.90), 4.048 (2.46), 4.448 (3.92), 4.466 (3.84), 6.955 (2.46), 7.198 (4.51 ), 7.415 (1.27), 7.436 (1.43), 7.584 (2.06), 7.599 (2.10), 7.690 (0.87), 7.925 (1.90), 8.193 (1.27), 8.280 (2.69), 8.398 (2.18), 8.545 (10.85), 8.559 (9.82), 10.807 (1.39), 12.327 (1.47).
Example 26.01.04
cyclobutyl{4-[(2-{[6-(2-ethoxypyrimidin-4-yl)-1H-benzimidazol-2-yl]amino}pyridin-4' yl)methyl]piperazin-1-yl}methanone
Figure imgf000744_0001
Starting with crude 6-(2-ethoxypyrimidin-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (120 mg) and cyclobutanecarboxylic acid (30.9 mg, 308 pmol), Example 26.01.04 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 12.0 mg of the title compound.
LC-MS (Method 4): F¾ = 1.15 min; MS (ESIpos): m/z = 513 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.244 (1.18), 1.377 (5.97), 1.395 (12.39), 1.412 (6.03), 1.736 (1.51 ), 1.841 (1.25), 1.863 (2.49), 1.889 (1.84), 1.913 (1.1 1 ), 2.054 (2.75), 2.076 (3.15), 2.085 (2.49), 2.101 (2.03), 2.124 (3.67), 2.146 (3.93), 2.176 (2.03), 2.322 (3.08), 2.327 (4.39), 2.332 (3.74), 2.354 (7.61 ), 2.518 (16.00), 2.523 (10.56), 2.660 (1.31 ), 2.665 (2.82), 2.669 (4.00), 2.674 (2.62), 2.679 (1.25), 3.304 (3.02), 3.346 (5.77), 3.477 (3.80), 3.505 (1 1.41 ), 4.450 (3.34), 4.467 (3.21 ), 6.948 (2.43), 7.187 (3.08), 7.434 (1.51 ), 7.584 (2.16), 7.599 (2.30), 7.928 (1.90), 8.192 (1.44), 8.275 (2.62), 8.398 (2.36), 8.545 (8.92), 8.558 (8.26), 10.801 (1.77), 12.326 (2.23).
Example 26.01.05
2-cyclopropyl-1-{4 (2-{[6-(2-ethoxypyrimidin-4-yl)-1H-benzimidazol-2-yl]amino}pyridi yl)methyl]piperazin-1-yl}ethanone
Figure imgf000745_0001
Starting with crude 6-(2-ethoxypyrimidin-4-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (120 mg) and cyclopropylacetic acid (30.9 mg, 308 pmol), Example 26.01.05 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 30.0 mg of the title compound.
LC- S (Method 4): R, = 1.12 min; MS (ESIpos): m/z = 513 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.001 (1.95), 0.01 1 (6.92), 0.015 (6.18), 0.023 (7.13), 0.027 (6.39), 0.037 (2.29), 0.330 (2.42), 0.340 (6.18), 0.345 (6.32), 0.350 (3.23), 0.355 (2.96), 0.361 (6.39), 0.365 (6.12), 0.376 (2.29), 0.855 (2.22), 1.159 (1.28), 1.292 (6.72), 1.310 (13.98), 1.327 (6.79), 2.154 (1 1.09), 2.171 (10.69), 2.238 (3.09), 2.242 (4.17), 2.247 (2.96), 2.252 (1.68), 2.278 (4.71 ), 2.433 (16.00), 2.438 (10.69), 2.580 (2.89), 2.584 (3.97), 2.589 (2.76), 3.430 (12.44), 4.365 (3.63), 4.382 (3.50), 6.869 (2.55), 7.109 (3.50), 7.329 (1.55), 7.350 (1.68), 7.500 (2.35), 7.514 (2.42), 7.845 (1.95), 8.109 (1.55), 8.194 (2.82), 8.314 (2.55), 8.460 (9.82), 8.473 (8.94), 10.721 (1.75), 12.245 (2.02).
Example 26.02.01
(rac)-1-{4-[1 -(2-{[6-(2-ethoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)ethyl]piperazin-1 -yl}-3,3,3-trifluoropropan-1-one
Figure imgf000746_0001
Starting with crude (rac)-6-(2-ethoxypyrimidin-4-yl)-N-{4-[(1 -(piperazin-1 -yl)ethyl]pyridin-2-yl}- 1 H-benzimidazol-2-amine hydrochloride (370 mg) and 3,3,3-trifluoropropanoic acid (70.5 mg, 551 μηιοΙ), Example 26.02.01 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 105 mg of the title compound.
LC-MS (Method 4): R, = 1.15 min; MS (ESIpos): m/z = 555 [M+H]+
1H-NMR (400 MHz, CHLOROFORM-d) δ [ppm]: 1.297 (6.52), 1.305 (10.05), 1.314 (7.71 ), 1.322 (9.47), 1.356 (1.44), 1.373 (1.40), 1.466 (4.21 ), 1.484 (8.88), 1.502 (5.01 ), 1.508 (8.01 ), 1.526 (16.00), 1.543 (7.78), 1.624 (2.03), 2.320 (3.70), 2.409 (2.30), 3.126 (2.47), 3.150 (7.30), 3.176 (7.13), 3.201 (2.38), 3.21 1 (1.14), 3.236 (0.99), 3.293 (4.83), 3.338 (2.90), 3.354 (2.50), 3.475 (3.16), 4.261 (0.72), 4.266 (0.72), 4.502 (1.26), 4.520 (4.03), 4.538 (5.49), 4.557 (7.95), 4.575 (6.97), 4.592 (2.14), 4.725 (0.74), 4.730 (0.77), 6.909 (1.79), 6.922 (2.08), 6.929 (3.10), 6.946 (2.87), 7.006 (1.13), 7.018 (3.13), 7.053 (5.00), 7.397 (8.94), 7.41 1 (9.45), 7.528 (0.99), 7.544 (2.59), 7.565 (2.98), 7.679 (3.57), 7.700 (4.03), 7.987 (1.73), 7.991 (1.84), 8.008 (4.40), 8.012 (4.55), 8.029 (2.54), 8.034 (2.53), 8.292 (2.57), 8.305 (3.28), 8.310 (6.26), 8.314 (6.73), 8.318 (6.31 ), 8.324 (5.52), 8.401 (2.92), 8.509 (3.15), 8.523 (3.54), 8.528 (6.02), 8.540 (5.45), 12.465 (2.26).
Example 26.03.01. A
1 -{4-[(1 R or 1S)-1-(2-{[6-(2-ethoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin^ yl)ethyl]piperazin-1 -yl}-3,3,3-trifluoropropan-1 -one (single stereoisomer A)
Figure imgf000747_0001
Example 26.03.01. B
1 -{4-[(1S or 1 R)-1 -(2-{[6-(2-ethoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)ethyl]piperazin-1-yl}-3,3,3-trifluoropropan-1-one (single stereoisomer B)
Figure imgf000747_0002
105 mg of (rac)-1 4-[1 -(2-{[6-(2-ethoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)ethyl]piperazin-1 -yl}-3,3,3-trifluoropropan-1-one was separated into the single stereoisomers (Example 26.03.01. A and Example 26.03.01. B) via preparative, chiral HPLC.
Instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241 , Labcol Vario 4000,
Column: Chiralpak IE 5μ 250x30mm;
Eluent A: tert.-butyl methyl ether + 0.1 Vol-% diethylamine (99%);
Eluent B: methanol; isocratic: 90%A + 10%B;
Flow: 50.0 mL/min;
Solution:105 mg / 3.0 mL ethanol Injection: 3 x 1 .0 mi- Detection: UV 325 nm
Figure imgf000748_0001
Example 26.03.01. A
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.967 (0.77), 1.107 (12.34), 1.230 (1.74), 1.294 (12.58), 1.310 (12.42), 1.376 (7.64), 1.394 (16.00), 1.41 1 (7.80), 2.318 (1.84), 2.323 (2.32), 2.327 (3.31 ), 2.331 (3.31 ), 2.345 (2.75), 2.367 (2.19), 2.419 (3.05), 2.430 (3.42), 2.444 (2.46), 2.458 (2.00), 2.523 (3.55), 2.665 (1.15), 2.669 (1.60), 2.674 (1.12), 3.424 (3.31 ), 3.437 (5.88), 3.449 (3.79), 3.473 (6.14), 3.490 (5.88), 3.581 (2.27), 3.608 (6.46), 3.636 (6.09), 3.663 (1.92), 4.192 (1.18), 4.448 (4.01 ), 4.465 (3.87), 6.967 (2.64), 7.177 (4.94), 7.414 (1.42), 7.434 (1.50), 7.586 (2.30), 7.599 (2.19), 7.690 (0.99), 7.927 (2.03), 7.945 (1.58), 8.192 (1.36), 8.284 (2.78), 8.400 (2.32), 8.545 (9.24), 8.558 (8.65), 10.797 (1.71 ), 12.301 (1.42), 12.335 (2.38).
Example 26.03.01. B
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.962 (0.65), 1.103 (8.33), 1.148 (0.78), 1.178 (0.86), 1.225 (2.61 ), 1.289 (12.10), 1.305 (12.06), 1.372 (7.80), 1.389 (16.00), 1.407 (7.84), 2.323 (3.04), 2.327 (3.12), 2.340 (2.86), 2.363 (2.31 ), 2.414 (3.10), 2.425 (3.53), 2.439 (2.61 ), 2.454 (2.20), 2.660 (0.94), 2.665 (1.27), 2.669 (0.92), 3.421 (3.41 ), 3.433 (6.04), 3.445 (3.88), 3.468 (6.27), 3.485 (6.16), 3.576 (2.18), 3.604 (6.25), 3.631 (5.92), 3.658 (1.90), 4.187 (0.78), 4.426 (1.59), 4.443 (4.35), 4.460 (4.24), 4.477 (1.47), 6.963 (2.67), 7.173 (5.25), 7.410 (1.25), 7.430 (1.37), 7.581 (2.10), 7.595 (2.08), 7.684 (0.86), 7.920 (2.04), 8.187 (1.24), 8.278 (2.94), 8.290 (2.67), 8.396 (2.16), 8.540 (8.18), 8.553 (7.59), 10.793 (1 .43), 12.298 (1.31 ), 12.330 (2.20). Example 27.01
cyclopropyl(4-{[2-({6-[2-(trifluoromethyl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1 -yl)methanone
Figure imgf000749_0001
Starting with crude N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]-6-[2-(trifluoromethyl)pyrimidin-4-yl]- 1 H-benzimidazol-2-amine hydrochloride (140 mg, approx. 246 pmol) and cyclopropanecarboxylic acid (31.8 mg, 370 pmol), Example 27.01 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 39.0 mg of the title compound.
LC-MS (Method 4): R, = 1.16 min; MS (ESIpos): m/z = 523 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.678 (3.61 ), 0.686 (8.07), 0.691 (5.25), 0.698 (4.46), 0.705 (9.77), 0.709 (8.92), 0.714 (9.25), 0.721 (8.26), 0.726 (9.31 ), 0.733 (4.39), 1.950 (1.84), 1.957 (2.03), 1.969 (3.28), 1.981 (1.97), 1.988 (1.70), 2.322 (3.15), 2.327 (4.39), 2.331 (3.54), 2.336 (2.30), 2.364 (4.13), 2.447 (4.85), 2.523 (15.21 ), 2.539 (3.34), 2.659 (1.44), 2.665 (3.02), 2.669 (4.20), 2.673 (3.15), 3.307 (1.70), 3.501 (4.13), 3.532 (16.00), 3.709 (3.93), 6.976 (3.67), 6.989 (2.49), 7.186 (4.20), 7.216 (1.77), 7.467 (2.69), 7.488 (3.15), 7.552 (1.31 ), 7.646 (1.31 ), 7.666 (1.31 ), 8.013 (3.80), 8.035 (3.48), 8.280 (8.13), 8.292 (9.70), 8.413 (1.18), 8.515 (3.67), 8.961 (2.89), 8.975 (3.67), 10.809 (1.44), 10.896 (3.15), 12.394 (1.51 ), 12.491 (3.54).
Example 27.02
cyclobutyl(4-{[2-({6-[2-(trifluoromethyl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1 -yl)methanone
Figure imgf000750_0001
Starting with crude N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]-6-[2-(trifluoromethyl)pyrimidin-4-yl]- 1 H-benzimidazol-2-amine hydrochloride (140 mg, approx. 246 pmol) and cyclobutanecarboxylic acid (37.0 mg, 370 pmol), Example 27.02 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 45.0 mg of the title compound.
LC-MS (Method 4): R, = 1.22 min; MS (ESIpos): m/z = 537 [M+H]+
H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.065 (0.90), 1 .299 (2.85), 1.710 (1.45), 1.734 (1.80), 1.758 (0.85), 1.841 (1.40), 1.862 (2.75), 1.885 (2.30), 1.912 (1.35), 2.053 (3.30), 2.062 (2.50), 2.074 (3.85), 2.083 (2.95), 2.100 (2.40), 2.124 (4.20), 2.145 (4.55), 2.175 (2.30), 2.197 (0.70), 2.318 (1.45), 2.322 (2.85), 2.327 (4.25), 2.331 (4.35), 2.354 (9.25), 2.518 (16.00), 2.523 (10.35), 2.659 (1.10), 2.665 (2.35), 2.669 (3.20), 2.673 (2.35), 2.678 (1.10), 3.306 (3.20), 3.473 (5.00), 3.487 (4.95), 3.507 (12.80), 4.089 (0.80), 6.955 (2.60), 6.967 (2.65), 7.184 (2.00), 7.486 (1.00), 8.011 (3.50), 8.015 (3.50), 8.032 (3.15), 8.036 (3.25), 8.270 (6.00), 8.283 (6.45), 8.510 (1.25), 8.965 (2.85), 8.979 (2.85), 10.883 (0.75).
Example 27.03
2-cyclopropyl-1-(4-{[2-({6 2-(trifluoromethyl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1 -yl)ethanone
Figure imgf000751_0001
Starting with crude N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-6-[2-(trifluoromethyl)pyrimidin-4-yl]- 1 H-benzimidazol-2-amine hydrochloride (140 mg, approx. 246 μηηοΙ) and cyclopropylacetic acid (37.0 mg, 370 pmol), Example 27.03 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 38.0 mg of the title compound.
LC-MS (Method 4): R, = 1.19 min; MS (ESIpos): m/z = 537 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.001 (2.39), 0.01 1 (8.24), 0.023 (8.54), 0.037 (2.54), 0.330 (2.54), 0.340 (6.78), 0.344 (6.93), 0.350 (4.10), 0.354 (4.15), 0.360 (7.32), 0.364 (6.93), 0.375 (2.24), 0.754 (1.02), 0.854 (2.49), 0.921 (0.98), 0.980 (0.93), 2.153 (1 1.41 ), 2.171 (11.17), 2.242 (3.51 ), 2.278 (6.83), 2.31 1 (7.22), 2.437 (16.00), 2.584 (3.22), 3.371 (6.63), 3.406 (6.68), 3.433 (15.46), 4.004 (0.93), 6.882 (3.71 ), 7.093 (4.20), 7.123 (1.80), 7.380 (2.49), 7.401 (2.93), 7.467 (1.32), 7.560 (1.32), 7.928 (3.85), 7.948 (3.51 ), 8.190 (7.80), 8.204 (8.78), 8.326 (1.12), 8.428 (3.66), 8.876 (2.78), 8.890 (3.71 ), 10.721 (1.27), 10.807 (2.83), 12.307 (1.46), 12.404 (3.32).
Example 27.04
3,3,3-trifluoro-1-(4^[2-({6-[2-(trifluoromethyl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1 -yl)propan-1 -one
Figure imgf000752_0001
Starting with crude N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-6-[2-(trifluoromethyl)pyrimidin-4-yl]- 1 H-benzimidazol-2-amine hydrochloride (140 mg.approx. 246 μιηοΙ) and 3,3,3- trifluoropropanoic acid (47.3 mg, 370 pmol), Example 27.04 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 28.0 mg of the title compound.
LC-MS (Method 1 ): Rt = 0.91 min; MS (ESIneg): m/z = 563 [M-H]+
1 H-NMR (400 MHz, CHLOROFORM-d) δ [ppm]: 1.284 (16.00), 2.628 (1.29), 3.190 (1.01 ), 3.215 (0.98), 3.525 (1.65).
Example 28.01
tert-butyl 4-[(2-{[6-(2-ethylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4 yl)methyl] pi perazine-1 -carboxylate
Figure imgf000753_0001
Starting with tert-butyl 4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-benzimidazol- 2-yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate (500 mg, 936 pmol) and 4-chloro-2- ethylpyrimidine (240 mg, 1.68 mmol), Example 28.01 was prepared analogously to the procedure for the preparation of Example 01.01.
Yield: 10.0 mg (2 %) of the title compound.
LC-MS (Method 2): Rt = 1 .28 min; MS (ESIpos): m/z = 515 [M+H]+
H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.107 (6.94), 1.356 (1.64), 1.396 (16.00), 2.327 (0.77), 2.347 (0.97), 2.360 (1.46), 2.373 (1.01 ), 2.518 (3.41 ), 2.523 (2.10), 2.669 (0.75), 2.928 (1.03), 2.947 (1.01 ), 3.352 (1.34), 3.505 (1.83), 8.668 (1.13), 8.682 (1.08).
Example 29.01.01
(rac)-3,3,3-trifluoro-1-(4-{1 2-({6-[6-(trifluoromethyl)pyrimidin-4-yl]-1H-benzimi yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)propan-1 -one
Figure imgf000754_0001
Starting with N 4-[(1 R)-1-(piperazin-1 -yl)ethyl]pyridin-2-yl}-6-[6-(trifluoromethyl)pyrimidin-4-yl]- 1 H-benzimidazol-2-amine (185 mg, 395 pmol) and 3,3,3-trifluoropropanoic acid (75.8 mg, 592 pmol), Example 29.01.01 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 76.2 mg (32 %) of the title compound.
LC-MS (Method 4): Rt = 1.26 min; MS (ESIpos): m/z = 579 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.065 (1.67), 1.295 (16.00), 1.31 1 (15.14), 2.318 (2.27), 2.322 (2.76), 2.327 (3.91 ), 2.332 (4.05), 2.337 (3.36), 2.345 (3.53), 2.367 (2.82), 2.418 (3.85), 2.431 (4.45), 2.445 (3.42), 2.460 (2.61 ), 2.518 (5.14), 2.523 (3.59), 2.539 (1.52), 2.665 (1.24), 2.669 (1.72), 2.673 (1.24), 2.685 (0.72), 2.729 (0.60), 2.888 (0.78), 3.426 (4.22), 3.438 (7.24), 3.450 (4.60), 3.480 (8.82), 3.495 (6.18), 3.582 (2.73), 3.609 (7.70), 3.637 (7.30), 3.664 (2.27), 4.019 (1.55), 6.982 (2.84), 6.996 (1.87), 7.184 (7.61 ), 7.459 (1.78), 7.480 (1.92), 7.630 (1.06), 7.652 (1.12), 8.095 (1.12), 8.1 18 (2.53), 8.140 (1.55), 8.286 (4.80), 8.300 (4.54), 8.391 (1.81 ), 8.426 (3.04), 8.541 (2.87), 8.573 (1.87), 9.373 (4.83), 10.808 (1.12), 10.884 (1.78), 12.377 (1.61 ), 12.419 (2.61 ).
Example 29.01.02
(rac)-cyclopropyl(4-{1-[2-({6-[6-(trifluoromethyl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)methanone
Figure imgf000755_0001
Starting with (rac)-N-{4-[1-(piperazin-1 -yl)ethyl]pyridin-2-yl}-6-[6-(trifluoromethyl)pyrimidin-4-yl]- 1 H-benzimidazol-2-amine (185 mg, 395 μηιοΙ) and cyclopropanecarboxyiic acid (51.0 mg, 592 pmol), Example 29.01.02 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 63.0 mg (28 %) of the title compound.
LC-MS (Method 4): F¾ = 1.23 min; MS (ESIpos): m/z = 537 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.665 (6.69), 0.687 (10.35), 1.064 (1.12), 1.298 (16.00), 1.313 (10.32), 1.938 (2.52), 2.326 (3.08), 2.399 (3.94), 2.672 (1.51 ), 3.462 (6.88), 3.673 (4.59), 6.989 (2.66), 7.191 (5.06), 7.481 (1.59), 7.630 (1.01 ), 8.117 (2.13), 8.287 (3.30), 8.300 (3.22), 8.387 (1.34), 8.428 (2.21 ), 8.538 (2.15), 9.374 (3.86), 10.887 (1.12), 12.433 (1.20).
Example 29.02.01. A
3,3,3-trifluoro-1 -(4-{(1 R or 1S)-1 -[2-({6-[6-(trifluoromethyl)pyrimidin-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)propan-1 -one (single stereoisomer A)
Figure imgf000756_0001
Example 29.02.01. B
3,3,3-trifluoro-1 -(4-{(1 S or 1 R)-1 -[2-({6-[6-(trifluoromethyl)pyrimidin-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)propan-1-one (single stereoisomer B)
Figure imgf000756_0002
73 mg of (rac)-3,3,3-trifluoro-1 -(4-{1 -[2-({6-[6-(trifluoromethyl)pyrimidin-4-yl]-1 H-benzimidazol- 2-yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)propan-1-one was separated into the single stereoisomers (Example 29.02.01. A and Example 29.02.01. B) via preparative, chiral HPLC. Instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241 , Labcol Vario 4000,
Column: Chiralpak IA 5μ 250x30mm;
Eluent A: tert.-butyl methyl ether + 0.1 Vol-% diethylamine (99%);
Eluent B: acetonitrile; isocratic: 70%A+30%B;
Flow: 50.0 mL/min;
Solution: 73 mg / 2 mL dichloromethane/methanol 1 : 1 Injection: 2 x 1.0 ml_
Detection: UV 325 nm
Figure imgf000757_0001
Example 29.02.01. A
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.107 (3.24), 1.154 (0.90), 1.172 (1.62), 1.190 (0.72), 1.231 (1.80), 1.295 (7.91 ), 1.312 (7.37), 1.988 (2.34), 2.084 (16.00), 2.318 (1.98), 2.323 (3.42), 2.327 (4.67), 2.332 (3.96), 2.337 (2.34), 2.345 (1.62), 2.366 (1.26), 2.419 (1.80), 2.432 (2.16), 2.518 (1 1.51 ), 2.523 (7.73), 2.660 (1.26), 2.665 (2.70), 2.669 (3.60), 2.673 (2.52), 2.679 (1 .08), 3.426 (2.16), 3.438 (3.60), 3.450 (2.16), 3.482 (4.13), 3.493 (2.70), 3.582 (1.26), 3.609 (3.96), 3.637 (3.60), 3.664 (1.08), 6.986 (1.44), 7.000 (1.08), 7.183 (3.24), 7.459 (1.44), 7.480 (1.44), 7.631 (0.90), 7.652 (0.90), 8.119 (1.44), 8.123 (1.08), 8.145 (0.90), 8.290 (1.80), 8.304 (1.62), 8.388 (1.44), 8.428 (2.16), 8.537 (1.80), 8.573 (1.44), 9.371 (2.52), 9.382 (1.80), 10.804 (1.26), 10.882 (1.98), 12.376 (1.26), 12.420 (1.80).
Example 29.02.01. B
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.107 (0.76), 1.295 (1 .48), 1.312 (1.44), 2.084 (16.00), 3.609 (0.82), 3.636 (0.76), 7.184 (0.82). Example 30.01.01
3,3,3-trifluoro-1-{4-[(2-{[6-(6-methylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}p yl)methyl]pi perazin-1 -yl}propan-1 -one
Figure imgf000758_0001
Starting with crude 6-(6-methylpyrimidin-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (150 mg, approx. 300 pmol) and 3,3,3-trifluoropropanoic acid (57.6 mg, 449 pmol), Example 30.01.01 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 60.0 mg of the title compound.
LC-MS (Method 4): R, = 1.00 min; MS (ESIpos): m/z = 5 1 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.711 (1.37), 1.734 (1.67), 1.758 (0.82), 1.841 (1.42), 1.862 (2.66), 1.868 (1.20), 1.885 (2.10), 1.889 (2.06), 1.912 (1.29), 2.053 (3.09), 2.062 (2.36), 2.069 (2.27), 2.075 (3.56), 2.084 (2.87), 2.101 (2.23), 2.106 (2.06), 2.124 (4.03), 2.129 (2.79), 2.145 (4.33), 2.169 (2.02), 2.175 (2.27), 2.197 (0.73), 2.318 (1.20), 2.323 (2.45), 2.327 (3.52), 2.331 (3.52), 2.354 (8.62), 2.518 (16.00), 2.523 (9.69), 2.659 (0.94), 2.665 (2.10), 2.669 (2.92), 2.673 (2.06), 2.678 (0.99), 2.848 (0.86), 3.284 (0.77), 3.306 (3.05), 3.346 (6.82), 3.474 (4.50), 3.503 (12.31 ), 6.948 (2.49), 7.187 (4.46), 7.421 (1.12), 7.442 (1.24), 7.600 (0.90), 7.884 (1.97), 7.925 (3.13), 7.945 (2.83), 7.998 (1.46), 8.201 (1.46), 8.266 (5.19), 8.280 (5.06), 8.395 (1.89), 9.015 (7.55), 9.018 (7.72), 10.779 (1.54), 12.313 (0.94).
Example 30.01.02
cyclobutyl{4-[(2-{[6-(6-methylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1-yl}methanone
Figure imgf000759_0001
Starting with crude 6-(6-methylpyrimidin-4-yl)-N-[4-(piperazin-1 -ylrnethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (150 mg, approx. 300 μιτιοΙ) and cyclobutanecarboxylic acid (45.0 mg, 449 pmol), Example 30.01.02 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 46.0 mg of the title compound.
LC-MS (Method 4): Rt = 1.03 min; MS (ESIpos): m/z = 483 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.065 (1.08), 1.231 (0.77), 2.318 (0.95), 2.323 (2.12), 2.327 (2.98), 2.331 (2.26), 2.337 (1.08), 2.371 (3.66), 2.384 (5.51 ), 2.396 (4.20), 2.413 (3.71 ), 2.426 (5.24), 2.437 (4.20), 2.518 (16.00), 2.523 (9.72), 2.659 (0.99), 2.665 (2.26), 2.669 (3.16), 2.673 (2.21 ), 2.678 (1.04), 2.848 (8.41 ), 3.474 (5.11 ), 3.485 (4.70), 3.497 (4.84), 3.510 (5.42), 3.529 (15.23), 3.612 (2.40), 3.640 (6.64), 3.667 (6.33), 3.694 (2.08), 4.049 (2.85), 6.663 (2.35), 6.667 (2.62), 6.721 (0.86), 6.726 (1.36), 6.730 (0.68), 6.944 (3.53), 6.956 (3.57), 7.090 (0.81 ), 7.207 (4.84), 7.924 (4.97), 7.928 (4.97), 7.945 (4.34), 7.949 (4.56), 8.271 (6.37), 8.285 (6.10), 9.015 (9.40), 9.018 (9.36).
Example 30.01.03
2-cyclopropyl-1 -{4-[(2-{[6-(6-methylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]am
yl)methyl]piperazin-1-yl}ethanone
Figure imgf000760_0001
Starting with crude 6-(6-methylpyrimidin-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (150 mg, approx. 300 pmol) and cyclopropylacetic acid (45.0 mg, 449 pmol), Example 30.01.03 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 37.0 mg of the title compound.
LC-MS (Method 4): R, = 0.99 min; MS (ESIpos): m/z = 483 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.000 (1.65), 0.01 1 (5.50), 0.014 (5.20), 0.023 (5.65), 0.026 (5.35), 0.037 (1.90), 0.330 (2.00), 0.340 (4.90), 0.344 (5.10), 0.350 (2.85), 0.354 (2.50), 0.360 (5.30), 0.365 (4.95), 0.375 (1.90), 0.834 (1.05), 0.842 (1.05), 0.854 (1.85), 0.867 (1.05), 0.871 (1.10), 0.921 (1.00), 2.154 (8.80), 2.171 (8.55), 2.233 (1.10), 2.238 (2.30), 2.242 (3.30), 2.247 (2.55), 2.251 (1.50), 2.277 (3.95), 2.31 1 (4.10), 2.433 (16.00), 2.438 (9.95), 2.575 (1.00), 2.580 (2.30), 2.584 (3.30), 2.589 (2.35), 2.594 (1.05), 3.222 (1.10), 3.374 (3.90), 3.429 (9.90), 6.866 (2.15), 7.106 (3.00), 7.337 (1.20), 7.358 (1.30), 7.517 (0.90), 7.799 (2.00), 7.841 (2.55), 7.862 (2.35), 7.912 (1.50), 8.1 17 (1.50), 8.186 (4.10), 8.199 (3.95), 8.31 1 (1.85), 8.930 (5.90), 8.933 (6.45), 10.698 (1.40), 12.230 (0.95).
Example 30.01.04
cyclopropyl{4-[(2-{[6-(6-methylpyrimidin-4-yl)-1H-benzimidazol-2-yl]amino}pyridi yl)methyl]piperazin-1-yl}methanone
Figure imgf000761_0001
Starting with crude 6-(6-methylpyrimidin-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (150 mg, approx. 300 pmol) and cyclopropanecarboxylic acid (38.7 mg, 449 μηηοΙ), Example 30.01.04 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 38.0 mg of the title compound.
LC-MS (Method 4): R, = 0.96 min; MS (ESIpos): m/z = 469 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.666 (1.22), 0.678 (3.61 ), 0.685 (7.92), 0.690 (5.08), 0.698 (4.32), 0.705 (9.75), 0.709 (8.43), 0.714 (8.99), 0.721 (8.03), 0.726 (9.19), 0.733 (4.27), 0.745 (1.07), 1.065 (1.17), 1.937 (0.91 ), 1.949 (1.88), 1.956 (1.98), 1.969 (3.35), 1.981 (1.88), 1.988 (1.73), 2.000 (0.76), 2.318 (1.27), 2.323 (2.69), 2.327 (3.81 ), 2.331 (3.00), 2.337 (1.93), 2.364 (3.81 ), 2.446 (4.01 ), 2.518 (16.00), 2.523 (10.41 ), 2.659 (1.17), 2.665 (2.64), 2.669 (3.71 ), 2.673 (2.59), 2.678 (1.22), 3.308 (1.22), 3.503 (3.96), 3.528 (15.54), 3.711 (3.50), 6.954 (3.30), 6.967 (3.40), 7.204 (5.13), 7.445 (1.07), 7.887 (1.47), 7.925 (4.22), 7.930 (4.27), 7.946 (3.76), 7.950 (3.86), 7.997 (1.07), 8.205 (1.07), 8.275 (6.55), 8.288 (6.30), 8.396 (1.42), 9.015 (8.79), 9.019 (8.99), 10.780 (1.37).
Example 30.02.01
(rac)-3,3,3-trifluoro-1 -{4-[1 -(2-{[6-(6-methylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}propan-1 -one
Figure imgf000762_0001
Starting with (rac)-6-(6-methylpyrimidin-4-yl)-N-{4-[1 -(piperazin-1 -yl)ethyl]pyridin-2-yl}-1 H- benzimidazol-2-amine (200 mg, 482 μιτιοΙ) and 3,3,3-trifluoropropanoic acid (92.7 mg, 724 μιηοΙ), Example 30.02.01 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 9.00 mg (3 %) of the title compound.
LC-MS (Method 2): R, = 1.05 min; MS (ESIpos): m/z = 525 [M+H]+
1 H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.228 (16.00), 1.294 (13.99), 1.517 (10.40), 2.361 (13.20), 2.539 (13.55), 2.691 (9.27), 3.006 (6.30), 3.471 (14.86), 3.636 (11.89), 5.758 (6.03), 7.622 (5.60).
Example 30.02.02
(rac)-cyclobutyl{4-[1 -(2-{[6-(6-methylpyrimidin-4-yl)-1H-benzimidazol-2-yl]amino}pyridin- 4-yl)ethyl]piperazin-1-yl}methanone
Figure imgf000763_0001
Starting with (rac)-6-(6-methylpyrimidin-4-yl)-N-{4-[1 -(piperazin-1-yl)ethyl]pyridin-2-yl}-1 H- benzimidazol-2-amine (200 mg, 482 μιτηοΙ) and cyclobutanecarboxylic acid (72.5 mg, 724 pmol), Example 30.02.02 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 67.8 mg (28 %) of the title compound.
LC-MS (Method 4): R, = 1.07 min; MS (ESIpos): m/z = 497 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.275 (15.87), 1.292 (16.00), 1.717 (2.29), 1.822 (1.76), 1.844 (3.49), 1.866 (2.74), 1.893 (1.73), 2.030 (4.12), 2.052 (4.77), 2.061 (3.77), 2.076 (3.34), 2.099 (5.07), 2.121 (5.27), 2.151 (2.69), 2.281 (3.72), 2.295 (4.12), 2.326 (2.49), 2.401 (2.91 ), 2.522 (9.24), 2.668 (1.66), 3.274 (3.59), 3.294 (8.1 1 ), 3.307 (7.28), 3.317 (7.69), 3.427 (6.28), 3.443 (7.91 ), 6.950 (3.52), 6.963 (3.62), 7.172 (8.97), 7.441 (1.23), 7.883 (1.91 ), 7.924 (4.57), 7.927 (4.52), 7.944 (4.04), 8.198 (1.38), 8.269 (7.26), 8.282 (6.96), 8.395 (1.86), 9.014 (10.78), 9.017 (10.55), 10.766 (1.53), 12.322 (1.91 ).
Example 30.02.03
(rac)-cyclopropyl{4-[1 -(2-{[6-(6-methylpyrimidin-4-yl)-1 H-benzimidazol-2
yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}methanone
Figure imgf000764_0001
Starting with (rac)-6-(6-methylpyrimidin-4-yl)-N-{4-[1 -(piperazin-1 -yl)ethyl]pyridin-2-yl}-1 H- benzimidazol-2-amine (200 mg, 482 μιτιοΙ) and cyclopropanecarboxylic acid (62.3 mg, 724 pmol), Example 30.02.03 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 58.7 mg (25 %) of the title compound.
LC-MS (Method 4): R, = 1.00 min; MS (ESIpos): m/z = 483 [M+H]+
H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.656 (3.77), 0.664 (8.60), 0.669 (5.44), 0.677 (4.50), 0.684 (10.94), 0.691 (10.30), 0.698 (8.39), 0.703 (9.48), 0.710 (4.42), 1.295 (15.94), 1.312 (16.00), 1.918 (1.96), 1.924 (2.14), 1.937 (3.66), 1.949 (1.99), 1.956 (1.84), 2.322 (2.69), 2.326 (3.07), 2.402 (2.75), 2.522 (5.73), 2.668 (1.93), 3.454 (6.26), 3.470 (7.55), 3.676 (4.07), 6.979 (3.54), 7.186 (8.31 ), 7.885 (1.87), 7.924 (4.30), 7.929 (4.33), 7.950 (3.98), 8.278 (7.22), 8.290 (6.96), 8.397 (1.78), 9.014 (10.12), 9.017 (1 1.06), 10.770 (1.49), 12.338 (1.61 ).
Example 30.02.04
(rac)-2-cyclopropyl-1 -{4-[1 -(2-{[6-(6-methylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}ethanone
Figure imgf000765_0001
Starting with (rac)-6-(6-methylpyrimidin-4-yl)-N-{4-[1 -(piperazin-1-yl)ethyl]pyridin-2-yl}-1 H- benzimidazol-2-amine (300 mg, 724 μιηοΙ) and cyclopropylacetic acid (109 mg, 1.09 mmol), Example 30.02.04 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 63.0 mg ( 17 %) of the title compound.
LC-MS (Method 4): R, = 1.05 min; MS (ESIpos): m/z = 497 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.000 (2.56), 0.01 1 (9.36), 0.014 (8.28), 0.023 (9.52), 0.026 (8.36), 0.037 (2.76), 0.331 (2.88), 0.341 (7.88), 0.345 (7.72), 0.351 (3.84), 0.356 (3.72), 0.361 (8.16), 0.365 (7.68), 0.375 (2.60), 0.814 (0.76), 0.819 (1.00), 0.831 (1.76), 0.838 (1.76), 0.851 (2.80), 0.863 (1.60), 0.868 (1.68), 0.880 (0.80), 0.888 (0.64), 1.164 (0.76), 1.220 (16.00), 1.237 (15.92), 2.145 (14.24), 2.162 (13.68), 2.231 (2.40), 2.252 (3.80), 2.257 (4.28), 2.261 (4.88), 2.266 (4.24), 2.283 (2.52), 2.338 (5.24), 2.352 (4.20), 2.366 (3.08), 2.457 (4.88), 2.594 (0.88), 2.599 (1.88), 2.604 (2.56), 2.608 (1.80), 2.613 (0.80), 3.358 (8.28), 3.375 (8.08), 3.393 (8.64), 6.904 (3.44), 7.11 1 (8.72), 7.354 (1.44), 7.376 (1.52), 7.515 (1.04), 7.535 (1.08), 7.817 (2.48), 7.858 (4.20), 7.862 (4.36), 7.883 (3.88), 7.931 (1.80), 8.133 (1.72), 8.207 (7.20), 8.220 (6.88), 8.330 (2.36), 8.949 (10.88), 8.951 (1 1.16), 10.700 (1.96), 12.21 1 (1.72), 12.255 (2.48).
Example 30.03.01. A
3,3,3-trifluoro-1 -{4-[(1 R or 1 S)-1 -(2-{[6-(6-methylpyrimidin-4-yl)-1 H-benzimidazol-2 - yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}propan-1 -one (single stereoisomer A)
Figure imgf000766_0001
Example 30.03.01. B
3,3,3-trifluoro-1 -{4-[(1S or 1 R)-1 -(2-{[6-(6-methylpyrimidin-4-yl)-1 H-benzimidazol-2 - yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}propan-1 -one (single stereoisomer B)
Figure imgf000766_0002
55 mg of (rac)-3,3,3-trifluoro-1 -{4-[1 -(2-{[6-(6-methylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}propan-1-one was separated into the single stereoisomers (Example 30.03.01. A and Example 30.03.01. B) via preparative, chiral HPLC. Instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241 , Labcol Vario 4000,
Column: Chiralpak IA 5μ 250x30mm;
Eluent A: tert.-butyl methyl ether + 0.1 Vol-% diethylamine (99%);
Eluent B: acetonitrile; isocratic: 50%A+50%B;
Flow: 60.0 mL/min;
Solution: 55 mg / 1.5 mL dichloromethane/methanol 1 : 1 Injection: 3 x 0.5 mi- Detection: UV 325 nm
Figure imgf000767_0001
Example 30.03.01. A
H-NMR(400MHz, DMSO-d6) δ [ppm]: 1.107(16.00), 1.293 (4.06), 1.310(3.94), 2.083 (0.65), 2.327 (1.20), 2.332 (1.11), 3.437 (1.91), 3.449 (1.23), 3.471 (2.00), 3.488 (1.94), 3.608 (2.09), 3.635 (1.97), 4.199 (1.48), 7.176 (1.97), 7.925 (1.08), 7.929 (1.05), 8.277 (1.75), 8.290 (1.66), 9.014(2.58), 9.017(2.74).
Example 30.03.01. B
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.803 (0.41), 0.850 (1.01), 0.859 (0.71), 0.966 (0.61), 1.107(10.43), 1.135 (0.71), 1.143 (0.61), 1.152 (0.81), 1.171 (0.71), 1.182(1.11), 1.230 (4.86), 1.254 (1.22), 1.279 (1.82), 1.293 (15.90), 1.310 (16.00), 1.347 (1.11), 2.083 (4.05), 2.318 (2.33), 2.322 (3.14), 2.327 (4.56), 2.332 (4.35), 2.337 (3.44), 2.344 (3.54), 2.366 (2.84), 2.418 (3.85), 2.430 (4.35), 2.444 (3.34), 2.458 (2.94), 2.523 (5.97), 2.660 (0.71), 2.665 (1.62), 2.669 (2.33), 2.673 (1.62), 2.679 (0.71), 3.380 (1.32), 3.425 (4.35), 3.437 (7.70), 3.449 (4.96), 3.472 (7.80), 3.482 (7.59), 3.488 (7.59), 3.503 (2.63), 3.509 (1.72), 3.580 (2.94), 3.608 (8.41), 3.635 (7.90), 3.663 (2.43), 4.197 (0.91), 6.959 (3.75), 6.972 (3.85), 7.176 (8.20), 7.444 (1.01), 7.582 (0.81), 7.885 (1.62), 7.925 (4.76), 7.929 (4.56), 7.946 (4.15), 7.950 (4.15), 7.993 (1.11), 8.201 (1.11), 8.278 (7.49), 8.291 (7.09), 8.396 (1.52), 9.015 (11.44), 9.018 (11.14), 10.770 (2.33), 12.284(1.32), 12.323(1.82). Example 30.03.02.A
cyclobutyl{4-[(1 R or 1S)-1.(2-{[6-(6-rnethylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}methanone (single stereoisomer A)
Figure imgf000768_0001
Example 30.03.02.B
cyclobutyl{4-[(1S or 1 R)-1 -(2-{[6-(6-methylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}methanone (single stereoisomer B)
Figure imgf000768_0002
64.1 mg of (rac)-cyclobutyl{4-[1 -(2-{[6-(6-methylpyrimidin-4-yl)-1 H-benzimiclazot-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}methanone was separated into the single stereoisomers (Example 30.03.02.A and Example 30.03.02. B) via preparative, chiral HPLC.
Instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241 , Labcoi Vario 4000,
Column: Chiralpak IB 5μ 250x30mm;
Eluent A: hexane + 0.2 Vol-% diethylamine (99%); Eluent B: ethanol; isocratic: 70%A+30%B;
Flow: 30.0 mL/min;
Solution: 64 mg / 2.5 mL ethanol
Injection: 5 x 0.5 mL
Detection: UV 325 nm Retention time in
purity in % yield Optical rotation [a]D min
Example - 43.1 °
30.03.02.A
(from solution in
9.05 - 10.10 >99.0% 26 mg
Stereoisomer A DMSO, c = 2.6 mg/mL)
Example + 36.0°
30.03.02.B
(from solution in
10.20 - 12.50 94.3% 27 mg
Stereoisomer B DMSO, c = 2.9 mg/mL)
Example 30.03.02.A
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.106 (16.00), 1.275 (5.58), 1.292 (5.58), 1.844 (1.20), 2.031 (1.37), 2.052 (1.58), 2.061 (1.20), 2.099 (1.64), 2.121 (1.76), 2.294 (1.37), 3.272 (1.16), 3.294 (2.80), 3.307 (2.44), 3.316 (2.70), 3.427 (2.13), 3.444 (2.65), 4.193 (1.58), 7.172 (3.1 1 ), 7.923 (1.46), 7.928 (1.40), 7.945 (1.32), 7.949 (1.27), 8.268 (2.47), 8.282 (2.34), 9.014 (3.78), 9.017 (3.69).
Example 30.03.02.B
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.967 (0.76), 1.107 (16.00), 1.144 (0.52), 1 .230 (1.08), 1.258 (0.84), 1.276 (10.31 ), 1.293 (10.47), 1.693 (1.16), 1.707 (1.00), 1.717 (1.40), 1.728 (0.84), 1.741 (0.68), 1.823 (1.12), 1.845 (2.21 ), 1.850 (1.04), 1.867 (1.72), 1.872 (1.68), 1.889 (0.84), 1.894 (1.08), 2.031 (2.57), 2.040 (1.88), 2.047 (1.88), 2.053 (2.97), 2.062 (2.29), 2.076 (2.01 ), 2.083 (1.64), 2.100 (3.09), 2.121 (3.29), 2.150 (1.72), 2.282 (2.33), 2.296 (2.57), 2.310 (2.37), 2.323 (1.64), 2.327 (1.48), 2.331 (1.00), 2.361 (1.56), 2.376 (1.52), 2.399 (1.88), 2.413 (1.52), 2.523 (2.93), 2.665 (0.80), 2.669 (1.08), 2.673 (0.72), 3.273 (2.29), 3.294 (5.37), 3.307 (4.81 ), 3.318 (5.29), 3.410 (1.20), 3.428 (3.93), 3.445 (4.93), 4.194 (1.48), 6.952 (2.17), 6.964 (2.17), 7.172 (5.73), 7.420 (0.84), 7.441 (0.88), 7.883 (1.48), 7.924 (2.73), 7.945 (2.41 ), 7.994 (1.00), 8.201 (1.04), 8.269 (4.53), 8.282 (4.33), 8.395 (1.40), 9.014 (7.14), 9.017 (6.78), 10.759 (1.44), 12.278 (1.08), 12.321 (1.48). Example 30.03.03.A
cyclopropyl{4-[(1R or 1S)-1 -(2-{[6-(6-methylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}methanone (single stereoisomer A)
Figure imgf000770_0001
Example 30.03.03.B
cyclopropyl{4-[(1S or 1 R)-1 -(2-{[6-(6-methylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}methanone (single stereoisomer B)
Figure imgf000770_0002
55.4 mg of (rac)-cyclopropyl{4-[1-(2-{[6-(6-methylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}methanone was separated into the single stereoisomers (Example 30.03.03.A and Example 30.03.03. B) via preparative, chiral HPLC.
Instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241 , Labcol Vario 4000,
Column: Chiralpak IB 5μ 250x30mm;
Eluent A: hexane + 0.2 Vol-% diethylamine (99%); Eluent B: ethanol; isocratic: 70%A+30%B;
Flow: 30.0 mL/min;
Solution: 55 mg / 2.0 mL ethanol
Injection: 4 x 0.5 mL
Detection: UV 325 nm Retention time in
purity in % yield Optical rotation [a]o min
Example - 39.5°
30.03.03.A
(from solution in
12.00 - 13.55 95.2% 23 mg
Stereoisomer A DMSO, c = 2.7 mg/mL)
Example + 35.4°
30.03.03.B
(from solution in
13.55 - 16.00 93.3% 22 mg
Stereoisomer B DMSO, c = 3.2 mg/mL)
Example 30.03.03.A
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.657 (1.82), 0.665 (4.32), 0.670 (2.73), 0.677 (2.20), 0.684 (5.57), 0.691 (5.31 ), 0.699 (4.32), 0.703 (4.97), 0.710 (2.35), 1.106 (16.00), 1.230 (1.40), 1.295 (8.34), 1.312 (8.23), 1.919 (1.02), 1.938 (1.82), 2.318 (1.29), 2.322 (1.67), 2.326 (1.93), 2.332 (1.52), 2.398 (1.59), 2.522 (4.59), 2.664 (2.27), 2.668 (1.71 ), 2.673 (1.02), 3.455 (3.22), 3.471 (3.91 ), 3.677 (2.12), 4.195 (1.59), 6.971 (1.74), 7.183 (4.17), 7.884 (1.44), 7.925 (2.12), 7.946 (1.93), 8.278 (3.60), 8.291 (3.22), 8.397 (1.33), 9.015 (5.16), 9.017 (5.35), 10.773 (1.29), 12.326 (1.36).
Example 30.03.03.B
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.645 (0.98), 0.657 (2.94), 0.665 (7.35), 0.670 (4.57), 0.677 (3.59), 0.684 (9.63), 0.691 (9.14), 0.699 (7.18), 0.703 (8.33), 0.710 (3.76), 0.723 (0.98), 0.859 (0.49), 0.965 (0.65), 1.052 (0.49), 1.106 (16.00), 1.143 (0.65), 1.153 (0.49), 1.171 (0.82), 1.189 (0.49), 1.230 (2.94), 1.296 (13.88), 1.312 (14.04), 1.907 (0.82), 1.919 (1.80), 1.926 (1 .80), 1.938 (3.10), 1.944 (1.47), 1.950 (1.80), 1.957 (1.63), 1.969 (0.82), 1.986 (1.47), 2.318 (2.12), 2.322 (2.78), 2.327 (3.27), 2.332 (2.61 ), 2.336 (1.47), 2.397 (2.45), 2.456 (2.45), 2.523 (5.88), 2.660 (0.82), 2.664 (1.96), 2.669 (2.45), 2.673 (1.63), 2.678 (0.82), 3.439 (1.80), 3.455 (5.06), 3.471 (6.20), 3.676 (3.43), 4.200 (1.47), 6.973 (2.78), 7.181 (6.86), 7.421 (1.31 ), 7.443 (1 .47), 7.582 (0.98), 7.604 (0.98), 7.884 (2.29), 7.925 (3.43), 7.947 (2.94), 7.996 (1.63), 8.201 (1.63), 8.278 (5.71 ), 8.291 (5.39), 8.397 (2.12), 9.014 (8.65), 9.017 (8.65), 10.747 (1.47), 10.771 (1.96), 12.285 (1.47), 12.328 (2.12). Example 31.01
1 -{4-[(2-{[6-(2,6-dimethylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}-3,3,3-trifluoropropan-1 -one
Figure imgf000772_0001
Starting with crude 6-(2,6-dimethylpyrimidin-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (150 mg, approx. 176 pmol) and 3,3,3-trifluoropropanoic acid (24 μΙ, 98 % purity, 260 pmol), Example 31.01 was prepared analogously to the procedure for the preparation of Example 05.01.
Yield: 30 mg of the title compound.
LC-MS (Method 2): R, = 1.04 min; MS (ESIpos): m/z = 525 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm]= 2.35 - 2.44 (m, 4H), 2.46 (s, 3H), 2.62 (s, 3H), 3.45 - 3.55 (m, 6H), 3.65 (q, 2H), 7.19 (s, 1 H), 7.33 - 7.82 (m, 2H), 7.91 (dd, 1 H), 8.27 (d, 2H), 10.78 (br s, 1 H), 12.17 - 12.42 (m, 1 H).
Example 31.02
cyclopropyl{4-[(2-{[6-(2,6-dimethylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone
Figure imgf000772_0002
Starting with crude 6-(2,6-dimethylpyrimidin-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (150 mg, approx. 176 pmol) and cyclopropanecarboxylic acid (22 μΙ, 95 % purity, 260 pmol), Example 31.02 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 75 mg of the title compound.
LC-MS (Method 2): R, = 1.00 min; MS (ESIneg): m/z = 481 [M-H]+
H-NMR (400MHz, DMSO-d6): δ [ppm]= 0.63 - 0.73 (m, 4H), 1.93 (tt, 1 H), 2.44 (s, 7H), 2.59 (s, 3H), 3.50 (s, 4H), 3.68 (br s, 2H), 6.93 (d, 1 H), 7.17 (s, 1 H), 7.31 - 7.80 (m, 2H), 7.89 (dd, 1 H), 8.25 (d, 2H), 10.63 - 10.88 (m, 1 H), 12.15 - 12.41 (m, 1 H).
Example 32.01
cyclopropyl{4 (2-{[6-(5,6-dimethylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amm
yl)methyl]piperazin-1 -yl}methanone
Figure imgf000773_0001
Starting with crude 6-(5,6-dimethylpyrimidin-4-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (90.0 mg, approx. 200 pmol) and cyclopropanecarboxylic acid (25 μΙ, 95 % purity, 300 pmol), Example 32.01 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 30 mg of the title compound.
LC-MS (Method 2): R, = 0.97 min; MS (ESIpos): m/z = 483 [M+H]+
1 H-NMR (400MHz, DMSO-d6): δ [ppm]= 0.66 - 0.75 (m, 4H), 1.97 (tt, 1 H), 2.31 - 2.39 (m, 5H), 2.41 - 2.47 (m, 2H), 2.52 - 2.54 (m, 3H), 3.44 - 3.58 (m, 4H), 3.61 - 3.76 (m, 2H), 6.95 (dd, 1 H), 7.14 - 7.90 (m, 4H), 8.28 (d, 1 H), 8.86 (s, 1 H), 10.61 - 10.79 (m, 1 H), 12.15 - 12.33 (m, 1 H). Example 32.02
1 -{4-[(2-{[6-(5,6-dimethylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}py
yl)methyl]piperazin-1-yl}-3,3,3-trifluoropropan-1 -one
Figure imgf000774_0001
Starting with crude 6-(5,6-dimethylpyrimidin-4-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (90.0 mg, approx. 200 pmol) and 3,3,3-trifluoropropanoic acid (27 μΙ, 98 % purity, 300 pmol), Example 32.02 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 30 mg of the title compound.
LC-MS (Method 2): R, = 1.01 min; MS (ESIpos): m/z = 525 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm]= 2.31 - 2.45 (m, 7H), 2.52 (s, 3H), 3.42 - 3.58 (m, 6H), 3.65 (q, 2H), 6.94 (dd, 1 H), 7.13 - 7.84 (m, 4H), 8.28 (d, 1 H), 8.87 (s, 1 H), 10.70 (br dd, 1 H), 12.23 (br s, 1 H).
Example 32.03
1 -{4-[(2-{[6-(5,6-dimethylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1-yl}ethanone
Figure imgf000774_0002
Starting with crude 6-(5,6-dimethylpyrimidin-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (90.0 mg, approx. 200 pmol) and acetic acid (17 μΙ, 300 μητιοΙ), Example 32.03 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 30 mg of the title compound.
LC-MS (Method 2): R, = 0.89 min; MS (ESIpos): m/z = 457 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.99 (s, 3H), 2.31 - 2.43 (m, 7H), 2.52 - 2.54 (m, 3H), 3.42 - 3.53 (m, 6H), 6.94 (dd, 1 H), 7.12 - 7.86 (m, 4H), 8.27 (d, 1 H), 8.87 (s, 1 H), 10.71 (br s, 1 H), 12.23 (s, 1 H).
Example 33.01
tert-butyl 4-[(2-{[6-(2,5-dimethylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate
Figure imgf000775_0001
To a stirred solution of tert-butyl 4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate (600 mg, 1.12 mmol) in -propanol (12 ml_) was added an aqueous potassium carbonate solution (1.7 ml_, 2.0 M, 3.4 mmol), 4-chloro-2,5-dimethylpyrimidine (320 mg, 2.25 mmol), triphenylphosphine (24.7 mg, 225 μιτιοΙ) and PdCI2(PPh3)2 (158 mg, 225 pmol). The mixture was heated to 120°C in a sealed tube for 10 h. The solvent was removed in vacuum. Silicagel chromatography followed by aminophase-silicagel chromatography gave 390 mg (61 % yield) of the title compound.
LC-MS (Method 2): R, = 1.20 min; MS (ESIpos): m/z = 515 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.395 (16.00), 2.347 (1.07), 2.360 (1.81 ), 2.372 (1.49), 2.615 (4.61 ), 3.331 (9.1 1 ), 3.351 (1.10), 5.759 (12.83), 8.259 (0.79), 8.271 (0.75), 8.550 (1.42). Example 33.02
1 -{4-[(2-{[6-(2,5-dimethylpyrimidin-4-yl)-1 H^enzimidazol-2-yl]amino}pyrid
yl)methyl]piperazin-1-yl}-3,3,3-trifluoropropan-1-one
Figure imgf000776_0001
Starting with crude 6-(2,5-dimethylpyrimidin-4-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (100 mg, approx. 177 pmol) and 3,3,3-trifluoropropanoic acid (24 μΙ, 98 % purity, 270 pmol), Example 33.02 was prepared analogously to the procedure for the preparation of Example 05.01.
Yield: 60 mg of the title compound.
LC-MS (Method 2): R, = 1.01 min; MS (ESIpos): m/z = 525 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.394 (16.00), 2.380 (1.31 ), 2.615 (2.35), 3.528 (0.85), 5.759 (1.28), 8.550 (0.75).
Example 33.03
cyclopropyl{4-[(2-{[6-(2,5-dimethylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridm yl)methyl]piperazin-1 -yl}methanone
Figure imgf000776_0002
starting with crude 6-(2,5-dimethylpyrimidin-4-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (100 mg, approx. 177 pmol) and cyclopropanecarboxylic acid (22 μΙ, 95 % purity, 270 pmol), Example 33.03 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 45 mg of the title compound.
LC-MS (Method 2): Rt = 0.97 min; MS (ESIneg): m/z = 481 [M-H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.664 (0.42), 0.676 (1.29), 0.683 (2.96), 0.689 (1.87), 0.696 (1.42), 0.703 (3.63), 0.708 (2.98), 0.713 (3.17), 0.720 (3.05), 0.726 (3.64), 0.733 (1.66), 0.745 (0.41 ), 1.945 (0.74), 1.952 (0.77), 1.956 (0.57), 1.964 (1.34), 1.971 (0.60), 1.976 (0.75), 1.983 (0.68), 2.327 (0.47), 2.386 (3.33), 2.446 (1.39), 2.518 (0.90), 2.523 (0.66), 2.615 (16.00), 3.499 (1.36), 3.523 (6.71 ), 3.705 (1.28), 6.941 (1.72), 6.944 (1.74), 6.955 (1.75), 6.958 (1.76), 7.197 (2.25), 7.428 (0.63), 7.446 (0.61 ), 7.894 (0.55), 8.268 (2.73), 8.281 (2.58), 8.549 (4.87), 12.266 (0.76).
Example 33.04
cyclobutyl{4-[(2-{[6-(2,5-dimethylpyrimidin-4-yl)-1H-benzimidazol-2-yl]amino}pyrid yl)methyl]piperazin-1-yl}methanone
Figure imgf000777_0001
Starting with crude 6-(2,5-dimethylpyrimidin-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (100 mg, approx. 177 pmol) and cyclobutanecarboxylic acid (27 μΙ, 95 % purity, 270 pmol), Example 33.04 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 41 mg of the title compound.
LC-MS (Method 2): R, = 1.04 min; MS (ESIpos): m/z = 497 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.702 (0.54), 1.705 (0.62), 1.715 (0.51 ), 1.718 (0.53), 1.729 (0.77), 1.731 (0.72), 1.833 (0.65), 1.855 (1.26), 1.860 (0.56), 1.877 (0.96), 1.881 (0.95), 1.899 (0.47), 1.905 (0.59), 2.036 (0.77), 2.045 (1.39), 2.049 (1.01 ), 2.054 (1.02), 2.058 (0.88), 2.061 (0.98), 2.067 (1.60), 2.076 (1.24), 2.082 (0.58), 2.088 (0.70), 2.092 (0.76), 2.097 (1.07), 2.102 (0.59), 2.1 19 (1.81 ), 2.124 (1.21 ), 2.140 (1.96), 2.145 (1.51 ), 2.148 (1.36), 2.164 (0.92), 2.169 (1.04), 2.334 (3.00), 2.346 (4.68), 2.358 (4.00), 2.380 (3.20), 2.613 (16.00), 3.291 (1.04), 3.294 (1.13), 3.315 (2.74), 3.457 (1.44), 3.471 (2.01 ), 3.491 (6.45), 6.921 (1.76), 6.924 (1.75), 6.934 (1.79), 6.937 (1.75), 7.183 (2.27), 7.432 (0.61 ), 8.258 (2.84), 8.271 (2.71 ), 8.545 (4.84), 10.734 (0.58), 12.266 (0.67).
Example 34.01.01
tert-butyl 4-[(2-{[6-(6-methoxypyrimidin-4-yl)-1 H^enzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1-carboxylate
Figure imgf000778_0001
Starting with tert-butyl 4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-benzimidazol- 2-yl]amino}pyridin-4-yl)methyl]piperazine-1-carboxylate (500 mg, 936 pmol) and 4-chloro-6- methoxypyrimidine (189 mg, 1.31 mmol), Example 34.01.01 was prepared analogously to the procedure for the preparation of Example 01.01.
Yield: 20.0 mg (4 %) of the title compound.
LC-MS (Method 4): R, = 1.27 min; MS (ESIpos): m/z = 517 [M+H]+
1H-NMR (400 MHz, CHLOROFORM-d) δ [ppm]: 1.452 (16.00), 4.046 (2.13), 4.059 (3.07), 7.165 (0.74), 7.167 (0.75), 8.850 (0.89), 8.853 (0.81 ).
Example 34.02.01
(rac)-3,3,3-trifluoro-1 -{4-[1 -(2-{[6-(6-methoxypyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}propan-1 -one
Figure imgf000779_0001
Starting with (rac)-6-(6-methoxypyrimidin-4-yl)-N-{4-[1 -(piperazin-1 -yl)ethyl]pyridin-2-yl}-1 H- benzimidazol-2-amine (265 mg, 616 μιτιοΙ) and 3,3,3-trifluoropropanoic acid (1 18 mg, 923 pmol), Example 34.02.01 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 46.5 mg (13 %) of the title compound.
LC-MS (Method 4): R, = 1.12 min; MS (ESIpos): m/z = 541 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.291 (4.49), 1.308 (4.44), 2.326 (1.50), 2.428 (2.35), 2.522 (3.91 ), 3.436 (2.38), 3.469 (2.52), 3.485 (2.60), 3.608 (2.32), 3.635 (2.21 ), 3.969 (16.00), 7.174 (1.86), 8.274 (1.92), 8.288 (1.90), 8.803 (4.06), 8.806 (4.26).
Example 34.02.02
(rac)-cyclopropyl{4-[1 -(2-{[6-(6-methoxypyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}methanone
Figure imgf000779_0002
Starting with (rac)-6-(6-methoxypyrimidin-4-yl)-N-{4-[1-(piperazin-1-yl)ethyl]pyridin-2-yl}-1 H- benzimidazol-2-amine (265 mg, 616 pmol) and cyclopropanecarboxylic acid (79.5 mg, 923 pmol), Example 34.02.02 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 49.7 mg (16 %) of the title compound.
LC-MS (Method 4): Rt = 1.08 min; MS (ESIpos): m/z = 499 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.656 (1.28), 0.662 (2.84), 0.667 (1.82), 0.675 (1.49), 0.682 (3.47), 0.686 (3.09), 0.691 (3.24), 0.698 (2.91 ), 0.703 (3.24), 0.710 (1.53), 1.293 (5.37), 1.310 (5.33), 1.934 (1.19), 3.451 (2.02), 3.468 (2.58), 3.674 (1.41 ), 3.970 (16.00), 6.963 (1.27), 6.975 (1.31 ), 7.182 (2.78), 8.275 (2.36), 8.289 (2.26), 8.803 (3.94), 8.806 (4.22).
Example 34.03.01. A
3,3,3-trifluoro-1 -{4-[(1 R or 1S)-1 -(2-{[6-(6-methoxypyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}propan-1-one (single stereoisomer A)
Figure imgf000780_0001
Example 34.03.01. B
3,3,3-trifluoro-1 -{4-[(1 S or 1 R)-1 -(2-{[6-(6-methoxypyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}propan-1 -one (single stereoisomer B)
Figure imgf000781_0001
60 mg of (rac)-3,3,3-trifluoro-1-{4-[1 -(2-{[6-(6-met oxypyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}propari-1-one was separated into the single stereoisomers (Example 34.03.01. A and Example 34.03.01. B) via preparative, chiral HPLC. Instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241 , Labcol Vario 4000,
Column: Chiralpak IB 5μ 250x30mm;
Eluent A: hexane + 0.2 Vol-% diethyiamine (99%); Eluent B: ethanol; isocratic: 80%A+20%; Flow: 30.0 mL/min;
Solution: 60 mg / 3 mL ethanol
Injection: 6 x 0.5 mL
Detection: UV 325 nm
Figure imgf000781_0002
Example 34.03.01. A
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.107 (6.75), 1.292 (4.60), 1.309 (4.65), 2.327 (1.36), 2.429 (1.26), 2.523 (1.69), 3.436 (2.22), 3.469 (2.24), 3.486 (2.31 ), 3.581 (0.86), 3.608 (2.42), 3.636 (2.28), 3.970 (16.00), 6.970 (1.02), 7.173 (1.94), 8.275 (2.02), 8.288 (1.93), 8.804 (4.35), 8.806 (4.43).
Example 34.03.01. B
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.966 (0.46), 1.107 (6.66), 1.230 (1.08), 1.291 (6.24), 1.308 (6.30), 2.328 (1.87), 2.342 (1.91 ), 2.364 (1.57), 2.418 (2.09), 2.427 (2.34), 2.456 (1.79), 3.436 (3.72), 3.468 (3.89), 3.484 (4.40), 3.581 (1.18), 3.608 (3.20), 3.635 (3.10), 3.663 (1.06), 3.969 (16.00), 4.195 (0.70), 6.956 (1.72), 6.968 (1.77), 7.174 (3.09), 7.346 (0.99), 7.421 (0.76), 7.458 (0.74), 7.912 (1.21 ), 8.192 (0.64), 8.275 (2.68), 8.288 (2.61 ), 8.358 (0.92), 8.804 (4.71 ), 8.806 (4.80), 10.759 (0.94), 12.271 (0.83), 12.300 (1.12).
Example 34.03.02.A
cyclopropyl{4-[(1 R or 1S)-1 -(2-{[6-(6-methoxypyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}methanone (single stereoisomer A)
Figure imgf000782_0001
Example 34.03.02.B
cyclopropyl{4-[(1S or 1R)-1 -(2-{[6-(6-methoxypyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}methanone (single stereoisomer B)
Figure imgf000783_0001
44.7 mg of (rac)-cyclopropyl{4-[1 -(2-{[6-(6-methoxypyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}methanone was separated into the single stereoisomers (Example 34.03.02.A and Example 34.03.02. B) via preparative, chiral HPLC. Instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241 , Labcol Vario 4000,
Column: Chiralpak IA 5μ 250x30mm;
Eluent A: tert.-butyl methyl ether + 0.1 Vol-% diethylamine (99%); Eluent B: methanol; isocratic: 50%A+50%B;
Flow: 50.0 mL/min;
Solution: 44 mg / 2 mL dichloromethane/methanol 1 :1
Injection: 4 x 0.5 mL
Detection: UV 325 nm
Figure imgf000783_0002
Example 34.03.02.A
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.658 (1 .04), 0.665 (2.54), 0.670 (1.53), 0.678 (1.21 ), 0.685 (3.23), 0.692 (3.06), 0.699 (2.48), 0.704 (2.77), 0.71 1 (1.24), 1.108 (3.85), 1.231 (1.17), 1.296 (4.89), 1.313 (4.86), 1.938 (1.08), 2.323 (1.17), 2.327 (1.43), 2.331 (1.08), 2.523 (2.15), 2.669 (1.04), 3.455 (1.73), 3.471 (2.15), 3.678 (1.14), 3.970 (16.00), 7.181 (2.15), 7.344 (0.95), 8.276 (1.76), 8.289 (1.69), 8.803 (4.07), 8.806 (4.07).
Example 34.03.02.B
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.666 (3.17), 0.685 (4.42), 0.692 (4.20), 0.704 (3.66), 0.711 (1.74), 0.851 (0.49), 1.108 (3.44), 1.153 (0.54), 1.232 (2.55), 1.296 (6.12), 1.314 (5.99), 1.919 (0.80), 1.926 (0.85), 1.938 (1.30), 1.950 (0.80), 2.323 (2.23), 2.327 (2.68), 2.331 (2.10), 2.397 (1.34), 2.523 (8.13), 2.665 (1.65), 2.669 (2.15), 2.673 (1.65), 3.455 (2.46), 3.473 (2.99), 3.676 (1.74), 3.971 (16.00), 6.971 (1.52), 7.182 (2.68), 7.344 (1.52), 7.399 (0.80), 7.421 (0.89), 7.458 (1.07), 7.562 (0.54), 7.583 (0.58), 7.893 (0.63), 7.913 (1.30), 7.934 (0.76), 8.187 (0.98), 8.276 (2.06), 8.289 (2.01 ), 8.357 (1.30), 8.804 (4.87), 10.715 (0.80), 10.755 (1.16), 12.266 (0.89), 12.301 (1.30).
Example 35.01.01
3,3,3-trifluoro-1^4-[(2-{[6-(5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin- 4-yl)methyl]piperazin-1-yl}propan-1-one
Figure imgf000784_0001
Starting with 6-(5-methoxypyrimidin-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine (85.0 mg, 204 pmol) and 3,3,3-trifluoropropanoic acid (27 μΙ, 310 μηιοΙ), Example 35.01.01 was prepared analogously to the procedure for the preparation of Example 05.01.
Yield: 40.0 mg (34 %) of the title compound.
LC-MS (Method 2): R, = 0.99 min; MS (ESIpos): m/z = 527 [M+H]+ 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.394 (16.00), 2.374 (1.24), 2.387 (1.87), 2.399 (1.43), 2.415 (1.38), 2.428 (1.82), 2.439 (1.33), 3.462 (1.34), 3.475 (1.85), 3.487 (1.51 ), 3.499 (1.48), 3.513 (1.97), 3.528 (5.59), 3.607 (0.88), 3.634 (2.53), 3.661 (2.38), 4.023 (8.76), 5.755 (0.72), 6.939 (1.32), 6.952 (1.32), 7.196 (1.78), 8.271 (2.12), 8.284 (2.03), 8.631 (4.78), 8.828 (4.15).
Example 35.01.02
cyclopropyl{4-[(2-{[6-(5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin yl)methyl]piperazin-1 -yl}methanone
Figure imgf000785_0001
Starting with 6-(5-methoxypyrimidin-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine (85.0 mg, 204 pmol) and cyclopropanecarboxylic acid (24 μΙ, 310 μπιοΙ), Example 35.01.02 was prepared analogously to the procedure for the preparation of Example 05.01.
Yield: 16.0 mg (16 %) of the title compound.
LC-MS (Method 2): R, = 0.98 min; MS (ESIpos): m/z = 485 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.685 (2.55), 0.704 (3.12), 0.708 (2.97), 0.713 (3.01 ), 0.721 (2.74), 0.726 (2.99), 1.394 (16.00), 1.967 (1.06), 2.374 (1.42), 3.527 (4.21 ), 3.708 (1.34), 4.022 (10.40), 6.948 (1.47), 6.961 (1.50), 7.196 (1.94), 8.274 (2.09), 8.286 (2.02), 8.633 (4.64), 8.829 (4.41 ).
Example 35.01.03
4-[(2-{[6-(5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4-yl)m dimethylpiperazine-1 -carboxamide
Figure imgf000786_0001
To a stirred solution of crude 6-(5-methoxypyrimidin-4-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2- yl]-1 H-benzimidazol-2-amine hydrochloride (150 mg, approx. 216 pmol) in dichloromethane (3.0 mL, 47 mmol) was added DIPEA (1.0 mL, 5.7 mmol) and dimethylcarbamic chloride (CAS- RN: 79-44-7) (20 μΙ, 220 pmol). The mixture was stirred at r.t. for 14 h. Water was added and the mixture was extracted with dichloromethane. The organic phase was dried (sodium sulfate) and the solvent was removed in vacuum. Preparative reverse phase HPLC (gradient of water and acetonitrile containing ammonia as additive) gave 57.0 mg of the title compound.
LC-MS (Method 2): R, = 0.96 min; MS (ESIpos): m/z = 488 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.107 (3.40), 2.405 (1.67), 2.416 (1.23), 2.727 (16.00), 3.127 (1.23), 3.140 (1.63), 3.150 (1.19), 3.504 (2.47), 4.024 (2.57), 8.265 (0.85), 8.631 (1.58), 8.827 (1.19).
Example 35.01.04
N,N-diethyl-4-[(2-{[6-(5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxamide
Figure imgf000786_0002
Starting with crude 6-(5-methoxypyrimidin-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (150 mg, approx. 216 μΓηοΙ) and diethylcarbamic chloride (CAS-RN: 88-10-8) (27 μΙ, 220 μιηοΙ), Example 35.01.04 was prepared analogously to the procedure for the preparation of Example 35.01.03.
Yield: 63.0 mg (53 %) of the title compound.
LC-MS (Method 2): R, = 1.09 min; MS (ESIpos): m/z = 516 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.014 (3.43), 1.032 (7.93), 1.049 (3.50), 1.107 (16.00), 2.405 (1.69), 3.100 (3.53), 3.118 (4.60), 3.502 (2.01 ), 4.022 (4.79), 4.194 (1.33), 8.265 (1.14), 8.278 (1.08), 8.632 (2.72), 8.827 (2.45).
Example 35.01.05
{4-[(2-{[6-(5-methoxypyrimidin-4-yl)-1H-benzimidazol-2-yl]amino}pyridin-4'
yl)methyl]piperazin-1-yl}(pyrrolidin-1-yl)methanone
Figure imgf000787_0001
Starting with crude 6-(5-methoxypyrimidin-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (150 mg, approx. 216 μΓηοΙ) and pyrrolidine-1 -carbonyl chloride (CAS-RN: 1 92-63-8) (24 μΙ, 220 μηιοΙ), Example 35.01.05 was prepared analogously to the procedure for the preparation of Example 35.01.03.
Yield: 35.0 mg of the title compound.
LC-MS (Method 2): Rt = 1.03 min; MS (ESIpos): m/z = 514 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.107 (16.00), 1.715 (4.50), 1.731 (12.03), 1.748 (4.54), 2.322 (1.41 ), 2.327 (1.98), 2.332 (1.48), 2.401 (8.44), 2.41 1 (6.18), 2.518 (7.43), 2.523 (4.94), 2.664 (1.38), 2.669 (1.98), 2.673 (1.41 ), 3.193 (8.00), 3.232 (5.24), 3.249 (13.04), 3.265 (4.71 ), 3.502 (1 1.66), 4.022 (15.70), 4.194 (1.55), 6.932 (2.92), 6.946 (2.96), 7.180 (2.72), 8.265 (4.61 ), 8.278 (4.40), 8.375 (1.38), 8.632 (9.24), 8.827 (7.60). Example 35.01.06
{4-[(2-{[6-(5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4
yl)methyl]piperazin-1 -yl}(piperidin-1-yl)methanone
Figure imgf000788_0001
Starting with crude 6-(5-methoxypyrimidin-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (150 mg, approx. 216 μηιοΙ) and piperidine-1 -carbonyl chloride (CAS-RN: 13939-69-0) (27 μΙ, 220 pmol), Example 35.01.06 was prepared analogously to the procedure for the preparation of Example 35.01.03.
Yield: 75.0 mg of the title compound.
LC-MS (Method 2): Rt = 1.10 min; MS (ESIpos): m/z = 528 [M+H]+
H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.107 (16.00), 1.461 (2.28), 2.396 (2.77), 2.518 (3.17), 2.523 (2.07), 3.100 (3.12), 3.112 (2.31 ), 3.148 (2.72), 3.501 (3.90), 4.024 (4.49), 4.194 (1.51 ), 8.264 (1.42), 8.276 (1.34), 8.631 (2.63), 8.827 (2.07).
Example 35.01.07
{4-[(2-{[6-(5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1-yl}(morpholin-4-yl)methanone
Figure imgf000788_0002
To a stirred solution of crude 6-(5-methoxypyrimidin-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2- yl]-1 H-benzimidazol-2-amine hydrochloride (200 mg, approx. 288 pmol) in dichloromethane (4.0 mL, 62 mmol) was added pyridine (1.0 mL, 12 mmol) and morpholine-4-carbonyl chloride (CAS-RN: 15159-40-7) (43 μΙ, 370 pmol). The mixture was stirred at r.t. for 14 h. Further pyridine (1.0 mL, 12 mmol) and morpholine-4-carbonyl chloride (43 μΙ, 370 pmol) were added and the mixture was stirred at reflux for 14 h. Further morpholine-4-carbonyl chloride (43 μΙ, 370 μηιοΙ) and DIPEA (0.5 mL) were added and the mixture was stirred at reflux for 14 h. Sodium bicarbonate solution was added and the mixture was extracted with dichloromethane. The organic phase was dried (sodium sulfate) and the solvent was removed in vacuum. Aminophase-silicagel chromatography followed by preparative reverse phase HPLC (gradient of water and acetonitrile containing ammonia as additive) gave 15.0 mg of the title compound. LC-MS (Method 2): R, = 0.94 min; MS (ESIpos): m/z = 530 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.107 (3.48), 2.318 (1.81 ), 2.322 (3.90), 2.327 (5.57), 2.332 (4.03), 2.336 (1.81 ), 2.397 (6.40), 2.518 (16.00), 2.523 (11.55), 2.660 (1.67), 2.665 (4.03), 2.669 (5.70), 2.673 (3.90), 2.679 (1.67), 3.109 (5.84), 3.120 (8.07), 3.131 (6.26), 3.200 (6.26), 3.313 (4.17), 3.506 (9.46), 3.539 (7.10), 3.552 (8.21 ), 3.562 (6.12), 4.022 (13.08), 6.928 (2.23), 6.942 (2.37), 7.182 (1.67), 8.264 (3.62), 8.276 (3.34), 8.371 (1.1 1 ), 8.631 (8.07), 8.827 (6.54).
Example 35.01.08
N-(4-{[4-(ethylsulfonyl)piperazin-1-yl]methyl}pyridin-2-yl)-6-(5-methoxypyrimid
1 H-benzimidazol-2-amine
Figure imgf000789_0001
Starting with crude 6-(5-methoxypyrimidin-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (130 mg, approx. 187 μηιοΙ) and ethanesulfonyl chloride (CAS-RN: 594-44-5) (18 μΙ, 190 μηιοΙ), Example 35.01.08 was prepared analogously to the procedure for the preparation of Example 35.01.03.
Yield: 44.0 mg of the title compound.
LC-MS (Method 4): R, = 0.96 min; MS (ESIpos): m/z = 509 [M+H]+ 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.200 (6.97), 1.218 (16.00), 1.237 (7.23), 2.327 (0.91 ), 2.518 (3.79), 2.523 (2.66), 2.539 (0.97), 2.669 (0.90), 3.046 (2.14), 3.065 (6.94), 3.083 (6.76), 3.102 (1.97), 3.203 (4.71 ), 3.215 (6.51 ), 3.226 (4.64), 3.545 (9.43), 4.022 (13.1 ), 6.935 (2.26), 6.947 (2.31 ), 7.179 (1.80), 8.269 (3.54), 8.282 (3.37), 8.375 (1.04), 8.632 (7.01 ), 8.828 (5.89), 12.284 (1.19).
Example 35.01.09
6-(5-methoxypyrimidin-4-yl)-N-[4-({4-[(3,3,3-trifluoropropyl)sulfonyl]piperazin
yl}methyl)pyridin-2-yl]-1H-benzimidazol-2-amine
Figure imgf000790_0001
To a stirred solution of crude 6-(5-methoxypyrimidin-4-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2- yl]-1 H-benzimidazol-2-amine hydrochloride (130 mg, approx. 187 pmol) in dichloromethane was added DIPEA and 3,3,3-trifluoropropane-1-sulfonyl chloride (CAS-RN: 845866-80-0) (24 μΙ, 190 pmol). The mixture was stirred at r.t. for 14 h. Further 3,3,3-trifluoropropane-1-sulfonyl chloride (12 μΙ, 95 pmol) was added and the mixture was heated to reflux for 6 h. Water was added and the mixture was extracted with dichloromethane. The organic phase was dried (sodium sulfate) and the solvent was removed in vacuum. Preparative reverse phase HPLC (gradient of water and acetonitrile containing ammonia as additive) gave 28.0 mg of the title compound.
LC-MS (Method 4): R, = 1.09 min; MS (ESIpos): m/z = 577 [M+H]+
H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.065 (0.70), 2.322 (1.15), 2.327 (1.60), 2.331 (1.23), 2.523 (5.51 ), 2.651 (0.70), 2.665 (1.70), 2.669 (2.23), 2.673 (2.03), 2.678 (2.50), 2.692 (1.90), 2.698 (2.05), 2.706 (2.68), 2.718 (2.98), 2.725 (2.05), 2.733 (1.70), 2.746 (2.20), 3.260 (6.74), 3.273 (9.26), 3.283 (6.71 ), 3.347 (5.98), 3.354 (3.81 ), 3.367 (4.46), 3.554 (12.04), 4.023 (16.00), 6.941 (3.18), 6.954 (3.21 ), 7.178 (4.21 ), 7.417 (1.33), 7.572 (0.70), 7.833 (0.68), 7.933 (1.15), 8.118 (0.85), 8.272 (4.71 ), 8.285 (4.61 ), 8.375 (1.80), 8.632 (8.96), 8.828 (7.24), 10.765 (1.25), 12.236 (0.98), 12.278 (1.90).
Example 35.01.10
N-[4-({4-[(3-methoxypropyl)sulfonyl]piperazin-1-yl}methyl)pyridin
methoxypyrimidin-4-yl)-1 H-benzimidazol-2-amine
Figure imgf000791_0001
Starting with crude 6-(5-methoxypyrimidiri-4-yl)-N-[4-(piperaziri-1-ylmethyl)pyridin-2-yl]- H- benzimidazol-2-amine hydrochloride (100 mg, approx. 144 pmol) and 3-methoxypropane-1- sulfonyl chloride (CAS-RN: 64297-55-8) (24.9 mg, 144 μιηοΙ), Example 35.01.10 was prepared analogously to the procedure for the preparation of Example 35.01.09.
Yield: 18.0 mg of the title compound.
LC-MS (Method 4): R, = 0.99 min; MS (ESIpos): m/z = 553 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.874 (1.54), 1.893 (1.63), 1.914 (1.57), 2.322 (1.30), 2.327 (1.84), 2.331 (1.42), 2.518 (6.99), 2.523 (4.69), 2.665 (1.33), 2.669 (1.84), 2.673 (1.39), 3.058 (2.36), 3.072 (1.81 ), 3.078 (2.36), 3.084 (1.84), 3.098 (2.18), 3.212 (4.33), 3.223 (3.42), 3.240 (16.00), 3.395 (2.21 ), 3.410 (4.29), 3.426 (2.15), 3.551 (5.90), 4.026 (7.02), 6.936 (1.36), 6.949 (1.36), 7.184 (1.66), 7.415 (0.79), 8.268 (2.09), 8.281 (2.00), 8.375 (1.15), 8.632 (3.48), 8.826 (2.66), 12.283 (0.94). Example 35.01.11
N-{4-[(4-{[2-(2-methoxyethoxy)ethyl]sulfonyl}piperazin-1 -yl)methyl]pyridin-2-yl}-6-(5- methoxypyrimidin-4-yl)-1 H-benzimidazol-2-amine
Figure imgf000792_0001
C H 3 Starting with crude 6-(5-methoxypyrimidin-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (130 mg, approx. 187 pmol) and 2-(2- methoxyethoxy)ethanesulfonyl chloride (Uhlenbroek et al. Recueil des Travaux Chimiques des Pays-Bas, 1957 , vol. 76, p. 129,138,145) (38.0 mg, 187 pmol), Example 35.01.1 1 was prepared analogously to the procedure for the preparation of Example 35.01.09.
Yield: 41.0 mg of the title compound.
LC-MS (Method 4): Rt = 0.97 min; MS (ESIpos): m/z = 583 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.539 (1.76), 3.201 (1.81 ), 3.214 (2.52), 3.224 (1.83), 3.251 (16.00), 3.320 (1.44), 3.350 (1.57), 3.449 (1.31 ), 3.459 (2.00), 3.464 (1.59), 3.471 (2.34), 3.542 (5.64), 3.549 (2.23), 3.554 (2.20), 3.566 (1.37), 3.718 (1.53), 3.733 (3.05), 3.748 (1.31 ), 4.023 (4.75), 8.268 (1.33), 8.282 (1.27), 8.632 (2.68), 8.828 (2.01 ).
Example 35.01.12
N-(4-{[4-(cyclopropylsulfonyl)piperazin-1-yl]methyl}pyridin-2-yl)-6-(5-methoxypyrimidin 4-yl)-1 H-benzimidazol-2 -amine
Figure imgf000793_0001
Starting with crude 6-(5-methoxypyrimidin-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (100 mg, approx. 144 pmol) and cyclopropanesulfonyl chloride (CAS-RN: 139631 -62-2) (15 μΙ, 140 pmol), .Example 35.01.12 was prepared analogously to the procedure for the preparation of Example 35.01.03.
Yield: 21.0 mg of the title compound.
LC-MS (Method 4): R, = 0.98 min; MS (ESIpos): m/z = 521 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.908 (1.30), 0.920 (4.26), 0.927 (5.49), 0.934 (5.36), 0.937 (5.70), 0.947 (3.12), 0.969 (1.41 ), 0.980 (2.40), 0.990 (4.64), 0.995 (3.81 ), 1.010 (5.29), 1.015 (3.64), 1.030 (1.17), 1.065 (0.79), 2.318 (0.65), 2.322 (1.41 ), 2.327 (2.03), 2.331 (1.51 ), 2.337 (0.72), 2.518 (14.1 1 ), 2.523 (9.24), 2.539 (3.47), 2.598 (0.96), 2.610 (1.75), 2.617 (1.92), 2.629 (3.12), 2.638 (1.41 ), 2.642 (1.79), 2.649 (1.65), 2.665 (1.75), 2.669 (2.20), 2.673 (1.61 ), 2.678 (0.79), 2.772 (1 .34), 3.224 (6.70), 3.236 (9.41 ), 3.248 (6.63), 3.551 (13.29), 4.023 (16.00), 6.939 (3.09), 6.951 (3.16), 7.188 (2.64), 7.395 (1.13), 7.417 (1.24), 7.935 (1.17), 7.954 (1.06), 8.1 15 (0.93), 8.270 (4.77), 8.283 (4.53), 8.375 (1.85), 8.632 (9.41 ), 8.827 (8.38), 10.756 (1.20), 12.235 (0.96), 12.287 (1.85).
Example 35.01.13
N-(4-{[4-(cyclohexylsulfonyl)piperazin-1-yl]methyl}pyridin-2-yl)-6-(5-methoxypyrimidin-4- yl)-1 H-benzimidazol-2-amine
Figure imgf000794_0001
Starting with crude 6-(5-methoxypyrimidin-4-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (145 mg, approx. 209 pmol) and cyclohexanesulfonyl chloride (CAS-RN: 4837-38-1 ) (30 μΙ, 210 pmol), Example 35.01.13 was prepared analogously to the procedure for the preparation of Example 35.01.03.
Yield: 34.0 mg of the title compound.
LC-MS (Method 4): R, = 1.16 min; MS (ESIpos): m/z = 563 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.966 (0.99), 1.065 (0.78), 1.143 (1.53), 1.230 (1.48), 1.260 (2.50), 1.292 (2.85), 1.320 (3.60), 1.348 (3.30), 1.380 (2.63), 1.599 (1.66), 1.632 (1.48), 1.755 (2.93), 1.787 (2.93), 1.973 (3.62), 2.003 (2.85), 2.326 (1.66), 2.522 (7.87), 2.669 (1.66), 2.813 (0.78), 3.127 (2.04), 3.281 (9.66), 3.542 (11.65), 4.022 (16.00), 4.208 (1.77), 4.213 (1.83), 4.491 (1.77), 4.495 (1.77), 6.932 (3.14), 6.944 (3.14), 7.191 (2.98), 7.414 (1.40), 7.480 (1.77), 7.489 (1.72), 7.498 (1.83), 7.506 (1.69), 7.524 (2.20), 7.551 (3.49), 7.569 (2.55), 7.932 (1.21 ), 8.1 13 (0.91 ), 8.263 (4.27), 8.276 (4.05), 8.375 (1.85), 8.632 (7.49), 8.827 (6.82), 10.747 (1.18), 12.280 (1.72).
Example 35.01.14
6-(5-methoxypyrimidin-4-yl)-N-(4-{[4-(tetrahydro-2H-pyran-4-ylsulfonyl)piperazin-1 yl]methyl}pyridin-2-yl)-1 H-benzimidazol-2-amine
Starting with crude 6-(5-methoxypyrimidin-4-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (100 mg, approx. 144 pmol) and tetrahydro-2H-pyran-4- sulfonyl chloride (CAS-RN: 338453-21 -7) (26.6 mg, 144 μιτιοΙ), Example 35.01.14 was prepared analogously to the procedure for the preparation of Example 35.01.09.
Yield: 15.0 mg of the title compound.
LC-MS (Method 4): R, = 0.96 min; MS (ESIpos): m/z = 565 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.595 (1.59), 1.607 (1.79), 1.627 (1.93), 1.638 (1.79), 1.836 (2.48), 1.862 (1.86), 2.166 (0.97), 2.318 (1.52), 2.323 (3.24), 2.327 (4.48), 2.331 (3.31 ), 2.336 (1.66), 2.463 (6.00), 2.518 (16.00), 2.523 (10.69), 2.540 (2.62), 2.659 (1 .38), 2.665 (3.24), 2.669 (4.48), 2.673 (3.31 ), 2.678 (1.52), 3.127 (1.38), 3.303 (7.45), 3.362 (2.28), 3.467 (2.00), 3.545 (7.93), 3.909 (2.28), 3.927 (2.00), 4.026 (1 1.17), 6.934 (1.86), 7.183 (2.21 ), 7.393 (1.10), 7.414 (1.24), 7.935 (1.03), 8.266 (2.90), 8.279 (2.62), 8.372 (1.72), 8.631 (4.55), 8.826 (3.59), 10.753 (1.03), 12.278 (1.31 ).
Example 35.01.15
4-[(2-{[6-(5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4-yl)methy dimethylpiperazine-1 -sulfonamide
Figure imgf000796_0001
Starting with crude 6-(5-methoxypyrimidin-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (130 mg, approx. 187 pmol) and dimethylsulfamyl chloride (CAS-RN: 13360-57-1 ) (20 μΙ, 190 pmol), Example 35.01.15 was prepared analogously to the procedure for the preparation of Example 35.01.03.
Yield: 50.0 mg of the title compound.
LC-MS (Method 4): R, = 1.00 min; MS (ESIpos): m/z = 524 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.772 (16.00), 3.538 (1.67), 4.023 (1.84), 8.632 (1.03).
Example 35.01.16
N-{4-[(4-{[4-(methoxymethyl)piperidin-1-yl]sulfonyl}piperazin-1-yl)methyl]pyrid
(5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2 -amine
Figure imgf000797_0001
Starting with crude 6-(5-methoxypyrimidin-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (130 mg, approx. 187 pmol) and 4- (methoxymethyl)piperidine-l -sulfonyl chloride (CAS-RN: 1243250-01 -2) (42.6 mg, 187 pmol), Example 35.01.16 was prepared analogously to the procedure for the preparation of Example 35.01.03.
Yield: 64.0 mg of the title compound.
LC-MS (Method 4): Rt = 1.11 min; MS (ESIpos): m/z = 608 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1 .675 (1.51 ), 2.465 (2.44), 2.518 (2.07), 2.523 (1.29), 2.799 (1.30), 2.804 (1.33), 3.170 (4.62), 3.178 (3.1 1 ), 3.185 (2.94), 3.220 (3.98), 3.224 (16.00), 3.533 (3.65), 3.557 (1.19), 4.023 (4.68), 8.264 (1.43), 8.277 (1.38), 8.632 (2.67), 8.827 (2.07).
Example 35.01.17
N-[4-({4-[(4-methoxypiperidin-1-yl)sulfonyl]piperazin-1-yl}methyl)pyridin
methoxypyrimidin-4-yl)-1H-benzimidazol-2-amine
Figure imgf000798_0001
Starting with crude 6-(5-methoxypyrimidin-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (130 mg, approx. 187 pmol) and 4-methoxypiperidine-1 - sulfonyl chloride (CAS-RN: 355849-73-9) (40.0 mg, 187 pmol), Example 35.01.17 was prepared analogously to the procedure for the preparation of Example 35.01.03.
Yield: 63.0 mg of the title compound.
LC-MS (Method 4): R, = 1.06 min; MS (ESIpos): m/z = 594 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.465 (1.18), 1.476 (1.01 ), 1.486 (1.24), 1.833 (1.10), 2.322 (0.83), 2.327 (1.20), 2.331 (0.91 ), 2.466 (3.97), 2.518 (4.81 ), 2.523 (3.27), 2.665 (0.87), 2.669 (1.22), 2.673 (0.89), 3.001 (0.89), 3.010 (1.05), 3.031 (1.89), 3.040 (1.20), 3.054 (1.14), 3.062 (1.01 ), 3.171 (3.97), 3.242 (16.00), 3.359 (1.74), 3.537 (5.46), 4.024 (6.47), 6.928 (1.32), 6.941 (1.32), 7.186 (1.44), 8.264 (2.01 ), 8.277 (1.93), 8.375 (0.95), 8.632 (3.41 ), 8.826 (2.60), 12.281 (0.93).
Example 35.01.18
N-[4-({4-[(2,6-dimethylmorpholin-4-yl)sulfonyl]piperazin-1-yl}methyl)pyridin-2-yl]-6-(5 methoxypyrimidin-4-yl)-1 H-benzimidazol-2-amine
Figure imgf000799_0001
Starting with crude 6-(5-methoxypyrimidin-4-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (150 mg, approx. 216 pmol) and 2,6-dimethylmorpholine- 4-sulfonyl chloride (CAS-RN: 919026-20-3) (46.2 mg, 216 pmol), Example 35.01.18 was prepared analogously to the procedure for the preparation of Example 35.01.03.
Yield: 75.0 mg of the title compound.
LC-MS (Method 2): Rt = 1.14 min; MS (ESIpos): m/z = 594 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.086 (10.24), 1.102 (12.46), 1.107 (16.00), 2.327 (1.39), 2.669 (1.44), 3.212 (3.98), 3.389 (2.63), 3.416 (2.17), 3.547 (4.32), 4.022 (9.69), 4.194 (0.85), 6.952 (1.37), 7.193 (2.13), 8.270 (1.71 ), 8.283 (1.76), 8.635 (3.43), 8.829 (3.54).
Example 35.02.01
(rac)-3,3,3 rifluoro-1 -{4-[1-(2-{[6-(5-methoxypyrimidin-4-yl)-1 H-ben2imidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}propan-1-one
Figure imgf000800_0001
Starting with crude (rac)-6-(5-methoxypyrimidin-4-yl)-N-{4-[1 -(piperazin-1 -yl)ethyl]pyridin-2-yl}- 1 H-benzimidazol-2-amine hydrochloride (900 mg, approx.1.79 mmol) and 3,3,3- trifluoropropanoic acid (320 mg, 2.50 mmol), Example 35.02.01 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 990 mg of the title compound.
LC-MS (Method 2): R, = 1.04 min; MS (ESIpos): m/z = 541 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.035 (7.87), 1.052 (16.00), 1.070 (8.19), 1.232 (0.63), 1.298 (3.10), 1.314 (3.04), 2.323 (1.33), 2.327 (1.67), 2.332 (1.43), 2.434 (1.06), 2.523 (2.58), 2.665 (0.82), 2.669 (1.12), 2.673 (0.84), 3.405 (1.03), 3.423 (3.02), 3.435 (3.78), 3.440 (4.12), 3.452 (3.50), 3.469 (2.15), 3.485 (2.09), 3.513 (1.24), 3.540 (0.86), 3.582 (0.82), 3.609 (2.55), 3.636 (2.15), 3.664 (0.68), 4.023 (11.63), 4.344 (1.01 ), 4.356 (1.77), 4.368 (0.97), 6.960 (1.25), 6.973 (1 .27), 7.174 (2.05), 8.280 (1.81 ), 8.294 (1.73), 8.635 (4.69), 8.829 (5.00).
Example 35.02.02
(rac)-2-cyclopropyl-1-{4-[1-(2-{[6-(5-methoxypyrimidin-4-yl)-1H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}ethanone
Figure imgf000801_0001
Starting with crude (rac)-6-(5-methoxypyrimidin-4-yl)-N-{4-[1 -(piperazin-1 -yl)ethyl]pyridin-2-yl}- 1 H-benzimidazol-2-amine (233 mg, 541 pmol) and cyclopropylacetic acid (81.3 mg, 812 pmol), Example 35.02.02 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 35.2 mg (12 %) of the title compound.
LC-MS (Method 4): R, = 1.02 min; MS (ESIpos): m/z = 513 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.000 (1.63), 0.011 (5.34), 0.014 (4.98), 0.023 (5.34), 0.037 (1.71 ), 0.331 (1.74), 0.341 (4.45), 0.345 (4.57), 0.351 (2.45), 0.356 (2.36), 0.361 (4.77), 0.366 (4.52), 0.376 (1.60), 0.851 (1.68), 1.219 (8.92), 1.236 (9.25), 2.144 (7.89), 2.161 (7.78), 2.262 (2.45), 2.339 (2.74), 2.458 (5.07), 2.604 (0.81 ), 3.358 (4.84), 3.372 (5.35), 3.390 (5.07), 3.957 (16.00), 6.886 (2.70), 6.900 (2.73), 7.103 (3.23), 7.350 (0.73), 7.864 (0.73), 8.206 (4.20), 8.219 (4.12), 8.310 (0.96), 8.567 (9.18), 8.762 (8.09), 12.232 (1.17).
Example 35.02.03
(rac)-cyclopropyl{4-[1 -(2-{[6-(5-methoxypyrimidin-4-yl)-1H-benzimidazol-2
yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}methanone
Figure imgf000802_0001
Starting with crude (rac)-6-(5-methoxypyrimidin-4-yl)-N-{4-[1 -(piperazin-1 -yl)ethyl]pyridin-2-yl}- 1 H-benzimidazol-2-amine (233 mg, 541 pmol) and cyclopropanecarboxylic acid (69.9 mg, 812 pmol), Example 35.02.03 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 59.6 mg (22 %) of the title compound.
LC-MS (Method 4): Rt = 0.99 min; MS (ESIpos): m/z = 499 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.664 (6.36), 0.684 (7.92), 0.691 (7.41 ), 0.699 (6.29), 0.703 (6.76), 0.710 (3.18), 1.295 (1 1.02), 1.31 1 (10.82), 1.937 (2.47), 2.327 (2.51 ), 2.523 (3.46), 2.669 (0.98), 3.451 (4.64), 3.468 (5.79), 3.675 (3.24), 4.022 (16.00), 6.959 (3.20), 6.972 (3.17), 7.176 (3.41 ), 7.413 (0.97), 7.934 (0.98), 8.275 (4.76), 8.288 (4.52), 8.379 (1.32), 8.632 (9.56), 8.827 (7.81 ), 12.304 (1.38).
Example 35.02.04
(rac)-cyclobutyl{4-t1-(2-{[6-(5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2
yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}methanone
Figure imgf000803_0001
Starting with crude (rac)-6-(5-methoxypyrimidin-4-yl)-N-{4-[1 -(piperazin-1 -yl)ethyl]pyridin-2-yl}- 1 H-benzimidazol-2-amine (233 mg, 541 pmol) and cyclobutanecarboxylic acid (81.3 mg, 812 pmol), Example 35.02.04 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 78.2 mg (28 %) of the title compound.
LC-MS (Method 4): R, = 1.05 min; MS (ESIpos): m/z = 513 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.274 (4.42), 1.290 (4.49), 1.843 (0.97), 2.030 (1.13), 2.051 (1.33), 2.060 (1.05), 2.075 (0.91 ), 2.099 (1.39), 2.120 (1.44), 2.280 (1.01 ), 2.294 (1.14), 2.308 (1.10), 2.523 (1.41 ), 3.272 (0.98), 3.293 (2.29), 3.305 (1.93), 3.315 (1.99), 3.337 (16.00), 3.423 (1.73), 3.440 (2.32), 4.022 (7.27), 6.943 (1.24), 6.956 (1.30), 7.164 (1.34), 8.267 (2.02), 8.280 (1.95), 8.632 (4.38), 8.827 (3.67).
Example 35.03.01. A
3,3,3-trifluoro-1-{4-[(1 R or 1S)-1 -(2-{[6-(5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}propan-1 -one (single stereoisomer A)
Figure imgf000804_0001
Example 35.03.01. B
3,3,3-trifluoro-1 -{4-[(1 S or 1 R)-1 -(2-{[6-(5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}propan-1-one (single stereoisomer B)
Figure imgf000804_0002
97 mg of (rac)-3,3,3-trifluoro-1-{4-[1 -(2-{[6-(5-methoxypyrirriidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}propan-1 -one was separated into the single stereoisomers (Example 35.03.01. A and Example 35.03.01. B) via preparative, chiral HPLC. Instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241 , Labcol Vario 4000,
Column: Chiralpak IB 5μ 250x30mm;
Eluent A: hexane + 0.1 Vol-% diethylamine (99%);
Eluent B: ethanol; isocratic: 70%A+30%B;
Flow: 60.0 mL/min;
Solution: 97 mg / 4.8 mL dichloromethane/methanol 1 :1
Injection: 3 x 1.6 mL
Detection: UV 325 nm Retention time in
purity in % yield Optical rotation [a]D min
Example -39.1 °
35.03.01. A
(from solution in
7.9 - 13.5 >99.9% 27 mg
Stereoisomer A DMSO, c = 2.4 mg/mL)
Example + 33.2°
35.03.01. B
(from solution in
15.2 - 21 .3 >99.9% 32 mg
Stereoisomer B DMSO, c = 3.2 mg/mL)
Example 35.03.01. A
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.107 (9.20), 1.233 (1.29), 1.294 (7.37), 1.31 1 (7.43), 2.322 (1.66), 2.326 (2.14), 2.331 (2.16), 2.432 (1.92), 2.523 (3.10), 2.664 (0.98), 2.669 (1.33), 2.674 (0.94), 3.438 (3.71 ), 3.472 (3.64), 3.487 (3.86), 3.580 (1.50), 3.607 (4.23), 3.635 (4.05), 3.662 (1.26), 4.022 (16.00), 4.188 (0.72), 6.954 (2.25), 6.967 (2.29), 7.171 (3.12), 8.276 (3.75), 8.289 (3.57), 8.632 (9.09), 8.827 (8.39), 12.289 (0.92).
Example 35.03.01. B
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.107 (8.52), 1.234 (1 .38), 1.295 (6.45), 1.31 1 (6.45), 2.322 (1.92), 2.326 (2.52), 2.331 (2.35), 2.432 (1.81 ), 2.518 (6.48), 2.522 (4.22), 2.664 (1.26), 2.669 (1.75), 2.674 (1.20), 3.438 (3.38), 3.489 (3.30), 3.580 (1.38), 3.607 (3.93), 3.635 (3.76), 3.662 (1.18), 4.022 (16.00), 6.955 (2.04), 6.969 (2.04), 7.171 (2.87), 8.276 (3.35), 8.290 (3.27), 8.632 (8.66), 8.828 (8.40).
Example 35.03.02.A
2-cyclopropyl-1 -{4-[(1 R or 1S)-1-(2-{[6-(5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}ethanone (single stereoisomer A)
Figure imgf000806_0001
Example 35.03.02.B
2-cyclopropyl-1 -{4-[(1S or 1R)-1 -(2-{[6-(5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}ethanone (single stereoisomer B)
Figure imgf000806_0002
40 mg of (rac)-2-cyclopropyl-1 -{4-[1 -(2^[6-(5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}ethanone was separated into the single stereoisomers (Example 35.03.02.A and Example 35.03.02.B) via preparative, chiral HPLC.
Instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241 , Labcol Vario 4000,
Column: Chiralpak IB 5μ 250x30mm;
Eluent A: hexane + 0.2 Vol-% diethylamine (99%); Eluent B: ethanol; isocratic: 70%A+30%B; Flow: 30.0 mL/min;
Solution: 40 mg / 2 mL ethanol
Injection: 4 x 0.5 mL
Detection: UV 325 nm Retention time in
purity in % yield Optical rotation [O]D min
Example - 36.4°
35.03.02.A (from solution in
9.50 - 1 1.10 99.6% 15 mg
Stereoisomer A DMSO, c = 2.9 mg/mL)
Example + 32.4°
35.03.02.B (from solution in
1 1.20 - 12.50 95.1 % 15 mg
Stereoisomer B D SO, c = 2.6 mg/mL)
Example 35.03.02.A
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.000 (2.36), 0.01 1 (7.87), 0.014 (7.61 ), 0.023 (8.26), 0.026 (7.87), 0.037 (2.62), 0.331 (2.75), 0.341 (6.69), 0.345 (7.21 ), 0.352 (3.80), 0.356 (3.67), 0.362 (7.34), 0.366 (7.08), 0.376 (2.62), 0.851 (2.75), 1.042 (14.95), 1.166 (4.98), 1.220 (14.56), 1.238 (14.69), 2.146 (12.46), 2.162 (12.33), 2.257 (4.98), 2.262 (5.90), 2.267 (4.98), 2.339 (4.20), 2.458 (11.28), 2.599 (2.75), 2.604 (3.80), 2.608 (2.75), 3.358 (7.34), 3.374 (8.39), 3.391 (7.87), 3.960 (16.00), 4.132 (1.57), 6.886 (3.41 ), 7.097 (3.93), 7.327 (1.84), 7.347 (2.10), 7.866 (1.84), 8.049 (1.57), 8.206 (5.38), 8.219 (5.1 1 ), 8.310 (3.02), 8.566 (9.70), 8.760 (7.08), 10.675 (2.36), 12.229 (3.02).
Example 35.03.02.B
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.000 (1.04), 0.01 1 (3.49), 0. .014 (3.28), 0.023 (3 .44), 0.026 (3.39), 0.037 (1.20), 0.331 (1.20), 0.341 (3.00), 0.345 (3.22), 0. .352 (1.58), 0.356 (1 .53), 0.362 (3.22), 0.366 (3.17), 0.376 (1.20), 0.831 (0.71 ), 0.834 (0.71 ), 0. .839 (0.71 ), 0.851 (1 .20), 0.868 (0.71 ), 0.871 (0.66), 0.901 (0.55), 1.042 (16.00), 1.165 (2.02), 1 .220 (6.33), 1.237 (6 .39), 2.145 (5.62), 2.162 (5.46), 2.253 (1.53), 2.257 (1.91 ), 2.262 (2.18), 2. .267 (1.91 ), 2.338 ( 69), 2.353 (1.53), 2.367 (1.15), 2.458 (3.33), 2.600 (0.93), 2.604 (1.31 ), 2. .608 (0.98), 3.358 (3 .00), 3.373 (3.49), 3.390 (3.28), 3.405 (2.13), 3.959 (6.77), 4.132 (1.47), 6. .886 (1.47), 6.899 (1 .53), 7.098 (1.64), 7.347 (0.76), 8.206 (2.40), 8.219 (2.29), 8.310 (1.15), 8. 566 (4.53), 8.760 (3 .22), 10.676 (0.82), 12.230 (1.15). Example 35.03.03.A
cyclopropyl{4-[(1R or 1S)-1 -(2-{[6-(5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2 yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}methanone (single stereoisomer A)
Figure imgf000808_0001
Example 35.03.03.B
cyclopropyl{4-[(1S or 1 R)-1 -(2-{[6-(5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}methanone (single stereoisomer B)
Figure imgf000808_0002
40 mg of (rac)-cyclopropyl{4-[1-(2 [6-(5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}met anone was separated into the single stereoisomers (Example 35.03.03.A and Example 35.03.03. B) via preparative, chiral HPLC.
Instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241 , Labcol Vario 4000,
Column: Chiralpak IB 5μ 250x30mm;
Eluent A: hexane + 0.2 Vol-% diethylamine (99%); Eluent B: ethanol; isocratic: 70%A+30%B;
Flow: 30.0 rnLAnin;
Solution: 40 mg / 2.0 mL ethanol
Injection: 4 x 0.5 mL
Detection: UV 325 nm Retention time in
purity in % yield Optical rotation [O]D min
Example - 41.9°
35.03.03.A
(from solution in
1 1.00 - 12.25 > 99.0% 20 mg
Stereoisomer A DMSO, c = 2.8 mg/mL)
Example + 37.7°
35.03.03.B
(from solution in
12.25 - 15.25 97.5% 20 mg
Stereoisomer B DMSO, c = 2.7 mg/mL)
Example 35.03.03.A
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.658 (2.70), 0.665 (6.49), 0.670 (4.05), 0.678 (3.21 ), 0.685 (8.29), 0.692 (7.90), 0.699 (6.30), 0.704 (7.33), 0.71 1 (3.41 ), 0.967 (0.84), 1.107 (16.00), 1.231 (1.99), 1.296 (12.40), 1.313 (12.40), 1.918 (1.54), 1.925 (1.67), 1.938 (2.76), 1.950 (1.54), 1.957 (1.41 ), 2.323 (2.44), 2.327 (2.83), 2.331 (2.25), 2.397 (2.18), 2.523 (4.31 ), 2.665 (1.35), 2.669 (1.86), 2.673 (1.35), 3.453 (4.63), 3.470 (5.85), 3.678 (3.02), 4.023 (14.20), 4.193 (1.54), 6.959 (3.08), 6.973 (3.08), 7.174 (3.15), 7.415 (1.22), 7.932 (1.22), 8.276 (5.01 ), 8.289 (4.76), 8.377 (1.86), 8.631 (9.77), 8.827 (7.33), 10.740 (1.41 ), 12.295 (2.06).
Example 35.03.03.B
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.646 (0.81 ), 0.658 (2.55), 0.665 (5.98), 0.671 (3.55), 0.678 (2.93), 0.685 (7.66), 0.692 (7.10), 0.700 (5.91 ), 0.704 (6.72), 0.71 1 (3.1 1 ), 0.724 (0.75), 0.967 (0.44), 1.107 (13.01 ), 1.153 (0.50), 1.231 (2.43), 1.259 (1.00), 1.296 (1 1.52), 1.314 (1 1.33), 1.906 (0.68), 1.919 (1.49), 1.925 (1.49), 1.938 (2.55), 1.944 (1.25), 1.950 (1.43), 1.957 (1.37), 1.969 (0.62), 2.084 (1.12), 2.318 (1.68), 2.323 (2.24), 2.327 (2.55), 2.331 (1.99), 2.337 (1.31 ), 2.401 (1.99), 2.523 (3.36), 2.665 (1.18), 2.669 (1.56), 2.674 (1.12), 3.437 (1.37), 3.454 (4.1 1 ), 3.470 (5.23), 3.504 (1.00), 3.510 (0.87), 3.676 (2.74), 4.022 (16.00), 4.194 (1.25), 6.959 (2.99), 6.973 (3.05), 7.175 (3.18), 7.397 (0.81 ), 7.415 (0.87), 7.932 (0.93), 8.1 17 (0.62), 8.276 (4.98), 8.289 (4.73), 8.379 (1.31 ), 8.631 (10.52), 8.827 (8.53), 10.740 (1.06), 12.252 (0.81 ), 12.296 (1.56). Example 35.03.04.A
cyclobutyl{4-[(1 R or 1S)-1 -(2-{[6-(5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2 yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}methanone (single stereoisomer A)
Figure imgf000810_0001
Example 35.03.04.B
cyclobutyl{4-[(1 R or 1S)-1 -(2-{[6-(5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}methanone (single stereoisomer B)
Figure imgf000810_0002
73 mg of (rac)-cyclobutyl{4-[1 -(2-{[6-(5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}methanone was separated into the single stereoisomers (Example 35.03.04.A and Example 35.03.04. B) via preparative, chiral HPLC.
Instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241 , Labcol Vario 4000,
Column: Chiralpak IB 5μ 250x30mm;
Eluent A: hexane + 0.2 Vol-% diethylamine (99%); Eluent B: ethanol; isocratic: 70%A+30%B;
Flow: 30.0 mL/min;
Solution: 73 mg / 2 mL ethanol
Injection: 4 x 0.5 mL
Detection: UV 325 nm Retention time in
purity in % yield Optical rotation [CI]D min
Example - 35.0°
35.03.04.A
(from solution in
7.50 - 8.80 > 99.0% 30 mg
Stereoisomer A DMSO, c = 3.9 mg/mL)
Example + 32.3°
35.03.04.B
(from solution in
8.90 - 1 1.50 95.0% 32 mg
Stereoisomer B DMSO, c = 3.2 mg/mL)
Example 35.03.04.A
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.107 (16.00), 1.277 (6.54), 1.294 (6.69), 1.846 (1.33), 1.873 (1.07), 2.054 (1.92), 2.100 (1.96), 2.122 (2.07), 2.327 (1.88), 2.523 (4.47), 2.669 (1.48), 3.277 (1.48), 3.297 (3.70), 3.427 (2.62), 3.443 (3.40), 4.024 (7.24), 4.192 (1.48), 6.945 (1.59), 7.160 (1.66), 8.268 (2.44), 8.281 (2.33), 8.374 (1.22), 8.630 (4.55), 8.826 (3.55), 12.290 (1.26).
Example 35.03.04.B
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.108 (16.00), 1.277 (2.51 ), 1.295 (2.57), 2.055 (0.72), 2.101 (0.76), 2.122 (0.78), 2.323 (0.80), 2.327 (0.95), 2.331 (0.66), 2.523 (1.71 ), 2.669 (0.76), 3.297 (1.36), 3.309 (1.38), 3.427 (0.97), 3.444 (1.27), 4.025 (2.61 ), 4.192 (1.60), 8.267 (0.86), 8.281 (0.84), 8.630 (1.58), 8.825 (1.21 ).
Example 36.01
tert-butyl 4-{(1 R or 1S)-1 -[2-({6-[5-(propan-2-yloxy)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazine-1-carboxylate (single stereoisomer A)
Figure imgf000812_0001
To a stirred solution of 1 H-imidazole (33.6 mg, 493 μιτιοΙ) and di-1 H-imidazol-1 - ylmethanethione (586 mg, 90 % purity, 2.96 mmol) in dichloromethane (10 mL) was added tert-butyl 4-[(1 R or 1 S)-1 -(2-aminopyridin-4-yl)ethyl]piperazine-1 -carboxylate (755 mg, 2.47 mmol) , dissolved in dichloromethane (20 mL) at 0° C. The mixture was stirred at r.t. for 14 h. 4-[5-(propan-2-yloxy)pyrimidin-4-yl]benzene-1 ,2-diamine (745 mg, 97 % purity, 2.96 mmol), dissolved in dichloromethane (18 mL) was added and the mixture was stirred at r.t. for 2 h. Water was added and the mixture was extracted with dichloromethane. The organic phase was dried (sodium sulfate) and filtered. N,N'-dipropan-2-ylcarbodiimide (0.55 mL, 3.45 mmol) was added. The mixture was stirred at r.t. for 4 h. Further N,N'-dipropan-2-ylcarbodiimide (0.55 mL, 3.45 mmol) was added and the mixture was stirred at 40° C for 2 h and at r.t. for 14 h. Water was added, the mixture was stirred for 30 minutes. The mixture was extracted with dichloromethane, dried (sodium sulfate) and the solvent was removed in vacuum. Aminophase-silicagel chromatography gave 470 mg of the title compound.
LC-MS (Method 2): R, = 1.31 min; MS (ESIpos): m/z = 559 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.171 (1.05), 1.279 (1.72), 1.295 (1.76), 1.307 (0.93), 1.323 (0.90), 1.349 (2.19), 1.364 (2.66), 1.369 (4.04), 1.376 (16.00), 1.987 (1.78), 5.758 (2.03), 7.171 (0.86), 8.622 (1.34), 8.801 (1.46).
Example 36.02
3,3,3-trifluoro-1 -(4-{(1 R or 1S)-1 -[2-({6-[5-(propan-2-yloxy)pyrimidin-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)propan-1 -one (single stereoisomer A)
Figure imgf000813_0001
Starting with crude N-{4-[(1 R or 1 S)-1 -(piperazin-1-yl)ethyl]pyridin-2-yl}-6-[5-(propan-2- yloxy)pyrimidin-4-yl]-1 H-benzimidazol-2-amine hydrochloride (single stereoisomer A) (160 mg, approx. 200 pmol) and 3,3,3-trifluoropropanoic acid (77.0 mg, 601 μητιοΙ), Example 36.02 was prepared analogously to the procedure for the preparation of Example 16.05.02.
Yield: 53.0 mg of the title compound.
Optical rotation [a]D +30.1 ^from solution in DMSO, c = 2.12 mg/mL)
LC-MS (Method 2): R, = 1.13 min; MS (ESIpos): m/z = 569 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (1.10), 1.172 (2.36), 1.189 (1.29), 1.293 (5.93), 1.309 (6.05), 1.349 (8.44), 1.363 (8.47), 1.987 (4.40), 2.327 (1.16), 2.331 (1.33), 2.345 (1.33), 2.427 (1.53), 2.518 (2.74), 2.523 (1.84), 3.425 (1.56), 3.438 (2.82), 3.450 (2.04), 3.469 (3.01 ), 3.486 (3.49), 3.580 (1.08), 3.608 (3.07), 3.635 (2.93), 4.016 (0.97), 4.034 (0.96), 4.830 (1.28), 4.845 (1.74), 4.861 (1.31 ), 5.759 (16.00), 6.946 (1.69), 6.949 (1.70), 6.959 (1.75), 6.962 (1.75), 7.179 (2.34), 8.282 (1.88), 8.296 (1.84), 8.623 (5.39), 8.802 (6.53).
Example 36.03
cyclopropyl(4-{(1 R or 1S)-1 -[2-({6-[5-(propan-2-yloxy)pyrimidin-4-yl]-1H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)methanone (single stereoisomer A)
Figure imgf000814_0001
Starting with crude N-{4-[(1 R or 1 S)-1 -(piperazin-1-yl)ethyl]pyridin-2-yl}-6-[5-(propan-2- yloxy)pyrimidin-4-yl]-1 H-benzimidazol-2-amine hydrochloride (single stereoisomer A) (160 mg, approx. 200 pmol) and cyclopropanecarboxylic acid (51.8 mg, 601 μιτιοΙ), Example 36.03 was prepared analogously to the procedure for the preparation of Example 16.05.02.
Yield: 67.0 mg of the title compound.
Optical rotation [a]D +45.2tfrom solution in DMSO, c = 2.66 mg/mL)
LC-MS (Method 2): R, = 1.09 min; MS (ESIpos): m/z = 527 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.656 (2.31 ), 0.663 (5.33), 0.668 (3.36), 0.676 (2.68), 0.683 (6.46), 0.687 (5.50), 0.692 (5.97), 0.699 (5.32), 0.704 (6.15), 0.71 1 (2.91 ), 1.154 (2.05), 1.172 (4.27), 1.189 (2.26), 1.295 (10.30), 1.312 (10.64), 1.349 (15.35), 1.363 (15.27), 1.916 (1.28), 1.922 (1.36), 1.935 (2.28), 1.947 (1.30), 1.954 (1.19), 1.987 (7.74), 2.318 (1.26), 2.323 (1.39), 2.327 (1.49), 2.331 (1.22), 2.397 (1.80), 2.456 (1.55), 2.518 (2.36), 2.685 (1.03), 3.436 (1.19), 3.452 (3.77), 3.469 (4.81 ), 3.485 (2.42), 3.675 (2.47), 4.016 (1.68), 4.034 (1.63), 4.830 (2.22), 4.845 (3.02), 4.861 (2.24), 4.876 (0.85), 5.759 (16.00), 6.953 (3.00), 6.956 (2.93), 6.966 (3.02), 6.970 (2.92), 7.187 (5.09), 8.283 (3.40), 8.296 (3.23), 8.623 (9.76), 8.803 (1 1.46), 12.247 (1.48).
Example 36.04
cyclobutyl(4-{(1 R or 1 S)-1 -[2-({6-[5-(propan-2-yloxy)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)methanone (single stereoisomer A)
Figure imgf000815_0001
Starting with crude N-{4-[(1 R or 1 S)-1 -(piperazin-1 -yl)ethyl]pyridin-2-yl}-6-[5-(propan-2- yloxy)pyrimidin-4-yl]-1 H-benzimidazol-2-amine hydrochloride (single stereoisomer A) (160 mg, approx. 200 pmol) and cydobutanecarboxylic acid (60.2 mg, 601 pmol), Example 36.04 was prepared analogously to the procedure for the preparation of Example 16.05.02.
Yield: 53.0 mg of the title compound.
Optical rotation [a]D +40.6° (from solution in DMSO, c = 2.15 mg/mL)
LC-MS (Method 2): R, = 1.16 min; MS (ESIpos): m/z = 541 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.153 (1.45), 1.171 (2.93), 1.189 (1.50), 1.275 (7.99), 1.292 (8.05), 1.347 (10.61 ), 1.362 (10.36), 1.716 (1.07), 1.822 (0.91 ), 1.843 (1 .75), 1 .865 (1.30), 1.870 (1.31 ), 1.986 (5.35), 2.029 (1.97), 2.039 (1.44), 2.046 (1.44), 2.052 (2.26), 2.060 (1.70), 2.076 (1.48), 2.081 (1.27), 2.099 (2.32), 2.120 (2.44), 2.124 (2.31 ), 2.149 (1.29), 2.282 (1.76), 2.296 (1.95), 2.31 1 (1.78), 2.322 (1.17), 2.388 (1.32), 2.401 (1.36), 3.271 (1.68), 3.294 (3.97), 3.307 (3.41 ), 3.314 (3.52), 3.426 (3.12), 3.442 (3.92), 4.016 (1.21 ), 4.034 (1.20), 4.829 (1.71 ), 4.844 (2.32), 4.859 (1.71 ), 5.758 (16.00), 6.938 (2.29), 6.951 (2.30), 6.953 (2.29), 7.172 (3.82), 8.275 (2.42), 8.287 (2.28), 8.622 (7.20), 8.802 (8.36), 12.243 (1.32).
Example 37.01
3,3,3-trifluoro-1 -{4-[(2-{[6-(1-methyl-1 H^yrazol-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin- 4-yl)methyl]piperazin-1 -yl}propan-1 -one
Figure imgf000816_0001
Starting with crude 6-(1-methyl-1 H-pyrazol-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (120 mg, approx. 208 pmol) and 3,3,3-trifluoropropanoic acid (28 μΙ, 98 % purity, 310 pmol), Example 37.01 was prepared analogously to the procedure for the preparation of Example 05.01.
Yield: 46.0 mg of the title compound.
LC-MS (Method 1 ): R, = 0.66 min; MS (ESIpos): m/z = 499 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm]= 2.37 - 2.44 (m, 4H), 3.43 - 3.56 (m, 6H), 3.66 (q, 2H), 3.87 (s, 3H), 6.92 (d, 1 H), 7.13 - 7.67 (m, 4H), 7.78 (br s, 1 H), 8.03 (br s, 1 H), 8.26 (d, 1 H), 10.59 (br s, 1 H), 12.04 (br s, 1 H).
Example 37.02
2-cyclopropyl-1 -{4-[(2-{[6-(1-methyl-1 H-pyrazol-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}ethanone
Figure imgf000816_0002
Starting with crude 6-(1 -methyl-1 H-pyrazol-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (120 mg, approx. 208 pmol) and cyclopropylacetic acid (30 μΙ, 98 % purity, 310 μιτιοΙ), Example 37.02 was prepared analogously to the procedure for the preparation of Example 05.01. Yield: 70.0 mg of the title compound.
LC-MS (Method 1 ): F¾ = 0.62 min; MS (ESIneg): m/z = 469 [M-H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.000 (0.96), 0.01 1 (3.51 ), 0.014 (3.21 ), 0.023 (3.61 ), 0.026 (3.23), 0.037 (1.08), 0.330 (1.08), 0.340 (3.06), 0.344 (3.06), 0.350 (1.62), 0.355 (1.72), 0.360 (3.23), 0.364 (2.97), 0.375 (1.08), 0.834 (0.69), 0.837 (0.70), 0.842 (0.69), 0.854 (1.08), 2.153 (5.45), 2.169 (5.26), 2.238 (0.98), 2.243 (1.34), 2.248 (1.15), 2.273 (2.66), 2.292 (2.54), 2.305 (2.60), 2.438 (3.88), 2.580 (0.74), 2.585 (1.00), 2.590 (0.74), 3.368 (2.58), 3.415 (8.30), 3.776 (9.26), 5.675 (16.00), 6.821 (1.99), 6.824 (1.98), 6.837 (1.99), 7.102 (2.42), 8.157 (3.11 ), 8.169 (2.97), 10.485 (1.07), 1 1.935 (1.46).
Example 37.03
cyclopropyl{4-[(2-{[6-(1 -methyl-1 H-pyrazol-4-yl)-1H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone
Figure imgf000817_0001
Starting with crude 6-(1 -methyl-1 H-pyrazol-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (120 mg, approx. 208 pmol) and cyclopropanecarboxylic acid (25 μΙ, 98 % purity, 310 pmol), Example 37.03 was prepared analogously to the procedure for the preparation of Example 05.01.
Yield: 65.0 mg of the title compound.
LC-MS (Method 2): Rt = 0.95 min; MS (ESIpos): m/z = 457 [M+H]+
1 H-NMR (400MHz, DMSO-d6): δ [ppm]= 0.65 - 0.76 (m, 4H), 1.92 - 2.02 (m, 1 H), 2.34 - 2.45 (m, 4H), 3.51 (s, 4H), 3.70 (br s, 2H), 3.86 (s, 3H), 6.89 - 6.96 (m, 1 H), 7.14 - 7.65 (m, 4H), 7.71 - 7.84 (m, 1 H), 7.94 - 8.12 (m, 1 H), 8.25 (d, 1 H), 10.57 (br s, 1 H), 12.02 (br s, 1 H). Example 37.04
cyclobutyl{4-[(2-{[6-(1 -methyl-1 H-pyrazol-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4 yl)methyl]piperazin-1 -yl}methanone
Figure imgf000818_0001
Starting with crude 6-(1 -methyl-1 H-pyrazol-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (120 mg, approx. 208 pmol) and cyclobutanecarboxylic acid (30 μΙ, 98 % purity, 310 pmol), Example 37.04 was prepared analogously to the procedure for the preparation of Example 05.01.
Yield: 48.0 mg of the title compound.
LC-MS (Method 2): R, = 1.02 min; MS (ESIpos): m/z = 471 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.67 - 1.79 (m, 1 H), 1.82 - 1.95 (m, 1 H), 2.01 - 2.22 (m, 4H), 2.35 (br s, 4H), 3.43 - 3.56 (m, 4H), 3.87 (s, 3H), 6.91 (d, 1 H), 6.99 - 7.03 (m, 1 H), 7.09 - 7.67 (m, 4H), 7.78 (br d, 1 H), 7.94 - 8.12 (m, 1 H), 8.19 - 8.30 (m, 1 H), 10.57 (br s, 1 H), 12.03 (br s, 1 H).
Example 38.01
tert-butyl 4-[(2-{[6-(1 -ethyl-1 H-pyrazol-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl] pi perazine-1 -carboxylate
Figure imgf000818_0002
To a stirred solution of 1 H-imidazole (39.6 mg, 581 pmol) and di-1 H-imidazol-1- ylmethanethione (654 mg, 95 % purity, 3.49 mmol) in dichloromethane (60 mL) was added tert-butyl 4-[(2-aminopyridin-4-yl)methyl]piperazine-1-carboxylate (850 mg, 2.91 mmol) , dissolved in dichloromethane (30 mL) at 0° C. The m ixture was stirred at r.t. for 14 h. 4-(1 - ethyl-1 H-pyrazol-4-yl)benzene-1 ,2-diamine (706 mg, 3.49 mmol) , dissolved in dichloromethane (30 mL) was added and the mixture was stirred at r.t. for 56 h. Water was added and the mixture was extracted with dichloromethane. The organic phase was dried (sodium sulfate) and filtered. N,N'-dipropan-2-ylcarbodiimide (0.64 mL, 4.0 mmol) was added. The mixture was stirred at r.t. for 4 h. Further N,N'-dipropan-2-ylcarbodiimide (0.32 mL, 2.0 mmol) was added and the mixture was stirred at r.t. for 14 h. Further N,N'-dipropan-2- ylcarbodiimide (0.32 mL, 2.0 mmol) was added and the mixture was stirred at r.t. for 14 h. Saturated sodium chloride solution was added, the mixture was stirred for 30 minutes and was extracted with dichloromethane, dried (sodium sulfate) and the solvent was removed in vacuum. Aminophase-silicagel chromatography followed by silicagel chromatography gave a solid that was triturated with ethanol to give 151 mg of the title compound.
LC-MS (Method 2): R, = 1.25 min; MS (ESIpos): m/z = 503 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.388 (3.1 1 ), 1.392 (6.25), 1.394 (16.00), 1.410 (4.28), 1.428 (1.86), 1.987 (0.85), 2.354 (1.26), 3.333 (10.47), 3.347 (1.12), 3.488 (1.61 ), 5.760 (1.46), 8.235 (0.79), 8.249 (0.76).
Example 38.02
1-{4-[(2-{[6-(1-ethyl-1 H^yrazol-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1-yl}-3,3,3-trifluoropropan-1-one
Figure imgf000819_0001
Starting with crude 6-(1 -ethyl-1 H-pyrazol-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (135 mg, approx. 246 pmol) and 3,3,3-trifluoropropanoic acid (33 μΙ, 370 pmol) Example 38.02. was prepared analogously to the procedure for the preparation of Example16.01.02.
Yield: 80.0 mg of the title compound. LC-MS (Method 2): R, = 1.04 min; MS (ESIpos): m/z = 513 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.392 (6.95), 1.410 (16.00), 1.428 (6.76), 2.327 (0.67), 2.365 (1.54), 2.378 (2.43), 2.390 (1.84), 2.406 (1.72), 2.419 (2.37), 2.431 (1.76), 2.518 (3.87), 2.523 (2.64), 2.669 (0.68), 3.456 (1.71 ), 3.469 (2.41 ), 3.481 (2.01 ), 3.493 (1.98), 3.514 (8.15), 3.610 (1.20), 3.638 (3.51 ), 3.665 (3.30), 3.693 (1.02), 4.1 17 (0.83), 4.135 (2.41 ), 4.154 (2.40), 4.171 (0.85), 6.906 (1.98), 6.910 (1.93), 6.919 (2.03), 6.922 (2.1 1 ), 7.190 (2.08), 8.243 (3.22), 8.257 (3.12), 10.580 (0.97), 12.021 (1.29).
Example 38.03
cyclopropyl{4-[(2-{[6-(1 -ethyl-1 H-pyrazol-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4' yl)methyl]piperazin-1-yl}methanone
Figure imgf000820_0001
Starting with crude 6-(1 -ethyl-1 H-pyrazol-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (135 mg, approx. 246 pmol)and cyclopropanecarboxylic acid (31 μΙ, 95 % purity, 370 pmol) Example 38.03. was prepared analogously to the procedure for the preparation of Example 16.01.02.
Yield: 65.0 mg of the title compound.
LC-MS (Method 2): Rt = 1.00 min; MS (ESIpos): m/z = 471 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.674 (1.54), 0.682 (3.51 ), 0.688 (2.19), 0.695 (1.75), 0.702 (4.26), 0.707 (3.02), 0.714 (3.62), 0.721 (3.60), 0.726 (4.27), 0.733 (1.98), 1.393 (7.22), 1.41 1 (16.00), 1.429 (7.04), 1 .958 (1 .58), 2.361 (1.58), 3.51 1 (8.63), 3.698 (1.46), 4.1 18 (1.24), 4.136 (3.72), 4.154 (3.71 ), 4.172 (1.20), 5.756 (1.59), 6.913 (2.21 ), 6.917 (2.15), 6.926 (2.25), 6.929 (2.28), 7.198 (3.37), 8.245 (3.58), 8.259 (3.39), 10.567 (1.36), 12.010 (1.38). Example 39.01.01
tert-butyl 4-{[2-({6-[1-(cyclopropylmethyl)-1 H-pyrazol-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate
Figure imgf000821_0001
To a stirred solution of 1 H-imidazole (53.0 mg, 779 mol) and di-1 H-imidazol-1- ylmethanethione (925 mg, 90 % purity, 4.67 mmol) in dichloromethane (30 mL) was added tert-butyl 4-[(2-aminopyridin-4-yl)methyl]piperazine-1-carboxylate (1.14 g, 3.89 mmol) , dissolved in dichloromethane (45 mL) at 0° C. The m ixture was stirred at r.t. for 14 h. 4-[1 - (cyclopropylmethyl)-1 H-pyrazol-4-yl]benzene-1 ,2-diamine (1.10 g, 97 % purity, 4.67 mmol) , dissolved in dichloromethane (15 mL) was added and the mixture was stirred at r.t. for 2 h. Water was added and the mixture was extracted with dichloromethane. The organic phase was dried (sodium sulfate) and filtered. N,N'-dipropan-2-ylcarbodiimide (0.87 mL, 5.5 mmol) was added. The mixture was stirred at r.t. for 4 h. Further N,N'-dipropan-2-ylcarbodiimide (0.87 mL, 5.5 mmol) was added and the mixture was stirred at 40° C for 4 h. Saturated sodium chloride solution was added, the mixture was stirred for 30 minutes and was extracted with dichloromethane, dried (sodium sulfate) and the solvent was removed in vacuum. Aminophase-silicagel chromatography gave 362 mg of the title compound.
LC-MS (Method 2): R, = 1.28 min; MS (ESIpos): m/z = 529 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.389 (0.88), 0.393 (0.77), 0.402 (0.87), 0.405 (0.84), 0.537 (0.73), 0.541 (0.72), 0.557 (0.80), 1.394 (16.00), 1.987 (0.91 ), 2.342 (0.94), 2.354 (1.41 ), 2.366 (1.03), 3.331 (9.00), 3.348 (1.14), 3.967 (0.82), 3.984 (0.81 ), 5.759 (1.12), 7.172 (0.81 ), 8.235 (0.88), 8.248 (0.83).
Example 39.01.02
1 -(4-{[2-({6-[1 -(cyclopropylmethyl)-l H^yrazo
4-yl]methyl}piperazin-1 -yl)-3,3,3-trifluoropropan-1 -one
Figure imgf000822_0001
Starting with crude 6-[1-(cyclopropylmethyl)-1 H-pyrazol-4-yl]-N-[4-(piperazin-1 - ylmethyl)pyridin-2-yl]-1 H-benzimidazol-2-amine hydrochloride (160 mg, approx. 344 pmol) and 3,3,3-trifluoropropanoic acid (132 mg, 1.03 mmol), Example 39.01.02 was prepared analogously to the procedure for the preparation of Example 16.05.02.
Yield: 104 mg of the title compound.
LC-MS (Method 2): Rt = 1.1 min; MS (ESIpos): m/z = 539 [M+H]+
H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.379 (1.53), 0.390 (6.33), 0.394 (5.52), 0.402 (6.13), 0.406 (6.1 1 ), 0.416 (2.29), 0.527 (2.28), 0.536 (5.22), 0.541 (5.32), 0.546 (2.93), 0.553 (2.91 ), 0.557 (5.80), 0.561 (5.00), 0.572 (1.75), 1.235 (0.70), 1.241 (0.91 ), 1.253 (1.50), 1.261 (1.40), 1.265 (1.10), 1.273 (2.36), 1.281 (1.10), 1.285 (1.35), 1.293 (1.40), 1.305 (0.71 ), 2.322 (0.64), 2.327 (0.92), 2.332 (0.70), 2.365 (3.21 ), 2.378 (4.92), 2.390 (3.78), 2.406 (3.55), 2.420 (4.73), 2.431 (3.48), 2.518 (3.14), 2.523 (1.92), 2.664 (0.59), 2.669 (0.85), 2.673 (0.61 ), 3.456 (3.60), 3.469 (4.89), 3.481 (4.06), 3.493 (4.00), 3.514 (16.00), 3.610 (2.44), 3.638 (6.87), 3.665 (6.48), 3.693 (1.99), 3.967 (5.70), 3.984 (5.65), 6.907 (4.01 ), 6.910 (3.91 ), 6.920 (3.88), 6.924 (3.96), 7.188 (5.22), 7.249 (1.25), 7.535 (0.77), 7.626 (0.65), 7.806 (1.00), 8.079 (0.88), 8.120 (0.92), 8.243 (6.26), 8.257 (6.04), 10.584 (2.42), 12.021 (2.56).
Example 39.01.03
cyclopropyl(4-{[2-({6-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1 -yl)methanone
Figure imgf000823_0001
Starting with crude 6-[1-(cyclopropylmethyl)-1 H-pyrazol-4-yl]-N-[4-(piperazin-1 - ylmethyl)pyridin-2-yl]-1 H-benzimidazol-2-amine hydrochloride (160 mg, approx. 344 pmol) and cyclopropanecarboxylic acid (88.9 mg, 1.03 mmol), Example 39.01.03 was prepared analogously to the procedure for the preparation of Example 16.05.02.
Yield: 1 15 mg of the title compound.
LC-MS (Method 2): R, = 1.08 min; MS (ESIpos): m/z = 497 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.390 (1.58), 0.394 (1.38), 0.402 (1.52), 0.406 (1.51 ), 0.536 (1.33), 0.541 (1.31 ), 0.556 (1.45), 0.561 (1.24), 0.682 (1.61 ), 0.688 (0.99), 0.702 (1.97), 0.707 (1.64), 0.712 (1.74), 0.719 (1.60), 0.724 (1.95), 0.731 (0.89), 3.335 (16.00), 3.966 (1.50), 3.984 (1.49), 6.915 (1.00), 6.918 (0.99), 6.927 (0.97), 6.931 (0.99), 7.192 (1.47), 8.246 (1.57), 8.259 (1.54).
Example 39.02.01
tert-butyl 4-{(1R or 1S)-1-[2-({6-[1 -(cyclopropylmethyl)-1 H-pyrazol-4-yl]-1 H-benzimidazol- 2-yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate (single stereoisomer A)
Figure imgf000823_0002
To a stirred solution of 1 H-imidazole (55.1 mg, 809 pmol) and di-1 H-imidazol-1 - ylmethanethione (962 mg, 90 % purity, 4.86 mmol) in dichloromethane (30 mL) was added tert-butyl 4-[(1 R or 1 S)-1 -(2-aminopyridin-4-yl)ethyl]piperazine-1-carboxylate (1.24 g, 4.05 mmol) , dissolved in dichloromethane (45 mL) at 0° C. The mixture was stirred at r.t. for 14 h. 4-[1-(cyclopropylmethyl)-1 H-pyrazol-4-yl]benzene-1 ,2-diamine (1.14 g, 97 % purity, 4.86 mmol), dissolved in dichloromethane (15 mL) was added and the mixture was stirred at r.t. for 2 h. Water was added and the mixture was extracted with dichloromethane. The organic phase was dried (sodium sulfate) and filtered. N,N'-dipropan-2-ylcarbodiimide (0.88 mL, 5.6 mmol) was added. The mixture was stirred at r.t. for 4 h. Further N,N'-dipropan-2-ylcarbodiimide (0.88 mL, 5.6 mmol) was added and the mixture was stirred at 40° C for 4 h. The solvent was removed in vacuum. Ethyl acetate and water were added and the mixture was stirred at r.t. for 30 minutes.The mixture was extracted with ethyl acetate, dried (sodium sulfate) and the solvent was removed in vacuum. Aminophase-silicagel chromatography followed by silicagel chromatography gave 391 mg of the title compound.
LC-MS (Method 2): Rt = 1.32 min; MS (ESIpos): m/z = 543 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.390 (0.92), 0.394 (0.80), 0.402 (0.91 ), 0.405 (0.90), 0.537 (0.76), 0.541 (0.75), 0.557 (0.82), 0.561 (0.72), 1.274 (2.01 ), 1.290 (1.91 ), 1.376 (16.00), 2.083 (1.81 ), 3.320 (1.26), 3.967 (0.87), 3.984 (0.87), 5.758 (4.92), 7.158 (0.88), 8.238 (0.96), 8.251 (0.89).
Example 39.02.02
1-(4-{(1R or 1S)-1-[2-({6-[1 -(cyclopropylmethyl)-1H-pyrazol-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)-3,3,3-trifluoropropan-1-one (single
stereoisomer A)
Figure imgf000824_0001
Starting with crude 6-[1-(cyclopropylmethyl)-1 H-pyrazol-4-yl]-N-{4-[(1 R or 1 S)-1 -(piperazin-1- yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride (single stereoisomer A) (120 mg, approx. 251 pmol) and 3,3,3-trifluoropropanoic acid (96.2 mg, 752 pmol), Example 39.02.02 was prepared analogously to the procedure for the preparation of Example 16.05.02.
Yield: 61.0 mg of the title compound. Optical rotation [a]D +30.41[from solution in DMSO, c = 2.25 mg/mL)
LC- S (Method 2): R, = 1.15 min; MS (ESIpos): m/z = 553 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.379 (1.00), 0.390 (3.98), 0.394 (3.43), 0.402 (3.84), 0.406 (3.81 ), 0.416 (1 .36), 0.527 (1.41 ), 0.537 (3.36), 0.542 (3.28), 0.547 (1.78), 0.553 (1.83), 0.558 (3.59), 0.562 (3.06), 0.573 (1.06), 1.273 (1.85), 1.288 (8.10), 1.305 (8.07), 1.987 (0.92), 2.323 (1.49), 2.327 (1.80), 2.332 (1.50), 2.337 (1.68), 2.351 (1.49), 2.364 (1.27), 2.416 (1.80), 2.423 (1.82), 3.422 (2.02), 3.435 (3.89), 3.447 (2.47), 3.453 (2.92), 3.470 (3.84), 3.480 (3.18), 3.578 (1.40), 3.606 (4.04), 3.633 (3.75), 3.661 (1.16), 3.967 (3.75), 3.984 (3.71 ), 5.759 (16.00), 6.918 (2.49), 6.922 (2.48), 6.932 (2.48), 6.935 (2.50), 7.172 (3.44), 8.247 (4.15), 8.260 (3.89), 10.571 (1.34).
Example 39.02.03
cyclopropyl(4-{(1 R or 1 S)-1 -[2-({6-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)methanone (single
stereoisomer A)
Figure imgf000825_0001
Starting with crude 6-[1 -(cyclopropylmethyl)-1 H-pyrazol-4-yl]-N-{4-[(1 R or 1 S)-1 -(piperazin-1 - y I )eth yl] py rid i n-2-y I}- H-benzimidazol-2-amine hydrochloride (single stereoisomer A) (120 mg, approx. 251 pmol) and cyclopropanecarboxylic acid (64.7 mg, 752 pmol), Example 39.02.03 was prepared analogously to the procedure for the preparation of Example 16.05.02.
Yield: 58.0 mg of the title compound.
Optical rotation [a]D +37.1 ° (from solution in DMSO, c = 2.66 mg/mL)
LC-MS (Method 2): F¾ = 1.11 min; MS (ESIpos): m/z = 51 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.390 (3.29), 0.394 (2.88), 0.402 (3.18), 0.406 (3.23), 0.416 (1.18), 0.527 (1.17), 0.537 (2.74), 0.542 (2.77), 0.547 (1.53), 0.553 (1.51 ), 0.557 (3.00), 0.562 (2.62), 0.573 (0.93), 0.656 (1.42), 0.663 (3.37), 0.669 (2.05), 0.676 (1.62), 0.683 (4.14), 0.687 (3.40), 0.691 (3.84), 0.698 (3.29), 0.703 (3.81 ), 0.710 (1.77), 1.172 (0.96), 1.273 (1.45), 1.291 (7.14), 1.308 (6.65), 1.935 (1.44), 1.987 (1.49), 2.327 (1.00), 2.523 (1.43), 3.437 (1.94), 3.453 (2.49), 3.469 (1.84), 3.672 (1.50), 3.967 (3.30), 3.984 (3.27), 5.759 (16.00), 6.927 (2.04), 6.930 (2.08), 6.940 (2.04), 6.944 (2.06), 7.181 (2.92), 8.247 (3.46), 8.260 (3.26).
Example 40.01
3,3,3-trifluoro-1 -{4-[(2-{[6-(1 -methyl-1 H-pyrazol-3-yl)-1 H-benzimidazol-2-yl]amino}pyridin- 4-yl)methyl]piperazin-1-yi}propan-1 -one
Figure imgf000826_0001
Starting with crude 6-(1 -methyl-1 H-pyrazol-3-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (150 mg, approx. 282 pmol) and 3,3,3-trifluoropropanoic acid (54.1 mg, 423 pmol), Example 40.01 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 39 mg of the title compound.
LC-MS (Method 2): R, = 1.02 min; MS (ESIpos): m/z = 499 [M+H]+
1H-NMR (400 MHz, CHLOROFORM-d) δ [ppm]: 1.146 (1.00), 1.163 (0.99), 1.262 (0.58), 2.019 (1.32), 2.347 (3.85), 2.359 (7.41 ), 2.370 (7.02), 2.465 (0.83), 2.476 (1.43), 2.489 (1.34), 3.099 (2.51 ), 3.124 (7.42), 3.149 (7.37), 3.175 (2.52), 3.204 (0.70), 3.229 (1.73), 3.247 (3.23), 3.254 (4.62), 3.260 (4.35), 3.271 (3.22), 3.460 (1 1.58), 3.491 (3.85), 3.502 (4.66), 3.515 (3.20), 3.540 (2.72), 3.598 (0.45), 3.681 (0.56), 3.694 (0.72), 3.706 (0.61 ), 3.968 (16.00), 6.550 (4.25), 6.555 (4.30), 6.861 (3.34), 6.864 (3.30), 6.874 (3.44), 6.877 (3.37), 7.007 (0.79), 7.017 (0.55), 7.102 (4.89), 7.397 (3.48), 7.529 (0.73), 7.675 (1.77), 7.909 (0.57), 8.263 (5.60), 8.276 (5.42), 8.31 1 (0.95), 8.324 (0.88). Example 40.02
2-cyclopropyl-1 -{4-[(2-{[6-(1 -methyl-1 H-pyrazol-3-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}ethanone
Figure imgf000827_0001
Starting with crude 6-(1 -methyl-1 H-pyrazol-3-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (150 mg, approx. 282 pmol) and cyclopropylacetic acid (42.3 mg, 423 μιηοΙ), Example 40.02 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 55 mg of the title compound.
LC-MS (Method 2): R, = 1.01 min; MS (ESIpos): m/z = 471 [M+H]+
1H-NMR (400 MHz, CHLOROFORM-d) δ [ppm]: 0.133 (2.01 ), 0.145 (7.40), 0.148 (6.12), 0.157
(7.30) , 0.160 (7.78), 0.171 (4.38), 0.182 (2.21 ), 0.185 (2.50), 0.197 (0.92), 0.527 (2.66), 0.538 (5.87), 0.541 (6.24), 0.547 (3.95), 0.553 (3.39), 0.558 (8.32), 0.561 (7.73), 0.568 (1.69), 0.573
(3.31 ) , 0.577 (1.53), 0.579 (2.35), 0.582 (2.08), 0.594 (0.86), 0.968 (0.68), 0.973 (0.81 ), 0.976 (0.70), 0.981 (0.52), 0.985 (1.47), 0.988 (1.35), 0.992 (1.39), 0.997 (1 .09), 1.001 (1.26), 1.005
(2.50), 1.010 (1.28), 1.013 (1.28), 1.017 (1.39), 1.022 (1.76), 1.025 (1.60), 1.030 (0.89), 1.034 (0.96), 1.037 (0.96), 1.042 (1.29), 1.048 (1.10), 1.055 (0.77), 1.060 (0.61 ), 1.063 (0.57), 1.067 (1.94), 1.075 (0.98), 1.086 (0.92), 1.093 (0.44), 1.259 (0.49), 2.203 (12.70), 2.220 (12.47), 2.239 (0.50), 2.264 (4.29), 2.274 (0.74), 2.281 (4.14), 2.291 (0.50), 2.345 (3.59), 2.360 (7.87), 2.371 (8.10), 2.385 (4.12), 2.432 (1.34), 2.444 (2.80), 2.456 (3.07), 2.469 (1.58), 3.313 (3.36), 3.325 (4.51 ), 3.337 (3.26), 3.467 (14.60), 3.487 (1.71 ), 3.528 (7.00), 3.545 (4.34), 3.556 (3.11 ), 3.582 (0.75), 3.656 (1.06), 3.669 (1.41 ), 3.680 (1.08), 3.951 (0.84), 3.973 (16.00), 6.553 (4.22), 6.557 (4.16), 6.900 (3.71 ), 6.903 (3.90), 6.914 (4.01 ), 6.917 (3.96), 7.007 (1.60), 7.010 (1.10), 7.023 (1.10), 7.128 (7.10), 7.395 (4.33), 7.399 (4.26), 7.454 (0.57), 7.529 (0.78), 7.671 (1.84), 7.901 (0.87), 8.013 (0.54), 8.266 (6.85), 8.279 (6.59), 8.304 (2.03), 8.317 (1.91 ). Example 40.03
cyclopropyl{4-[(2^[6-(1 -methyl-1 H^yrazol-3-yl)-1H^enzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1-yl}methanone
Figure imgf000828_0001
Starting with crude 6-(1-methyl-1 H-pyrazol-3-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (150 mg, approx. 282 μιτιοΙ) and cyclopropanecarboxylic acid (36.4 mg, 423 pmol), Example 40.03 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 30 mg of the title compound.
LC-MS (Method 2): R, = 0.98 min; MS (ESIpos): m/z = 457 [M+H]+
1H-NMR (400 MHz, CHLOROFORM-d) δ [ppm]: 0.716 (1.84), 0.726 (5.51 ), 0.733 (6.37), 0.742 (3.99), 0.746 (6.10), 0.751 (3.91 ), 0.754 (6.99), 0.758 (2.88), 0.763 (2.89), 0.767 (1.45), 0.771 (1.87), 0.778 (2.14), 0.787 (0.73), 0.951 (2.35), 0.960 (6.88), 0.963 (4.71 ), 0.967 (6.40), 0.972 (7.55), 0.979 (6.56), 0.983 (3.24), 0.986 (2.06), 0.989 (3.47), 0.995 (2.39), 1.002 (1.99), 1.012 (0.78), 1.648 (1.11 ), 1.659 (2.03), 1.667 (2.26), 1.671 (1.67), 1.679 (3.86), 1.688 (1.65), 1.691 (2.17), 1.699 (1.97), 1.706 (1.01 ), 1.71 1 (1.15), 1.714 (1.04), 1.718 (0.69), 1.726 (1.34), 1.735 (0.69), 1.738 (0.78), 1.746 (0.76), 1.758 (0.45), 2.038 (0.45), 2.401 (5.70), 2.462 (1.27), 3.481 (15.71 ), 3.540 (4.79), 3.576 (8.71 ), 3.690 (1.32), 3.972 (16.00), 6.556 (4.82), 6.562 (4.78), 6.928 (4.13), 6.931 (3.97), 6.941 (4.19), 6.944 (3.96), 7.007 (1.02), 7.023 (0.95), 7.036 (0.95), 7.131 (7.55), 7.394 (4.07), 7.460 (0.50), 7.529 (1.24), 7.675 (2.01 ), 7.916 (0.72), 8.273 (7.01 ), 8.286 (6.73), 8.309 (1.74), 8.324 (1.65).
Example 40.04
cyclobutyl{4-[(2-{[6-(1 -methyl-1 H^yrazol-3-yl)-1H^enzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone
Figure imgf000829_0001
Starting with crude 6-(1-methyl-1 H-pyrazol-3-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (150 mg, approx. 282 pmol) and cyclobutanecarboxylic acid (42.3 mg, 423 pmol), Example 40.04 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 50 mg of the title compound.
LC-MS (Method 2): Rt = 1.04 min; MS (ESIpos): m/z = 471 [M+H]+
1H-NMR (400 MHz, CHLOROFORM-d) δ [ppm]: 1.252 (0.50), 1.299 (1.03), 1.804 (0.58 (0.81 ), 1.826 (1.25), 1.828 (1.34), 1.832 (1.16), 1.839 (1.22), 1.842 (1.30), 1.849 (1.37
(2.01 ) , 1.856 (1.86), 1.863 (1.38), 1.877 (1.57), 1.888 (0.96), 1.897 (1.96), 1.918 (3.52 (1.30), 1.940 (3.09), 1.946 (2.14), 1.963 (1.67), 1.967 (1.66), 1.983 (0.48), 1.990 (0.96
(0.71), 2.015 (0.93), 2.021 (0.41), 2.037 (0.77), 2.043 (0.62), 2.057 (1.04), 2.066 (1.32
(1.02) , 2.077 (1.61 ), 2.087 (3.04), 2.093 (1.99), 2.097 (2.10), 2.099 (1.99), 2.102 (2.07 (3.11 ), 2.118 (2.47), 2.123 (1.74), 2.130 (1.59), 2.132 (1.62), 2.139 (1.38), 2.154 (0.72 (0.42), 2.229 (0.55), 2.236 (0.63), 2.239 (0.93), 2.244 (0.57), 2.248 (0.65), 2.251 (0.65 (0.65), 2.260 (1.24), 2.263 (1.26), 2.267 (1.54), 2.272 (1.16), 2.289 (3.63), 2.294 (2.98 (3.75), 2.311 (7.30), 2.313 (7.01 ), 2.323 (4.51 ), 2.334 (3.04), 2.340 (3.55), 2.346 (3.51 (4.14), 2.354 (3.93), 2.363 (5.38), 2.375 (4.46), 2.382 (2.29), 2.398 (2.61 ), 2.404 (1.65 (1.87), 2.420 (1.54), 2.431 (1.80), 2.446 (1.18), 2.451 (0.49), 3.141 (0.55), 3.160 (1.92 (1.99), 3.182 (2.86), 3.184 (2.88), 3.190 (0.96), 3.206 (2.83), 3.211 (4.00), 3.225 (4.69 (3.47), 3.261 (0.61 ), 3.354 (1.16), 3.366 (1.36), 3.379 (1.12), 3.456 (12.07), 3.520 (7.21 (3.83), 3.541 (2.56), 3.567 (0.44), 3.629 (0.88), 3.641 (1.15), 3.653 (0.88), 3.973 (16.00 (4.07), 6.558 (4.02), 6.898 (3.24), 6.902 (3.37), 6.912 (3.44), 6.915 (3.38), 7.006 (0.70 (0.93), 7.052 (0.86), 7.060 (0.96), 7.064 (0.91 ), 7.109 (5.86), 7.395 (3.42), 7.399 (3.37 (0.83), 7.621 (0.53), 7.667 (2.03), 7.688 (1.36), 7.860 (0.82), 7.909 (0.61), 8.191 (1.36 (1.39), 8.203 (1.32), 8.205 (1.41 ), 8.222 (1.31), 8.261 (5.52), 8.274 (5.27). Example 41.01
tert-butyl 4 (2-{[6-(1-methyl-1 H-1 ,2,4-triazol-5-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1-carboxylate
To a stirred solution of tert-butyl 4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate (800 mg, 1.50 mmol) in 1-propanol (17 mL) was added a potassium carbonate solution (2.2 ml_, 2.0 M, 4.5 mmol), 5- bromo-1 -methyl-1 H-1 ,2,4-triazole (375 mg, 97 % purity, 2.25 mmol), triphenylphosphine (39.3 mg, 150 pmol) and PdCl2(PPh3)2 (105 mg, 150 pmol). The mixture was heated to 1 10°C in a sealed tube for 14 h. Water was added and the mixture was extracted with dichloromethane. The organic phase was dried (sodium sulfate), filtered and the solvent was removed in vacuum. Aminophase-silicagel chromatography followed by silicagel chromatography gave 196.0 mg (26 % yield) of the title compound.
LC-MS (Method 2): R, = 1.12 min; MS (ESIpos): m/z = 490 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.066 (15.61 ), 1.396 (16.00), 1.988 (0.58), 2.361 (1.27), 3.506 (1.73), 3.939 (2.53), 3.995 (1.60), 5.759 (2.17), 7.954 (1.49), 8.269 (0.80).
Example 41.02
3,3,3-trifluoro-l -{4-[(2-{[6-(1 -methyl-1 H-1 ,2,4-triazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}propan-1 -one
Figure imgf000831_0001
Starting with crude 6-(1 -methyl-1 H-1 , 2, 4-triazol-5-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]- 1 H-benzimidazol-2-amine hydrochloride (1 11 mg, approx. 261 μιτιοΙ) and 3,3,3- trifluoropropanoic acid (69 μΙ, 780 pmol), Example 41.02 was prepared analogously to the procedure for the preparation of Example 16.05.02.
Yield: 56.0 mg of the title compound.
LC-MS (Method 2): R, = 0.90 min; MS (ESIpos): m/z = 500 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm]= 2.41 (dt, 4H), 3.44 - 3.57 (m, 6H), 3.66 (q, 2H), 4.00 (br s, 3H), 6.96 (d, 1 H), 7.20 (s, 1 H), 7.31 - 8.03 (m, 4H), 8.29 (d, 1 H), 10.65 - 10.89 (m, 1 H), 12.31 (s, 1 H).
Example 41.03
cyclopropyl{4-[(2-{[6-(1 -methyl-1 H-1 ,2,4-triazol-5-yl)-1 H-benzimidazol-2-yl]amino}pyridin- 4-yl)methyl]piperazin-1-yl}methanone
Figure imgf000831_0002
Starting with crude 6-(1 -methyl-1 H-1 , 2, 4-triazol-5-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]- 1 H-benzimidazol-2-amine hydrochloride (97.6 mg, approx. 229 pmol) and cyclopropanecarboxylic acid (54 μΙ, 690 pmol), Example 41.03 was prepared analogously to the procedure for the preparation of Example 16.05.02. Yield: 39.0 mg of the title compound.
LC-MS (Method 2): Rt = 0.86 min; MS (ESIpos): m/z = 458 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm]= 0.66 - 0.76 (m, 4H), 1 .93 - 2.02 (m, 1 H), 2.34 - 2.48 (m, 4H), 3.45 - 3.77 (m, 6H), 4.00 (s, 3H), 6.97 (d, 1 H), 7.21 (s, 1 H), 7.32 - 8.04 (m, 4H), 8.29 (d, 1 H), 10.64 - 10.87 (m, 1 H), 12.32 (s, 1 H).
Example 42.01
tert-butyl 4-{[2-({6-[1 -methyl-3-(2-methylpropyl)-1 H-1 ,2,4-triazol-5-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate
Figure imgf000832_0001
A mixture of tert-butyl 4-({2-[(6-{[1 -methyl-2-(3-methylbutanimidoyl)hydrazinyl] carbonyl}-1 H- benzimidazol-2-yl)amino]pyridin-4-yl}methyl)piperazine-1 -carboxylate (125 mg, 222 pmol) and sodium acetate (20.0 mg, 244 pmol) in 1 -propanol 6 mL) and water (3 mL) was heated to 100° C for 14 h. The solvent was removed in vacuum. Aminophase-silicagel chromatography gave 35.0 mg (26 % yield) of the title compound.
LC-MS (Method 2): Rt = 1.25 min; MS (ESIpos): m/z = 546 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.946 (5.75), 0.963 (5.95), 1.397 (16.00), 2.350 (0.90), 2.363 (1.32), 2.375 (0.95), 2.475 (1.77), 3.352 (1.12), 3.505 (1.76), 3.922 (3.87), 5.752 (1.30), 7.199 (0.73), 8.260 (0.82), 8.273 (0.78).
Example 42.02
3,3,3-trifluoro-1 -(4-{[2-({6-[1 -methyl-3-(2-methylpropyl)-1 H-1 ,2,4-triazol-5-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]methyl}piperazin-1-yl)propan-1 -one
Figure imgf000833_0001
Starting with crude 6-[1 -methyl-3-(2-methylpropyl)-1 H-1 ,2,4-triazol-5-yl]-N-[4-(piperazin-1- ylmethyl)pyridin-2-yl]-1 H-benzimidazoi-2-amine hydrochloride (23.0 mg, approx. 44.4 pmol)and 3,3,3-trifluoropropanoic acid (17.0 mg, 133 μηηοΙ) Example 42.2. was prepared analogously to the procedure for the preparation of Example 02.02.
Yield: 16.0 mg of the title compound.
LC-MS (Method 2): Rt = 1.09 min; MS (ESIpos): m/z = 556 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.832 (0.46), 0.947 (15.70), 0.963 (16.00), 2.040 (0.84), 2.057 (1.06), 2.073 (0.84), 2.327 (0.53), 2.375 (1.28), 2.388 (1.97), 2.400 (1.49), 2.417 (1.45), 2.429 (1.93), 2.441 (1.41 ), 2.476 (5.53), 2.523 (1.34), 2.669 (0.50), 3.463 (1.38), 3.477 (1.93), 3.489 (1.59), 3.499 (1.55), 3.513 (1.94), 3.530 (5.81 ), 3.601 (0.99), 3.629 (2.83), 3.656 (2.69), 3.683 (0.84), 3.924 (5.17), 6.941 (1.42), 6.957 (1.44), 7.204 (2.57), 7.449 (0.91 ), 8.271 (2.45), 8.283 (2.34), 12.273 (1.27).
Example 43.01
cyclopropyl{4-[(2-{[6-(1 H-imidazol-2-yl)-1 H^enzimidazol-2-yl]amino}pyridin-4 yl)methyl]piperazin-1 -yl}methanone
Figure imgf000834_0001
To a stirred solution of 2-iodo-1 H-imidazole (174 mg, 896 pmol) and cyclopropyl{4-[(2-{[6- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone (150 mg, 299 pmol) in dioxane (2.0 mL) and water (0.5 mL) was added sodium carbonate (130 mg, 1.22 mmol) and Pd(dppf)Cl2 . CH2CI2 (48.8 mg, 59.7 pmol) and Tetrakis(triphenylphosphin)palladium (69.0 mg, 59.7 pmol). The mixture was heated to reflux for 36 h. Further 2-iodo-1 H-imidazole (174 mg, 896 pmol) Pd(dppf)CI2 . CH2CI2 (48.8 mg, 59.7 pmol) and Tetrakis(triphenylphosphin)palladium (69.0 mg, 59.7 pmol). were added and the mixture was heated to reflux for 7 h. Methanol was added, the mixture was filtered and the solvent was removed in vacuum. Silicagel chromatography gave a solid that was crystallized from ethanol to give 20.0 mg (14 % yield) of the title compound.
LC-MS (Method 5): R, = 2.17 min; MS (ESIpos): m/z = 443 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.490 (1.57), 2.495 (3.44), 2.500 (4.85), 2.505 (3.44), 2.509 (1.55), 3.303 (16.00).
Example 43.02
cyclopropyl{4-[(2-{[6-(4-methyl-1 H-imidazol-2-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1-yl}methanone
Figure imgf000834_0002
To a stirred solution of 2-bromo-4-methyl-1 H-imidazole (240 mg, 1.49 mmol) and cyclopropyl{4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}methanone (150 mg, 299 Mmol) in dioxane (2.0 mL) and water (0.5 mL) was added sodium carbonate (130 mg, 1.22 mmol) and Pd(dppf)CI2 . CH2CI2 (48.8 mg, 59.7 mol) and Tetrakis(triphenylphosphin)palladium (69.0 mg, 59.7 pmol). The mixture was heated to reflux for 24 h. Methanol was added, the mixture was filtered and the solvent was removed in vacuum. Silicagel chromatography gave 19.0 mg (13 % yield) of the title compound.
LC-MS (Method 5): R, = 2.31 min; MS (ESIpos): m/z = 457 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.691 (1.89), 0.71 1 (2.62), 0.718 (2.69), 0.731 (2.52), 1.234 (0.47), 1.952 (0.59), 1.964 (0.84), 2.341 (6.66), 2.395 (0.88), 2.495 (10.55), 2.500 (13.36), 2.504 (1 1.34), 3.169 (0.43), 3.309 (16.00), 3.565 (1.65), 3.718 (0.95), 6.986 (1.09), 6.999 (1.14), 7.227 (1.50), 7.408 (1.77), 7.639 (1.33), 7.997 (2.12), 8.299 (1.25), 8.312 (1.25).
Example 43.03
cyclopropyl{4-[(2-{[6-(4-cyclopropyl-1 H-imidazol-2-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1-yl}methanone
Figure imgf000835_0001
Starting with cyclopropyl{4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)methyl]piperazin-1-yl}methanone (200 mg, 398 pmol) and 4-cyclopropyl-2-iodo-1 H-imidazole (200 mg, 855 pmol), Example 43.03 was prepared analogously to the procedure for the preparation of Example 43.02.
Yield: 8 mg (4 %) of the title compound.
LC-MS (Method 5): Rt = 2.46 min; MS (ESIpos): m/z = 483 [M+H]+
1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 0.61-0.77 (m, 6H), 0.77-0.93 (m, 2H), 1.85 (m, 1 H), 1.96 (m, 1 H), 2.41 (m, 4H), 3.52 (m, 4H), 3.70 (s, 1 H), 6.87 (s, 1 H), 6.94 (m, 1 H), 7.21 (s, 1 H), 7.43 (bs, 1 H), 7.60 (m, 1 H), 7.94 (bs, 1 H), 8.26 (d, 1 H), 10.85 (bs, 1 H), 12.18 (bs, 1 H). 13C-NMR (101 MHz, DMSO-d6): δ [ppm] = 6.86, 6.89, 10.1 , 40.3, 44.8, 52.4, 53.1 , 60.6, 1 10.4, 1 16.4, 145.9, 146.9, 149.4, 150.4, 153.6, 170.9.
Example 44.01
1 - (cyclopropylmethyl)^-{2-[(4-{[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]methyl}pyridin
2- yl)amino]-1 H-benzimidazol-6-yl}pyridin-2(1 H)-one
Figure imgf000836_0001
Starting with crude 1-(cyclopropylmethyl)-4-(2-{[4-(piperazin-1 -ylmethyl)pyridin-2-yl]amino}-1 H- benzimidazol-6-yl)pyridin-2(1 H)-one hydrochloride (150 mg, approx. 241 pmol) and 3,3,3- trifluoropropanoic acid (33 μΙ, 98 % purity, 360 pmol), Example 44.01 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 55.0 mg of the title compound.
LC-MS (Method 2): R, = 1.06 min; MS (ESIpos): m/z = 566 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm]= 0.36 - 0.44 (m, 2H), 0.46 - 0.55 (m, 2H), 1 .16 - 1.35 (m, 1 H), 2.41 (dt, 4H), 3.45 - 3.58 (m, 6H), 3.66 (q, 2H), 3.76 (d, 2H), 6.63 (br d, 2H), 6.95 (br d, 1 H), 7.20 (s, 1 H), 7.34 - 7.91 (m, 4H), 8.24 - 8.33 (m, 1 H), 10.72 (br s, 1 H), 1 1.45 - 12.91 (m, 1 H).
Example 44.02
4-{2-[(4-{[4-(cyclopropylcarbonyl)piperazin-1 -yl]methyl}pyridin-2-yl)amino]-1 H- benzimidazol-6-yl}-1 -(cyclopropylmethyl)pyridin-2(1 H)-one
Figure imgf000837_0001
Starting with crude 1-(cyclopropylmethyl)-4-(2 [4-(piperazin-1 -ylmethyl)pyridin-2-yl]amino}-1 H- benzimidazol-6-yl)pyridin-2(1 H)-one hydrochloride (150 mg, approx. 241 pmol) and cyclopropanecarboxylic acid (29 μΙ, 98 % purity, 360 pmol), Example 44.02 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 57.0 mg of the title compound.
LC-MS (Method 2): R, = 1.02 min; MS (ESIpos): m/z = 524 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.383 (1.46), 0.395 (5.79), 0.398 (5.62), 0.407 (6.77), 0.410 (5.92), 0.419 (2.66), 0.435 (0.71 ), 0.443 (0.65), 0.455 (0.82), 0.471 (2.38), 0.479 (5.34), 0.484 (4.49), 0.490 (3.34), 0.500 (5.86), 0.504 (4.63), 0.516 (1.70), 0.666 (0.95), 0.677 (3.00), 0.685 (7.08), 0.690 (4.29), 0.697 (3.54), 0.704 (8.75), 0.709 (7.32), 0.713 (7.97), 0.721 (7.25), 0.725 (8.51 ), 0.732 (4.05), 0.745 (1.12), 1.21 1 (0.82), 1.224 (1.77), 1.231 (2.14), 1.243 (2.69), 1.255 (1.57), 1.263 (1.60), 1.275 (0.89), 1.935 (0.78), 1.948 (1.70), 1.955 (1.80), 1.967 (3.10), 1.973 (1.50), 1.980 (1.77), 1.986 (1.70), 1.998 (0.78), 2.074 (0.75), 2.318 (0.89), 2.323 (1.80), 2.327 (2.55), 2.331 (2.08), 2.337 (1.43), 2.363 (3.34), 2.446 (3.47), 2.518 (16.00), 2.523 (13.07), 2.659 (0.75), 2.665 (1.63), 2.669 (2.28), 2.673 (1.63), 2.678 (0.75), 3.525 (14.84), 3.709 (3.20), 3.746 (10.08), 3.764 (9.94), 6.618 (6.16), 6.941 (3.71 ), 6.944 (3.78), 6.954 (3.88), 6.957 (3.91 ), 7.228 (2.86), 7.41 1 (2.42), 7.757 (4.83), 7.776 (4.83), 8.268 (5.99), 8.282 (5.79), 12.235 (0.75).
Example 44.03
4-{2-[(4-{[4-(cyclobutylcarbonyl)piperazin-1-yl]methyl}pyridin-2-yl)amino]-1 H- benzimidazol-6-yl}-1 -(cyclopropylmethyl)pyridin-2(1 H)-one
Figure imgf000838_0001
Starting with crude 1-(cyclopropylmethyl)-4-(2-{[4-(piperazin-1 -ylmethyl)pyridin-2-yl]amino}-1 H- benzimidazol-6-yl)pyridin-2(1 H)-one hydrochloride (150 mg, approx. 241 pmol) and cyclobutanecarboxylic acid (35 μΙ, 98 % purity, 360 pmol), Example 44.03 was prepared analogously to the procedure for the preparation of Example 01 .02.
Yield: 30.0 mg of the title compound.
LC-MS (Method 2): R, = 1.08 min; MS (ESIneg): m/z = 536 [M-H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm]= 0.36 - 0.44 (m, 2H), 0.46 - 0.56 (m, 2H), 1.17 - 1.33 (m, 1 H), 1.67 - 1.80 (m, 1 H), 1.81 - 1.95 (m, 1 H), 1.99 - 2.22 (m, 4H), 2.28 - 2.42 (m, 4H), 3.43 - 3.59 (m, 4H), 3.76 (d, 2H), 6.62 (br s, 2H), 6.94 (d, 1 H), 7.20 (s, 1 H), 7.32 - 7.91 (m, 4H), 8.28 (d, 1 H), 10.72 (br s, 1 H), 12.24 (br s, 1 H).
Example 45.01.01
3,3,3-trifluoro-1 -{4-[(2-{[6-(pyrimidin-5-yl)-1 H^enzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1-yl}propan-1 -one
Figure imgf000838_0002
Crude N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-6-(pyrimidin-5-yl)-1 H-benzimidazol-2-amine hydrochloride (211 mg, approx. 426 pmol) , 3,3,3-trifluoropropanoic acid (75 μΙ, 850 μιηοΙ), T3P (450 μΙ, 50 % solution in D F, 770 μπιοΙ) and DIPEA (370 μΙ, 2.1 mmol) were solubilized in DMF (21 ml.) and the reaction was stirred at r.t. for 2 days. The reaction mixture was then diluted with water and extracted with dichloromethane. The aqueous phase was then basified with saturated sodium bicarbonate solution and extracted with a mixture of dichloromethane/isopropanol (8/2). The organic phase was dried (magnesium sulfate) filtered and concentrated under reduced pressure. The crude mixture was purified by preparative HPLC (water/acetonitrile with ammonia as additive) and 8 mg of the title compound were obtained.
LC-MS (Method 2): R, = 0.95 min; MS (ESIpos): m/z = 497 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.064 (1.39), 1.176 (0.67), 1.192 (0.63), 1.228 (1.79), 1.239 (1.84), 1.254 (2.33), 1.272 (1.21 ), 2.072 (5.65), 2.082 (0.90), 2.322 (1.79), 2.327 (2.42), 2.332 (1.93), 2.336 (1.17), 2.383 (7.39), 2.425 (7.31 ), 2.523 (6.45), 2.539 (1.48), 2.660 (0.81 ), 2.664 (1.57), 2.669 (2.24), 2.673 (1.61 ), 3.471 (7.84), 3.483 (7.53), 3.509 (8.87), 3.527 (16.00), 3.609 (2.91 ), 3.636 (7.26), 3.663 (6.90), 3.691 (2.51 ), 4.047 (3.41 ), 6.939 (4.48), 6.951 (4.57), 7.204 (4.62), 7.464 (2.69), 7.81 1 (1.03), 8.271 (5.38), 8.283 (5.15), 9.141 (13.45), 10.715 (1.48), 12.259 (1.17).
Example 45.01.02
2-cyclopropyl-1 -{4-[(2-{[6-(pyrimidin-5-yl)-1 H-benzimidazol-2-yl]amino}pyridin
yl)methyl]piperazin-1-yl}ethanone
Figure imgf000839_0001
Starting with crude N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-6-(pyrimidin-5-yl)-1 H-benzimidazol- 2-amine hydrochloride (130 mg, approx. 262 μιηοΙ) and cyclopropylacetic acid (78.7 mg, 787 pmol), Example 45.01.02 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 4 mg of the title compound.
LC-MS (Method 4): Rt = 0.94 min; MS (ESIpos): m/z = 469 [M+H]+ 1H-NMR (400MHz, DMSO-d6): δ [ppm]= 0.05 - 0.16 (m, 2H), 0.39 - 0.48 (m, 2H), 0.88 - 1.00 (m, 1 H), 2.25 (d, 2H), 2.34 - 2.43 (m, 4H), 3.40 - 3.55 (m, 6H), 6.95 (d, 1 H), 7.21 (s, 1 H), 7.39 - 7.52 (m, 1.5H), 7.62 (br d, 0.5H), 7.75 - 7.90 (m, 1 H), 8.28 (d, 1 H), 9.06 - 9.23 (m, 3H), 10.71 (br d, 1 H), 12.25 (br d, 1 H).
Example 45.01.03
cyclopropyl{4-[(2-{[6-(pyrimidin-5-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4
yl)methyl]piperazin-1-yl}methanone
Figure imgf000840_0001
Starting with crude N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-6-(pyrimidin-5-yl)-1 H-benzimidazol- 2-amine hydrochloride (21 1 mg, approx. 426 pmol) and cyclopropanecarboxylic acid (68 μΙ, 850 pmol) Example 45.01.03 was prepared analogously to the procedure for the preparation of Example 45.01.01.
Yield: 20.0 mg of the title compound.
LC-MS (Method 2): R, = 0.92 min; MS (ESIpos): m/z = 455 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.662 (0.84), 0.674 (2.41 ), 0.682 (5.23), 0.687 (3.43), 0.694 (2.76), 0.701 (6.28), 0.707 (5.04), 0.713 (5.61 ), 0.720 (5.52), 0.724 (6.48), 0.731 (3.25), 0.744 (0.80), 1.928 (0.66), 1.941 (1.33), 1.948 (1.40), 1.952 (1.07), 1.960 (2.25), 1.966 (1.14), 1.972 (1.30), 1.979 (1.16), 2.073 (0.52), 2.327 (0.64), 2.332 (0.71 ), 2.361 (2.57), 2.467 (0.85), 3.385 (0.92), 3.502 (2.67), 3.521 (1 1.47), 3.703 (2.40), 5.756 (0.40), 6.943 (2.91 ), 6.946 (2.91 ), 6.956 (3.02), 6.959 (2.95), 7.212 (5.51 ), 7.481 (1.32), 7.789 (0.77), 8.273 (4.78), 8.286 (4.56), 8.780 (0.56), 9.062 (0.50), 9.094 (1.03), 9.114 (1.92), 9.120 (2.39), 9.126 (16.00), 9.137 (2.25), 9.143 (2.1 1 ), 10.727 (0.80), 12.245 (0.80). Example 45.02.01
1^4-[(2-{[6-(2-c loropyrimidin-5-yl)-1H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1-yl}-3,3,3-trifluoropropan-1-one
Figure imgf000841_0001
Starting with crude 6-(2-chloropyrimidin-5-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (305 mg, approx. 575 pmol) and 3,3,3-trifluoropropanoic acid (150 pi, 1.7 mmol), Example 45.02.01 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 5.30 mg of the title compound.
LC-MS (Method 2): f¾ = 1.11 min; MS (ESIpos): m/z = 531 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.232 (1.88), 2.318 (1.18), 2.322 (2.59), 2.326 (3.59), 2.332 (2.59), 2.336 (1.24), 2.370 (2.35), 2.382 (3.53), 2.394 (2.65), 2.412 (2.59), 2.425 (3.59), 2.437 (2.65), 2.518 (16.00), 2.522 (10.71 ), 2.660 (1.18), 2.664 (2.59), 2.669 (3.47), 2.673 (2.53), 2.678 (1.18), 3.395 (1.06), 3.459 (2.71 ), 3.473 (3.65), 3.484 (3.06), 3.495 (2.94), 3.510 (3.65), 3.528 (9.24), 3.610 (1.82), 3.638 (5.00), 3.653 (0.88), 3.665 (4.94), 3.679 (0.71 ), 3.693 (1.94), 3.700 (0.82), 6.944 (2.41 ), 6.955 (2.29), 7.206 (4.00), 7.458 (1.00), 7.482 (1.12), 7.607 (0.88), 7.627 (0.71 ), 7.810 (1.12), 7.868 (0.82), 8.271 (4.12), 8.284 (3.88), 9.075 (1.71 ), 9.131 (2.29), 10.732 (1.06), 12.254 (1.00), 12.285 (0.76).
Example 45.02.02
{4-[(2-{[6-(2-chloropyrimidin-5-yl)-1 H-be
yl)methyl]piperazin-1-yl}(cyclopropyl)methanone
Figure imgf000842_0001
Starting with crude 6-(2-chloropyrimidin-5-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (305 mg, approx. 575 pmol) and cyclopropanecarboxylic acid (140 μΙ, 1.7 mmol), Example 45.02.02 was prepared analogously to the procedure for the preparation of Example 01 .02.
Yield: 9.14 mg of the title compound.
LC-MS (Method 2): R, = 1.06 min; MS (ESIpos): m/z = 489 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.677 (1.61 ), 0.685 (3.36), 0.690 (2.09), 0.698 (2.02), 0.705 (4.30), 0.709 (3.59), 0.713 (3.81 ), 0.720 (3.44), 0.726 (3.70), 0.733 (1.76), 1.907 (0.90), 1.968 (1.38), 2.084 (2.39), 2.322 (1.79), 2.326 (2.50), 2.332 (1.83), 2.336 (1.12), 2.363 (1.50), 2.518 (9.46), 2.522 (6.62), 2.664 (1.68), 2.668 (2.32), 2.673 (1.64), 2.727 (2.54), 2.729 (2.24), 2.888 (3.10), 3.257 (0.67), 3.51 1 (2.09), 3.527 (5.53), 3.707 (1.46), 3.965 (1.12), 5.759 (16.00), 6.951 (1.27), 6.963 (1.16), 7.212 (2.58), 8.272 (2.36), 8.285 (2.21 ), 8.496 (1.12), 9.074 (1.42), 9.132 (2.02).
Example 45.03.01
3,3,3-trifluoro-1-{4-[(2-{[6-(2-methylpyrimidin-5-yl)-1H-benzimidazol-2-yl]amino}pyri yl)methyl]piperazin-1-yl}propan-1 -one
Figure imgf000843_0001
Starting with crude 6-(2-methylpyrimidin-5-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (204 mg, approx. 400 μηιοΙ) and 3,3,3-trifluoropropanoic acid (1 10 μΙ, 1.2 mmol), Example 45.03.01 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 20.5 mg of the title compound.
LC-MS (Method 2): R, = 0.99 min; MS (ESIpos): m/z = 51 1 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.323 (0.94), 2.327 (1.28), 2.331 (0.94), 2.369 (1.71 ), 2.383 (2.63), 2.395 (1.97), 2.413 (1.95), 2.425 (2.65), 2.437 (1.99), 2.518 (5.72), 2.523 (3.89), 2.657 (16.00), 2.665 (2.26), 2.669 (1.79), 2.674 (1.12), 3.159 (2.48), 3.172 (2.71 ), 3.459 (1.83), 3.473 (2.54), 3.485 (2.10), 3.495 (2.04), 3.510 (2.59), 3.526 (7.37), 3.61 1 (1.20), 3.638 (3.50), 3.666 (3.28), 3.693 (1.04), 4.097 (0.67), 4.110 (0.63), 5.760 (1.81 ), 6.935 (1.89), 6.938 (1.89), 6.947 (1.85), 6.951 (1.89), 7.208 (3.22), 7.451 (0.94), 8.266 (3.20), 8.280 (3.1 1 ), 8.977 (1.32), 9.010 (1.47), 10.702 (1.36).
Example 45.03.02
cyclopropyl{4-[(2-{[6-(2-methylpyrimidin-5-yl)-1 H-benzimidazol-2-yl]amino}pyrid yl)methyl]piperazin-1-yl}methanone
Figure imgf000844_0001
Starting with crude 6-(2-methylpyrimidin-5-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (204 mg, approx. 400 pmol) and cyclopropanecarboxylic acid (96 μΙ, 1.2 mmol), Example 45.03.02 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 23.6 mg of the title compound.
LC-MS (Method 2): Rt = 0.95 min; MS (ESIpos): m/z = 469 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.677 (1 .69), 0.685 (3.76), 0.691 (2.29), 0.698 (2.03), 0.705 (4.66), 0.709 (3.83), 0.713 (4.09), 0.720 (3.61 ), 0.726 (4.17), 0.733 (1.84), 1.065 (0.60), 1.751 (0.68), 1.948 (0.94), 1.955 (0.94), 1.967 (1.58), 1.979 (0.86), 1.986 (0.79), 2.318 (0.86), 2.322 (1.80), 2.326 (2.48), 2.332 (1.92), 2.336 (1.13), 2.364 (1.62), 2.446 (1.69), 2.518 (9.16), 2.522 (6.31 ), 2.656 (16.00), 2.664 (2.93), 2.668 (2.70), 2.673 (1.84), 2.678 (0.86), 3.504 (1.80), 3.51 1 (1.88), 3.525 (7.14), 3.709 (1.58), 6.943 (1.77), 6.946 (1.80), 6.956 (1.80), 6.959 (1.77), 7.209 (3.38), 7.452 (1.09), 8.268 (3.12), 8.283 (3.08), 8.975 (1.31 ), 9.013 (1.54).
Example 45.04.01
cyclopropyl{4-[(2-{[6-(2-cyclopropylpyrimidin-5-yl)-1 H^enzimidazol-2-yl]amino}pyridin 4-yl)methyl]piperazin-1-yl}methanone
Figure imgf000845_0001
Starting with crude 6-(2-cyclopropylpyrimidin-5-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (366 mg, approx. 683 pmol) and cyclopropanecarboxylic acid (160 μΙ, 2.0 mmol), Example 45.04.01 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 24.4 mg of the title compound.
LC-MS (Method 2): R, = 1.09 min; MS (ESIneg): m/z = 493 [M-H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.665 (0.90), 0.677 (2.52), 0.685 (5.61 ), 0.690 (3.48), 0.698 (2.90), 0.704 (6.84), 0.708 (5.87), 0.713 (6.32), 0.720 (5.61 ), 0.725 (6.52), 0.732 (3.03), 0.745 (0.77), 0.821 (0.65), 0.829 (0.90), 0.833 (0.77), 0.835 (0.77), 0.840 (0.90), 0.863 (0.58), 0.870 (0.71 ), 0.883 (0.58), 0.889 (1.10), 0.897 (0.58), 0.999 (0.65), 1.013 (0.90), 1.026 (3.03), 1.033 (6.06), 1.038 (5.16), 1.045 (6.00), 1.053 (6.52), 1.060 (2.58), 1.067 (2.84), 1.073 (5.61 ), 1.080 (2.52), 1.093 (0.71 ), 1.230 (0.71 ), 1.907 (0.65), 1.936 (0.65), 1.948 (1.35), 1.955 (1.42), 1.959 (1.03), 1.967 (2.45), 1.973 (1.10), 1.979 (1.35), 1.986 (1.23), 2.207 (0.77), 2.220 (1.42), 2.227 (1.48), 2.233 (1.03), 2.240 (2.71 ), 2.248 (1.03), 2.252 (1.42), 2.259 (1.29), 2.271 (0.71 ), 2.318 (1.42), 2.322 (3.03), 2.326 (4.19), 2.332 (3.10), 2.336 (1.74), 2.364 (2.39), 2.444 (2.52), 2.518 (16.00), 2.522 (1 1.10), 2.539 (1.35), 2.660 (1.29), 2.664 (2.90), 2.668 (3.94), 2.673 (2.77), 2.678 (1.23), 3.525 (8.77), 3.632 (1.10), 3.641 (0.71 ), 3.644 (1.10), 3.648 (0.71 ), 3.656 (1.23), 3.665 (0.65), 3.670 (0.77), 3.675 (0.97), 3.681 (1.42), 3.685 (1.68), 3.692 (2.58), 3.694 (2.90), 3.709 (3.42), 3.712 (3.10), 3.718 (2.52), 3.723 (2.06), 3.728 (1.35), 3.733 (0.97), 3.738 (0.71 ), 4.124 (0.84), 4.136 (0.84), 4.149 (0.77), 4.214 (1.42), 6.941 (2.77), 6.944 (2.84), 6.954 (2.84), 6.957 (2.84), 7.209 (4.90), 7.377 (0.77), 7.573 (0.65), 7.582 (0.71 ), 7.593 (0.65), 7.601 (0.58), 7.706 (0.84), 7.710 (0.84), 8.269 (4.65), 8.281 (4.45), 8.898 (0.71 ), 8.939 (2.13), 10.690 (1.16), 12.222 (0.77). Example 45.05.01
3,3,3 rifluoro-1-(4-{[2-({6-[2-(methylsulfanyl)pyrimidin-5-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1 -yl)propan-1 -one
Figure imgf000846_0001
Starting with crude 6-[2-(methylsulfanyl)pyrimidin-5-yl]-N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]- 1 H-benzimidazol-2-amine hydrochloride (183 mg, approx. 338 pmol)and 3,3,3- trifluoropropanoic acid (60 μΙ, 680 pmol) Example 45.05.01 was prepared analogously to the procedure for the preparation of Example 45.01.01.
Yield: 4.0 mg of the title compound.
LC-MS (Method 2): R, = 1.14 min; MS (ESIpos): m/z = 543 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.229 (4.12), 2.390 (1.33), 2.433 (1.28), 2.569 (16.00), 3.475 (1.49), 3.485 (1.31 ), 3.508 (1.40), 3.533 (2.78), 3.638 (1.88), 3.665 (1.77), 6.942 (1.25), 6.955 (1.46), 7.208 (2.37), 8.271 (1.73), 8.284 (1.62), 8.965 (3.13).
Example 45.05.02
2-cyclopropyl-1-(4-{[2-({6-[2-(methylsulfanyl)pyrimidin-5-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1 -yl)ethanone
Figure imgf000846_0002
Starting with crude 6-[2-(methylsulfanyl)pyrimidin-5-yl]-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]- 1 H-benzimidazol-2-amine hydrochloride (130 mg, approx. 240 μιτιοΙ) and cyclopropylacetic acid (72.0 mg, 720 μιηοΙ), Example 45.05.02 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 9 mg of the title compound.
LC-MS (Method 4): R, = 1.13 min; MS (ESIpos): m/z = 515 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm]= 0.06 - 0.14 (m, 2H), 0.39 - 0.48 (m, 2H), 0.88 - 0.99 (m, 1 H), 2.25 (d, 2H), 2.34 - 2.42 (m, 4H), 2.57 (s, 3H), 3.40 - 3.56 (m, 6H), 6.94 (d, 1 H), 7.20 (s, 1 H), 7.38 (br d, 0.5H), 7.44 (br s, 1 H), 7.59 (br d, 0.5H), 7.70 - 7.84 (m, 1 H), 8.27 (d, 1 H), 8.94 (s, 1 H), 8.99 (s, 1 H), 10.69 (br s, 1 H), 12.22 (br d, 1 H).
Example 45.05.03
cyclopropyl(4-{[2-({6-[2-(methylsulfanyl)pyrimidin-5-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1 -yl)methanone
Figure imgf000847_0001
Starting with crude 6-[2-(methylsulfanyl)pyrimidin-5-yl]-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]- 1 H-benzimidazol-2-amine hydrochloride (183 mg, approx. 338 Mmol)and cyclopropanecarboxyiic acid (54 μΙ, 680 pmol) Example 45.05.03 was prepared analogously to the procedure for the preparation of Example 45.01.01 .
Yield: 17.0 mg of the title compound.
LC-MS (Method 2): R, = 1.11 min; MS (ESIpos): m/z = 501 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.677 (1.09), 0.684 (2.44), 0.689 (1.59), 0.696 (1.30), 0.703 (2.96), 0.708 (2.67), 0.712 (2.82), 0.720 (2.52), 0.724 (2.86), 0.731 (1.36), 1.964 (0.98), 2.363 (1.22), 2.446 (1.27), 2.568 (16.00), 3.499 (1.33), 3.523 (4.62), 3.706 (1.17), 6.941 (1.32), 6.956 (1.35), 7.210 (1.94), 8.268 (1.87), 8.281 (1.78), 8.965 (1.50). Example 46.01
cyclopropyl{4-[(2-{[6-(3-methoxypyridazin-4-yl)-1H-benzimidazol-2-yl]amino}pyridin-4^ yl)methyl]piperazin-1-yl}methanone
Figure imgf000848_0001
To a stirred solution of {4-[(2-{[6-(6-chloro-3-methoxypyridazin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}(cyclopropyl) methanone (190 mg, 366 pmol) in methanol (2 mL) was added palladium on carbon (10 % w/w palladium, 200 mg) and the mixture was hydrogenated at 40° C at 4 bar hydrogen atmosphere for 2 h. Methanol was added, the mixture was filtered through celite and the solution was concentrated in vacuum. A saturated solution of sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The organic phase was dried (magnesium sulfate) and the solvent was removed in vacuum. Silicagel chromatography gave 37 mg (21 % yield) of the title compound.
LC-MS (Method 5): R, = 2.52 min; MS (ESIpos): m/z = 485 [M+H]+
1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 0.70 (m, 4H), 1.95 (m, 1 H), 2.41 (m, 4H), 3.52 (s, 4H), 3.70 (s, 2H), 4.1 1 (s, 3H), 6.95 (d, 1 H), 7.22 (s, 1 H), 7.30-8.05 (m, 4H), 8.28 (d, 1 H), 8.90 (d, 1 H), 10.69 (s, 1 H), 12.26 (s, 1 H). 13C-NMR (101 MHz, DMSO-d6): δ [ppm] = 6.9, 10.2, 41.6, 44.8, 52.4, 53.1 , 54.5, 60.6, 1 10.5, 1 16.6, 127.4, 130.1 , 146.9, 148.0, 149.5, 153.5, 162.0, 170.9.
Example 46.02
{4-[(2^[6-(6-chloro-3-methoxypyridazin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}(cyclopropyl)methanone
Figure imgf000849_0001
Starting with cyclopropyl{4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)methyl]piperazin-1-yl}methanone (300 mg, 597 μιηοΙ) and 6-chloro-4-iodo-3-methoxypyridazine (300 mg, 1.1 1 mmol) Example 46.02 was prepared analogously to the procedure for the preparation of Example 08.01.
Yield: 242 mg (74 %) of the title compound.
LC-MS (Method 5): Rt = 2.81 min; MS (ESIpos): m/z = 519 [M+H]+
1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 0.70 (m, 4H), 1.95 (m, 1 H), 2.40 (m, 4H), 3.52 (s, 4H), 3.69 (s, 2H), 4.10 (s, 3H), 6.95 (d, 1 H), 7.21 (s, 1 H), 7.28-7.69 (m, 3H), 7.82 (d, 1 H), 8.28 (d, 1 H), 10.71 (s, 1 H), 12.30 (s, 1 H).
13C-NMR (101 MHz, DMSO-d6): δ [ppm] = 7.0, 10.2, 41.6, 44.9, 52.4, 53.1 , 55.2, 60.6, 1 10.6, 1 16.7, 128.2, 133.7, 147.0, 149.6, 151.0, 153.5, 161.8, 171.1.
Example 47.01
cyclopropyl{4-[(2-{[6-(6-methoxypyridazin-3-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1-yl}methanone
Figure imgf000850_0001
To a stirred solution of 3-chloro-6-methoxypyridazine (216 mg, 1.49 mmol) and cyclopropyl{4- [(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone (150 mg, 299 pmol) in ioxane (1.9 mL) and water (380 μΙ) was added sodium carbonate (130 mg, 1.22 mmol) and Pd(dppf)CI2 . CH2CI2 (48.8 mg, 59.7 pmol) and PdCb(PPh3)2 (41.9 mg, 59.7 pmol). The mixture was heated to reflux for 42 h. Methanol was added, the mixture was filtered and the solvent was removed in vacuum. Silicagel chromatography gave 29.0 mg (19 % yield) of the title compound.
LC-MS (Method 5): R, = 2.72 min; MS (ESIpos): m/z = 485 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.490 (0.58), 2.495 (1.24), 2.500 (1.74), 2.505 (1.24), 2.509 (0.58), 3.305 (16.00), 4.077 (2.13).
Example 47.02
cyclopropyl{4-[(2-{[6-(5-methoxypyridazin-3-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone
Figure imgf000850_0002
Starting with cyclopropyl{4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)methyl]piperazin-1-yl}methanone (150 mg, 299 pmol) and 3-chloro-5-methoxypyridazine (1 15 mg, 796 pmol) Example 47.02 was prepared analogously to the procedure for the preparation of Example 08.01.
Yield: 16 mg (11 % Yield) of the title compound.
LC-MS (Method 5): R, = 2.53 min; MS (ESIpos): m/z = 485 [M+H]+
1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 0.71 (m, 4Η), 1.96 (m, 1 H), 2.41 (m, 4Η), 3.53 (m, 4H), 3.70 (s, 2H), 4.02 (s, 3H), 6.95 (d, H), 7.23 (s, 1 H), 7.36-7.72(m, 2H), 7.90 (d, 1 H), 8.07- 8.46 (m, 2H), 8.88 (d, 1 H), 10.71 (s, 1 H), 12.61 (s, 1 H).
13C-NMR (101 MHz, DMSO-d6): δ [ppm] = 6.9, 10.2, 41 .6, 44.8, 52.4, 53.1 , 60.6, 67.4, 1 10.5, 1 16.6, 141.5, 146.9, 149.5, 153.5, 158.2, 160.2, 170.9.
Example 48.01
cyclopropyl{4-[(2^[6-(6-methoxypyrazin-2-yl)-1 H-benzimidazol-2-yl]amino}pyridin yl)methyl]piperazin-1-yl}methanone
Figure imgf000851_0001
Starting with cyclopropyl{4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}methanone (200 mg, 398 pmol) and 2-chloro-6-methoxypyrazine (70.0 mg, 484 pmol), Example 48.01 was prepared analogously to the procedure for the preparation of Example 08.01.
Yield: 1 17 mg (58 %) of the title compound.
LC-MS (Method 5): R, = 2.84 min; MS (ESIpos): m/z = 485 [M+H]+
1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 0.70 (m, 4H), 1.94 (m, 1 H), 2.40 (m, 4H), 3.52 (m, 4H), 3.69 (s, 2H), 4.04 (s, 3H), 6.95 (d, 1 H), 7.22 (s, 1 H), 7.34-7.45 (m, 1 H), 7.87 (d, 1 H), 8.16 (s, 1 H), 8.27 (d, 1 H), 8.77 (s, 1 H), 10.71 (s, 1 H), 12.27 (s, 1 H).
13C-NMR (101 MHz, DMSO-d6): δ [ppm] = 6.9, 10.2, 41.6, 44.8, 52.4, 53.1 , 60.6, 1 10.5, 1 16.6, 132.5, 146.9, 149.47, 149.51 , 153.5, 159.2, 170.9. Example 49.01
cyclopropyl{4-[(2^[6-(2-methoxypyridin-4-yl)-7-(2-methylpropoxy)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1-yl}methanone
Figure imgf000852_0001
To a stirred solution of cyclopropyl{4-[(2-{[7-(2-methylpropoxy)-6-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}methanone (160 mg, 278 pmol) in dioxane (5 ml.) and water (0.5 mL) was added sodium bicarbonate (88.5 mg, 835 pmol), 4-bromo-2-methoxypyridine (78.5 mg, 418 μιτιοΙ), and Pd(dppf)C . CH2CI2 (34.1 mg, 41.8 pmol). The mixture was heated to 120° C in a sealed tube for 14 h. Ethyl acetate was added, the mixture was filtered through celite and the solvent was removed in vacuum. Aminophase-silicagel chromatography followed by silicagel chromatography gave a residue that was dissolved in dichloromethane and acidified with aqueous 2N hydrochloric acid. The organic phase was removed and saturated potassium carbonate solution was added to the aqueous phase until basic pH was reached. The aqueous phase was extracted with dichloromethane / methanol (10:1 ). The organic phase was dried (sodium sulfate), filtered and the solvent was removed in vacuum. Aminophase-silicagel chromatography followed by preparative reverse phase HPLC (gradient of water and acetonitrile containing ammonia as additive) gave 35.0 mg (20 % yield) of the title compound.
LC-MS (Method 2): R, = 1.35 min; MS (ESIpos): m/z = 556 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.683 (3.26), 0.688 (2.16), 0.703 (4.05), 0.71 1 (3.89), 0.719 (3.35), 0.723 (3.77), 0.730 (1.84), 0.814 (1.49), 0.830 (3.28), 0.836 (1.82), 0.851 (16.00), 0.858 (6.12), 0.867 (15.82), 0.894 (1.28), 0.910 (1.21 ), 0.936 (1.65), 0.953 (1.68), 1.237 (2.80), 1.394 (0.74), 1.873 (0.96), 1.889 (1.16), 1.905 (0.96), 1.965 (1.40), 2.327 (1.44), 2.356 (1.68), 2.435 (1.79), 2.523 (4.01 ), 2.669 (1.12), 3.512 (6.15), 3.705 (1.58), 3.875 (12.99), 4.296 (4.71 ), 4.312 (4.54), 6.926 (3.31 ), 6.932 (2.02), 6.946 (1.89), 7.005 (2.54), 7.025 (2.68), 7.136 (1.65), 7.140 (1.66), 7.150 (1.65), 7.153 (1.72), 7.227 (2.84), 7.260 (2.84), 7.280 (2.31 ), 8.130 (2.26), 8.143 (2.16), 8.258 (2.23), 8.271 (2.09), 10.719 (2.72), 12.187 (2.40). Example 50.01
3,3,3-trifluoro-1^4-[(2-{[6-(3-methoxypyridin-4-yl)-7-(2-methylpropoxy)-1 H-benzimidazol- 2-yl]amino}pyridin-4-yl)methyl]piperazin-1-yl}propan-1-one
Figure imgf000853_0001
Starting with crude 6-(3-methoxypyridin-4-yl)-7-(2-methylpropoxy)-N-[4-(piperazin-1- ylmethyl)pyridin-2-yl]-1 H-benzimidazol-2-amine hydrochloride (120 mg, approx. 171 pmol) and 3,3,3-trifluoropropanoic acid (23 μΙ, 98 % purity, 260 pmol), Example 50.01 was prepared analogously to the procedure for the preparation of Example 05.01.
Yield: 58.0 mg of the title compound.
LC-MS (Method 2): R, = 1.20 min; MS (ESIpos): m/z = 598 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm]= 0.75 (d, 6H), 1.70 - 1.87 (m, 1 H), 2.41 (br dd, 4H), 3.43 - 3.57 (m, 6H), 3.59 - 3.71 (m, 2H), 3.81 (s, 3H), 4.25 (d, 2H), 6.80 (d, 1 H), 6.94 (d, 1 H), 7.17 - 7.25 (m, 3H), 8.21 (d, 1 H), 8.27 (d, 1 H), 8.38 (s, 1 H), 10.70 (s, 1 H), 12.15 (s, 1 H).
Example 50.02
cyclopropyl{4-[(2-{[6-(3-methoxypyridin-4-yl)-7-(2-methylpropoxy)-1 H-benzimidazol-2 yl]amino}pyridin-4-yl)methyl]piperazin-1-yl}methanone
Figure imgf000854_0001
Starting with crude 6-(3-methoxypyridin-4-yl)-7-(2-methylpropoxy)-N-[4-(piperazin-1- ylmethyl)pyridin-2-yl]-1 H-benzimidazol-2-amine hydrochloride (120 mg, approx. 171 μιηοΙ) and cyclopropanecarboxylic acid (21 μΙ, 98 % purity, 260 pmol), Example 50.02 was prepared analogously to the procedure for the preparation of Example 05.01.
Yield: 62.0 mg of the title compound.
LC-MS (Method 2): R, = 1.17 min; MS (ESIpos): m/z = 556 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm]= 0.66 - 0.80 (m, 10H), 1.78 (dt, 1 H), 1.90 - 2.03 (m, 1 H), 2.32 - 2.48 (m, 4H), 3.52 (s, 4H), 3.71 (br s, 2H), 3.81 (s, 3H), 4.25 (d, 2H), 6.80 (d, 1 H), 6.94 (br d, 1 H), 7.21 (dt, 3H), 8.21 (d, 1 H), 8.27 (d, 1 H), 8.38 (s, 1 H), 10.71 (s, 1 H), 12.16 (s, 1 H).
Example 50.03
cyclobutyl{4-[(2-{[6-(3-methoxypyridin-4-yl)-7-(2-methylpropoxy)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1-yl}methanone
Figure imgf000854_0002
Starting with crude 6-(3-methoxypyridin-4-yl)-7-(2-methylpropoxy)-N-[4-(piperazin-1- ylmethyl)pyridin-2-yl]-1 H-benzimidazol-2-amine hydrochloride (120 mg, approx. 171 pmol) and cyclobutanecarboxylic acid (25 μΙ, 98 % purity, 260 pmol), Example 50.03 was prepared analogously to the procedure for the preparation of Example 05.01.
Yield: 88.0 mg of the title compound.
LC-MS (Method 2): R, = 1.23 min; MS (ESIpos): m/z = 570 [M+H]+
1 H-NMR (400MHz, DMSO-d6): δ [ppm]= 0.75 (d, 6H), 1.67 - 1.81 (m, 2H), 1.82 - 1.96 (m, 1 H), 1.99 - 2.22 (m, 4H), 2.35 (br d, 4H), 3.49 (s, 4H), 3.81 (s, 3H), 4.25 (d, 2H), 6.80 (d, 1 H), 6.93 (d, 1 H), 7.16 - 7.25 (m, 3H), 8.21 (d, 1 H), 8.26 (d, 1 H), 8.38 (s, 1 H), 10.70 (s, 1 H), 12.15 (s, 1 H).
Example 51.01
1 -{4 (2-{[7-ethoxy-6-(3-methoxypyridin-4-yl)-1H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1-yl}-3,3,3-trifluoropropan-1-one
Figure imgf000855_0001
Starting with crude 7-ethoxy-6-(3-methoxypyridin-4-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]- 1 H-benzimidazol-2-amine hydrochloride (250 mg, approx. 378 pmol) and 3,3,3- trifluoropropanoic acid (50 μΙ, 570 μιτιοΙ), Example 51.01. was prepared analogously to the procedure for the preparation of Example 16.01.02.
Yield: 100.0 mg of the title compound.
LC-MS (Method 2): R, = 1.10 min; MS (ESIpos): m/z = 570 [M+H]+
H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.131 (5.68), 1.149 (12.32), 1.154 (1.75), 1 .167 (5.91 ), 1.172 (2.35), 1.190 (1.05), 1.986 (3.46), 2.366 (1.53), 2.378 (2.32), 2.390 (1.80), 2.408 (1.73), 2.420 (2.32), 2.432 (1.69), 2.522 (1.37), 3.456 (1.70), 3.469 (2.35), 3.480 (2.00), 3.492 (2.04), 3.513 (6.88), 3.604 (1.16), 3.631 (3.33), 3.659 (3.13), 3.686 (1.00), 3.820 (16.00), 4.018 (0.77), 4.036 (0.74), 4.533 (1.15), 4.550 (3.62), 4.568 (3.57), 4.585 (1.15), 5.755 (3.03), 6.792 (2.86), 6.812 (2.99), 6.915 (1 .62), 6.919 (1.68), 6.929 (1.76), 6.932 (1.72), 7.180 (2.88), 7.192 (4.57), 7.213 (3.26), 7.233 (2.70), 8.206 (3.20), 8.218 (2.92), 8.257 (2.75), 8.270 (2.62), 8.384 (4.97), 10.689 (3.24), 12.132 (2.74). Example 51.02
2-cyclopropyl-1 -{4-[(2-{[7-ethoxy-6-(3-methoxypyridin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1-yl}ethanone
Figure imgf000856_0001
Starting with crude 7-ethoxy-6-(3-methoxypyridin-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]- 1 H-benzimidazol-2-amine hydrochloride (200 mg, approx. 302 pmol) and cydopropylacetic acid (42 μΙ, 450 pmol), Example 51.02 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 50.0 mg of the title compound.
LC-MS (Method 2): R, = 1.09 min; MS (ESIpos): m/z = 542 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.000 (0.94), 0.01 1 (3.25), 0.014 (2.94), 0.023 (3.26), 0.026 (3.00), 0.037 (1.07), 0.330 (1.16), 0.339 (2.82), 0.344 (2.96), 0.350 (1.48), 0.354 (1.44), 0.360 (3.01 ), 0.364 (2.87), 0.375 (1.09), 0.854 (1.06), 1.047 (5.83), 1.064 (12.53), 1.071 (4.46), 1.082 (5.79), 1.089 (8.19), 1.107 (3.86), 1.905 (13.05), 2.153 (5.25), 2.170 (5.09), 2.273 (2.18), 2.293 (1.97), 2.306 (2.17), 3.368 (2.13), 3.380 (1.94), 3.413 (6.49), 3.738 (16.00), 3.916 (1.04), 3.935 (2.95), 3.952 (2.96), 3.970 (0.98), 4.449 (1.14), 4.467 (3.67), 4.485 (3.64), 4.503 (1.11 ), 6.707 (2.95), 6.728 (3.14), 6.832 (1.60), 6.835 (1.64), 6.845 (1.69), 6.848 (1.68), 7.097 (3.08), 7.109 (5.16), 7.131 (3.18), 7.151 (2.78), 8.124 (3.28), 8.135 (3.01 ), 8.172 (2.67), 8.185 (2.51 ), 8.301 (5.03), 10.620 (3.23), 12.056 (2.74).
Example 51.03
cycIopropyl{4-[(2-{[7-ethoxy-6-(3-methoxypyridin-4-yl)-1 H-benzimidazol-2
yl]amino}pyridin-4-yl)methyl]piperazin-1-yl}methanone
Figure imgf000857_0001
Starting with crude 7-ethoxy-6-(3-methoxypyridin-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]- 1 H-benzimidazol-2-amine hydrochloride (150 mg, approx. 227 pmol) and cyclopropanecarboxylic acid (28 μΙ, 95 % purity, 340 pmol) Example 51.03. was prepared analogously to the procedure for the preparation of Example16.01.02.
Yield: 30.0 mg of the title compound.
LC-MS (Method 2): R, = 1.06 min; MS (ESIpos): m/z = 528 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.676 (1.50), 0.683 (3.35), 0.689 (2.09), 0.696 (1.72), 0.703 (4.06), 0.708 (3.54), 0.713 (3.68), 0.720 (3.43), 0.725 (3.98), 0.732 (1.83), 1.132 (5.83), 1.149 (12.24), 1.155 (2.06), 1.167 (6.01 ), 1.173 (2.60), 1.191 (1.16), 1.942 (0.80), 1.949 (0.87), 1.961 (1.47), 1.973 (0.87), 1.980 (0.86), 1.988 (4.23), 2.085 (4.51 ), 2.361 (1.58), 2.440 (1.62), 3.513 (6.33), 3.700 (1.46), 3.821 (16.00), 4.019 (0.95), 4.037 (0.95), 4.533 (0.99), 4.551 (2.93), 4.569 (2.89), 4.586 (0.97), 5.756 (5.66), 6.792 (2.10), 6.812 (2.27), 6.927 (1.82), 6.940 (1.87), 7.181 (2.34), 7.193 (2.98), 7.201 (3.06), 7.213 (2.81 ), 7.233 (2.22), 8.208 (2.63), 8.219 (2.57), 8.260 (2.94), 8.273 (2.77), 8.385 (4.23), 10.691 (2.87), 12.133 (2.64).
Example 51.04
cyclobutyl{4-[(2-{[7-ethoxy-6-(3-methoxypyridin-4-yl)-1 H-benzimidazol-2
yl]amino}pyridin-4-yl)methyl]piperazin-1-yl}methanone
Figure imgf000858_0001
Starting with crude 7-ethoxy-6-(3-methoxypyridin-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]- 1 H-benzimidazol-2-amine hydrochloride (200 mg, approx. 302 μητιοΙ) and cyclobutanecarboxylic acid (43 μΙ, 450 pmol), Example 51.04 was prepared analogously to the procedure for the preparation of Example 01 .02.
Yield: 50.0 mg of the title compound.
LC-MS (Method 2): R, = 1.12 min; MS (ESIpos): m/z = 542 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.128 (5.83), 1 .146 (12.86), 1.154 (3.59), 1.163 (6.14), 1.172 (6.76), 1.189 (3.34), 1.838 (0.69), 1.859 (1.33), 1.882 (1.02), 1.886 (0.99), 1.987 (1 1.56), 2.049 (1.46), 2.058 (1.08), 2.065 (1.05), 2.071 (1.67), 2.080 (1.29), 2.097 (1 .03), 2.102 (0.92), 2.120 (1.90), 2.125 (1.26), 2.142 (2.06), 2.147 (1.66), 2.165 (0.95), 2.171 (1.07), 2.345 (4.13), 3.300 (1.17), 3.319 (3.19), 3.468 (2.22), 3.485 (6.10), 3.820 (16.00), 3.999 (0.93), 4.016 (2.55), 4.034 (2.47), 4.053 (0.79), 4.531 (1.16), 4.549 (3.63), 4.566 (3.56), 4.584 (1.12), 6.790 (2.87), 6.810 (3.00), 6.907 (1.65), 6.923 (1.78), 7.179 (4.15), 7.191 (3.45), 7.213 (3.17), 7.233 (2.70), 8.206 (3.18), 8.218 (3.04), 8.251 (2.77), 8.263 (2.63), 8.384 (5.09), 10.699 (3.23), 12.137 (2.81 ).
Example 52.01
1 -{4-[(2-{[6-(1 -ethyl-1 H-pyrazol-4-yl)-7-(2-methylpropoxy)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1-yl}-3,3,3-trifluoropropan-1-one
Figure imgf000859_0001
Starting with crude 6-(1-ethyl-1 H-pyrazol-4-yl)-7-(2-methylpropoxy)-N-[4-(piperazin-1- ylmethyl)pyridin-2-yl]-1 H-benzimidazol-2-amine hydrochloride (248 mg, approx. 453 pmol) and 3,3,3-trifluoropropanoic acid (61 μΙ, 98 % purity, 680 μιτιοΙ), Example 52.01 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 24.0 mg of the title compound.
LC-MS (Method 2): R, = 1.26 min; MS (ESIpos): m/z = 585 [M+H]+
1H-NMR (400MHz, DMSO-de): δ [ppm]= 1.00 (d, 6H), 1.41 (t, 3H), 2.07 (dt, 1 H), 2.35 - 2.45 (m, 4H), 3.44 - 3.57 (m, 6H), 3.66 (q, 2H), 3.78 (br d, 1 H), 4.16 (q, 2H), 4.36 (d, 2H), 6.92 (d, 1 H), 7.10 - 7.32 (m, 3H), 7.81 (s, 1 H), 8.02 (s, 1 H), 8.25 (d, 1 H), 10.61 (s, 1 H), 12.02 (s, 1 H), 12.1 1 - 12.20 (m, 1 H).
Example 52.02
cyclopropyl{4-[(2-{[6-(1 -ethyl-1 H-pyrazol-4-yl)-7-(2-methylpropoxy)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1-yl}methanone
Figure imgf000859_0002
Starting with crude 6-(1 -ethyl-1 H-pyrazol-4-yl)-7-(2-methylpropoxy)-N-[4-(piperazin-1- ylmethyl)pyridin-2-yl]-1 H-benzimidazol-2-amine hydrochloride (248 mg, approx. 453 pmol) and cyclopropanecarboxylic acid (55 μΙ, 98 % purity, 680 pmol), Example 52.02 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 49.0 mg of the title compound.
LC-MS (Method 2): R, = 1.23 min; MS (ESIpos): m/z = 543 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm]= 0.65 - 0.78 (m, 4H), 1.00 (d, 6H), 1.37 - 1.45 (m, 3H), 1.92 - 2.13 (m, 2H), 2.32 - 2.47 (m, 4H), 3.51 (s, 4H), 3.71 (br s, 2H), 4.16 (q, 2H), 4.36 (d, 2H), 6.93 (d, 1 H), 7.10 - 7.31 (m, 3H), 7.81 (s, 1 H), 8.02 (s, 1 H), 8.25 (d, 1 H), 10.61 (s, 1 H), 12.02 (s, 1 H), 12.16 (br s, 1 H).
Example 53.01
1 -{4-[(2-{[7-ethoxy-6-(1 -ethyl-1 H-pyrazol-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}-3,3,3-trifluoropropan-1-one
Figure imgf000860_0001
Starting with crude 7-ethoxy-6-(1 -ethyl-1 H-pyrazol-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2- yl]-1 H-benzimidazol-2-amine hydrochloride (200 mg, approx. 311 μηιοΙ) and 3,3,3- trifluoropropanoic acid (41 μΙ, 470 μιτιοΙ) Example 53.01. was prepared analogously to the procedure for the preparation of Example 16.01.02.
Yield: 7.0 mg of the title compound.
LC-MS (Method 2): Rt = 1.13 min; MS (ESIpos): m/z = 557 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.006 (0.46), 1.232 (1.56), 1.347 (2.97), 1.365 (6.15), 1.383 (3.61 ), 1.389 (4.80), 1.407 (9.24), 1.425 (4.34), 2.318 (0.67), 2.323 (1.47), 2.327 (2.02), 2.331 (1.47), 2.337 (0.76), 2.376 (2.05), 2.387 (1.77), 2.403 (1.84), 2.416 (2.26), 2.518 (16.00), 2.523 (13.37), 2.529 (8.84), 2.540 (10.68), 2.660 (0.80), 2.665 (1.56), 2.669 (2.05), 2.674 (1.44), 2.678 (0.70), 3.308 (1.07), 3.455 (1.80), 3.468 (2.29), 3.479 (2.02), 3.507 (5.78), 3.610 (0.98), 3.628 (0.73), 3.637 (2.69), 3.655 (0.83), 3.664 (2.51 ), 3.692 (0.83), 4.135 (0.92), 4.153
(2.72) , 4.171 (2.78), 4.189 (0.98), 4.543 (0.86), 4.560 (2.57), 4.578 (2.57), 4.595 (0.86), 6.903 (1.25), 6.919 (1.28), 7.159 (1.99), 7.164 (2.23), 7.179 (3.03), 7.196 (3.06), 7.217 (1.01 ), 7.837
(3.73) , 8.059 (3.37), 8.223 (0.46), 8.239 (1.87), 8.252 (1.71 ), 10.678 (1 .93), 12.039 (1.90). Example 53.02
cyclopropyl{4-[(2-{[7-ethoxy-6-(1 -ethyl-1 H-pyrazol-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1-yl}methanone
Figure imgf000861_0001
Starting with crude 7-ethoxy-6-(1 -ethyl-1 H-pyrazol-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2- yl]-1 H-benzimidazol-2-amine hydrochloride (200 mg, approx. 31 1 pmol) and cyclopropanecarboxylic acid (39 μΙ, 95 % purity, 470 pmol) Example 53.02. was prepared analogously to the procedure for the preparation of Example 16.01.02.
Yield: 30.0 mg of the title compound.
LC-MS (Method 2): R, = 1.10 min; MS (ESIpos): m/z = 515 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.682 (3.37), 0.702 (4.15), 0.706 (4.08), 0.71 1 (4.1 1 ), 0.723 (4.06), 1.348 (3.15), 1.366 (6.16), 1.389 (5.71 ), 1.407 (8.40), 1.425 (4.20), 1.950 (1.00), 1.962 (1.40), 1.973 (0.94), 1.980 (0.80), 2.356 (2.28), 3.334 (16.00), 3.699 (2.08), 4.135 (1.19), 4.153 (3.23), 4.172 (3.22), 4.189 (1.20), 4.544 (1.04), 4.562 (2.74), 4.579 (2.71 ), 4.597 (1.00), 6.910 (1.80), 6.924 (1.89), 7.171 (3.40), 7.181 (3.78), 7.197 (3.07), 7.218 (1.03), 7.839 (4.28), 8.060 (3.71 ), 8.240 (2.08), 8.253 (2.1 1 ), 10.682 (2.57), 12.043 (2.50).
Example 54.01
3,3,3-trifluoro-1 -{4-[(2-{[7-methyl-6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1-yl}propan-1 -one
Figure imgf000862_0001
Starting with crude 7-methyl-6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-N-[4-(piperazin-1 - ylmethyl)pyridin-2-yl]-1 H-benzimidazol-2-amine hydrochloride (235 mg, approx. 457 pmol) and 3,3,3-trifluoropropanoic acid (120 μΙ, 1.4 mmol), Example 54.01 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 100 mg of the title compound.
LC-MS (Method 2): Rt = 1.13 min; MS (ESIpos): m/z = 515 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm]= 2.42 (s, 3H), 2.85 (s, 3H), 3.38 (br. s., 8H), 3.61 - 3.82 (m, 4H), 7.09 (d, 1 H), 7.29 (br. s., 1 H), 7.52 (d, 1 H), 7.80 (d, 1 H), 8.44 (d, H), 1 1.26 (br. s., 1 H), 12.50 (br. s., 1 H).
Example 54.02
cyclopropyl{4-[(2-{[7-methyl-6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1-yl}methanone
Figure imgf000862_0002
Starting with crude 7-methyl-6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-N-f4-(piperazin-1 - ylmethyl)pyridin-2-yl]- H-benzimidazol-2-amine hydrochloride (235 mg, approx. 457 pmol) and cyclopropanecarboxylic acid (1 10 μΙ, 1.4 mmol), Example 54.02 was prepared analogously to the procedure for the preparation of Example 01.02. Yield: 43 mg of the title compound.
LC-MS (Method 2): R, = 1.10 min; MS (ESIpos): m/z = 473 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 0.66 - 0.74 (m, 4H), 1.90 - 2.00 (m, 1H), 2.36 (br. s., 2H), 2.41 (s, 3H), 2.43 (br. s., 2H), 2.83 (s, 3H), 3.52 (br. s., 4H), 3.70 (br. s., 2H), 6.95 (d, 1H), 7.17 (br. s., 1H), 7.50 (d, 1H), 7.73 (d, 1H), 8.28 (d, 1H), 10.89 (br. s., 1H), 12.41 (br. s., 1H).
Example 55.01
tert-butyl 4-[(1R or 1S)-1-(2-{[6-(1-{[(1RS)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4- yl)-1H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1-carboxylate
Figure imgf000863_0001
Starting with crude 4-(1-{[(1RS)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)benzene-1,2- diamine (360 mg, 1.36 mmol) Compound 55.03, Example 55.01 was prepared analogously to the procedure for the preparation of Example 39.02.01.
Yield: 369 mg of the 90% pure title compound.
LC-MS (Method 2): Rt = 1.31 min; MS (ESIpos): m/z = 579 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.28 (d, 3H), 1.38 (s, 9H), 1.47 - 1.59 (m, 1H), 1.64 - 1.78 (m, 1 H), 2.20 - 2.34 (m, 3H), 2.35 - 2.44 (m, 2H), 2.51 - 2.53 (m, 2H), 3.32 (br s, 2H), 3.44 (q, 1H), 4.16-4.33 (m, 2H), 6.92 (dd, 1H), 7.16(s, 1H), 7.24 (br s, 1H), 7.39-7.67 (m, 2H), 7.77-7.91 (m, 1 H), 8.10 (br d, 1H), 8.25 (d, 1H), 10.56 (brs, 1H), 12.04 (brs, 1 H). - contains ethanol.
Example 55.01.01
tert-butyl 4-[(1R or 1S)-1-(2-{[6-(1-{[(1R or 1S)-2,2-difluorocyclopropyl]methyl}-1H- pyrazol-4-yl)-1H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1-carboxylate
Figure imgf000864_0001
Starting with 4-(1-{[(1R or 1S)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)benzene-1,2- diamine (160 mg, see Compound 55.03.01), Example 55.01.01 was prepared analogously to the procedure for the preparation of Example 39.02.01.
Yield: 74 mg of the 86% pure title compound.
LC-MS (Method 2): R, = 1.33 min; MS (ESIpos): m/z = 579 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.28 (d, 3H), 1.38 (s, 9H), 1.48- 1.59 (m, 1H), 1.64- 1.77 (m, 1H), 2.25-2.44 (m, 5H), 3.24-3.32 (m, 4H), 3.43 (q, 1H), 4.17-4.36 (m, 2H), 6.92 (d, 1H), 7.16 (s, 1H), 7.18-7.48 (m, 2H), 7.50-7.68 (m, 1H), 7.85 (brd, 1H), 8.04-8.16 (m, 1H), 8.25 (d, 1H), 10.56 (brs, 1H), 12.03 (br s, 1H).
Example 55.01.02
tert-butyl 4-[(1R or 1S)-1-(2-{[6-(1-{[(1R or 1S)-2,2-difluorocyclopropyl]methyl}-1H- pyrazol-4-yl)-1H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1-carboxylate
Figure imgf000864_0002
Starting with 4-(1-{[(1R or 1S)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)benzene-1,2- diamine (140 mg, see Compound 55.03.02), Example 55.01.02 was prepared analogously to the procedure for the preparation of Example 39.02.01.
Yield: 85 mg of the 88% pure title compound. LC-MS (Method 2): R, = 1.33 min; MS (ESIpos): m/z = 579 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.28 (d, 3H), 1.38 (s, 9H), 1.50 - 1.59 (m, 1H), 1.70 (tdd, 1 H), 2.20 - 2.44 (m, 5H), 3.24 - 3.32 (m, 4H), 3.39 - 3.48 (m, 1 H), 4.18 - 4.34 (m, 2H), 6.92 (d, 1H), 7.16 (s, 1H), 7.25 (brd, 1H), 7.32-7.45 (m, 1H), 7.58 (br s, 1H), 7.85 (s, 1H), 8.10 (s, 1H), 8.25 (d, 1H), 10.58 (br s, 1H), 12.06 (br s, 1H).
Example 55.02
1.{4-[(1 R or 1 S)-1 -(2-{[6-(1 -{[(1 RS)-2,2-dif luorocyclopropyl]methyl}-1 H-pyrazol-4-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}-3,3,3-trifluoropropan-1-one
Figure imgf000865_0001
Starting with 6-(1-{[(1RS)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-N-{4-[(1R or 1S)-1- (piperazin-1-yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride salt (210 mg, Compound 55.04), Example 55.02 was prepared analogously to the procedure for the preparation of Example 39.02.02.
Yield: 127 mg of the 94% pure title compound.
LC-MS (Method 2): R, = 1.16 min; MS (ESIpos): m/z = 590 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.39 (brs, 4H), 1.48- 1.60 (m, 1H), 1.64- 1.78 (m, 1H), 2.22-2.32 (m, 1H), 3.17-3.57 (m, 7H), 3.64 (q, 2H), 4.29 (brd, 2H), 7.18 (brd, 1H), 7.22 (s, 1 H), 7.46 - 7.60 (m, 3H), 7.70 (s, 1 H), 7.92 (s, 1 H), 8.20 (s, 1 H), 8.43 (br d, 1 H), 8.54 (dd, 1H), 8.77 (dd, 1H).
Example 55.02.01
1-{4-[(1R or 1S)-1-(2-{[6-(1-{[(1R or 1S)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)- 1H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}-3,3,3 rifluoropropan-1 -one
Figure imgf000866_0001
Starting with 6-(1-{[(1R or 1S)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-N-{4-[(1R or 1S)-1-(piperazin-1-yl)ethyl]pyridin-2-yl}-1H-benzimidazol-2-amine hydrochloride (45 mg, see Compound 55.04.01), Example 55.02.01 was prepared analogously to the procedure for the preparation of Example 39.02.02.
Yield: 18 mg of the 92% pure title compound.
LC-MS (Method 2): Rt = 1.17 min; MS (ESIpos): m/z = 589 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.30 (d, 3H), 1.47- 1.59 (m, 1H), 1.64- 1.77 (m, 1H), 2.22 - 2.47 (m, 5H), 3.39 - 3.52 (m, 5H), 3.62 (q, 2H), 4.17 - 4.34 (m, 2H), 6.93 (d, 1H), 7.17 (s, 1H), 7.21 -7.67 (m, 3H), 7.78-7.90 (m, 1H), 8.04-8.16 (m, 1H), 8.25 (d, 1H), 10.57 (br s, 1H), 12.04 (brd, 1H).
Example 55.02.02
1-{4-[(1R or 1S)-1-(2-{[6-(1-{[(1R or 1S)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)- 1 H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}-3,3,3-trif luoropropan-1 -one
Figure imgf000866_0002
Starting with 6-(1-{[(1R or 1S)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-N-{4-[(1R or 1S)-1-(piperazin-1-yl)ethyl]pyridin-2-yl}-1H-benzimidazol-2-amine hydrochloride (37 mg, see Compound 55.04.02), Example 55.02.02 was prepared analogously to the procedure for the preparation of Example 39.02.02.
Yield: 19 mg of the 93% pure title compound.
LC-MS (Method 2): R, = 1.17 min; MS (ESIpos): m/z = 589 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.30 (d, 3H), 1.48 - 1.59 (m, 1H), 1.70 (tdd, 1H), 2.23 - 2.47 (m, 5H), 3.39 - 3.53 (m, 5H), 3.62 (q, 2H), 4.14 - 4.34 (m, 2H), 6.93 (dd, 1H), 7.17 (s, 1H), 7.20-7.48 (m, 2H), 7.51 -7.67 (m, 1H), 7.79-7.90 (m, 1H), 8.04- 8.17 (m, 1H), 8.25 (d, 1H), 10.57 (brs, 1H), 12.04 (brd, 1H).
Example 55.03
cyclopropyl{4-[(1 R or 1 S)-1 -(2-{[6-(1 -{[(1 RS)-2,2-difluorocyclopropyl]methyl}-1 H-pyrazol- 4-yl)-1H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}methanone
Figure imgf000867_0001
Starting with 6-(1-{[(1RS)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-N-{4-[(1R or 1S)-1- (piperazin-1-yl)ethyl]pyridin-2-yl}-1H-benzimidazol-2-amine hydrochloride salt (210 mg, Compound 55.04), Example 55.03 was prepared analogously to the procedure for the preparation of Example 39.02.03.
Yield: 112 mg of the 94% pure title compound.
LC-MS (Method 2): Rt = 1.12 min; MS (ESIpos): m/z = 548 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 0.64 - 0.75 (m, 4H), 1.38 (br d, 2H), 1.45 - 1.60 (m, 1H), 1.71 (tdd, 1H), 1.87-2.01 (m, 1H), 2.21 -2.32 (m, 1H), 3.13-3.87 (m, 9H), 4.20-4.36 (m, 2H), 7.12 (d, 1H), 7.22 (s, 1 H), 7.40 - 7.56 (m, 3H), 7.66 (d, 1H), 7.90 (s, 1H), 8.17 (s, 1H), 8.38 (d, 1H), 8.54 (dd, 1H), 8.77 (dd, 1H). Example 55.03.01
cyclopropyl{4-[(1R or 1S)-1-(2-{[6-(1-{[(1R or 1S)-2,2-difluorocyclopropyl]methyl}-1H- pyrazol-4-yl)-1H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}methanone
Figure imgf000868_0001
Starting with 6-(1-{[(1R or 1S)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-N-{4-[(1R or 1S)-1-(piperazin-1-yl)ethyl]pyridin-2-yl}-1H-benzimidazol-2-amine hydrochloride (45 mg, see Compound 55.04.01), Example 55.03.01 was prepared analogously to the procedure for the preparation of Example 39.02.03.
Yield: 19 mg of the 90% pure title compound.
LC-MS (Method 2): R, = 1.13 min; MS (ESIpos): m/z = 547 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 0.61 - 0.75 (m, 4H), 1.28 - 1.33 (m, 3H), 1.53 (ddt, 1H), 1.65 - 1.78 (m, 1H), 1.89 - 1.97 (m, 1H), 2.20 - 2.45 (m, 5H), 3.40 - 3.53 (m, 3H), 3.60 - 3.75 (m, 2H), 4.19 - 4.34 (m, 2H), 6.94 (dd, 1H), 7.17 (s, 1H), 7.20 - 7.48 (m, 2H), 7.50 - 7.68 (m, 1H), 7.77 - 7.90 (m, 1H), 8.04 - 8.16 (m, 1H), 8.26 (d, 1H), 10.57 (br s, 1H), 12.03 (br s, 1H).
Example 55.03.02
cyclopropyl{4-[(1R or 1S)-1-(2-{[6-(1-{[(1R or 1S)-2,2-difluorocyclopropyl]methyl}-1H- pyrazol-4-yl)-1H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}methanone
Figure imgf000868_0002
Starting with 6-(1-{[(1R or 1S)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-N-{4-[(1R or 1S)-1-(piperazin-1-yl)ethyl]pyridin-2-yl}-1H-benzimidazol-2-amine hydrochloride (37 mg, see Compound 55.04.02), Example 55.03.02 was prepared analogously to the procedure for the preparation of Example 39.02.03.
Yield: 18 mg of the 93% pure title compound.
LC-MS (Method 2): R, = 1.13 min; MS (ESIpos): m/z = 547 [M+H]+
H-NMR (400MHz, DMSO-d6): δ [ppm] = 0.60 - 0.75 (m, 4H), 1.30 (d, 3H), 1.47- 1.58 (m, 1H), 1.70 (tdd, 1H), 1.87 - 1.99 (m, 1H), 2.19 - 2.43 (m, 5H), 3.39 - 3.55 (m, 3H), 3.67 (br s, 2H), 4.17-4.36 (m, 2H), 6.94 (dd, 1H), 7.17 (s, 1H), 7.20-7.48 (m, 2H), 7.49-7.68 (m, 1H), 7.77- 7.92 (m, 1H), 8.02- 8.17 (m, 1H), 8.26 (d, 1H), 10.57 (brs, 1H), 12.04 (brd, 1H).
Example 56.01
tert-butyl 4-[(1R or 1S)-1-(2-{[6-(1-{[(1RS,2RS)-2-methylcyclopropyl]methyl}-1H
4-yl)-1H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1 -carboxylate
Figure imgf000869_0001
Starting with 4-(1-{[(1RS,2RS)-2-methylcyclopropyl]methyl}-1H-pyrazol-4-yl)benzene-1,2- diamine (350 mg, 1.44 mmol, Compound 56.03), Example 56.01 was prepared analogously to the procedure for the preparation of Example 39.02.01.
Yield: 188 mg of the 83% pure title compound.
LC-MS (Method 2): Rt = 1.38 min; MS (ESIpos): m/z = 557 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 0.22 - 0.35 (m, 1H), 0.55 (dt, 1 H), 0.77 - 0.89 (m, 1 H), 0.94 - .00 (m, 1 H), 0.99 - 1.05 (m, 3H), 1.28 (d, 3H), 1.38 (s, 9H), 2.24 - 2.34 (m, 2H), 2.34-2.44 (m, 2H), 3.32 (brs, 4H), 3.43 (q, 1H), 3.88-4.20 (m, 2H), 6.92 (dd, 1H), 7.16 (s, 1H), 7.18-7.48 (m, 2H), 7.49-7.67 (m, 1H), 7.79 (brs, 1H), 8.08 (brs, 1H), 8.24 (d, 1H), 10.56 (brs, 1H), 12.02 (brs, 1H). Example 56.02
3,3,3-trifluoro-1 -{4-[(1 R or 1 S)-1 -(2-{[6-(1 -{[(1 RS,2RS)-2-methylcyclopropyl]methyl}-1 H- pyrazol-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}propan-1 -one
Figure imgf000870_0001
Starting with 6-(1 -{[(1 RS,2RS)-2-methylcyclopropyl]methyl}-1 H-pyrazol-4-yl)-N-{4-[(1 R or 1 S)- 1 -(piperazin-1-yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride salt (310 mg, Compound 56.04), Example 56.02 was prepared analogously to the procedure for the preparation of Example 39.02.02.
Yield: 101 mg of the 93% pure title compound.
LC-MS (Method 2): Rt = 1.22 min; MS (ESIpos): m/z = 568 [M+H]+
1 H-NMR (400MHz, DMSO-d6): δ [ppm] = 0.26 - 0.35 (m, 1 H), 0.55 (dt, 1 H), 0.77 - 0.89 (m, 1 H), 0.92 - 1.00 (m, 1 H), 0.99 - 1.06 (m, 3H), 1.30 (d, 3H), 2.27 - 2.46 (m, 4H), 3.40 - 3.52 (m, 5H), 3.62 (q, 2H), 3.86 - 4.19 (m, 2H), 6.93 (dd, 1 H), 7.17 (s, 1 H), 7.20 - 7.47 (m, 2H), 7.49 - 7.67 (m, 1 H), 7.78 (br d, 1 H), 8.06 (br d, 1 H), 8.25 (d, 1 H), 10.56 (br s, 1 H), 12.03 (br s, 1 H).
Example 57.01
tert-butyl 4-[(1 R or 1S)-1 -(2-{[6-(1 H-pyrazol-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)ethyl]piperazine-1-carboxylate
Figure imgf000870_0002
tert-butyl 4-[(1 R or 1S)-1-(2-{[6-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1 H-pyrazol-4-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1-carboxylate (500 mg, 808 pmol) Compound 57.03 was solved in 13 mL THF and tetrabutylammonium fluoride (8.1 ml, 1.0 M, 8.1 mmol) was added. This mixture was stirred at 70 *C for 3 hours. The THF was removed under reduced pressure. The residue was diluted with ethyl acetate and water. The layers were separated and the aqueous layer was extracted with dichloromethane /isopropanol (7:3) twice. The combined organic layers were dried using a water resistant filter and the clear filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography. The residue was diluted with water. A beige solid precipitated. It was filtered off under vacuo. The filter cake was dried at 50 "C overnight.
Yield: 276 mg (64%) of the 91 % pure title compound.
LC-MS (Method 2): R, = 1.22 min; MS (ESIpos): m/z = 489 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.28 (d, 3H), 1.38 (s, 9H), 1.48 - 1.68 (m, 2H), 2.20 - 2.34 (m, 2H), 2.34 - 2.43 (m, 2H), 3.09 - 3.21 (m, 2H), 3.43 (q, 1 H), 6.92 (dd, 1 H), 7.16 (s, 1 H), 7.20 - 7.48 (m, 2H), 7.51 - 7.70 (m, 1 H), 7.73 - 8.16 (m, 2H), 8.24 (d, 1 H), 10.54 (br s, 1 H), 12.02 (br s, 1 H), 12.81 (br s, 1 H)
Example 58.01.01
cyclobutyl(4-{[2-({6-[1 -(2,2,2-trifluoroethyl)-1 H-pyrazol-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1 -yl)methanone
Figure imgf000871_0001
Starting with crude N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-6-[1 -(2,2,2-trifluoroethyl)-1 H- pyrazol-4-yl]-1 H-benzimidazol-2-amine hydrochloride (150 mg) and cyclobutanecarboxylic acid (36 μΙ, 360 pmol), Example 58.01.01 was prepared analogously to the procedure for the preparation of Example 16.05.02.
Yield: 60 mg of the title compound.
LC-MS (Method 2): Rt = 1.13 min; MS (ESIpos): m/z = 539 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.036 (0.50), 1 .053 (1.05), 1.071 (0.53), 1.708 (0.47), 1.722 (0.42), 1.732 (0.58), 1.837 (0.42), 1.858 (0.83), 1.882 (0.70), 1.908 (0.42), 2.049 (1.04), 2.058 (0.81 ), 2.074 (3.06), 2.099 (0.75), 2.121 (1.30), 2.143 (1.40), 2.167 (0.70), 2.172 (0.75), 2.346 (3.31 ), 3.297 (0.83), 3.320 (2.36), 3.334 (16.00), 3.436 (0.41 ), 3.441 (0.46), 3.471 (1.81 ), 3.487 (4.84), 5.133 (0.95), 5.155 (0.95), 5.758 (0.87), 6.903 (1.34), 6.917 (1.36), 7.180 (1.86), 7.271 (0.49), 8.241 (1.99), 8.254 (1.89), 10.599 (1.21 ), 12.056 (1.14). Example 58.01.02
3,3,3-trifluoro-1 -(4-{[2-({6-[1 -(2,2,2-trifluoroethyl)-1 H-pyrazol-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1 -yl)propan-1 -one
Figure imgf000872_0001
Starting with crude N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-6-[1 -(2,2,2-trifluoroethyl)-1 H- pyrazol-4-yl]-1 H-benzimidazol-2-amine hydrochloride (150 mg) and 3,3,3-trifluoropropanoic acid (32 μΙ, 360 pmol), Example 58.01.02 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 30 mg of the title compound.
LC-MS (Method 2): R, = 1.1 1 min; MS (ESIneg): m/z = 565 [M-H]-
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.368 (3.26), 2.380 (4.90), 2.392 (3.68), 2.409 (3.28), 2.421 (4.57), 2.432 (3.52), 2.461 (1.23), 2.465 (1.31 ), 2.470 (1.18), 2.518 (4.12), 2.523 (2.80), 3.382 (0.42), 3.457 (3.28), 3.471 (4.53), 3.482 (3.96), 3.494 (3.96), 3.517 (16.00), 3.609 (2.28), 3.637 (6.68), 3.664 (6.22), 3.692 (1.90), 4.047 (1.86), 5.135 (2.15), 5.155 (2.15), 6.913 (4.05), 6.916 (3.85), 6.926 (4.03), 6.929 (3.90), 7.189 (4.18), 7.266 (1.12), 7.323 (0.72), 7.449 (0.66), 7.565 (0.92), 7.659 (0.77), 7.943 (0.88), 8.001 (0.98), 8.146 (0.94), 8.195 (1.03), 8.248 (6.52), 8.262 (6.15), 10.601 (3.15), 12.055 (3.92).
Example 58.01.03
cyclopropyl(4-{[2-({6-[1 -(2,2,2-trifluoroethyl)-1 H-pyrazol-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1 -yl)methanone
Figure imgf000872_0002
Starting with crude N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-6-[1-(2,2,2-trifluoroethyl)-1 H- pyrazol-4-yl]-1 H-benzimidazol-2-amine hydrochloride (150 mg) and cyclopropanecarboxylic acid (30 μΙ, 360 prnol), Example 58.01.03 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 60.0 mg of the title compound.
LC-MS (Method 2): Rt = 1.07 min; MS (ESIpos): m/z = 524 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.675 (0.67), 0.682 (1.52), 0.687 (0.95), 0.694 (0.75), 0.701 (1.83), 0.707 (1.47), 0.712 (1.61 ), 0.720 (1.53), 0.724 (1.84), 0.731 (0.85), 1.962 (0.67), 2.074 (0.70), 2.359 (0.74), 2.441 (0.76), 2.518 (0.75), 2.522 (0.51 ), 3.333 (16.00), 3.701 (0.70), 5.133 (0.63), 5.154 (0.62), 6.919 (0.96), 6.922 (0.95), 6.932 (0.96), 6.935 (0.98), 7.194 (1.32), 8.250 (1.54), 8.263 (1.46), 10.606 (0.78), 12.060 (0.73).
Example 59.01.01
tert-butyl 4-{(1 R or 1S)-1 -[2-({6-[1-(cyclobutylmethyl)-1 H-pyrazol-4-yl]-1H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate (Single Stereoisomer A)
Figure imgf000873_0001
To a stirred solution of 1 H-imidazole (24.4 mg, 359 μιηοΙ) and di-1 H-imidazol-1 - ylmethanethione (427 mg, 90 % purity, 2.15 mmol) in dichloromethane (5 mL) was added tert- butyl 4-[(1 R or 1 S)-1-(2-aminopyridin-4-yl)ethyl]piperazine-1-carboxylate (Single Stereoisomer A) (Compound 36.05) (550 mg, 1.79 mmol), dissolved in dichloromethane (10 mL) at r.t. The mixture was stirred at r.t. for 14 h. 4-[1 -(Cyclobutylmethyl)-1 H-pyrazol-4-yl]benzene-1 ,2- diamine (538 mg, 2.15 mmol, Compound 59.03), dissolved in dichloromethane (10 mL) was added and the mixture was stirred at r.t. for 14 h. Silicagel chromatography of the crude reaction mixture gave 1.80 g of a solid that was dissolved in dichloromethane (22 mL). EDC (385 mg, 2.01 mmol) was added and the mixture was stirred for 62 h. Further EDC (385 mg, 2.01 mmol) was added and the mixture was stirred for 4 h. Dichloromethane and methanol (10:1 mixture) and water were added, the mixture was stirred for 30 minutes. Saturated ammonium chloride solution was added and the mixture was extracted with dichloromethane. Aminophase-silicagel chromatography followed by silicagel chromatography gave 680 mg of the title compound.
LC- S (Method 2): R, = 1.40 min; MS (ESIpos): m/z = 557 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.273 (1.79), 1.290 (1.76), 1.376 (16.00), 1.793 (0.43), 1.81 1 (0.67), 1.822 (0.74), 1.826 (0.69), 1.831 (0.80), 1.840 (0.47), 1.991 (0.50), 2.000 (0.45), 2.004 (0.40), 2.012 (0.46), 2.292 (0.42), 2.305 (0.50), 2.378 (0.50), 2.390 (0.44), 2.518 (0.84), 2.523 (0.57), 3.421 (0.46), 3.437 (0.45), 4.120 (0.81 ), 4.138 (0.79), 6.908 (0.56), 6.91 1 (0.57), 6.922 (0.57), 6.924 (0.57), 7.155 (0.85), 8.237 (0.95), 8.250 (0.89).
Example 59.01.02
1 -(4-{(1 R or 1S)-1 -[2-({6-[1 -(cyclobutylmethyl)-l H-pyrazol-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)-3,3,3-trifluoropropan-1-one (Single
Stereoisomer A)
Figure imgf000874_0001
Starting with crude 6-[1 -(cyclobutylmethyl)-1 H-pyrazol-4-yl]-N-{4-[(1 R or 1 S)-1 -(piperazin-1- yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride (single stereoisomer A) (150 mg, Compound 59.04) and 3,3,3-trifluoropropanoic acid (22 μΙ, 240 μιτιοΙ), Example 59.01.02 was prepared analogously to the procedure for the preparation of Example 16.05.02.
Yield: 35.0 mg of the title compound.
LC-MS (Method 2): R, = 1.24 min; MS (ESIpos): m/z = 567 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.070 (0.67), 1.087 (1.34), 1.105 (0.71 ), 1.230 (0.78), 1.287 (15.71 ), 1.303 (16.00), 1.353 (0.80), 1.771 (2.90), 1.791 (4.72), 1.811 (7.62), 1.822 (8.44), 1.831 (8.92), 1.858 (4.62), 1.880 (2.75), 1.897 (1.18), 1.969 (2.58), 1.983 (4.09), 1.991 (5.21 ), 1.999 (5.33), 2.012 (5.19), 2.326 (4.98), 2.336 (5.27), 2.423 (5.94), 2.668 (1.34), 2.741 (1.20), 2.758 (2.56), 2.777 (3.32), 2.795 (2.71 ), 2.815 (1.26), 3.144 (0.40), 3.370 (1.47), 3.388 (1.41 ), 3.434 (10.48), 3.452 (8.21 ), 3.470 (10.58), 3.578 (3.07), 3.605 (8.29), 3.632 (7.96), 3.660 (2.79), 4.120 (1 1.04), 4.138 (10.84), 6.920 (5.71 ), 6.934 (5.90), 7.167 (9.07), 7.226 (3.00), 7.245 (3.89), 7.372 (1.34), 7.566 (1.93), 7.776 (4.87), 8.037 (4.16), 8.246 (7.48), 8.260 (7.24), 10.570 (3.93), 12.030 (3.21 ). Example 59.01.03
(4-{(1 R or 1S)-1 -[2-({6-[1-(cyclobutylmethyl)-1H-pyrazol-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)(cyclopropyl)methanone (Single Stereoisomer A)
Figure imgf000875_0001
Starting with crude 6-[1-(cyclobutylmethyl)-1 H-pyrazol-4-yl]-N-{4-[(1 R or 1 S)-1 -(piperazin-1 - yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride (single stereoisomer A) (150 mg, Compound 59.04) and cyclopropanecarboxylic acid (20 μΙ, 240 pmol), Example 59.01.03 was prepared analogously to the procedure for the preparation of Example 16.05.02.
Yield: 40.0 mg of the title compound.
LC-MS (Method 2): R, = 1.20 min; MS (ESIpos): m/z = 525 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.661 (8.93), 0.689 (1 1.46), 0.700 (11.20), 0.768 (0.88), 0.849 (0.68), 1.006 (0.43), 1.070 (3.51 ), 1.087 (6.63), 1.105 (3.67), 1.178 (1.68), 1.232 (2.87), 1.288 (15.91 ), 1.304 (16.00), 1.770 (2.99), 1.791 (4.82), 1.810 (7.73), 1.829 (8.97), 1.857 (4.72), 1.878 (2.86), 1.898 (2.27), 1.918 (3.12), 1.930 (4.02), 1.967 (2.98), 1.982 (4.24), 1.990 (5.35), 1.998 (5.46), 2.010 (5.26), 2.324 (2.74), 2.389 (4.27), 2.670 (0.95), 2.739 (1.16), 2.758 (2.54), 2.776 (3.26), 2.795 (2.66), 2.814 (1.23), 3.144 (0.41 ), 3.370 (3.87), 3.387 (3.66), 3.405 (1.96), 3.433 (5.55), 3.450 (7.55), 3.466 (6.74), 3.666 (5.60), 4.119 (9.58), 4.137 (9.41 ), 6.926 (5.82), 6.939 (5.94), 7.176 (9.15), 7.241 (2.87), 7.297 (1.03), 7.413 (1.05), 7.533 (1.32), 7.607 (1 .11 ), 7.778 (2.55), 8.037 (2.08), 8.246 (7.18), 8.260 (6.82), 10.573 (3.64), 12.031 (3.43).
Example 59.02.01
1 -(4-{[2-({6-[1-(cyclobutylmethyl)-1 H^yrazol-4-yl]-1 H-benzimidazol-2-yl}amino)pyridin-4- yl]methyl}piperazin-1 -yl)-3,3,3-trifluoropropan-1-one
Figure imgf000876_0001
Starting with crude 6-[1-(cyclobutylmethyl)-1 H-pyrazol-4-yl]-N-[4-(piperazin-1 -ylmethyl)pyridin- 2-yl]-1 H-benzimidazol-2-amine hydrochloride (125 mgCompound 59.06) and 3,3,3- trifluoropropanoic acid (24 μΙ, 260 μιτιοΙ), Example 59.02.01 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 30.0 mg of the title compound.
LC-MS (Method 2): Rt = 1.20 min; MS (ESIpos): m/z = 553 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.753 (0.47), 1.772 (1.89), 1.793 (3.00), 1 .81 1 (4.58), 1.819 (3.81 ), 1.822 (5.20), 1.826 (4.74), 1.831 (5.51 ), 1.840 (3.21 ), 1.849 (2.15), 1.859 (2.64), 1.874 (1.22), 1.881 (1.73), 1.898 (0.67), 1.969 (1.71 ), 1.983 (2.59), 1.991 (3.44), 2.000 (3.00), 2.004 (2.74), 2.012 (3.21 ), 2.030 (1.32), 2.336 (0.62), 2.365 (3.34), 2.378 (4.94), 2.390 (3.73), 2.406 (3.60), 2.419 (4.89), 2.430 (3.68), 2.518 (6.42), 2.522 (4.27), 2.539 (0.60), 2.740 (0.78), 2.759 (1.71 ), 2.777 (2.20), 2.796 (1.84), 2.815 (0.80), 3.456 (3.55), 3.469 (4.76), 3.481 (4.04), 3.513 (16.00), 3.608 (2.36), 3.636 (6.76), 3.663 (6.34), 3.690 (1.97), 4.046 (0.54), 4.120 (5.46), 4.139 (5.28), 6.906 (3.99), 6.908 (3.86), 6.919 (4.01 ), 6.922 (3.94), 7.187 (4.58), 7.234 (1.22), 7.293 (0.67), 7.414 (0.80), 7.522 (0.96), 7.615 (0.78), 7.752 (0.98), 7.800 (1.1 1 ), 8.013 (0.93), 8.060 (1.06), 8.241 (6.45), 8.255 (6.06), 10.571 (1.99), 12.010 (2.77).
Example 59.02.02
(4-{[2-({6-[1-(cyclobutylmethyl)-1 H^yrazol-4-yl]-1H^enzimidazol-2-yl}amino)pyridin-4- yl]methyl}piperazin-1 -yl)(cyclopropyl)methanone
Figure imgf000877_0001
Starting with crude 6-[1-(cyclobutylmethyl)-1 H-pyrazol-4-yl]-N-[4-(piperazin-1 -ylmethyl)pyridin- 2-yl]-1 H-benzimidazol-2-amine hydrochloride (125 mg, Compound 59.06) and cyclopropanecarboxylic acid (22 μΙ, 260 pmol), Example 59.02.02 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 30.0 mg of the title compound.
LC- S (Method 2): R, = 1.16 min; MS (ESIpos): m/z = 51 1 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.663 (1.08), 0.675 (3.17), 0.682 (7.25), 0.688 (4.33), 0.695 (3.51 ), 0.702 (8.75), 0.707 (7.13), 0.712 (7.52), 0.719 (7.03), 0.724 (8.45), 0.731 (3.81 ), 0.743 (0.93), 1.752 (0.49), 1.772 (2.02), 1.792 (3.22), 1.798 (1.99), 1.81 1 (4.94), 1.818 (4.01 ), 1.822 (5.70), 1.826 (5.24), 1 .831 (6.05), 1.840 (3.47), 1.849 (2.26), 1.859 (2.85), 1.874 (1.33), 1.881 (1.89), 1.898 (0.76), 1.931 (0.93), 1.944 (1.94), 1.951 (2.02), 1.955 (1.67), 1.963 (4.13), 1.969 (3.12), 1.983 (4.25), 1.991 (3.96), 1.996 (3.22), 2.000 (3.32), 2.004 (2.92), 2.012 (3.49), 2.030 (1.40), 2.322 (1.40), 2.326 (1.89), 2.331 (1.72), 2.361 (3.29), 2.442 (3.59), 2.518 (5.73), 2.522 (3.96), 2.539 (0.91 ), 2.659 (0.54), 2.664 (1.08), 2.668 (1.45), 2.673 (1.03), 2.678 (0.47), 2.740 (0.79), 2.759 (1.82), 2.777 (2.33), 2.796 (1.99), 2.815 (0.91 ), 3.513 (16.00), 3.701 (3.07), 4.120 (10.37), 4.138 (10.10), 6.912 (4.45), 6.914 (4.28), 6.925 (4.40), 6.927 (4.37), 7.221 (3.32), 7.238 (3.96), 7.363 (1.1 1 ), 7.571 (1.89), 7.774 (5.46), 8.036 (4.60), 8.239 (6.69), 8.252 (6.32).
Example 60.01
1-{4-[(2-{[6-(6-chloro-5-methoxypyrimidin-4-yl)-1H-benzimidazol-2-yl]amino}pyrid yl)methyl]piperazin-1-yl}-3,3,3-trifluoropropan-1 -one
Figure imgf000878_0001
Starting with crude 6-(6-chloro-5-methoxypyrimidin-4-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2- yl]-1 H-benzimidazol-2-amine hydrochloride (150 mg, Compound 60.02) and 3,3,3- trifluoropropanoic acid (82 μΙ, 920 pmol), Example 60.01 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 12.2 mg of the title compound.
LC-MS (Method 2): R, = 1.14 min; MS (ESIpos): m/z = 561 [M+H]+
1H-NMR (500 MHz, DMSO-d6) δ [ppm]: 2.354 (0.60), 2.358 (1.33), 2.361 (1.91 ), 2.365 (1.73), 2.375 (4.08), 2.385 (6.04), 2.395 (4.26), 2.417 (4.05), 2.427 (5.80), 2.436 (4.31 ), 2.515 (5.86), 2.518 (5.57), 2.522 (4.29), 2.540 (1.41 ), 2.631 (1.05), 2.635 (1.57), 2.639 (1.20), 3.464 (4.16), 3.474 (5.54), 3.484 (4.29), 3.500 (4.21 ), 3.510 (5.33), 3.519 (4.89), 3.531 (16.00), 3.619 (2.64), 3.642 (7.35), 3.663 (7.08), 3.685 (3.24), 3.694 (3.01 ), 3.737 (8.08), 4.024 (3.74), 4.048 (1.65), 6.954 (2.85), 6.964 (2.67), 7.187 (5.12), 7.446 (1.28), 7.462 (1.39), 7.958 (1.28), 7.975 (1.15), 8.1 17 (0.84), 8.284 (4.63), 8.294 (4.37), 8.410 (2.17), 8.795 (3.40), 10.836 (1.12), 12.329 (0.92), 12.368 (2.12).
Example 61.01.01
3,3,3-trifluoro-1 -{4-[(2-{[6-(5-methoxy-6-methylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}propan-1 -one
Figure imgf000879_0001
Starting with crude 6-(5-methoxy-6-methylpyrimidin-4-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2- yl]-1 H-benzimidazol-2-amine hydrochloride (90.0 mg, Compound 61.02) and 3,3,3- trifluoropropanoic acid (24 μΙ, 270 μιηοΙ), Example 61.01.01 was prepared analogously to the procedure for the preparation of Example 16.05.02.
Yield: 40.0 mg of the title compound.
LC-MS (Method 2): R, = 1.04 min; MS (ESIneg): m/z = 539 [M-H]-
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.394 (16.00), 2.373 (0.58), 2.385 (0.87), 2.397 (0.64), 2.415 (0.64), 2.427 (0.86), 2.513 (8.64), 2.523 (0.80), 3.462 (0.64), 3.474 (0.86), 3.486 (0.71 ), 3.498 (0.70), 3.512 (0.89), 3.528 (2.45), 3.556 (0.56), 3.587 (1.1 1 ), 3.61 1 (0.45), 3.638 (1.15), 3.666 (1.08), 5.759 (1.93), 6.941 (0.58), 6.954 (0.58), 7.188 (1.06), 8.274 (1.06), 8.287 (1.00), 8.800 (1 .09).
Example 61.01.02
cyclopropyl{4-[(2-{[6-(5-methoxy-6-methylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}methanone
Figure imgf000879_0002
Starting with crude 6-(5-methoxy-6-methylpyrimidin-4-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2- yl]-1 H-benzimidazol-2-amine hydrochloride (51.5 mg, Compound 61.02) and cyclopropanecarboxylic acid (28 μΙ, 360 pmol), Example 61.01.02 was prepared analogously to the procedure for the preparation of Example 16.05.02.
Yield: 16.0 mg of the title compound.
LC-MS (Method 2): R, = 0.98 min; MS (ESIpos): m/z = 499 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.678 (0.74), 0.686 (1.72), 0.691 (1.06), 0.698 (0.84), 0.705 (2.05), 0.710 (1.71 ), 0.714 (1.80), 0.722 (1.64), 0.726 (1.90), 0.733 (0.84), 1.232 (1.03), 1.969 (0.74), 2.366 (0.77), 2.434 (0.81 ), 2.451 (1.12), 2.514 (16.00), 2.518 (4.36), 2.523 (2.64), 2.674 (0.62), 3.159 (3.61 ), 3.172 (3.99), 3.528 (3.48), 3.551 (1.05), 3.589 (1.84), 3.71 1 (0.72), 4.096 (0.83), 4.1 10 (0.80), 6.949 (0.77), 6.963 (0.77), 7.196 (1.22), 8.276 (1.55), 8.289 (1.43), 8.799 (1.36).
Example 62.01.01
tert-butyl 4-{[2-({6-[2-(cyclopropylmethoxy)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate
Figure imgf000880_0001
To a stirred solution of cyclopropylmethanol (1000 μΙ, 12 mmol) in NMP (1 mL) was added sodium hydride (55%w/w in oil; 33.5 mg, 768 μιτιοΙ) at r.t. and the mixture was stirred for 10 minutes. Tert-butyl 4-[(2-{[6-(2-chloropyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate (100 mg, 192 pmol) was added and the mixture was stirred at 80 Ό for 1 h. Water was added and the mixture wa s extracted with ethyl acetate. The organic phase was dried (sodium sulfate), filtered and the solvent was removed in vacuum.
Silicagel chromatography followed by aminophase-silicagel chromatography gave a solid that was triturated with ethanol to give 70.0 mg of the title compound.
LC-MS (Method 2): Rt = 1.39 min; MS (ESIpos): m/z = 557 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.385 (0.84), 0.397 (0.81 ), 0.401 (0.80), 1.395 (16.00), 2.359 (1.29), 2.371 (0.92), 3.331 (9.28), 3.351 (1.01 ), 8.537 (1.31 ), 8.551 (1.20). Example 62.01.02
cyclobutyl(4-{[2-({6-[2-(cyclopropylmethoxy)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1 -yl)methanone
Figure imgf000881_0001
Starting with crude 6-[2-(cyclopropylmethoxy)pyrimidin-4-yl]-N-[4-(piperazin-1 -ylmethyl)pyridin- 2-yl]-1 H-benzimidazol-2-amine hydrochloride (200 mg, Compound 62.02) and cyclobutanecarboxylic acid (37 μΙ, 370 pmol), Example 62.01.02 was prepared analogously to the procedure for the preparation of Example 16.05.02.
Yield: 55.0 mg of the title compound.
LC-MS (Method 2): F¾ = 1.23 min; MS (ESIpos): m/z = 539 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.374 (2.07), 0.385 (8.20), 0.389 (7.07), 0.396 (7 67),
0 401 (7 39), 0.41 1 (2.77), 0.570 (1.98), 0.580 (5.44), 0.585 (5.50), 0.590 (3.27), 0.601 (6 10),
0 605 (5 38), 0.617 (1.89), 1.035 (0.88), 1.052 (2.01 ), 1.070 (0.88), 1.291 (0.60), 1.297 (0 88),
1 309 (1 67), 1.317 (1.54), 1.329 (2.45), 1.341 (1.57), 1.348 (1.60), 1.361 (0.85), 1.684 (0 60),
1 702 (0 94), 1.710 (1.70), 1.720 (1.48), 1.723 (1.51 ), 1.734 (2.14), 1.744 (1.26), 1.756 (0 97),
1 767 (0 53), 1.816 (0.44), 1.839 (1.79), 1.860 (3.49), 1.866 (1.51 ), 1.883 (2.67), 1.888 (2 55),
1 905 (1 32), 1.910 (1.60), 1.931 (0.69), 2.022 (0.97), 2.031 (1.10), 2.036 (1.07), 2.051 (3 87),
2 061 (2 80), 2.067 (2.80), 2.073 (4.43), 2.082 (3.33), 2.088 (1.54), 2.100 (2.55), 2.123 (5 06),
2 128 (3 36), 2.144 (5.53), 2.149 (4.18), 2.152 (3.68), 2.168 (2.51 ), 2.173 (2.80), 2.191 (0 63),
2 197 (0 85), 2.318 (1.07), 2.322 (2.01 ), 2.326 (2.95), 2.332 (3.61 ), 2.352 (11.10), 2.518 (7 23),
2 522 (5 06), 2.660 (0.72), 2.664 (1.41 ), 2.668 (1.89), 2.673 (1.35), 2.678 (0.63), 3.279 (0 82),
3 303 (3 27), 3.344 (7.92), 3.366 (1.26), 3.422 (0.63), 3.435 (0.79), 3.439 (0.88), 3.452 (1 89),
3 474 (5 50), 3.502 (16.00), 4.240 (5.06), 4.257 (4.31 ), 4.343 (0.85), 4.355 (0.97), 6.942 (3 21 ),
7 188 (6 54), 7.412 (1.29), 7.433 (1.38), 7.580 (2.23), 7.593 (2.11 ), 7.686 (0.94), 7.917 (2 39),
7 939 (2.14), 8.191 (1.38), 8.274 (3.36), 8.391 (2.23), 8.538 (13.86), 8.551 (12.23), 10 729
(0.88), 10.801 (1.38), 12.293 (1.70), 12.323 (2.51 ). Example 62.01.03
1-(4-{[2-({6-[2-(cyclopropylmethoxy)pyrimidin^-yl]-1 H-benzimidazol-2-yl}amino)pyridin- 4-yl]methyl}piperazin-1 -yl)-3,3,3-trifluoropropan-1 -one
Figure imgf000882_0001
Starting with crude 6-[2-(cyclopropylmethoxy)pyrimidin-4-yl]-N-[4-(piperazin-1 -ylmethyl)pyridin- 2-yl]-1 H-benzimidazol-2-amine hydrochloride (200 mg, Compound 62.02) and 3,3,3- trifluoropropanoic acid (33 μΙ, 370 pmol), Example 62.01.03 was prepared analogously to the procedure for the preparation of Example 16.05.02.
Yield: 65.0 mg of the title compound.
LC-MS (Method 2): R, = 1.20 min; MS (ESIpos): m/z = 567 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.374 (1.95), 0.384 (7.72), 0.389 (6.82), 0.396 (7.43), 0.401 (7.15), 0.410 (2.62), 0.570 (2.00), 0.580 (5.48), 0.585 (5.45), 0.590 (3.05), 0.596 (3.35), 0.601 (5.99), 0.605 (5.45), 0.616 (1.79), 1.035 (0.43), 1.053 (0.77), 1 .070 (0.44), 1.291 (0.58), 1.297 (0.85), 1.309 (1.60), 1.317 (1.49), 1.321 (1.20), 1.329 (2.50), 1 .337 (1.22), 1.341 (1.46), 1.349 (1.52), 1.361 (0.81 ), 2.323 (0.62), 2.327 (0.87), 2.332 (0.66), 2.370 (3.83), 2.383 (5.79), 2.396 (4.35), 2.412 (4.20), 2.424 (5.62), 2.436 (4.14), 2.518 (2.66), 2.523 (2.02), 2.665 (0.55), 2.669 (0.79), 2.673 (0.52), 3.460 (4.19), 3.473 (5.67), 3.484 (4.58), 3.497 (4.46), 3.510 (5.70), 3.528 (16.00), 3.610 (2.90), 3.637 (8.21 ), 3.665 (7.78), 3.693 (2.46), 4.239 (5.05), 4.256 (4.70), 4.357 (0.52), 6.949 (3.16), 6.961 (2.93), 7.198 (7.60), 7.416 (1.05), 7.438 (1.12), 7.584 (1.79), 7.687 (0.75), 7.918 (2.69), 7.939 (2.35), 8.193 (0.99), 8.278 (3.60), 8.291 (3.36), 8.393 (1.73), 8.538 (13.90), 8.551 (12.12), 10.801 (1.05), 12.300 (1.54), 12.325 (2.19).
Example 62.01.04
cyclopropyl(4-{[2-({6-[2-(cyclopropylmethoxy)pyrimidin-4-yl]-1H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1 -yl)methanone
Figure imgf000883_0001
Starting with crude 6-[2-(cyclopropylmethoxy)pyrimidin-4-yl]-N-[4-(piperazin-1 -ylmethyl)pyridin- 2-yl]-1 H-benzimidazol-2-amine hydrochloride (200 mg, Compound 62.02) and cyclopropanecarboxylic acid (31 μΙ, 370 pmol), Example 62.01.04 was prepared analogously to the procedure for the preparation of Example 16.05.02.
Yield: 65.0 mg of the title compound.
LC- S (Method 2): R, = 1.16 min; MS (ESIpos): m/z = 525 [M+H]+
H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.375 (1.91 ), 0.386 (7.71 ), 0.389 (6.73), 0.398 (7.42), 0.401 (7.36), 0.41 1 (2.71 ), 0.571 (1.79), 0.581 (5.05), 0.585 (5.23), 0.591 (3.00), 0.601 (5.72), 0.606 (5.23), 0.617 (1 .70), 0.665 (1.10), 0.677 (3.21 ), 0.684 (7.86), 0.690 (4.79), 0.697 (3.67), 0.704 (9.44), 0.709 (7.88), 0.713 (8.43), 0.721 (7.83), 0.726 (9.27), 0.733 (4.16), 0.745 (1.01 ), 1.292 (0.55), 1.297 (0.81 ), 1.31 1 (1.56), 1.318 (1.44), 1.330 (2.43), 1.342 (1.44), 1.349 (1.47), 1.361 (0.81 ), 1.368 (0.49), 1.934 (0.87), 1.946 (1.85), 1.953 (2.02), 1.966 (3.41 ), 1.972 (1.56), 1.978 (1.91 ), 1.985 (1.76), 1.997 (0.78), 2.318 (0.66), 2.322 (1.36), 2.327 (2.02), 2.332 (1.65), 2.337 (1.21 ), 2.363 (3.52), 2.449 (4.30), 2.454 (4.30), 2.459 (3.61 ), 2.463 (2.77), 2.518 (6.56), 2.523 (4.62), 2.660 (0.55), 2.665 (1.21 ), 2.669 (1.76), 2.673 (1.24), 2.678 (0.55), 3.286 (0.72), 3.499 (3.52), 3.528 (16.00), 3.707 (3.35), 4.241 (4.79), 4.258 (4.16), 6.958 (2.92), 7.204 (6.24), 7.416 (1.24), 7.437 (1.30), 7.582 (2.05), 7.595 (1.94), 7.698 (0.84), 7.919 (2.34), 7.941 (2.02), 8.193 (1.21 ), 8.283 (3.15), 8.293 (2.86), 8.392 (2.08), 8.539 (12.51 ), 8.552 (1 1.44), 10.745 (0.81 ), 10.806 (1.36), 12.298 (1.59), 12.328 (2.40).
Example 63.01.01
tert-butyl 4-[(2-{[6-(2-chloro-5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate
Figure imgf000884_0001
To a stirred solution of tert-butyl 4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate (2.50 g, 4.68 mmol, Compound 01.04) in 1-propanol (75 ml) was added a sodium carbonate solution (7.0 ml, 2.0 M, 14 mmol), 2,4-dichloro-5-methoxypyrimidine (2.59 g, 14.0 mmol), triphenylphosphine (123 mg, 468 μηιοΙ) and PdCI2(PPh3)2 (382 mg, 468 μηιοΙ). The mixture was heated to 1 10°C in a sealed tube for 14 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried (sodium sulfate), filtered and the solvent was removed in vacuum. Silicagel chromatography gave a solid that was triturated with cyclopentylmethylether to give 900 mg (35 % yield) of the title compound.
LC-MS (Method 2): R, = 1.30 min; MS (ESIpos): m/z = 551 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.066 (1.06), 1.298 (1.65), 1.394 (16.00), 2.344 (0.87), 2.357 (1.21 ), 2.369 (0.81 ), 3.333 (4.46), 3.349 (0.97), 4.039 (2.24), 8.262 (0.67), 8.275 (0.62), 8.576 (0.71 ).
Example 64.01.01
tert-butyl 4-{[2-({6-[2-(cyclopropylmethoxy)-5-methoxypyrimidin-4-yl]-1 H-benzimidazol-2 yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate
Figure imgf000884_0002
To a stirred solution of cyclopropylmethanol (500 μΙ, 6.3 mmol) in N-methylpyrrolidone (1 mL) was added sodium hydride (55%w/w in oil; 31.7 mg, 726 pmol) at r.t. and the mixture was stirred for 10 minutes. tert-Butyl 4-[(2-{[6-(2-chloro-5-methoxypyrimidin-4-yl)-1 H-benzimidazol- 2-yl]amino}pyridin-4-yl)methyl]piperazine-1-carboxylate (100 mg, 181 pmol) was added and the mixture was stirred at 80 Ό for 1 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried (sodium sulfate), filtered and the solvent was removed in vacuum. Aminophase-silicagel chromatography gave a solid that was triturated with ethanol to give 65.0 mg of the title compound.
LC-MS (Method 2): R, = 1.37 min; MS (ESIpos): m/z = 587 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.356 (0.91 ), 0.360 (0.78), 0.368 (0.87), 0.371 (0.82), 0.560 (0.71 ), 0.564 (0.71 ), 0.580 (0.74), 0.584 (0.67), 1.395 (16.00), 2.347 (0.92), 2.359 (1.33), 2.371 (0.94), 2.518 (0.57), 2.522 (0.41 ), 3.330 (10.26), 3.351 (1.05), 3.928 (2.47), 4.149 (1.02), 4.166 (0.99), 6.928 (0.42), 6.941 (0.41 ), 8.264 (0.52), 8.277 (0.49), 8.418 (1.69).
Example 64.01.02
cyclopropyl(4-{[2-({6-[2-(cyclopropylmethoxy)-5-methoxypyrimidin-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]methyl}piperazin-1 -yl)methanone
Figure imgf000885_0001
Starting with crude 6-[2-(cyclopropylmethoxy)-5-methoxypyrimidin-4-yl]-N-[4-(piperazin-1 - ylmethyl)pyridin-2-yl]-1 H-benzimidazol-2-amine hydrochloride (1 10 mg, Compound 64.01 ) and cyclopropanecarboxylic acid (23 μΙ, 280 pmol), Example 64.01.02 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 65.0 mg of the title compound.
LC-MS (Method 2): R, = 1.19 min; MS (ESIpos): m/z = 555 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.346 (1.69), 0.357 (6.65), 0.361 (5.76), 0.369 (6.38), 0.372 (6.31 ), 0.382 (2.24), 0.551 (1.96), 0.561 (5.24), 0.565 (5.27), 0.571 (2.57), 0.581 (5.52), 0.585 (5.06), 0.596 (1.59), 0.665 (0.98), 0.677 (2.91 ), 0.685 (6.93), 0.690 (4.14), 0.698 (3.16), 0.705 (8.31 ), 0.709 (6.87), 0.714 (7.26), 0.721 (6.74), 0.726 (8.03), 0.733 (3.59), 0.746 (0.89), 0.983 (0.43), 1.002 (0.98), 1.020 (0.52), 1.230 (0.61 ), 1.259 (0.58), 1.265 (0.83), 1.277 (1.47), 1.285 (1.38), 1.297 (2.39), 1.309 (1.29), 1.317 (1.38), 1.329 (0.70), 1.335 (0.46), 1.935 (0.80), 1.947 (1.69), 1.954 (1.72), 1.967 (3.00), 1.979 (1.66), 1.986 (1.53), 1.998 (0.70), 2.323 (1.47), 2.327 (2.05), 2.332 (1.59), 2.337 (1.10), 2.366 (2.97), 2.449 (3.16), 2.518 (6.68), 2.523 (4.87), 2.540 (2.27), 2.660 (0.58), 2.665 (1.32), 2.669 (1.84), 2.673 (1.26), 2.679 (0.55), 3.501 (3.00), 3.526 (14.53), 3.710 (2.85), 3.897 (0.58), 3.930 (16.00), 4.150 (6.93), 4.168 (6.80), 4.274 (0.49), 6.948 (3.03), 6.960 (3.00), 7.191 (2.30), 7.388 (1.01 ), 7.409 (1.10), 7.550 (0.49), 7.866 (0.52), 7.951 (1.07), 7.972 (0.95), 8.130 (0.70), 8.275 (3.71 ), 8.288 (3.56), 8.400 (1.78), 8.419 (12.81 ), 10.681 (0.43), 10.767 (0.98), 12.250 (0.89), 12.290 (1.87).
Example 64.01.03
1 -(4-{[2-({6-[2-(cyclopropylmethoxy)-5-methoxypyrimidin-4-yl]-1 H-benzimidazol^
yl}amino)pyridin-4-yl]methyl}piperazin-1-yl)-3,3,3-trifluoropropan-1-one
Figure imgf000886_0001
Starting with crude 6-[2-(cyclopropylmethoxy)-5-methoxypyrimidin-4-yl]-N-[4-(piperazin-1 - ylmethyl)pyridin-2-yl]-1 H-benzimidazol-2-amine hydrochloride (1 10 mg, Compound 64.01 ) and 3,3,3-trifluoropropanoic acid (25 μΙ, 280 pmol), Example 64.01.03 was prepared analogously to the procedure for the preparation of Example 01.02.
Yield: 55.0 mg of the title compound.
LC-MS (Method 2): R, = 1.22 min; MS (ESIpos): m/z = 597 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.346 (1.60), 0.356 (6.61 ), 0.360 (5.71 ), 0.368 (6.29), 0.372 (6.16), 0.382 (2.27), 0.551 (1.92), 0.561 (5.07), 0.565 (5.20), 0.570 (2.61 ), 0.577 (2.53), 0.581 (5.39), 0.585 (4.96), 0.596 (1.63), 0.983 (0.40), 1.001 (0.99), 1.019 (0.48), 1.027 (0.56), 1.042 (0.40), 1.259 (0.56), 1.265 (0.77), 1.277 (1.39), 1.285 (1.33), 1 .297 (2.43), 1.304 (0.99), 1.309 (1.25), 1.316 (1.36), 1.328 (0.67), 1.335 (0.48), 2.337 (0.40), 2.372 (3.17), 2.384 (4.80), 2.396 (3.60), 2.413 (3.23), 2.425 (4.61 ), 2.437 (3.55), 2.518 (4.48), 2.523 (3.33), 3.144 (1.20), 3.159 (0.83), 3.173 (0.83), 3.319 (0.85), 3.349 (0.85), 3.360 (0.48), 3.370 (0.64), 3.384 (0.48), 3.460 (3.17), 3.473 (4.37), 3.484 (3.81 ), 3.497 (3.76), 3.510 (4.67), 3.527 (14.24), 3.565 (0.56), 3.610 (2.21 ), 3.637 (6.37), 3.665 (6.05), 3.693 (1.89), 3.896 (0.61 ), 3.905 (0.61 ), 3.929 (16.00), 4.048 (2.16), 4.149 (6.83), 4.167 (6.64), 4.273 (0.43), 6.940 (3.01 ), 6.953 (2.93), 7.188 (2.69), 7.388 (0.99), 7.408 (1.07), 7.549 (0.45), 7.866 (0.45), 7.953 (1.04), 7.974 (0.91 ), 8.130 (0.69), 8.273 (3.84), 8.286 (3.73), 8.399 (1.71 ), 8.419 (13.23), 10.684 (0.45), 10.763 (1.07), 12.247 (1.01 ), 12.284 (1.97).
Example 65.01.01
tert-butyl 4-{[2-({6-[6-(cyclopropylmethoxy)-5-methoxypyrimidin-4-yl]-1H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1-carboxylate
Figure imgf000887_0001
To a stirred solution of cyclopropylmethanol (290 μΙ, 3.7 mmol) in N-methylpyrrolidone NMP (1 mL) was added sodium hydride (55%w/w in oil; 108 mg, 2.47 mmol) at r.t. and the mixture was stirred for 10 minutes. tert-Butyl 4-[(2-{[6-(6-chloro-5-methoxypyrimidin-4-yl)-1 H-benzimidazol- 2-yl]amino}pyridin-4-yl)methyl]piperazine-1-carboxylate (340 mg, 617 μηιοΙ) dissolved in NMP (1 mL), was added and the mixture was stirred at 80 Ό for 1 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried (sodium sulfate), filtered and the solvent was removed in vacuum. Silicagel chromatography followed by aminophase-silicagel chromatography gave a solid that was triturated with ethanol to give 160 mg of the title compound. LC-MS (Method 2): R, = 1.43 min; MS (ESIpos): m/z = 587 [M+H]+
H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.399 (0.84), 0.403 (0.72), 0.41 1 (0.79), 0.415 (0.78), 0.591 (0.70), 0.596 (0.71 ), 0.61 1 (0.74), 0.616 (0.67), 1.396 (16.00), 2.349 (0.80), 2.361 (1.18), 2.373 (0.83), 2.518 (0.66), 2.523 (0.47), 3.352 (0.92), 3.502 (1.56), 3.789 (0.86), 4.278 (1.56), 4.296 (1.56), 6.938 (0.40), 8.266 (0.55), 8.279 (0.52), 8.505 (1.37). Example 65.01.02
1 -(4-{[2-({6-[6-(cyclopropylmethoxy)-5-methoxypyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1 -yl)-3,3,3-trifluoropropan-1-one
Figure imgf000888_0001
Starting with crude 6-[6-(cyclopropylmethoxy)-5-methoxypyrimidin-4-yl]-N-[4-(piperazin-1 - ylmethyl)pyridin-2-yl]-1 H-benzimidazol-2-amine hydrochloride (200 mg, Compound 65.01 ) and 3,3,3-trifluoropropanoic acid (68 μΙ, 770 pmol), Example 65.01.02 was prepared analogously to the procedure for the preparation of Example 16.05.02.
Yield: 6.00 mg of the title compound.
LC-MS (Method 2): R, = 1.27 min; MS (ESIpos): m/z = 597 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.389 (1.68), 0.399 (6.85), 0.403 (6.01 ), 0.41 1 (6.57), 0.415 (6.36), 0.425 (2.17), 0.582 (2.10), 0.592 (5.80), 0.597 (5.66), 0.602 (2.93), 0.612 (6.08), 0.617 (5.45), 0.628 (1.75), 1.232 (0.84), 1.305 (0.63), 1.31 1 (0.84), 1.323 (1.54), 1.331 (1.40), 1.343 (2.31 ), 1.355 (1.40), 1.363 (1.47), 1.375 (0.70), 1.382 (0.49), 1.955 (0.49), 2.332 (2.93), 2.336 (1.40), 2.385 (6.01 ), 2.397 (4.68), 2.415 (4.33), 2.427 (5.80), 2.438 (4.40), 2.518 (16.00), 2.522 (10.76), 2.673 (2.93), 2.678 (1.33), 2.897 (0.56), 2.941 (0.56), 3.461 (4.33), 3.474 (5.66), 3.485 (4.68), 3.513 (6.85), 3.527 (16.00), 3.61 1 (2.79), 3.638 (7.76), 3.666 (7.34), 3.693 (2.38), 3.762 (4.82), 3.793 (10.41 ), 3.829 (0.91 ), 3.847 (0.77), 4.025 (0.98), 4.279 (12.44), 4.297 (12.51 ), 6.937 (3.70), 6.949 (3.63), 7.189 (4.68), 7.394 (1.61 ), 7.416 (1.75), 7.552 (0.77), 7.572 (0.84), 7.773 (0.84), 7.794 (0.70), 7.881 (1.54), 7.903 (1.33), 8.052 (1.26), 8.274 (4.54), 8.287 (4.26), 8.318 (2.45), 8.505 (7.97), 10.680 (0.98), 10.742 (1.96), 12.229 (1.40), 12.271 (2.72). Example 66.01.01
tert-butyl 4-[(2-{[6-(5-methyl-1 ,3,4-oxadiazol-2-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4' y l)methyl] pi perazi ne-1 -carboxylate
Figure imgf000889_0001
To a stirred solution of tert-butyl 4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate (500 mg, 936 pmol, Compound 01.04) in 1-propanol (1 1 ml, 150 mmol) in a microwave tube was added a sodium carbonate solution (1.4 ml, 2.0 M, 2.8 mmol), 2-bromo-5-methyl-1 ,3,4-oxadiazole (236 mg, 1.40 mmol), triphenylphosphine (24.5 mg, 93.6 pmol) and PdCI2(PPh3)2 (115 mg, 140 mol). The mixture was heated to 1 10"C for 14 h. Further 2 -bromo-5-methyl-1 ,3,4-oxadiazole (157 mg), triphenylphosphine (24.5 mg, 93.6 pmol) and PdCl2(PPh3)2 ( 15 mg, 140 pmol) were added and the mixture was heated to '\ \ 0Ό for 14 h. The crude reaction mixture was filtered through aminophase-silicagel and the solvent was removed in vacuum. Silicagel chromatography gave 54.0 mg (1 1 % yield) of the title compound.
LC-MS (Method 2): Rt = 1.14 min; MS (ESIpos): m/z = 491 [M-H]+
H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.172 (0.62), 1.394 (16.00), 1.987 (1 .19), 2.309 (1.73), 2.345 (0.94), 2.357 (1.39), 2.369 (0.98), 2.574 (5.80), 2.939 (3.74), 3.333 (7.54), 3.349 (1.13), 5.759 (0.80).
Example 66.01.02
cyclopropyl{4-[(2-{[6-(5-methyl-1 ,3,4-oxadiazol-2-yl)-1 H-benzimidazol-2-yl]amino}pyri yl)methyl]piperazin-1-yl}methanone
Figure imgf000890_0001
Starting with crude 6-(5-methyl-1 ,3,4-oxadiazol-2-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]- 1 H-benzimidazol-2-amine hydrochloride (20.0 mg, Compound 66.01 ) and cyclopropanecarboxylic acid (11 μΙ, 140 pmol), Example 66.01.02 was prepared analogously to the procedure for the preparation of Example 16.05.02.
Yield: 2.00 mg of the title compound.
LC-MS (Method 2): F¾ = 0.90 min; MS (ESIpos): m/z = 459 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.677 (1.14), 0.685 (2.68), 0.690 (1.63), 0.697 (1.35), 0.704 (3.15), 0.709 (2.71 ), 0.713 (2.86), 0.721 (2.60), 0.725 (3.07), 0.733 (1 .47), 0.757 (1.73), 0.765 (3.72), 0.769 (2.75), 0.776 (3.23), 0.779 (1.58), 0.782 (2.04), 0.784 (2.10), 0.789 (3.30), 0.797 (1.44), 0.803 (1.53), 0.807 (1.46), 0.809 (3.54), 0.817 (1.65), 1.467 (1.02), 1.475 (0.79), 1.481 (0.63), 1.487 (1.58), 1.495 (0.64), 1.499 (0.96), 1.506 (0.78), 1.967 (1.09), 2.327 (0.88), 2.331 (1.03), 2.363 (1.18), 2.446 (1.27), 2.518 (3.16), 2.523 (2.23), 2.575 (16.00), 2.669 (0.70), 3.504 (1.33), 3.528 (4.91 ), 3.707 (1.1 1 ), 5.759 (3.22), 6.965 (1.16), 6.978 (1.14), 7.185 (1.40), 8.284 (1.86), 8.297 (1.70).
Example 66.01.03
3,3,3-trifluoro-1 -{4-[(2-{[6-(5-methyl-1 ,3,4-oxadiazol-2-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}propan-1 -one
Figure imgf000890_0002
Starting with crude 6-(5-methyl-1 ,3,4-oxadiazol-2-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]- 1 H-benzimidazol-2-amine hydrochloride (26.0 mg, Compound 66.01 ) and 3,3,3- trifluoropropanoic acid (16 μΙ, 180 pmol), Example 66.01.03 was prepared analogously to the procedure for the preparation of Example 16.05.02.
Yield: 10.0 mg of the title compound.
LC-MS (Method 2): Rt = 0.94 min; MS (ESIpos): m/z = 501 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.858 (0.75), 1.231 (0.94), 1.395 (0.78), 2.370 (1 .25), 2.382 (1.87), 2.395 (1.40), 2.41 1 (1.40), 2.424 (1.90), 2.436 (1.32), 2.518 (6.78), 2.523 (4.78), 2.575 (16.00), 3.459 (1.40), 3.473 (1.92), 3.483 (1.56), 3.495 (1.56), 3.505 (1.92), 3.530 (4.75), 3.610 (0.91 ), 3.637 (2.57), 3.665 (2.42), 3.693 (0.78), 6.958 (0.99), 6.972 (0.91 ), 7.185 (1.14), 7.652 (0.91 ), 8.129 (0.99), 8.283 (1.45), 8.296 (1.35), 12.407 (1.53).
Example 67.01
tert-butyl 4-[(1 R or 1 S)-1 -(2-{[6-(1 -{[(1 RS)-2,2-dimethylcyclopropyl]methyl}-1 H-pyrazol-4- yl)-1 H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1-carboxylate
Figure imgf000891_0001
Starting with 4-{1 -[((1 RS)-2,2-dimethylcyclopropyl)methyl]-1 H-pyrazol-4-yl}benzene-1 ,2- diamine (147 mg, 85% pure; see Compound 67.02), Example 67.01 was prepared analogously to the procedure for the preparation of Example 39.02.01. The intermediate thiourea was purified by flash chromatography.
Yield: 105 mg of the 94% pure title compound.
LC-MS (Method 2): R, = 1.44 min; MS (ESIpos): m/z = 571 [M+H]+
1 H-NMR (400MHz, DMSO-d6): δ [ppm] = 0.33 (t, 1 H), 0.53 (dd, 1 H), 1.04 - 1.08 (m, 3H), 1.08 - 1.13 (m, 1 H), 1.14 - 1.17 (m, 3H), 1.28 (d, 3H), 1.38 (s, 9H), 2.23 - 2.44 (m, 4H), 3.27 - 3.33 (m, 4H), 3.43 (q, 1 H), 4.12 (br d, 2H), 6.92 (dd, 1 H), 7.16 (s, 1 H), 7.18 - 7.47 (m, 2H), 7.50 - 7.68 (m, 1 H), 7.72 - 7.84 (m, 1 H), 7.95 - 8.1 1 (m, 1 H), 8.24 (d, 1 H), 10.55 (br s, 1 H), 12.02 (br s, 1 H). Example 67.02
1 -{4-[(1 R or 1S)-1 -(2-{[6-(1 -{[(1 RS)-2,2-dimethylcyclopropyl]methyl}-1 H-pyrazol-4-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}-3,3,3-trifluoropropan-1 -one
Figure imgf000892_0001
Starting with 6-(1-{[(1RS)-2,2-dimethylcyclopropyl]methyl}-1H-pyrazol-4-yl)-N-{4-[(1R or 1S)-1- (piperazin-1-yl)ethyl]pyridin-2-yl}-1H-benzimidazol-2-amine hydrochloride salt (62.5 mg, see Compound 67.03), Example 67.02 was prepared analogously to the procedure for the preparation of Example 39.02.02.
Yield: 16 mg of the 88% pure title compound.
LC-MS (Method 2): Rt = 1.29 min; MS (ESIpos): m/z = 581 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 0.33 (t, 1H), 0.53 (dd, 1H), 1.07 (s, 3H), 1.10 - 1.15 (m, 1H), 1.16 (s, 3H), 1.30 (d, 3H), 2.27 - 2.47 (m, 4H), 3.39 - 3.53 (m, 5H), 3.62 (q, 2H), 4.12 (brd, 2H), 6.93 (dd, 1H), 7.17 (s, 1H), 7.20-7.46 (m, 2H), 7.49-7.67 (m, 1H), 7.79 (brd, 1H), 7.96-8.11 (m, 1H), 8.25 (d, 1H), 10.56 (br s, 1H), 12.02 (br s, 1H).
Example 67.03
cyclopropyl{4-[(1 R or 1 S)-1 -(2-{[6-(1 -{[(1 RS)-2,2-dimethylcyclopropyl]methyl}-1 H- pyrazol-4-yl)-1H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}methanone
Figure imgf000892_0002
Starting with 6-(1-{[(1RS)-2,2-dimethylcyclopropyl]methyl}-1H-pyrazol-4-yl)-N-{4-[(1R or 1S)-1- (piperazin-1-yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride (62.5 mg, see Compound 67.03), Example 67.03 was prepared analogously to the procedure for the preparation of Example 39.02.03. Yield: 16 mg of the 76% pure title compound.
LC-MS (Method 2): Rt = 1.26 min; MS (ESIpos): m/z = 539 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 0.33 (t, 1H), 0.53 (dd, 1H), 0.62 - 0.73 (m, 4H), 1.07 (s, 3H), 1.11 - 1.14 (m, 1H), 1.16 (s, 3H), 1.30 (d, 3H), 1.88 - 1.99 (m, 1H), 2.24 - 2.45 (m, 4H), 3.39-3.53 (m, 3H), 3.67 (brs, 2H), 4.12 (brd, 2H), 6.94 (dd, 1H), 7.17 (s, 1H), 7.20-7.47 (m, 2H), 7.50 - 7.69 (m, 1H), 7.79 (br s, 1H), 8.05 (br s, 1H), 8.25 (d, 1H), 10.56 (br s, 1H), 12.03 (brs, 1H).
Example 68.01
tert-butyl 4-[(1R or 1S)-1-{2-[(6-{1-[(1-methylcyclopropyl)methyl]-1H-pyrazol-4-yl}-1H- benzimidazol-2-yl)amino]pyridin-4-yl}ethyl]piperazine-1-carboxylate
Figure imgf000893_0001
Starting with 4-{1-[(1-methylcyclopropyl)methyl]-1H-pyrazol-4-yl}benzene-1,2-diamine (158 mg, see Compound 68.02), Example 68.01 was prepared analogously to the procedure for the preparation of Example 39.02.01. The intermediate thiourea was purified by flash chromatography.
Yield: 89 mg of the 72% pure title compound.
LC-MS (Method 2): R, = 1.75 min; MS (ESIpos): m/z = 558 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 0.34 - 0.40 (m, 2H), 0.63 - 0.70 (m, 2H), 1.00 (s, 3H), 1.26 - 1.31 (m, 3H), 1.38 (s, 9H), 2.24 - 2.44 (m, 4H), 3.25 - 3.32 (m, 4H), 3.43 (q, 1 H), 3.96 (br s, 2H), 6.92 (d, 1H), 7.18 (br s, 1H), 7.21 - 7.46 (m, 2H), 7.51 - 7.68 (m, 1H), 7.73 - 7.87 (m, 1H), 8.01 -8.15(m, 1H), 8.24 (d, 1H), 10.57 (brs, 1H), 12.09 (brd, 1H). Example 68.02
3,3,3-trifluoro-1 -{4-[(1 R or 1 S)-1 -{2-[(6-{1 -[(1 -methylcyclopropyl)methyl]-1 H-pyrazol-4-yl}- 1H^enzimidazol-2-yl)amino]pyridin-4-yl}ethyl]piperazin-1-yl}propan-1-one
Figure imgf000894_0001
Starting with 6-{1-[(1-methylcyclopropyl)methyl]-1H-pyrazol-4-yl}-N-{4-[(1R or 1S)-1-(piperazin- 1-yl)ethyl]pyridin-2-yl}-1H-benzimidazol-2-amine hydrochloride (86.0 mg, see Compound 68.03), Example 68.02 was prepared analogously to the procedure for the preparation of Example 39.02.02.
Yield: 33 mg of the 92% pure title compound.
LC-MS (Method 2): Rt = 1.17 min; MS (ESIpos): m/z = 567 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 0.31 - 0.41 (m, 2H), 0.62 - 0.72 (m, 2H), 1.00 (s, 3H), 1.30 (d, 3H), 2.26 - 2.47 (m, 4H), 3.39 - 3.52 (m, 5H), 3.62 (q, 2H), 3.97 (br s, 2H), 6.86 - 6.98 (m, 1H), 7.14-7.19 (m, 1H), 7.20-7.48 (m, 2H), 7.50-7.68 (m, 1H), 7.72-7.87 (m, 1H), 7.98 -8.14(m, 1H), 8.20-8.29 (m, 1H), 10.57 (brs, 1H), 12.02 (brd, 1H).
Example 69.01
tert-butyl 4-[(1R or 1S)-1-{2-[(6-{1-[(1-chlorocyclopropyl)methyl]-1H-pyrazol-4-yl}-1H- benzimidazol-2-yl)amino]pyridin-4-yl}ethyl]piperazine-1-carboxylate
Figure imgf000894_0002
Starting with 4-{1-[(1-chlorocyclopropyl)methyl]-1H-pyrazol-4-yl}benzene-1,2-diamine (65.0 mg, 85 % purity, see Compound 69.03), Example 69.01 was prepared analogously to the procedure for the preparation of Example 39.02.01. The intermediate thiourea was purified by flash chromatography. Yield: 51 mg of the 87% pure title compound.
LC-MS (Method 2): Rt = 1.37 min; MS (ESIpos): m/z = 577 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] 1.10 - 1.16 (m, 2H), 1.23 - 1.32 (m, 5H), 1.38 (s, 9H), 2.23 - 2.44 (m, 4H), 3.21 - 3.32 (m, 4H), 3.43 (q, 1H), 4.40 (s, 2H), 6.92 (dd, 1H), 7.16 (s, 1H), 7.22 - 7.49 (m, 2H), 7.52 - 7.72 (m, 1H), 7.79 - 7.93 (m, 1H), 8.13 (br s, 1H), 8.25 (d, 1H), 10.56 (brs, 1H), 12.04 (br s, 1H).
Example 69.02
1 -{4-[(1 R or 1S)-1 -{2-[(6-{1 -[(1 -chlorocyclopropyl)methyl]-1 H-pyrazol-4-yl}-1 H- benzimidazol-2-yl)amino]pyridin-4-yl}ethyl]piperazin-1-yl}-3,3,3-trifluoropropan
Figure imgf000895_0001
Starting with 6-{1-[(1-chlorocyclopropyl)methyl]-1H-pyrazol-4-yl}-N-{4-[(1R or 1S)-1-(piperazin- 1-yl)ethyl]pyridin-2-yl}-1H-benzimidazol-2-amine hydrochloride (45 mg, Compound 69.04), Example 69.02 was prepared analogously to the procedure for the preparation of Example 39.02.02.
Yield: 16 mg of the 97% pure title compound.
LC-MS (Method 2): R, = 1.20 min; MS (ESIpos): m/z = 587 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.06 - 1.17 (m, 2H), 1.21 - 1.36 (m, 5H), 2.25 - 2.48 (m, 4H), 3.46 (br d, 5H), 3.62 (q, 2H), 4.41 (s, 2H), 6.94 (d, 1H), 7.17 (s, 1H), 7.28 (br d, 1H), 7.37 (br d, 1H), 7.61 (br s, 1H), 7.86 (s, 1H), 8.15 (br s, 1H), 8.26 (d, 1H), 10.60 (br s, 1H), 12.08 (brs, 1H).
Example 70.01
1 -{4-[(1 R or 1S)-1 -(2-{[7-chloro-6-(1 -{[(1 RS)-2,2-difluorocyclopropyl]methyl}-1 H-pyrazol- 4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}-3,3,3-trifluoropropan 1 -one
Figure imgf000896_0001
Starting with 7-chloro-6-(1 -{[(1 RS)-2,2-difluorocyclopropyl]methyl}-1 H-pyrazol-4-yl)-N-{4-[(1 R or 1 S)-1-(piperazin-1-yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride (100 mg, see Compound 70.03), Example 70.01 was prepared analogously to the procedure for the preparation of Example 39.02.02.
Yield: 37 mg of the 96% pure title compound.
LC-MS (Method 2): R, = 1.24 min; MS (ESIpos): m/z = 623 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.30 (d, 3H), 1.48 - 1.59 (m, 1 H), 1.64 - 1.77 (m, H), 2.23 - 2.48 (m, 5H), 3.40 - 3.53 (m, 5H), 3.62 (q, 2H), 4.21 - 4.39 (m, 2H), 6.96 (d, 1 H), 7.08 (s, 1 H), 7.19 (d, 1 H), 7.45 (d, 1 H), 7.83 (s, 1 H), 8.15 (s, 1 H), 8.28 (d, 1 H), 10.98 (s, 1 H), 12.31 (s, 1 H).
Example 70.02
{4-[(1 R or 1S)-1-(2-{[7-chloro-6-(1-{[(1RS)-2,2-difluorocyclopropyl]methyl}-1 H-pyrazol-4- yl)-1 H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}(cyclopropyl)methanone
Figure imgf000896_0002
Starting with 7-chloro-6-(1-{[(1 RS)-2,2-difluorocyclopropyl]methyl}-1 H-pyrazol-4-yl)-N-{4-[(1 R or 1 S)-1-(piperazin-1 -yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride (100 mg, see Compound 70.03), Example 70.02 was prepared analogously to the procedure for the preparation of Example 39.02.03.
Yield: 61 mg of the 95% pure title compound.
LC-MS (Method 2): R, = 1.21 min; MS (ESIpos): m/z = 581 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 0.61 - 0.74 (m, 4H), 1.30 (br d, 3H), 1.48 - 1.60 (m, 1H), 1.71 (tdd, 1H), 1.88 - 1.97 (m, 1H), 2.21 - 2.45 (m, 5H), 3.47 (br s, 3H), 3.67 (br s, 2H), 4.21 -4.39 (m, 2H), 6.97 (br d, 1H), 7.08 (s, 1H), 7.19 (d, 1H), 7.45 (d, 1H), 7.83 (s, 1H), 8.16 (s, 1H), 8.28 (d, 1H), 10.98 (br s, 1H), 12.32 (s, 1H).
Example 71.01
tert-butyl 4-{(1R or 1S)-1-[2-({6-[1-(cyclopentylmethyl)-1H-pyrazol-4-yl]-1H-benzimidazol- 2-yl}amino)pyridin-4-yl]ethyl}piperazine-1-carboxylate
Figure imgf000897_0001
Starting with 4-[1-(cyclopentylmethyl)-1H-pyrazol-4-yl]benzene-1,2-diamine (62.5 mg, see Compound 71.03), Example 71.01 was prepared analogously to the procedure for the preparation of Example 39.02.01. The intermediate thiourea was purified by flash chromatography.
Yield: 41 mg of the 96% pure title compound.
LC-MS (Method 2): Rt = 1.45 min; MS (ESIpos): m/z = 571 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.22 - 1.33 (m, 5H), 1.38 (s, 9H), 1.47 - 1.69 (m, 6H), 2.22 - 2.45 (m, 5H), 3.24 - 3.33 (m, 4H), 3.43 (q, 1H), 3.97 - 4.07 (m, 2H), 6.92 (dd, 1H), 7.16 (s, 1H), 7.18-7.47 (m, 2H), 7.49 - 7.67 (m, 1H), 7.78 (br d, 1H), 8.07 (brd, 1H), 8.24 (d, 1H), 10.55 (brs, 1H), 12.02 (br s, 1H). Example 71.02
1 -(4-{(1 R or 1S)-1 -[2-({6-[1 -(cyclopentylmethyl)-l H-pyrazol-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)-3,3,3-trifluoropropan-1-one
Figure imgf000898_0001
Starting with 6-[1-(cyclopentylmethyl)-1H-pyrazol-4-yl]-N-{4-[(1R or 1S)-1-(piperazin-1- yl)ethyl]pyridin-2-yl}-1H-benzimidazol-2-amine hydrochloride (37 mg, see Compound 70.04), Example 71.02 was prepared analogously to the procedure for the preparation of Example 39.02.02.
Yield: 5 mg of the 90% pure title compound.
LC-MS (Method 2): Rt = 1.30 min; MS (ESIpos): m/z = 581 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.21 - 1.69 (m, 11H), 2.37-2.45 (m, 1H), 3.22 - 3.56 (m, 9H), 3.65 (q, 2H), 4.04 (d, 2H), 7.11 - 7.24 (m, 1H), 7.26 (br s, 1H), 7.40 - 7.47 (m, 1H), 7.49 - 7.55 (m, 1H), 7.67 (s, 1H), 7.83 (s, 1H), 8.15 (s, 1H), 8.39 (br d, 1H), 11.75 (br d, 1H), 12.90 (brs, 1H).
Example 72.01
tert-butyl 4-{(1R or 1S)-1-[2-({6-[1-(propan-2-yl)-1H-pyrazol-5-yl]-1H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate
Figure imgf000898_0002
Starting with 4-[1-(propan-2-yl)-1H-pyrazol-5-yl]benzene-1,2-diamine (550 mg, see Compound 72.01), Example 72.01 was prepared analogously to the procedure for the preparation of Example 39.02.01. The intermediate thiourea was purified by flash chromatography.
Yield: 400 mg of the 97% pure title compound. LC-MS (Method 2): Rt = 1.34 min; MS (ESIpos): m/z = 531 [M+H]+
Ή-NMR (400MHz, DMSO-d6): δ [ppm] = 1.28 (d, 3H), 1.32 - 1.43 (m, 15H), 2.22 - 2.44 (m, 4H), 3.25 - 3.32 (m, 4H), 3.44 (q, 1H), 4.53 - 4.71 (m, 1H), 6.23 (s, 1H), 6.94 (d, 1H), 6.98 - 7.61 (m, 5H), 8.18-8.30 (m, 1H), 10.66 (brd, 1H), 12.22 (brd, 1H).
Example 72.02
3,3,3-trif luoro-1 -(4-{(1 R or 1 S)-1 -[2-({6-[1 -(propan-2-yl)-1 H-pyrazol-5-yl]-1 H-benzimidazol- 2-yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)propan-1-one
Figure imgf000899_0001
Starting with N-{4-[(1R or 1S)-1-(piperazin-1-yl)ethyl]pyridin-2-yl}-6-[1-(propan-2-yl)-1H- pyrazol-5-yl]-1H-benzimidazol-2-amine hydrochloride (126 mg, see Compound 72.02), Example 72.02 was prepared analogously to the procedure for the preparation of Example 39.02.02.
Yield: 50 mg of the 100% pure title compound.
LC-MS (Method 2): R, = 1.18 min; MS (ESIpos): m/z = 541 [M+H]+
H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.30 (br d, 3H), 1.38 (d, 6H), 2.27 - 2.47 (m, 4H), 3.38 - 3.54 (m, 5H), 3.62 (q, 2H), 4.54 - 4.68 (m, 1H), 6.24 (d, 1H), 6.96 (d, 1H), 7.06 (br d, 1H), 7.17 (s, 1H), 7.49 (d, 3H), 8.28 (d, 1H), 10.70 (brs, 1H), 12.25 (brs, 1H).
Example 72.03
cyclopropyl(4-{(1 R or 1 S)-1 -[2-({6-[1 -(propan-2-yl)-1 H-pyrazol-5-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)methanone
Figure imgf000900_0001
Starting with N-{4-[(1 R or 1 S)-1-(piperazin-1 -yl)ethyl]pyridin-2-yl}-6-[1-(propan-2-yl)-1 H- pyrazol-5-yl]-1 H-benzimidazol-2-amine hydrochloride (126 mg, see Compound 72.02), Example 72.03 was prepared analogously to the procedure for the preparation of Example 39.02.03.
Yield: 46 mg of the 100% pure title compound.
LC-MS (Method 2): R, = 1.14 min; MS (ESIpos): m/z = 499 [M+H]+
H-NMR (400MHz, DMSO-d6): δ [ppm] = 0.62 - 0.75 (m, 4H), 1.30 (d, 3H), 1.38 (br d, 6H), 1.89 - 1.98 (m, 1 H), 2.23 - 2.45 (m, 4H), 3.40 - 3.54 (m, 3H), 3.68 (br s, 2H), 4.53 - 4.70 (m, 1 H), 6.24 (s, 1 H), 6.96 (dd, 1 H), 6.99 - 7.12 (m, 1 H), 7.18 (br s, 1 H), 7.27 - 7.62 (m, 3H), 8.28 (d, 1 H), 10.67 (br d, 1 H), 12.22 (br d, 1 H).
Example 73.01
1 -{4-[(1 R or 1 S)-1 -(2-{[6-(1 ,4-dimethyM H-pyrazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}-3,3,3-trifluoropropan-1 -one
Figure imgf000900_0002
Starting with 6-(1 ,4-dimethyl-1 H-pyrazol-5-yl)-N-{4-[(1 R or 1 S)-1-(piperazin-1 -yl)ethyl]pyridin-2- yl}-1 H-benzimidazol-2-amine hydrochloride (33 mg, see Compound 73.03), Example 73.01 was prepared analogously to the procedure for the preparation of Example 39.02.02.
Yield: 17 mg of the 90% pure title compound. LC-MS (Method 2): R, = 1.11 min; MS (ESIpos): m/z = 527 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.30 (d, 3H), 1.98 (s, 3H), 2.31 - 2.46 (m, 4H), 3.40 - 3.52 (m, 5H), 3.56 - 3.67 (m, 2H), 3.71 (s, 3H), 6.36 - 6.65 (m, 1H), 6.96 (d, 1H), 7.03 (br d, 1H), 7.14-7.21 (m, 1H), 7.31 (s, 1H), 7.42 - 7.58 (m, 1H), 8.28 (d, 1H), 10.69 (brs, 1H), 12.21 (brs, 1H).
Example 74.01
tert-butyl 4-[(1R or 1S)-1-{2-[(6-{1-[(1RS)-1-cyclopropylethyl]-1H-pyrazol-4-yl}-1H- benzimidazol-2-yl)amino]pyridin-4-yl}ethyl]piperazine-1-carboxylate
Figure imgf000901_0001
Starting with 4-{1-[(1RS)-1-cyclopropylethyl]-1H-pyrazol-4-yl}benzene-1,2-diamine (80.0 mg, see Compound 74.02), Example 74.01 was prepared analogously to the procedure for the preparation of Example 39.02.01. The intermediate thiourea was purified by flash chromatography.
Yield: 84 mg of the 90% pure title compound.
LC-MS (Method 2): R, = 1.37 min; MS (ESIpos): m/z = 557 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 0.29 - 0.40 (m, 2H), 0.42 - 0.51 (m, 1H), 0.56 - 0.65 (m, 1H), 1.22 - 1.31 (m, 4H), 1.38 (s, 9H), 1.54 (d, 3H), 2.23 - 2.44 (m, 4H), 3.24 - 3.33 (m, 4H), 3.43 (q, 1H), 3.59 - 3.70 (m, 1H), 6.92 (dd, 1H), 7.16 (s, 1H), 7.20 - 7.48 (m, 2H), 7.50 - 7.68 (m, 1H), 7.80 (brs, 1H), 8.13 (brd, 1H), 8.24 (d, 1H), 10.55 (brs, 1H), 12.02 (brs, 1H).
Example 74.02
1 -{4-[(1 R or 1 S)-1 -{2-[(6-{1 -[(1 RS)-1 -cyclopropylethyl]-1 H-pyrazol-4-yl}-1 H-benzimidazol- 2-yl)amino]pyridin-4-yl}ethyl]piperazin-1-yl}-3,3,3-trifluoropropan-1-one
Figure imgf000902_0001
Starting with 6-{1-[(1RS)-1-cyclopropylethyl]-1H-pyrazol-4-yl}-N-{4-[(1R or 1S)-1-(piperazin-1- yl)ethyl]pyridin-2-yl}-1H-benzimidazol-2-amine hydrochloride (83.0 mg, see Compound 74.03), Example 74.02 was prepared analogously to the procedure for the preparation of Example 39.02.02.
Yield: 42 mg of the 86% pure title compound.
LC-MS (Method 2): R. = 1.22 min; MS (ESIpos): m/z = 567 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 0.29 - 0.40 (m, 2H), 0.41 - 0.50 (m, 1H), 0.55 - 0.65 (m, 1H), 1.20 - 1.34 (m, 4H), 1.54 (d, 3H), 2.29 - 2.47 (m, 4H), 3.39 - 3.52 (m, 5H), 3.62 (q, 3H), 6.93 (dd, 1H), 7.17 (s, 1H), 7.20-7.47 (m, 2H), 7.50-7.67 (m, 1H), 7.78 (brd, 1H), 8.07- 8.19 (m, 1H), 8.25 (d, 1H), 10.57 (br s, 1H), 12.02 (brs, 1H).
Example 75.01
tert-butyl 4-{(1R or 1S)-1-[2-({7-chloro-6-[1-(cyclobutylmethyl)-1H-pyrazol-4-yl]-1H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate
Figure imgf000902_0002
Starting with 3-chloro-4-[1-(cyclobutylmethyl)-1H-pyrazol-4-yl]benzene-1,2-diamine (171 mg, 86 % purity; see Compound 75.02), Example 75.01 was prepared analogously to the procedure for the preparation of Example 39.02.01. The intermediate thiourea was purified by flash chromatography.
Yield: 1 17 mg of the 94% pure title compound.
LC-MS (Method 2): Rt = 1.49 min; MS (ESIpos): m/z = 591 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.28 (d, 3H), 1.38 (s, 9H), 1.74 - 1.91 (m, 4H), 1.95 - 2.06 (m, 2H), 2.25 - 2.45 (m, 4H), 2.73 - 2.85 (m, 1 H), 3.24 - 3.33 (m, 4H), 3.40 - 3.51 (m, 1 H), 4.17 (d, 2H), 6.95 (d, 1 H), 7.08 (s, 1 H), 7.17 (d, 1 H), 7.44 (d, 1 H), 7.76 (s, 1 H), 8.07 (s, 1 H), 8.27 (d, 1 H), 10.96 (s, 1 H), 12.29 (s, 1 H).
Example 75.02
1 -(4-{(1 R or 1 S)-1 -[2-({7-chloro-6-[1 -(cyclobutylmethyl)-l H-pyrazol-4-yl]-1 H-benzimidazol- 2-yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)-3,3,3-trifluoropropan-1-one
Figure imgf000903_0001
Starting with 7-chloro-6-[1 -(cyclobutylmethyl)-1 H-pyrazol-4-yl]-N-{4-[(1 R or 1 S)-1 -(piperazin-1 - yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride (59 mg, see Compound 75.03), Example 75.02 was prepared analogously to the procedure for the preparation of Example 39.02.02.
Yield: 42 mg of the 96% pure title compound.
LC-MS (Method 2): R, = 1.33 min; MS (ESIpos): m/z = 601 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.29 (d, 3H), 1.72 - 1.92 (m, 4H), 1.95 - 2.07 (m, 2H), 2.28 - 2.46 (m, 4H), 2.73 - 2.85 (m, 1 H), 3.40 - 3.52 (m, 5H), 3.62 (q, 2H), 4.13 - 4.22 (m, 2H), 6.96 (d, 1 H), 7.08 (s, 1 H), 7.17 (d, 1 H), 7.44 (d, 1 H), 7.76 (s, 1 H), 8.07 (s, 1 H), 8.28 (d, 1 H), 10.97 (s, 1 H), 12.30 (s, 1 H). Example 75.03
(4-{(1Ror 1S)-1-[2-({7-chloro-6-[1-(cyclobutylmethyl)-1H-pyrazol-4-yl]-1H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)(cyclopropyl)methanone
Figure imgf000904_0001
Starting with 7-chloro-6-[1-(cyclobutylmethyl)-1H-pyrazol-4-yl]-N-{4-[(1R or 1S)-1-(piperazin-1- yl )eth y I] pyr id i n -2-yl}- 1 H-benzimidazol-2-amine hydrochloride (59 mg, see Compound 75.03), Example 75.03 was prepared analogously to the procedure for the preparation of Example 39.02.03.
Yield: 36 mg of the 91% pure title compound.
LC-MS (Method 2): R, = 1.30 min; MS (ESIpos): m/z = 559 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 0.62 - 0.74 (m, 4H), 1.30 (d, 3H), 1.74 - 2.06 (m, 7H), 2.24 - 2.45 (m, 4H), 2.72 - 2.85 (m, 1H), 3.40 - 3.54 (m, 3H), 3.67 (br s, 2H), 4.11 - 4.22 (m, 2H), 6.97 (d, 1H), 7.08 (s, 1H), 7.17 (d, 1H), 7.44 (d, 1H), 7.76 (s, 1H), 8.07 (s, 1H), 8.28 (d, 1H), 10.97 (s, 1H), 12.30 (s, 1H).
Example 76.01
1-{4-[(2-{[6-(6-cyclopropylpyrimidin-4-yl)-1H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1-yl}-3,3,3-trifluoropropan-1-one
Figure imgf000904_0002
Starting with 6-(6-cyclopropylpyrimidin-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (100 mg, see Compound 76.02), Example 76.01 was prepared analogously to the procedure for the preparation of Example 39.02.02.
Yield: 50 mg of the 91 % pure title compound.
LC-MS (Method 2): R, = 1.14 min; MS (ESIpos): m/z = 537 [M+H]+
1 H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.03 - 1.15 (m, 4H), 2.18 (quin, 1 H), 2.35 - 2.45 (m, 4H), 3.44 - 3.55 (m, 6H), 3.65 (q, 2H), 6.95 (br d, 1 H), 7.20 (s, 1 H), 7.38 - 7.65 (m, 1 H), 7.87 - 8.08 (m, 2H), 8.18 - 8.47 (m, 2H), 8.93 (d, 1 H), 10.70 - 10.86 (m, 1 H), 12.29 (br d, 1 H).
Example 76.02
cyclopropyl{4-[(2-{[6-(6-cyclopropylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin- 4-yl)methyl]piperazin-1-yl}methanone
Figure imgf000905_0001
Starting with 6-(6-cyclopropylpyrimidin-4-yl)-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (100 mg, see Compound 76.02), Example 76.02 was prepared analogously to the procedure for the preparation of Example 39.02.03.
Yield: 38 mg of the 97% pure title compound.
LC-MS (Method 4): R, = 1.07 min; MS (ESIpos): m/z = 495 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 0.64 - 0.76 (m, 4H), 1.02 - 1.13 (m, 4H), 1.91 - 2.03 (m, 1 H), 2.18 (quin, 1 H), 2.34 - 2.47 (m, 4H), 3.44 - 3.57 (m, 4H), 3.71 (br s, 2H), 6.96 (d, 1 H), 7.22 (s, 1 H), 7.39 - 7.66 (m, 1 H), 7.88 - 8.08 (m, 2H), 8.17 - 8.46 (m, 2H), 8.93 (d, 1 H), 10.78 (br s, 1 H), 12.34 (br s, 1 H).
< Example 77.01
6-{2-[(4-{[4-(3,3,3-trifluoropropanoyl)piperazin-1 -yl]methyl}pyridin-2-yl)amino]-1 H- benzimidazol-6-yl}pyrimidine-4-carbonitrile
Figure imgf000906_0001
Starting with 6-(2-{[4-(piperazin-1 -ylmethyl)pyridin-2-yl]amino}-1 H-benzimidazol-6- yl)pyrimidine-4-carbonitrile hydrochloride (120 mg, see Compound 77.02), Example 77.01 was prepared analogously to the procedure for the preparation of Example 39.02.02.
Yield: 12 mg of the 90% pure title compound.
LC-MS (Method 4): R, = 1.07 min; MS (ESIpos): m/z = 522 [M+H]+
1 H-NMR (400MHz, DMSO-d6): δ [ppm] = 2.35 - 2.46 (m, 4H), 3.42 - 3.57 (m, 6H), 3.65 (q, 2H), 6.92 - 7.03 (m, 1 H), 7.20 (br s, 1 H), 7.42 - 7.68 (m, 1 H), 8.05 (dd, 1 H), 8.23 - 8.55 (m, 2H), 8.63 - 8.85 (m, 1 H), 9.31 (br s, 1 H), 10.76 - 10.96 (m, 1 H), 12.40 (br s, 1 H).
Example 78.01
3,3,3-trifluoro-1 -(4-{[2-({6-[6-(propan-2-yl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1 -yl)propan-1 -one
Figure imgf000906_0002
Starting with N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]-6-[6-(propan-2-yl)pyrimidin-4-yl]-1 H- benzimidazol-2-amine hydrochloride (1 10 mg, see Compound 78.02), Example 78.01 was prepared analogously to the procedure for the preparation of Example 39.02.02. Yield: 17 mg of the 85% pure title compound.
LC-MS (Method 2): R, = 1.16 min; MS (ESIpos): m/z = 539 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.30 (d, 6H), 2.41 (dt, 4H), 3.05 (dt, 1 H), 3.42 - 3.56 (m, 6H), 3.65 (q, 2H), 6.95 (br d, 1 H), 7.20 (s, 1 H), 7.39 - 7.65 (m, 1 H), 7.83 - 8.03 (m, 2H), 8.19 - 8.45 (m, 2H), 9.06 (d, 1 H), 10.79 (d, 1 H), 12.23 - 12.37 (m, 1 H).
Example 78.02
cyclopropyl(4-{[2-({6-[6-(propan-2-yl)pyrimidin-4-yl]-1H-benzimidazol-2-yl}amino)pyridin- 4-yl]methyl}piperazin-1-yl)methanone
Figure imgf000907_0001
Starting with N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]-6-[6-(propan-2-yl)pyrimidin-4-yl]-1 H- benzimidazol-2-amine hydrochloride (1 10 mg, see Compound 78.02), Example 78.02 was prepared analogously to the procedure for the preparation of Example 39.02.03.
Yield: 20 mg of the 88% pure title compound.
LC-MS (Method 2): Rt = 1.13 min; MS (ESIpos): m/z = 497 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 0.64 - 0.78 (m, 4H), 1.30 (d, 6H), 1.93 - 2.01 (m, 1 H), 2.34 - 2.47 (m, 4H), 2.97 - 3.13 (m, 1 H), 3.44 - 3.58 (m, 4H), 3.71 (br s, 2H), 6.90 - 6.99 (m, 1 H), 7.14 - 7.25 (m, 1 H), 7.35 - 7.64 (m, 1 H), 7.83 - 8.01 (m, 2H), 8.19 - 8.45 (m, 2H), 9.06 (d, 1 H), 10.68 - 10.86 (m, 1 H), 12.23 - 12.37 (m, 1 H).
Example 79.01
3,3,3-trifluoro-1 -(4-{[2-({6-[6-(methoxymethyl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1 -yl)propan-1 -one
Figure imgf000908_0001
Starting with 6-[6-(methoxymethyl)pyrimidin-4-yl]-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (200 mg, see Compound 79.02), Example 79.01 was prepared analogously to the procedure for the preparation of Example 39.02.02.
Yield: 40 mg of the 79% pure title compound.
LC- S (Method 2): Rt = 1.03 min; MS (ESIpos): m/z = 541 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 2.34 - 2.45 (m, 4H), 3.39 (s, 2H), 3.43 - 3.56 (m, 7H), 3.65 (q, 2H), 4.55 (s, 2H), 6.86 - 7.04 (m, 1 H), 7.19 (s, 1 H), 7.32 - 8.08 (m, 3H), 8.14 - 8.52 (m, 2H), 9.01 - 9.34 (m, 1 H), 10.82 (br s, 1 H), 12.35 (br s, 1 H).
Example 79.02
cyclopropyl(4-{[2-({6-[6-(methoxymethyl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1-yl)methanone
Figure imgf000908_0002
Starting with 6-[6-(methoxymethyl)pyrimidin-4-yl]-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (200 mg, see Compound 79.02), Example 79.02 was prepared analogously to the procedure for the preparation of Example 39.02.03. Yield: 38 mg of the 89% pure title compound.
LC-MS (Method 2): Rt = 0.99 min; MS (ESIpos): m/z = 499 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 0.65 - 0.75 (m, 4H), 1.92 - 2.01 (m, 1 H), 2.34 - 2.47 (m, 4H), 3.44 - 3.56 (m, 7H), 3.71 (br s, 2H), 4.55 (s, 2H), 6.89 - 7.00 (m, 1 H), 7.19 (s, 1 H), 7.40 - 8.05 (m, 3H), 8.15 - 8.50 (m, 2H), 9.09 (s, 1 H), 10.82 (br s, 1 H), 12.35 (br s, 1 H).
Example 79.03
(4-{[2-({6-[6-(methoxymethyl)pyrimidin-4-yl]-1 H^enzimidazol-2-yl}amino)pyridin-4- yl]methyl}piperazin-1 -yl)[1-(trifluoromethyl)cyclopropyl]methanone
Figure imgf000909_0001
Starting with 6-[6-(methoxymethyl)pyrimidin-4-yl]-N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (107 mg, see Compound 79.02), Example 79.03 was prepared analogously to the procedure for the preparation of Example 83.05.
Yield: 8 mg of the 86% pure title compound.
LC-MS (Method 4): Rt = 1.08 min; MS (ESIpos): m/z = 567 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.12 - 1.22 (m, 2H), 1.25 - 1.33 (m, 2H), 2.42 (br s, 4H), 3.42 - 3.72 (m, 9H), 4.55 (s, 2H), 6.96 (br d, 1 H), 7.19 (s, 1 H), 7.38 - 7.70 (m, 1 H), 7.86 - 8.02 (m, 2H), 8.14 - 8.46 (m, 2H), 9.09 (s, 1 H), 10.82 (br s, 1 H), 12.19 - 12.46 (m, 1 H).
Example 80.01
tert-butyl 4-{[2-({6-[6-(cyclopropylmethoxy)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate
Figure imgf000910_0001
tert-butyl 4-[(2-{[6-(6-chloropyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate (608 mg, see Compound 80.01 ) was dissolved in 8 mL dioxane and treated with sodium hydride (280 mg, 60 % purity). Then, cyclopropylmethanol (504 mg) was added and the reaction mixture was stirred at rt for 30 min and afterwards concentrated under reduced pressure. The crude product was purified by flash chromatography.
Yield: 312 mg of the title compound with 96 % purity.
LC-MS (Method 2): R, = 1.41 min; MS (ESIpos): m/z = 558 [M+H]+
H-NMR (400 MHz, DMSO-d6) δ [ppm] = 0.31 - 0.41 (m, 2H), 0.53 - 0.63 (m, 2H), 1.23 - 1.33 (m, 1 H), 1.39 (s, 9H), 2.29 - 2.41 (m, 4H), 3.34 (s, 4H), 3.50 (s, 2H), 4.22 (d, 2H), 6.94 (br d, 1 H), 7.18 (br s, 1 H), 7.30 - 7.61 (m, 2H), 7.91 (br s, 1 H), 8.12 - 8.40 (m, 2H), 8.77 (d, 1 H), 10.76 (br s, 1 H), 12.27 (br d, 1 H).
Example 80.02
1 -(4-{[2-({6-[6-(cyclopropylmethoxy)pyrimidin-4-yl]-1 H^
4-yl]methyl}piperazin-1 -yl)-3,3,3-trifluoropropan-1 -one
Figure imgf000911_0001
Starting with 6-[6-(cyclopropylmethoxy)pyrimidin-4-yl]-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]- 1 H-benzimidazol-2-amine hydrochloride (100 mg, see Compound 80.02), Example 80.02 was prepared analogously to the procedure for the preparation of Example 39.02.02.
Yield: 35 mg of the 89% pure title compound.
LC-MS (Method 2): Rt = 1.25 min; MS (ESIpos): m/z = 567 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 0.33 - 0.44 (m, 2H), 0.53 - 0.62 (m, 2H), 1.21 - 1.37 (m, 1 H), 2.40 (dt, 4H), 3.41 - 3.56 (m, 6H), 3.65 (q, 2H), 4.23 (d, 2H), 6.95 (br d, 1 H), 7.13 - 7.61 (m, 3H), 7.92 (br d, 1 H), 8.1 1 - 8.41 (m, 2H), 8.77 (d, 1 H), 10.74 (br s, 1 H), 12.25 (br s, 1 H). .
Example 80.03
cyclopropyl(4-{[2-({6-[6-(cyclopropylmethoxy)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1 -yl)methanone
Figure imgf000911_0002
Starting with 6-[6-(cyclopropylmethoxy)pyrimidin-4-yl]-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]- 1 H-benzimidazol-2-amine hydrochloride (100 mg, see Compound 80.02), Example 80.03 was prepared analogously to the procedure for the preparation of Example 39.02.03.
Yield: 30 mg of the 98% pure title compound.
LC-MS (Method 2): R, = 1.22 min; MS (ESIpos): m/z = 525 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 0.33 - 0.42 (m, 2H), 0.53 - 0.63 (m, 2H), 0.65 - 0.76 (m, 4H), 1.22 - 1.36 (m, 1 H), 1.92 - 2.04 (m, 1 H), 2.33 - 2.46 (m, 4H), 3.44 - 3.57 (m, 4H), 3.71 (br s, 2H), 4.23 (d, 2H), 6.96 (br d, 1 H), 7.20 (br s, 1 H), 7.32 - 7.63 (m, 2H), 7.92 (br d, 1 H), 8.13 - 8.40 (m, 2H), 8.77 (d, 1 H), 10.75 (br s, 1 H), 12.27 (br s, 1 H).
Example 81.01
tert-butyl 4-({2-[(6-{6-[(2-hydroxyethyl)amino]pyrimidin-4-yl}-1H-benzimidazol-2- yl)amino]pyridin-4-yl}methyl)piperazine-1 -carboxylate
Figure imgf000912_0001
Starting with tert-butyl 4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-benzimidazol- 2-yl]amino}pyridin-4-yl)methyl]piperazine-1-carboxylate (100 mg, see Compound 01.04), Example 81.01 was prepared analogously to the procedure for the preparation of Compound 76.01.
Yield: 40 mg of the title compound with 97 % purity.
LC-MS (Method 4): Rt = 1.04 min; MS (ESIpos): m/z = 546 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.40 (s, 9H), 2.29 - 2.40 (m, 4H), 3.34 - 3.38 (m, 4H), 3.42 (br d, 2H), 3.50 (s, 2H), 3.56 (q, 2H), 4.79 (t, 1 H), 6.87 - 7.02 (m, 2H), 7.10 - 7.60 (m, 3H), 7.73 (br s, 1 H), 7.92 - 8.22 (m, 1 H), 8.26 (d, 1 H), 8.45 (s, 1 H), 10.70 (br s, 1 H), 12.22 (br d, 1 H). Example 82.01
tert-butyl 4-{[2-({6-[6-(cyclopropylamino)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate
Figure imgf000913_0001
Starting with tert-butyl 4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-benzimidazol- 2-yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate (100 mg, see Compound 01.04), Example 82.01 was prepared analogously to the procedure for the preparation of Compound 76.01.
Yield: 6 mg of the title compound with 95 % purity.
LC-MS (Method 2): Rt = 1.18 min; MS (ESIpos): m/z = 542 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 0.52 (br s, 2H), 0.71 - 0.89 (m, 2H), 1.13 - 1.27 (m, 1 H), 1.40 (s, 9H), 2.27 - 2.41 (m, 4H), 3.34 - 3.40 (m, 4H), 3.50 (s, 2H), 6.87 - 7.62 (m, 6H), 7.80 (br s, 1 H), 8.26 (br d, 1 H), 8.47 (s, 1 H), 10.72 (br s, 1 H), 12.26 (br s, 1 H).
Example 83.01
tert-butyl 4-[(1R or 1S)-1 -(2-{[6-(6-chloro-5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazine-1 -carboxylate
Figure imgf000913_0002
Starting with 4-(6-chloro-5-methoxypyrimidin-4-yl)benzene-1 ,2-diamine (1.07 g, see Compound 83.02), Example 83.01 was prepared analogously to the procedure for the preparation of Example 39.02.01. Yield: 1.16 g of the title compound with 88 % purity.
LC-MS (Method 2): Rt = 1.38 min; MS (ESIpos): m/z = 566 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.29 (d, 3H), 1.38 (s, 9H), 2.24 - 2.45 (m, 4H), 3.23 - 3.32 (m, 4H), 3.45 (q, 1 H), 3.65 - 3.78 (m, 3H), 6.96 (br d, 1 H), 7.09 - 7.26 (m, 1 H), 7.40 - 7.66 (m, 1 H), 7.80 - 8.00 (m, 1 H), 8.24 - 8.33 (m, 1 H), 8.41 (br s, 1 H), 8.80 (s, 1 H), 10.63 - 10.87 (m, 1 H), 12.16 - 12.45 (m, 1 H).
Example 83.02
tert-butyl 4-[(1 R or 1S)-1-(2-{[6-(5-methoxy-6-methylpyrimidin-4-yl)-1H-benzimidazol-2 yl]amino}pyridin-4-yl)ethyl]piperazine-1-carboxylate
Figure imgf000914_0001
Starting with tert-butyl 4-[(1 R or 1 S)-1 -(2-{[6-(6-chloro-5-methoxypyrimidin-4-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1 -carboxylate (958 mg, see Example 83.01 ), Example 83.02 was prepared analogously to the procedure for the preparation of Compound 61.01.
Yield: 635 mg of the title compound with 100 % purity.
LC-MS (Method 2): R, = 1.28 min; MS (ESIpos): m/z = 546 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.29 (d, 3H), 1.38 (s, 9H), 2.24 - 2.45 (m, 4H), 2.51 - 2.52 (m, 3H), 3.21 - 3.32 (m, 4H), 3.40 - 3.50 (m, 1 H), 3.51 - 3.69 (m, 3H), 6.95 (d, 1 H), 7.16 (br s, 1 H), 7.34 - 7.66 (m, 1 H), 7.75 - 7.97 (m, 1 H), 8.04 - 8.40 (m, 2H), 8.80 (s, 1 H), 10.59 - 10.82 (m, 1 H), 12.16 - 12.37 (m, 1 H). Example 83.03
3,3,3-trifluoro-1 -{4-[(1 R or 1 S)-1 -(2-{[6-(5-methoxy-6-methylpyrimidin-4-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}propan-1-one
Figure imgf000915_0001
Starting with 6-(5-methoxy-6-methylpyrimidin-4-yl)-N-{4-[(1 R or 1 S)-1 -(piperazin-1- yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride (200 mg, see Compound 83.03), Example 83.03 was prepared analogously to the procedure for the preparation of Example 39.02.02.
Yield: 98 mg of the 97% pure title compound.
LC-MS (Method 2): R, = 1.10 min; MS (ESIpos): m/z = 555 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.30 (d, 3H), 2.26 - 2.48 (m, 4H), 2.51 (s, 3H), 3.38 - 3.68 (m, 10H), 6.96 (d, 1 H), 7.17 (s, 1 H), 7.36 - 7.64 (m, 1 H), 7.75 - 7.97 (m, 1 H), 8.02 - 8.40 (m, 2H), 8.80 (s, 1 H), 10.75 (d, 1 H), 12.13 - 12.41 (m, 1 H).
Example 83.04
cyclopropyl{4-[(1R or 1S)-1 -(2-{[6-(5-methoxy-6-methylpyrimidin-4-yl)-1 H-benzimidazol- 2-yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}methanone
Figure imgf000915_0002
Starting with 6-(5-methoxy-6-methyIpyrimidin-4-yl)-N-{4-[(1 R or 1 S)-1-(piperazin-1- yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride (200 mg, see Compound 83.03), Example 83.04 was prepared analogously to the procedure for the preparation of Example 39.02.03.
Yield: 1 15 mg of the 100% pure title compound.
LC-MS (Method 2): R, = 1.06 min; MS (ESIpos): m/z = 513 [M+H]+
H-NMR (400MHz, DMSO-d6): δ [ppm] = 0.61 - 0.74 (m, 4H), 1.30 (d, 3H), 1.86 - 2.00 (m, 1 H), 2.24 - 2.47 (m, 4H), 2.51 (s, 3H), 3.46 (q, 3H), 3.53 - 3.62 (m, 3H), 3.63 - 3.73 (m, 2H), 6.97 (d, 1 H), 7.18 (s, 1 H), 7.37 - 7.62 (m, 1 H), 7.74 - 7.95 (m, 1 H), 8.03 - 8.40 (m, 2H), 8.80 (s, 1 H), 10.63 - 10.82 (m, 1 H), 12.21 - 12.41 (m, 1 H).
Example 83.05
{4-[(1 R or 1S)-1-(2-{[6-(5-methoxy-6-methylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}[1 -(trifluoromethyl)cyclopropyl]methanone
Figure imgf000916_0001
6-(5-methoxy-6-methylpyrimidin-4-yl)-N-{4-[(1 R or 1 S)-1 -(piperazin-1-yl)ethyl]pyridin-2-yl}-1 H- benzimidazol-2-amine hydrochloride (150 mg, Compound 83.03), 1- (trifluoromethyl)cyclopropanecarboxylic acid (79 μΙ), 1 -[Bis(dimethylamino)methylene]-1 H- 1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (309 mg) and sodium bicarbonate (136 mg) were combined in 2.1 mL DMF and stirred at room temperature overnight. The reaction mixture was filtrated and given to standard reversed-phased preparative HPLC purification to provide the target compound.
Yield: 92 mg of the title compound with 95 % purity.
LC-MS (Method 4): R, = 1.14 min; MS (ESIpos): m/z = 581 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.10 - 1.20 (m, 2H), 1.23 - 1.37 (m, 5H), 2.28 - 2.48 (m, 4H), 2.51 (br s, 3H), 3.46 (q, 1 H), 3.59 (br s, 7H), 6.96 (d, 1 H), 7.17 (s, 1 H), 7.38 - 7.65 (m, 1 H), 7.76 - 7.96 (m, 1 H), 8.03 - 8.39 (m, 2H), 8.80 (s, 1 H), 10.75 (d, 1 H), 12.30 (br d, 1 H). Example 84.01
tert-butyl 4-{(1R or 1S)-1 -[2-({6-[6-(methoxymethyl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate
Figure imgf000917_0001
Starting with tert-butyl 4-[(1 R or 1 S)-1-(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1-carboxylate (1.56 g, 85 % purity; see Compound 23.15.01 ), Example 84.01 was prepared analogously to the procedure for the preparation of Compound 60.01.
Yield: 327 mg of the title compound with 90 % purity.
LC-MS (Method 4): Rt = 1.27 min; MS (ESIpos): m/z = 545 [M+H]+
1 H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.29 (d, 3H), 1.38 (s, 9H), 2.22 - 2.44 (m, 4H), 3.32 (br s, 3H), 3.39 - 3.50 (m, 5H), 4.55 (s, 2H), 6.96 (br s, 1 H), 7.16 (s, 1 H), 7.20 - 7.29 (m, 1 H); 7.59 - 7.68 (m, 1 H), 7.86 - 8.05 (m, 2H), 8.24 - 8.30 (m, 1 H), 9.09 (s, 1 H), 10.79 (br s, 1 H), 12.22 - 12.41 (m, 1 H).
Example 84.02
3,3,3-trifluoro-1 -(4-{(1 R or 1 S)-1 -[2-({6-[6-(methoxymethyl)pyrimidin-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)propan-1 -one
Figure imgf000917_0002
Starting with 6-[6-(methoxymethyl)pyrimidin-4-yl]-N-{4-[(1 R or 1 S)-1 -(piperazin-1- yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride (184 mg, see Compound 84.01 ), Example 84.02 was prepared analogously to the procedure for the preparation of Example 39.02.02.
Yield: 67 mg of the 98% pure title compound.
LC-MS (Method 2): R, = 1.07 min; MS (ESIpos): m/z = 555 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.30 (d, 3H), 2.25 - 2.46 (m, 4H), 3.38 - 3.53 (m, 8H), 3.62 (q, 2H), 4.55 (s, 2H), 6.97 (br s, 1 H), 7.17 (s, 1 H), 7.36 - 7.50 (m, 1 H), 7.84 - 8.02 (m, 2H), 8.15 - 8.44 (m, 2H), 9.09 (br s, 1 H), 10.81 (br s, 1 H), 12.22 - 12.43 (m, 1 H).
Example 84.03
cyclopropyl(4-{(1 R or 1S)-1-[2-({6-[6-(methoxymethyl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)methanone
Figure imgf000918_0001
Starting with 6-[6-(methoxymethyl)pyrimidin-4-yl]-N-{4-[(1 R or 1 S)-1-(piperazin-1- yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride (184 mg, see Compound 84.01 ), Example 84.03 was prepared analogously to the procedure for the preparation of Example 39.02.03.
Yield: 57 mg of the 97% pure title compound.
LC-MS (Method 2): R, = 1.03 min; MS (ESIpos): m/z = 513 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 0.59 - 0.75 (m, 4H), 1.30 (d, 3H), 1.86 - 1.99 (m, 1 H), 2.21 - 2.44 (m, 4H), 3.38 - 3.54 (m, 6H), 3.67 (br s, 2H), 4.55 (s, 2H), 6.97 (br s, 1 H), 7.18 (s, 1 H), 7.36 - 7.50 (m, 1 H), 7.86 - 8.03 (m, 2H), 8.15 - 8.46 (m, 2H), 9.09 (br s, 1 H), 10.80 (br s, 1 H), 12.24 - 12.46 (m, 1 H). Example 85.01
tert-butyl 4-[(1R or 1S)-1-(2-{[6-(6-chloropyrimidin-4-yl)-1H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazine-1-carboxylate
Figure imgf000919_0001
Starting with tert-butyl 4-[(1R or 1S)-1-(2-{[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1-carboxylate (3.23 g, 85 % purity, see Compound 23.15.01), Example 85.01 was prepared analogously to the procedure for the preparation of Compound 76.01.
Yield: 89 mg of the title compound with 100 % purity.
LC-MS (Method 4): R, = 1.38 min; MS (ESIpos): m/z = 535 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.29 (d, 3H), 1.38 (s, 9H), 2.23 - 2.44 (m, 4H), 3.26 - 3.32 (m, 4H), 3.45 (q, 1H), 6.90 - 7.03 (m, 1H), 7.17 (s, 1H), 7.37 - 7.66 (m, 1H), 8.00 (br d, 1H), 8.13-8.50 (m, 3H), 9.01 (s, 1H), 10.80 (brd, 1H), 12.37 (d, 1H).
Example 85.01 Alternative Procedure
tert-butyl 4-[(1R or 1S)-1-(2-{[6-(6-chloropyrimidin-4-yl)-1H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazine-1-carboxylate
Figure imgf000919_0002
To a stirred solution of 1H-imidazole (21 mg) and di-1H-imidazol-1-ylmethanethione (391 mg, 90 % purity) in THF (10 mL) was added tert-butyl 4-[(1R or 1S)-1-(2-aminopyridin-4- yl)ethyl]piperazine-1-carboxylate (500 mg, 93 % purity, see Compound 36.05.), dissolved in THF (10 mL) at r.t. The mixture was stirred at 60 °C for 2 h. Further di-1 H-imidazol-1- ylmethanethione (60 mg) was added and the mixture was stirred at 60 Ό for 1 h.
4-(6-chloropyrimidin-4-yl)benzene-1 ,2-diamine (718 mg, 70 % puritysee Compound 85.02), dissolved in THF (3 mL) was added and the mixture was stirred at r.t. for 16 h. The mixture was filtered and N,N'-dipropan-2-ylcarbodiimide (510 μΙ) was added to the solution at r.t.. The mixture was stirred at r.t. for 65 h. The crude reaction mixture was filtered and the solution was concentrated in vacuum. Silicagel chromatography gave 600 mg of the title compound.
LC-MS (Method 2): Rt = 1.36 min; MS (ESIpos): m/z = 535 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.990 (0.48), 1.006 (0.43), 1.153 (1.95), 1.172 (4.04), 1.189 (2.08), 1.279 (1.73), 1.296 (1.75), 1.376 (16.00), 1.987 (7.35), 2.296 (0.41 ), 2.309 (0.49), 2.383 (0.47), 2.518 (0.62), 2.523 (0.43), 3.999 (0.59), 4.016 (1.76), 4.034 (1.72), 4.052 (0.55), 5.758 (0.93), 6.977 (0.56), 6.979 (0.67), 7.01 1 (3.00), 7.170 (0.89), 7.233 (0.42), 7.637 (1.85), 8.273 (0.79), 8.286 (0.80), 9.009 (1.07).
Example 85.02
tert-butyl 4-{(1 R or 1S)-1 -[2-({6-[6-(cyclopropylmethoxy)pyrimidin-4-yl]-1 H-benzimidazol- 2-yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate
Figure imgf000920_0001
tert-butyl 4-[(1 R or 1 S)-1 -(2-{[6-(6-chloropyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)ethyl]piperazine-1 -carboxylate (60.0 mg, see Example 85.01 ), was dissolved in 0.77 mL dioxane and sodium hydride (26.9 mg, 60 % purity) was added portionwise. cyclopropylmethanol (53 μΙ) was added into the reaction mixture. It was stirred for 30 min at rt.
The reaction mixture was diluted with ethyl acetate and the reaction was stopped by the addition of water. The layers were seperated and the aqueous layer was extracted with ethyl acetate twice. The combined organic layers were washed with brine and dried using a waterresistant filter. The clear filtrate was concentrated under reduced pressure.
Yield: 64 mg of the title compound with 92 % purity. LC-MS (Method 4): R, = 1.47 min; MS (ESIpos): m/z = 571 [M+H]+
1 H-NMR (400MHz, DMSO-d6): δ [ppm] = 0.33 - 0.41 (m, 2H), 0.55 - 0.63 (m, 2H), 0.77 - 0.88 (m, 1 H), 1.26 - 1.33 (m, 3H), 1.38 (s, 9H), 2.24 - 2.44 (m, 4H), 3.25 - 3.33 (m, 4H), 3.45 (q, 1 H), 4.23 (d, 2H), 6.95 (br d, 1 H), 7.17 (br s, 1 H), 7.31 - 7.60 (m, 2H), 7.91 (br s, 1 H), 8.14 - 8.40 (m, 2H), 8.73 - 8.79 (m, 1 H), 10.73 (br s, 1 H), 12.29 (br s, 1 H).
Example 85.03
1 -(4-{(1R or 1S)-1-[2-({6-[6-(cyclopropylmethoxy)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)-3,3,3-trifluoropropan-1 -one
Figure imgf000921_0001
Starting with 6-[6-(cyclopropylmethoxy)pyrimidin-4-yl]-N-{4-[(1 R or 1 S)-1 -(piperazin-1- yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride (184 mg, see Compound 85.03), Example 85.03 was prepared analogously to the procedure for the preparation of Example 39.02.02.
Yield: 18 mg of the 95% pure title compound.
LC-MS (Method 2): Rt = 1.30 min; MS (ESIpos): m/z = 581 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 0.34 - 0.42 (m, 2H), 0.54 - 0.64 (m, 2H), 1.20 - 1.36 (m, 4H), 2.29 - 2.47 (m, 4H), 3.40 - 3.52 (m, 5H), 3.62 (q, 2H), 4.23 (d, 2H), 6.96 (br s, 1 H), 7.17 (br d, 1 H), 7.33 - 7.61 (m, 2H), 7.86 - 7.96 (m, 1 H), 8.16 - 8.42 (m, 2H), 8.77 (d, 1 H), 10.66 - 10.81 (m, 1 H), 12.21 - 12.33 (m, 1 H). Example 86.01
tert-butyl 4-[(1R or 1S)-1-(2-{[6-(1-{[(1RS)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4- yl)-7-fluoro-1H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1-carboxylate
Figure imgf000922_0001
Starting with 4-(1-{[(1RS)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-3-fluorobenzene- 1,2-diamine (1.65 g, 90 % purity, see Compound 86.01), Example 86.01 was prepared analogously to the procedure for the preparation of Example 39.02.01. The intermediate thiourea was purified by flash chromatography.
Yield: 1.5 g of the 92% pure title compound.
LC-MS (Method 2): Rt = 1.38 min; MS (ESIpos): m/z = 597 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.28 (d, 3H), 1.38 (s, 9H), 1.46 - 1.60 (m, 1H), 1.70 (tdd, 1H), 2.19-2.44 (m, 5H), 3.25-3.33 (m, 4H), 3.39-3.50 (m, 1H), 4.21 -4.38 (m, 2H), 6.94 (d, 1H), 7.10 (s, 1H), 7.21 -7.38 (m, 2H), 7.85-7.95 (m, 1H), 8.14 (d, 1H), 8.26 (d, 1H), 10.79 (s, 1H), 12.29 (s, 1H)
Example 86.02
1 -{4-[(1 R or 1 S)-1 -(2-{[6-(1 -{[(1 RS)-2,2-dif luorocyclopropyl]methyl}-1 H-pyrazol-4-yl)-7- fluoro-1H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}-3,3,3- trifluoropropan-1-one
Figure imgf000922_0002
Starting with 6-(1-{[(1 RS)-2,2-difluorocyclopropyl]methyl}-1 H-pyrazol-4-yl)-7-fluoro-N-{4-[(1 R or 1S)-1-(piperazin-1-yl)ethyl]pyridin-2-yl}-1H-benzimidazol-2-amine hydrochloride (250 mg, see Compound 86.02), Example 86.02 was prepared analogously to the procedure for the preparation of Example 39.02.02. Yield: 74 mg of the 99% pure title compound.
LC-MS (Method 2): R, = 1.21 min; MS (ESIpos): m/z = 607 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.30 (br d, 3H), 1.47 - 1.60 (m, 1H), 1.63 - 1.78 (m, 1H), 2.22 - 2.47 (m, 5H), 3.39 - 3.53 (m, 5H), 3.62 (q, 2H), 4.22 - 4.40 (m, 2H), 6.96 (d, 1H), 7.11 (s, 1H), 7.23 - 7.37 (m, 2H), 7.90 (s, 1H), 8.14 (s, 1H), 8.27 (d, 1H), 10.80 (s, 1H), 12.29 (brs, 1H).
Example 86.03
cyclopropyl{4-[(1R or 1S)-1-(2-{[6-(1-{[(1RS)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol- 4-yl)-7-fluoro-1 H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}methanone
Figure imgf000923_0001
Starting with 7-chloro-6-(1 -{[(1 RS)-2,2-difluorocyclopropyl]methyl}-1 H-pyrazol-4-yl)-N-{4-[(1 R or 1S)-1-(piperazin-1-yl)ethyl]pyridin-2-yl}-1H-benzimidazol-2-amine hydrochloride (250 mg, see Compound 86.02), Example 86.03 was prepared analogously to the procedure for the preparation of Example 39.02.03.
Yield: 100 mg of the 96% pure title compound.
LC-MS (Method 2): R, = 1.18 min; MS (ESIpos): m/z = 565 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 0.62 - 0.76 (m, 4H), 1.30 (d, 3H), 1.48- 1.60 (m, 1H), 1.62 - 1.77 (m, 1H), 1.89 - 1.98 (m, 1H), 2.20 - 2.47 (m, 5H), 3.40 - 3.55 (m, 3H), 3.67 (br s, 2H), 4.22 - 4.39 (m, 2H), 6.96 (d, 1H), 7.11 (s, 1H), 7.23 - 7.36 (m, 2H), 7.89 (s, 1H), 8.14 (d, 1H), 8.27 (d, 1H), 10.80 (s, 1H), 12.29 (s, 1H)
Example 87.01
1 -(4-{(1 R or 1 S)-1 -[2-({6-[1 -(2,2-dif luoroethyl)-1 H-pyrazol-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)-3,3,3-trifluoropropan-1-one
Figure imgf000924_0001
Starting with 6-[1 -(2,2-dif luoroethyl)-1 H-pyrazol-4-yl]-N-{4-[(1 R or 1 S)-1 -(piperazin-1 - yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride (232 mg, see Compound 87.04), Example 87.01 was prepared analogously to the procedure for the preparation of Example 39.02.02.
Yield: 85 mg of the 98% pure title compound.
LC-MS (Method 2): R, = 1.11 min; MS (ESIpos): m/z = 563 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.30 (d, 3H), 2.26 - 2.47 (m, 4H), 3.37 - 3.52 (m, 5H), 3.56 - 3.69 (m, 2H), 4.64 (br t, 2H), 6.17 - 6.58 (m, 1 H), 6.93 (dd, 1 H), 7.17 (s, 1 H), 7.20 - 7.48 (m, 2H), 7.51 - 7.68 (m, 1 H), 7.85 - 7.97 (m, 1 H), 8.06 - 8.17 (m, 1 H), 8.26 (d, 1 H), 10.58 (br s, 1 H), 12.05 (br s, 1 H). - contains ethyl acetate
Example 87.02
cyclopropyl(4-{(1 R or 1 S)-1 -[2-({6-[1 -(2,2-difluoroethyl)-1 H-pyrazol-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)methanone
Figure imgf000924_0002
Starting with 6-[1-(2,2-difluoroethyl)-1 H-pyrazol-4-yl]-N-{4-[(1 R or 1 S)-1 -(piperazin-1- yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride (232 mg, see Compound 87.04), Example 87.02 was prepared analogously to the procedure for the preparation of Example 39.02.03. Yield: 73 mg of the 95% pure title compound.
LC-MS (Method 2): Rt = 1.07 min; MS (ESIpos): m/z = 521 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 0.59 - 0.75 (m, 4H), 1.30 (d, 3H), 1.87- 1.97 (m, 1H), 2.21 - 2.47 (m, 4H), 3.39 - 3.54 (m, 3H), 3.67 (br s, 2H), 4.64 (td, 2H), 6.21 - 6.59 (m, 1 H), 6.94 (dd, 1H), 7.17 (s, 1H), 7.25 (brd, 1H), 7.43 (br s, 1H), 7.51 - 7.69 (m, 1H), 7.85-7.97 (m, 1H), 8.12 (brs, 1H), 8.26 (d, 1H), 10.58 (br s, 1H), 12.06 (br s, 1H).
Example 88.01
tert-butyl 4-{(1R or 1S)-1-[2-({5-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]-1H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate
Figure imgf000925_0001
Starting with 4-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzene-1,2-diamine (590 mg, see Compound 88.01), Example 88.01 was prepared analogously to the procedure for the preparation of Example 39.02.01. The intermediate was purified by flash chromatography. Yield: 250 mg of the 94% pure title compound.
LC-MS (Method 2): Rt = 1.44 min; MS (ESIpos): m/z = 571 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.29 (d, 3H), 1.38 (s, 9H), 2.23 - 2.45 (m, 4H), 3.24 - 3.33 (m, 4H), 3.45 (q, 1H), 3.94 (s, 3H), 6.83 (brs, 1H), 6.95 (d, 1H), 7.13-7.29 (m, 2H), 7.41 -7.71 (m,2H), 8.28 (d, 1H), 10.70 (brd, 1H), 12.28 (s, 1H).
Example 88.02
3,3,3-trifluoro-1 -(4-{(1 R or 1S)-1 -[2-({6-[1 -methyl-3-(trifluoromethyl)-1 H-pyrazol-5-yl]-1H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)propan-1 -one
Figure imgf000926_0001
Starting 6-[1 -methyl-3-(trifluoromethyl)-1 H-pyrazol-5-yl]-N-{4-[(1 R or 1 S)-1 -(piperazin-1 - yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amin hydrochloride (100 mg, see Compound 88.02), Example 88.02 was prepared analogously to the procedure for the preparation of Example 39.02.02.
Yield: 76 mg of the 95% pure title compound.
LC-MS (Method 2): R, = 1.28 min; MS (ESIpos): m/z = 581 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.30 (d, 3H), 2.25 - 2.47 (m, 4H), 3.38 - 3.54 (m, 5H), 3.62 (q, 2H), 3.94 (s, 3H), 6.83 (br s, H), 6.96 (d, 1 H), 7.14 - 7.29 (m, 2H), 7.41 - 7.72 (m, 2H), 8.28 (d, 1 H), 10.72 (br d, 1 H), 12.27 (br s, 1 H). - contains ethyl acetate
Example 88.03
cyclopropyl(4-{(1 R or 1 S)-1 -[2-({6-[1 -methyl-3-(trifluoromethyl)-1 H-pyrazol-5-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)methanone
Figure imgf000926_0002
Starting with 6-[1-methyl-3-(trifluoromethyl)-1 H-pyrazol-5-yl]-N-{4-[(1 R or 1 S)-1-(piperazin-1- yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride (100 mg, see Compound 88.02), Example 88.03 was prepared analogously to the procedure for the preparation of Example 39.02.03.
Yield:40 mg of the 95% pure title compound.
LC-MS (Method 2): F¾ = 1.25 min; MS (ESIpos): m/z = 539 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 0.59 - 0.76 (m, 4H), 1.30 (d, 3H), 1.88 - 1.98 (m, 1 H), 2.20 - 2.45 (m, 4H), 3.38 - 3.55 (m, 3H), 3.68 (br s, 2H), 3.94 (s, 3H), 6.83 (br s, 1 H), 6.97 (d, 1 H), 7.14 - 7.29 (m, 2H), 7.41 - 7.74 (m, 2H), 8.29 (d, 1 H), 10.71 (br d, 1 H), 12.28 (br s, 1 H). - contains ethyl acetate
Example 89.01
tert-butyl 4-[(1R or 1S)-1 -(2-{[6-(1 ,3-dimethyl-1 H-pyrazol-5-yl)-1 H-benzimidazol-2- yl]ami no}pyridi n-4-y l)ethy I] pi perazine-1 -carboxy late
Figure imgf000927_0001
Starting with 4-(1 ,3-dimethyl-1 H-pyrazol-5-yl)benzene-1 ,2-diamine (350 mg, 95 % purity, see Compound 89.01 ), Example 89.01 was prepared analogously to the procedure for the preparation of Example 39.02.01. The intermediate thiourea was purified by flash chromatography.
Yield: 190 mg of the 95% pure title compound.
LC-MS (Method 2): R, = 1.30 min; MS (ESIpos): m/z = 517 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.29 (d, 3H), 1.38 (s, 9H), 2.17 (s, 3H), 2.24 - 2.44 (m, 4H), 3.24 - 3.32 (m, 4H), 3.44 (q, 1 H), 3.77 (s, 3H), 6.10 (s, 1 H), 6.90 - 6.98 (m, 1 H), 7.05 - 7.21 (m, 2H), 7.39 (br s, 1 H), 7.51 - 7.65 (m, 1 H), 8.27 (d, 1 H), 10.65 (br d, 1 H), 12.20 (br s, 1 H) Example 89.02
1 -{4-[(1 R or 1 S)-1 -(2-{[6-(1 ,3-dimethyl-1 H-pyrazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}-3,3,3-trifluoropropan-1-one
Figure imgf000928_0001
Starting with 6-(1 ,3-dimethyl-1 H-pyrazol-5-yl)-N-{4-[(1 R or 1 S)-1-(piperazin-1 -yl)ethyl]pyridin-2- yl}-1 H-benzimidazol-2-amine hydrochloride (82 mg, see Compound 89.02), Example 89.02 was prepared analogously to the procedure for the preparation of Example 39.02.02.
Yield: 54 mg of the 95% pure title compound.
LC-MS (Method 2): R, = 1.11 min; MS (ESIpos): m/z = 527 [M+H]+
1 H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.30 (d, 3H), 2.17 (s, 3H), 2.28 - 2.47 (m, 4H), 3.39 - 3.53 (m, 5H), 3.62 (q, 2H), 3.77 (s, 3H), 6.10 (s, 1 H), 6.95 (d, 1 H), 7.08 - 7.21 (m, 2H), 7.33 - 7.65 (m, 2H), 8.28 (d, 1 H), 10.67 (br s, 1 H), 12.21 (br s, 1 H).
Example 89.03
cyclopropyl{4-[(1 R or 1 S)-1 -(2-{[6-(1 ,3-dimethyl-1 H-pyrazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}methanone
Figure imgf000928_0002
Starting with 6-(1 ,3-dimethyl-1 H-pyrazol-5-yl)-N-{4-[(1 R or 1 S)-1-(piperazin-1 -yl)ethyl]pyridin-2- yl}-1 H-benzimidazol-2-amine hydrochloride (82 mg, see Compound 89.02), Example 89.03 was prepared analogously to the procedure for the preparation of Example 39.02.03.
Yield:20 mg of the 92% pure title compound. LC-MS (Method 2): Rt = 1.08 min; MS (ESIpos): m/z = 485 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 0.60 - 0.75 (m, 4H), 1.30 (d, 3H), 1.88 - 1.99 (m, 1 H), 2.17 (s, 3H), 2.24 - 2.43 (m, 4H), 3.40 - 3.53 (m, 3H), 3.68 (br s, 2H), 3.77 (s, 3H), 6.10 (s, 1 H), 6.96 (d, 1 H), 7.05 - 7.23 (m, 2H), 7.39 (br s, 1 H), 7.51 - 7.65 (m, 1 H), 8.28 (d, 1 H), 10.66 (br d, 1 H), 12.20 (br s, 1 H).
Example 90.01
tert-butyl 4-({2-[(6-{6-[(3-methoxypropyl)amino]pyrimidin-4-yl}-1 H-benzimidazol-2- yl)amino]pyridin-4-yl}methyl)piperazine-1 -carboxylate
Figure imgf000929_0001
Starting with tert-butyl 4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-benzimidazol- 2-yl]amino}pyridin-4-yl)methyl]piperazine-1-carboxylate (150 mg, see Compound 01.04), Example 90.01 was prepared analogously to the procedure for the preparation of Compound 60.01.
Yield: 92 mg of the title compound with 77 % purity.
LC-MS (Method 4): R, = 1.23 min; MS (ESIpos): m/z = 575 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm]: 1.396 (13.67), 1.773 (0.50), 1.790 (0.72), 1.806 (0.50), 2.327 (0.42), 2.346 (1.07), 2.358 (1.54), 2.369 (1.10), 3.159 (7.95), 3.172 (8.00), 3.221 (0.71 ), 3.331 (16.00), 3.350 (1.75), 3.394 (1.06), 3.410 (1.66), 3.426 (0.80), 3.499 (1.70), 4.082 (0.72), 4.096 (2.07), 4.109 (2.02), 4.122 (0.67), 5.759 (0.95), 6.922 (0.65), 6.935 (0.56), 8.257 (0.78), 8.270 (0.75), 8.452 (0.65), 10.709 (0.51 ). Example 90.02
3,3,3-trifluoro-1 -[4-({2-[(6-{6-[(3-methoxypropyl)amino]pyrimidin-4-yl}-1H-benzimidazol-2- yl)amino]pyridin-4-yl}methyl)piperazin-1-yl]propan-1 -one
Figure imgf000930_0001
Starting with 6-{6-[(3-methoxypropyl)amino]pyrimidin-4-yl}-N-[4-(piperazin-1-ylmethyl)pyridin-2- yl]-1 H-benzimidazol-2-amine hydrochloride (80 mg, see Compound 90.01 ), Example 90.02 was prepared analogously to the procedure for the preparation of Example 39.02.02.
Yield: 52 mg of the 74% pure title compound.
LC-MS (Method 2): F¾ = 1.02 min; MS (ESIpos): m/z = 584 [M+H]+
1 H-NMR (500MHz, DMSO-d6): δ [ppm] = 1.79 (quin, 2H), 2.31 - 2.46 (m, 4H), 3.25 (s, 3H), 3.35 - 3.44 (m, 4H), 3.44 - 3.56 (m, 6H), 3.65 (q, 2H), 6.83 - 6.98 (m, 2H), 7.18 (br s, 1 H), 7.26 - 7.60 (m, 2H), 7.74 (br s, 1 H), 7.91 - 8.24 (m, 1 H), 8.27 (d, 1 H), 8.45 (s, 1 H), 10.72 (br s, 1 H), 12.23 (br s, 1 H).
Example 91.01
tert-butyl 4-[(2-{[6-(6-ethylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4' yl)methyl]piperazine-1-carboxylate
Figure imgf000930_0002
Starting with tert-butyl 4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-benzimidazol- 2-yl]amino}pyridin-4-yl)methyl]piperazine-1-carboxylate (150 mg, see Compound 01.04), Example 91.01 was prepared analogously to the procedure for the preparation of Compound 60.01.
Yield: 168 mg of the title compound with 78 % purity.
LC-MS (Method 2): f¾ = 1.31 min; MS (ESIpos): m/z = 516 [M+H]+
H-NMR (400MHz, DMSO-d6): δ [ppm]: 1.109 (0.44), 1.128 (0.89), 1.147 (0.50), 1.274 (1.61 ), 1.293 (3.33), 1.312 (1.65), 1.363 (0.44), 1.370 (0.57), 1.395 (16.00), 2.358 (2.05), 2.440 (0.43), 2.459 (0.47), 2.763 (0.45), 2.782 (1.29), 2.801 (1.26), 2.819 (0.43), 3.159 (1.28), 3.172 (1.30), 3.333 (6.33), 3.349 (1.75), 3.502 (2.04), 5.758 (8.24), 6.935 (0.53), 6.947 (0.53), 7.181 (1.09), 7.944 (0.50), 7.966 (0.53), 8.237 (0.45), 8.264 (0.90), 8.276 (0.84), 9.047 (1.29).
Example 91.02
1 -{4-[(2-{[6-(6-ethylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1-yl}-3,3,3-trifluoropropan-1-one
Figure imgf000931_0001
Starting with 6-(6-ethylpyrimidin-4-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]-1 H-benzimidazol- 2-amine hydrochloride (80 mg, see Compound 91 .01 ), Example 91.02 was prepared analogously to the procedure for the preparation of Example 39.02.02.
Yield: 42 mg of the 79% pure title compound.
LC-MS (Method 4): Rt = 1.06 min; MS (ESIpos): m/z = 525 [M+H]+
H-NMR (500MHz, DMSO-d6): δ [ppm] = 1 .29 (t, 3H), 2.33 - 2.46 (m, 4H), 2.79 (q, 2H), 3.42 - 3.56 (m, 6H), 3.65 (q, 2H), 6.95 (br d, 1 H), 7.20 (s, 1 H), 7.39 - 7.67 (m, 1 H), 7.82 - 8.01 (m, 2H), 8.15 - 8.45 (m, 2H), 9.05 (d, 1 H), 10.77 (br s, 1 H), 1 1.62 - 12.95 (m, 1 H). Example 91.03
cyclopropyl{4-[(2-{[6-(6-ethylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4 yl)methyl]piperazin-1-yl}methanone
Figure imgf000932_0001
Starting with 6-(6-ethylpyrimidin-4-yl)-N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]-1 H-benzimidazol- 2-amine hydrochloride (80 mg, see Compound 91.01 ), Example 91.03 was prepared analogously to the procedure for the preparation of Example 39.02.03.
Yield:40 mg of the 91 % pure title compound.
LC-MS (Method 2): Rt = 1.06 min; MS (ESIpos): m/z = 483 [M+H]+
1H-NMR (500MHz, DMSO-d6): δ [ppm] = 0.64 - 0.77 (m, 4H), 1.29 (t, 3H), 1.93 - 2.03 (m, 1 H), 2.31 - 2.47 (m, 4H), 2.79 (q, 2H), 3.44 - 3.57 (m, 4H), 3.71 (br s, 2H), 6.96 (br d, 1 H), 7.20 (s, 1 H), 7.38 - 7.65 (m, 1 H), 7.84 - 8.02 (m, 2H), 8.19 - 8.45 (m, 2H), 9.05 (d, 1 H), 10.78 (br s, 1 H), 12.22 - 12.40 (m, 1 H).
Example 92.01
tert-butyl 4-{[2-({6-[6-(3,5-dimethyl-1 ,2-oxazol-4-yl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate
Figure imgf000932_0002
Starting with tert-butyl 4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-benzimidazol 2-yl]amino}pyridin-4-yl)methyl]piperazine-1-carboxylate (150 mg, see Compound 01.04and 4 chloro-6-(3,5-dimethyl-1 ,2-oxazol-4-yl)pyrimidine, which can be prepared from 4,6 dichloropyrimidine and (3,5-dimethylisoxazol-4-yl)boronic acid, Example 92.01 was prepared analogously to the procedure for the preparation of Compound 60.01.
Yield: 106 mg of the title compound with 84 % purity.
LC-MS (Method 2): F¾ = 1.35 min; MS (ESIpos): m/z = 582 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm]: 1.365 (0.53), 1.396 (16.00), 2.327 (0.64), 2.363 (2.01 ), 2.669 (0.65), 2.729 (2.92), 3.159 (3.22), 3.172 (3.35), 3.509 (1.94), 4.095 (0.88), 4.108 (0.85), 6.949 (0.49), 7.193 (0.57), 8.032 (0.59), 8.282 (0.65), 9.214 (0.85).
Example 92.02
1 -(4-{[2-({6-[6-(3,5-dimethyl-1 ,2-oxazol-4-yl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1 -yl)-3,3,3-trifluoropropan-1 -one
Figure imgf000933_0001
Starting with 6-[6-(3,5-dimethyl-1 ,2-oxazol-4-yl)pyrimidin-4-yl]-N-[4-(piperazin-1 - ylmethyl)pyridin-2-yl]-1 H-benzimidazol-2-amine hydrochloride (105 mg, see Compound 92.01 ), Example 92.02 was prepared analogously to the procedure for the preparation of Example 39.02.02.
Yield: 55 mg of the 83% pure title compound.
LC-MS (Method 4): F¾ = 1.14 min; MS (ESIpos): m/z = 592 [M+H]+
1H-NMR (500MHz, DMSO-d6): δ [ppm] = 2.29 - 2.46 (m, 4H), 2.51 (s, 3H), 2.73 (s, 3H), 3.42 - 3.56 (m, 6H), 3.65 (q, 2H), 6.96 (br s, 1 H), 7.21 (s, 1 H), 7.40 - 7.65 (m, 1 H), 7.95 - 8.14 (m, 2H), 8.22 - 8.51 (m, 2H), 9.21 (s, 1 H), 10.65 - 10.89 (m, 1 H), 12.33 (br s, 1 H). Example 93.01
3,3,3-trifluoro-1 -(4-{[2-({6-[6-(pyrrolidin-1 -yl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1 -yl)propan-1 -one
Figure imgf000934_0001
Starting with N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-6-[6-(pyrrolidin-1 -yl)pyrimidin-4-yl]-1 H- benzimidazol-2-amine hydrochloride (100 mg, see Compound 93.02), Example 93.01 was prepared analogously to the procedure for the preparation of Example 39.02.02.
Yield: 33 mg of the 79% pure title compound.
LC-MS (Method 4): R, = 1.11 min; MS (ESIpos): m/z = 566 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.85 - 2.10 (m, 4H), 2.34 - 2.46 (m, 4H), 3.36 - 3.58 (m, 10H), 3.65 (q, 2H), 6.79 - 6.99 (m, 2H), 7.20 (s, 1 H), 7.35 - 7.61 (m, H), 7.87 (br d, 1 H), 8.07 - 8.35 (m, 2H), 8.50 (s, 1 H), 10.71 (br s, 1 H), 12.24 (d, 1 H).
Example 94.01
3,3,3-trifluoro-1 -(4-{[2-({6-[6-(morpholin-4-yl)pyrimidin-4-yl]-1 H-benzimidazol-2 - yl}amino)pyridin-4-yl]methyl}piperazin-1 -yl)propan-1 -one
Figure imgf000934_0002
Starting with 6-[6-(morpholin-4-yl)pyrimidin-4-yl]-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (140 mg, see Compound 94.02), Example 94.01 was prepared analogously to the procedure for the preparation of Example 39.02.02. Yield: 38 mg of the 77% pure title compound.
LC-MS (Method 4): R, = 1.02 min; MS (ESIpos): m/z = 582 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 2.35 - 2.45 (m, 4H), 3.43 - 3.56 (m, 6H), 3.59 - 3.75 (m, 10H), 6.94 (brd, 1H), 7.20 (s, 1H), 7.23-7.60 (m, 2H), 7.91 (br d, 1H), 8.16-8.38 (m, 2H), 8.57 (s, 1H), 10.73 (brs, 1H), 12.23 (brd, 1H).
Example 95.01
3,3,3-trifluoro-1 -(4-{[2-({6-[6-(methylsulfanyl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1 -yl)propan-1 -one
Figure imgf000935_0001
Starting with 6-[6-(methylsuIfanyl)pyrimidin-4-yl]-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (100 mg, see Compound 95.02), Example 95.01 was prepared analogously to the procedure for the preparation of Example 39.02.02.
Yield: 9 mg of the 86% pure title compound.
LC-MS (Method 4): R, = 1.13 min; MS (ESIpos): m/z = 543 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 2.29 - 2.46 (m, 4H), 2.61 (s, 3H), 3.41 - 3.57 (m, 6H), 3.65 (q, 2H), 6.95 (brd, 1H), 7.20 (s, 1H), 7.37-7.65 (m, 1H), 7.79-8.01 (m, 2H), 8.18-8.45 (m, 2H), 8.92 (s, 1H), 10.79 (brs, 1H), 12.13-12.45 (m, 1H).
Example 95.02
cyclopropyl(4-{[2-({6-t6-(methylsulfanyl)pyrimidin-4-yl]-1 H-benzimidazol-2'
yl}amino)pyridin-4-yl]methyl}piperazin-1 -yl)methanone
Figure imgf000936_0001
Starting with 6-[6-(methylsulfanyl)pyrimidin-4-yl]-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine hydrochloride (100 mg, see Compound 95.02), Example 95.02 was prepared analogously to the procedure for the preparation of Example 39.02.03.
Yield: 6 mg of the 52% pure title compound.
LC-MS (Method 4): F¾ = 1.09 min; MS (ESIpos): m/z = 501 [M+H]+
1 H-NMR (500MHz, DMSO-d6): δ [ppm] = 0.57 - 0.82 (m, 4H), 1.88 - 2.01 (m, 1 H), 2.28 - 2.47 (m, 4H), 2.61 (s, 3H), 3.42 - 3.58 (m, 4H), 3.71 (br s, 2H), 6.89 - 7.00 (m, 1 H), 7.22 (s, 1 H), 7.36 - 7.70 (m, 1 H), 7.82 - 8.03 (m, 2H), 8.19 - 8.42 (m, 2H), 8.92 (d, 1 H), 10.78 (br s, 1 H), 12.32 (br s, 1 H).
Example 96.01
tert-butyl 4-{[2-({6-[6-(2-hydroxypropan-2-yl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1-carboxylate
Figure imgf000936_0002
Starting with tert-butyl 4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-benzimidazol- 2-yl]amino}pyridin-4-yl)methyl]piperazine-1-carboxylate (186 mg, see Compound 01.04), Example 96.01 was prepared analogously to the procedure for the preparation of Compound
60.01. Yield: 117 mg of the title compound with 90 % purity.
LC-MS (Method 2): Rt = 1.21 min; MS (ESIpos): m/z = 546 [M+H]+
1H-NMR (500MHz, DMSO-d6): δ [ppm] = 1.40 (s, 9H), 1.46 - 1.52 (m, 6H), 2.36 (brt, 4H), 3.35 (brs, 4H), 3.50 (s, 2H), 5.49 (brs, 1H), 6.95 (brd, 1H), 7.17 (s, 1H), 7.36-7.64 (m, 1H), 7.85- 8.02 (m, 1H), 8.11 -8.45 (m, 3H), 9.08 (s, 1H), 10.80 (brs, 1H), 12.22 - 12.43 (m, 1H).
Example 96.02
3,3,3-trifluoro-1-(4-{[2-({6-[6-(2-hydroxypropan-2-yl)pyrimidin-4-yl]-1H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1 -yl)propan-1 -one
Figure imgf000937_0001
Starting with 2-[6-(2-{[4-(piperazin-1-ylmethyl)pyridin-2-yl]amino}-1 H-benzimidazol-6- yl)pyrimidin-4-yl]propan-2-ol hydrochloride (115 mg, see Compound 96.02), Example 96.02 was prepared analogously to the procedure for the preparation of Example 39.02.02.
Yield: 60 mg of the 83% pure title compound.
LC-MS (Method 4): R, = 1.00 min; MS (ESIpos): m/z = 555 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.48 (s, 6H), 2.40 (dt, 4H), 3.44 - 3.58 (m, 6H), 3.65 (q, 2H), 5.49 (s, 1H), 6.96 (br d, 1H), 7.18 (s, 1H), 7.39 - 7.67 (m, 1H), 7.86 - 8.02 (m, 1H), 8.11 -8.44 (m, 3H), 9.08 (s, 1H), 10.80 (brs, 1H), 12.32 (brs, 1H).
Example 97.01
(rac)-tert-butyl 4-({2-[(6-{6-[1-hydroxyethyl]pyrimidin-4-yl}-1H-benzirnidazol-2- yl)amino]pyridin-4-yl}methyl)piperazine-1 -carboxylate
Figure imgf000938_0001
Starting with tert-butyl 4-[(2-{[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol- 2-yl]amino}pyridin-4-yl)methyl]piperazine-1-carboxylate (200 mg, see Compound 01.04), Example 97.01 was prepared analogously to the procedure for the preparation of Compound 60.01.
Yield: 142 mg of the title compound with 96 % purity.
LC-MS (Method 2): R, = 1.14 min; MS (ESIpos): m/z = 532 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.40 (s, 9H), 1.43 (d, 3H), 2.30 - 2.42 (m, 4H), 3.35 (brs, 4H), 3.50 (s, 2H), 4.66-4.78 (m, 1H), 5.64 (br s, 1H), 6.95 (br d, 1H), 7.17 (s, 1H), 7.39- 7.66 (m, 1H), 7.87-8.11 (m, 2H), 8.13-8.44 (m, 2H), 9.06 (s, 1H), 10.80 (brs, 1H), 12.35 (br s, 1H).
Example 97.02
(rac)-3,3,3-trifluoro-1-[4-({2-[(6-{6-[1-hydroxyethyl]pyrimidin-4-yl}-1H-benzimidazol-2- yl)amino]pyridin-4-yl}methyl)piperazin-1-yl]propan-1 -one
Figure imgf000938_0002
Starting with (rac)-1-[6-(2-{[4-(piperazin-1 -ylmethyl)pyridin-2-yl]amino}-1 H-benzimidazol-6- yl)pyrimidin-4-yl]ethanol hydrochloride (155 mg, Compound 97.02), Example 95.02 was prepared analogously to the procedure for the preparation of Example 39.02.02.
Yield: 48 mg of the 99% pure title compound.
LC-MS (Method 2): R, = 0.95 min; MS (ESIpos): m/z = 541 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.43 (d, 3H), 2.35 - 2.46 (m, 4H), 3.43 - 3.58 (m, 6H), 3.65 (q, 2H), 4.67 - 4.79 (m, 1 H), 5.64 (br s, 1 H), 6.96 (d, 1 H), 7.18 (s, 1 H), 7.38 - 7.70 (m, 1 H), 7.95 (br s, 1 H), 8.05 (br s, 1 H), 8.12 - 8.46 (m, 2H), 9.06 (s, 1 H), 10.72 - 10.89 (m, 1 H), 12.34 (br s, 1 H).
Example 97.03
1 -{4 (2-{[6-(6-acetylpyrimidin-4-yl)-1 H^enzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1-yl}-3,3,3-trifluoropropan-1 -one
Figure imgf000939_0001
As side product Example 97.03 was isolated from the previous reaction Example 97.02.
Yield: 40 mg of the 99% pure title compound.
LC-MS (Method 2): R, = 1.10 min; MS (ESIpos): m/z = 539 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 2.34 - 2.46 (m, 4H), 2.69 (s, 3H), 3.42 - 3.58 (m, 6H), 3.65 (q, 2H), 6.96 (br d, 1 H), 7.19 (s, 1 H), 7.37 - 7.70 (m, 1 H), 8.05 (br d, 1 H), 8.23 - 8.56 (m, 3H), 9.36 (s, 1 H), 10.85 (br s, 1 H), 12.38 (br s, 1 H).
Example 98.01
tert-butyl 4-[(1R or 1S)-1-(2-{[7-chloro-6-(6-methylpyrimidin-4-yl)-1H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazine-1-carboxylate
Figure imgf000940_0001
Starting with 3-chloro-4-(6-methylpyrimidin-4-yl)benzene-1,2-diamine (390 mg, see Compound 98.02), Example 98.01 was prepared analogously to the procedure for the preparation of Example 39.02.01.
Yield: 249 mg of the title compound with 91 % purity.
LC-MS (Method 2): R, = 1.31 min; MS (ESIpos): m/z = 549 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.29 (d, 3H), 1.38 (s, 9H), 2.22 - 2.45 (m, 4H), 2.54 (s, 3H), 3.24-3.33 (m, 4H), 3.46 (q, 1H), 6.97 (brd, 1H), 7.11 (s, 1H), 7.31 (d, 1H), 7.52-7.61 (m, 1H), 7.74 (s, 1H), 8.29 (d, 1H), 8.96-9.17 (m, 1H), 11.06 (s, 1H), 12.48 (s, 1H).
Example 98.02
1-{4-[(1R or 1S)-1-(2-{[7-chloro-6-(6-methylpyrimidin-4-yl)-1H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}-3,3,3-trifluoropropan-1-one
Figure imgf000940_0002
Starting with 7-chloro-6-(6-methylpyrimidin-4-yl)-N-{4-[(1R or 1S)-1-(piperazin-1- yl)ethyl]pyridin-2-yl}-1H-benzimidazol-2-amine hydrochloride (135 mg, see Compound 98.03), Example 98.02 was prepared analogously to the procedure for the preparation of Example 39.02.02. Yield: 85 mg of the 85% pure title compound.
LC-MS (Method 4): R, = 1.08 min; MS (ESIpos): m/z = 559 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.30 (d, 3H), 2.26 - 2.47 (m, 4H), 2.54 (s, 3H), 3.38 - 3.53 (m, 5H), 3.62 (q, 2H), 6.99 (d, 1H), 7.11 (s, 1H), 7.31 (d, 1H), 7.57 (d, 1H), 7.74 (s, 1H), 8.30 (d, 1H), 9.12 (d, 1H), 11.08 (s, 1H), 12.48 (brs, 1H).
Example 98.03
{4-[(1R or 1S)-1-(2-{[7-chloro-6-(6-methylpyrimidin-4-yl)-1H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}(cyclopropyl)methanone
Figure imgf000941_0001
Starting with 7-chloro-6-(6-methylpyrimidin-4-yl)-N-{4-[(1R or 1S)-1-(piperazin-1- yl)ethyl]pyridin-2-yl}-1H-benzimidazol-2-amine hydrochloride (135 mg, see Compound 98.03), Example 98.03 was prepared analogously to the procedure for the preparation of Example 39.02.03.
Yield: 85 mg of the 98% pure title compound.
LC-MS (Method 4): R, = 1.04 min; MS (ESIpos): m/z = 517 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 0.62 - 0.76 (m, 4H), 1.30 (d, 3H), 1.89 - 2.00 (m, 1H), 2.25 - 2.45 (m, 4H), 2.54 (s, 3H), 3.47 (br d, 3H), 3.68 (br s, 2H), 6.99 (d, 1H), 7.12 (br s, 1H), 7.31 (brd, 1H), 7.56 (brd, 1H), 7.74 (d, 1H), 8.30 (d, 1H), 9.12 (d, 1H), 11.06 (brs, 1H), 12.49 (brs, 1H).
Example 99.01
1-(4-{(1R or 1S)-1-[2-({7-chloro-6 6-(methoxymethyl)pyrimidin-4-yl]-1H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)-3,3,3-trifluoropropan-1-one
Figure imgf000942_0001
Starting with 7-chloro-6-[6-(methoxymethyl)pyrimidin-4-yl]-N-{4-[(1R or 1S)-1-(piperazin-1- yl)ethyl]pyridin-2-yl}-1H-benzimidazol-2-amine hydrochloride (150 mg, see Compound 99.03), Example 99.01 was prepared analogously to the procedure for the preparation of Example 39.02.02.
Yield: 22 mg of the 77% pure title compound.
LC-MS (Method 4): R, = 1.09 min; MS (ESIpos): m/z = 589 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.30 (br d, 3H), 2.25 - 2.46 (m, 4H), 3.38 - 3.55 (m, 8H), 3.62 (q, 2H), 4.60 (s, 2H), 6.99 (brd, 1H), 7.10 (s, 1H), 7.37 (d, 1H), 7.59 (d, 1H), 7.84 (s, 1H), 8.30 (d, 1H), 9.21 (d, 1H), 11.10 (s, 1H), 12.51 (brs, 1H).
Example 100.01
1-(4-{(1R or 1S)-1-[2-({6-[6-(dimethylamino)pyrimidin-4-yl]-1H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)-3,3,3-trifluoropropan-1-one
Figure imgf000942_0002
Starting with 6-[6-(dimethylamino)pyrimidin-4-yl]-N-{4-[(1R or 1S)-1-(piperazin-1- yl)ethyl]pyridin-2-yl}-1H-benzimidazol-2-amine hydrochloride (105 mg, see Compound 100.02), Example 100.01 was prepared analogously to the procedure for the preparation of Example 39.02.02.
Yield: 64 mg of the 90% pure title compound.
LC-MS (Method 2): R, = 1.10 min; MS (ESIpos): m/z = 554 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.30 (d, 3H), 2.28 - 2.47 (m, 4H), 3.15 (s, 6H), 3.39 - 3.53 (m, 5H), 3.56 - 3.69 (m, 2H), 6.95 (d, 1 H), 7.00 - 7.14 (m, 1 H), 7.18 (s, 1 H), 7.34 - 7.59 (m, 1 H), 7.89 (br s, 1 H), 8.1 1 - 8.35 (m, 2H), 8.52 (d, 1 H), 10.71 (br s, 1 H), 12.23 (br d, 1 H). - contains ethyl acetate
Example 100.03
cyclopropyl(4-{(1 R or 1 S)-1 -[2-({6-[6-(dimethylamino)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)methanone
Figure imgf000943_0001
6-[6-(Dimethylamino)pyrimidin-4-yl]-N-{4-[(1 R or 1 S)-1 -(piperazin-1 -yl)ethyl]pyridin-2-yl}-1 H- benzimidazol-2-amine hydrochloride (150 mg, see Compound 100.02), cyclopropanecarboxylic acid (32 μΙ), NaHC03 (137 mg) and HATU (155 mg) were stirred in DMF (2.7 ml) for 2 h at rt. The reaction mixture was diluted with water and extracted three times with EtOAc. The combined organic layers were washed with brine, dried (silicone filter) and evaporated under reduced pressure. The crude mixture was purified by flash chromatography on silica gel to give 86.5 mg (100 % purity) of the title compound.
LC-MS (Method 2): R, = 1.04 min; MS (ESIpos): m/z = 512 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ ppm 0.64 - 0.73 (m, 4 H) 1.30 (d, J=6.84 Hz, 3 H) 1.90 - 1 .97 (m, 1 H) 2.24 - 2.45 (m, 4 H) 3.15 (s, 6 H) 3.41 - 3.53 (m, 3 H) 3.67 (br s, 2 H) 6.96 (d, J=5.07 Hz, 1 H) 7.03 - 7.14 (m, 1 H) 7.18 (s, 1 H) 7.35 - 7.57 (m, 1 H) 7.89 (br s, 1 H) 8.16 (br s, 0,5 H) 8.27 (d, J=5.32 Hz, 1 H) 8.31 (br s, 0,5 H) 8.52 (d, J=1.01 Hz, 1 H) 10.71 (br s, 1 H) 12.23 (br d, J=16.98 Hz, 1 H) Example 100.04
(4-{(1 R or 1S)-1-[2-({6-[6-(dimethylamino)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)[1 -(trifluoromethyl)cyclopropyl]methanone
Figure imgf000944_0001
A mixture of 6-[6-(dimethylamino)pyrimidin-4-yl]-N-{4-[(1 R or 1 S)-1 -(piperazin-1 - yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride (190 mg, see Compound 100.02), 1 -(trifluoromethyl)cyclopropanecarboxyIic acid (159 mg), solid NaHCC>3 (173 mg) and HATU (392 mg) was stirred in DMF (2.1 ml) overnight at rt. The crude mixture was purified by flash chromatography on silica gel to give 40.3 mg (95 % purity) of the title compound.
LC-MS (Method 2): R, = 1.15 min; MS (ESIpos): m/z = 580 [M+H]+
1 H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.16 (br s, 2H), 1.21 - 1.35 (m, 5H), 2.26 - 2.48 (m, 4H), 3.06 - 3.20 (m, 6H), 3.45 (q, 1 H), 3.56 (br s, 4H), 6.96 (dd, 1 H), 7.07 (s, 1 H), 7.18 (s, 1 H), 7.36 - 7.66 (m, 2H), 7.89 (dd, 1 H), 8.16 - 8.33 (m, 2H), 8.52 (d, 1 H), 10.71 (br s, 1 H), 12.23 (br s, 1 H).
Example 101.01
4-[(2-{[6-(3-methyl-1,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1-carbaldehyde
Figure imgf000944_0002
To a mixture of piperazine-1-carbaldehyde (34 mg) in 2 mL DMF was added N-[4- (chloromethyl)pyridin-2-yl]-6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2-amine (51 mg) (see Compound 16.30) in 1 mL DMF. Potassium carbonate was added (104 mg) and the resulting mixture was heated to 40*C fur 16 h. The precipitate was filtered off. The remaining solution was subjected to standard reversed- phase preparative HPLC purification to give 4 mg of the title compound.
LC-MS (UPLC-MS Method 7): Rt = 0.64 min; MS (ESIpos): m/z = 419 [M+H]+
The examples in the following table 9 were prepared in analogy to example 101.01. UPLC-MS Method 7 was used for determination of retention times and LC-S m/z.
Table 9:
Figure imgf000946_0001
Figure imgf000947_0001
Figure imgf000948_0001
yl)methanone
Figure imgf000949_0001
Figure imgf000950_0001
yl)methanone
Example 102.01
cyclopropyl{4-[(2 [6-(2,6-dimethylpyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1-yl}methanone
Figure imgf000951_0001
A suspension of tert-butyl 4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate (see Compound 01.04) in dioxane (800 μΙ, 0.25 M), was added to 75 mg (2 eq) 4-bromo-2,6-dimethylpyridine. 600 μΙ aqueous potassium carbonate solution (1.0 M, 3 eq) were added and the mixture was shaken at rt for 1 h. A solution of Pd(dppf)CI2 x CH2CI2 (1.0 ml, 0.040 M in dioxane, 0,2 eq) was added and the mixture was heated overnight at 14CC in a pressure reactor. After cooling, the mixture was filtered, evaporated and treated with 2 mL TFA/DCM/water (2:1 :0.1 ) for 3h at rt. After vacuum evaporation the residue was treated with cyclopropanecarboxylic acid (600 μΙ, 1.0 M in NMP, 3 eq), NMM (400 μΙ, 3.0 M in NMP, 6 eq) and HATU (1.2 ml, 0.50 M in NMP, 3 eq), shaken overnight at rt, filtered and subjected to standard reversed-phase preparative HPLC to yield 17.8 mg (18 %) of the title compound cyclopropyl{4-[(2-{[6-(2,6-dimethylpyridin-4-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)methyl]piperazin-1-yl}methanone.
LC-MS (Method 4): R, = 1.1.08 min; MS (ESIpos): m/z = 483 [M+H]+
The following examples shown in Table 10 below were prepared in analogy to example 102.01 using the appropriate aryl bromide and carboxylic acid derivative:
Table 10:
Figure imgf000952_0001
Figure imgf000953_0001
Example 107.01.01
tert-butyl 4-{[2-({6-[6-(dimethylamino)-5-methoxypyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate
Figure imgf000954_0001
To a stirred solution of tert-butyl 4-[(2-{[6-(6-chloro-5-methoxypyrimidin-4-yl)-1 H-benzimidazol- 2-yl]amino}pyridin-4-yl)methyl]piperazine-1-carboxylate (300 mg, see Compound 60.01 ) in 2- propanol (3.0 ml) in a microwave tube was added N-methylmethanamine (1.4 ml, 2.0 M in THF). The mixture was stirred at 100°C for 30 minu tes in a microwave oven. The mixture was concentrated in vacuum. Silicagel chromatography gave a solid that was triturated with warm ethanol to give 210 mg of the title compound.
LC-MS (Method 2): R, = 1.27 min; MS (ESIpos): m/z = 560 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.395 (16.00), 2.345 (0.91 ), 2.358 (1.35), 2.370 (0.94), 3.197 (10.86), 3.332 (8.15), 3.351 (1.20), 3.371 (1.69), 6.919 (0.52), 6.931 (0.53), 7.169 (0.57), 8.251 (0.74), 8.263 (0.69), 8.325 (3.02).
Example 107.01.02
cyclopropyl(4-{[2-({6-[6-(dimethylamino)-5-methoxypyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1 -yl)methanone
Figure imgf000954_0002
To a stirred solution of crude 6-[6-(dimethylamino)-5-methoxypyrimidin-4-yl]-N-[4-(piperazin-1- ylmethyl)pyridin-2-yl]-1 H-benzimidazol-2-amine hydrochloride (100 mg, see Compound 107.01.01 ) in DMF (1.7 ml_) was added sodium bicarbonate (81.5 mg), cyclopropanecarboxylic acid (20 μΙ, 95 % purity) and HATU (98.4 mg). The mixture was stirred at r.t. for 16 h. An excess of water was added and the mixture was stirred for 15 minutes. A solid precipitated and was collected by filtration. Aminophase-silicagel chromatography gave a solid that was triturated with ether to give 60.0 mg of the title compound.
LC-MS (Method 2): Rt = 1.07 min; MS (ESIpos): m/z = 528 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.676 (0.69), 0.683 (1 .47), 0.697 (0.81 ), 0.703 (1.76), 0.708 (1.54), 0.713 (1.61 ), 0.721 (1.54), 0.725 (1.72), 0.732 (0.80), 1.952 (0.40), 1.964 (0.63), 2.364 (0.80), 2.446 (0.88), 2.523 (0.66), 3.198 (16.00), 3.331 (8.10), 3.521 (3.32), 3.705 (0.74), 6.936 (0.93), 6.948 (0.93), 7.188 (1.16), 8.260 (1.24), 8.273 (1.14), 8.325 (3.92), 10.704 (0.52).
Example 107.01.03
1 -(4-{[2-({6 6-(dimethylamino)-5-methoxypyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1 -yl)-3,3,3-trifluoropropan-1 -one
Figure imgf000955_0001
To a stirred solution of crude 6-[6-(dimethylamino)-5-methoxypyrimidin-4-yl]-N-[4-(piperazin-1 - ylmethyl)pyridin-2-yl]-1 H-benzimidazol-2-amine hydrochloride (100 mg, see Compound 107.01.01 ) in DMF (2.7 mL) was added sodium bicarbonate (109 mg), 3,3,3-trifluoropropanoic acid (21 pi) and HATU (98.4 mg). The mixture was stirred at r.t. for 16 h. An excess of water was added and the mixture was stirred for 15 minutes. A solid precipitated and was collected by filtration. Preparative reverse phase HPLC (gradient of water and acetonitrile containing ammonia as additive) gave 45.0 mg of the title compound. LC-MS (Method 2): Rt = 1.09 min; MS (ESIpos): m/z = 570 [M+H]+
H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.369 (0.64), 2.382 (0.95), 2.394 (0.71 ), 2.411 (0.68), 2.423 (0.92), 2.434 (0.69), 2.518 (0.49), 3.197 (16.00), 3.372 (2.1 1 ), 3.459 (0.67), 3.472 (0.90), 3.483 (0.76), 3.496 (0.77), 3.521 (2.97), 3.609 (0.43), 3.636 (1.23), 3.664 (1 .14), 6.926 (0.74), 6.939 (0.74), 7.183 (0.94), 8.258 (1.00), 8.271 (0.93), 8.325 (4.61 ).
Example 107.02.01
tert-butyl 4-{(1R or 1S)-1 -[2-({6-[6-(dimethylamino)-5-methoxypyrimidin-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate
Figure imgf000956_0001
To a stirred solution of tert-butyl 4-[(1 R or S)-1 -(2-{[6-(6-chloro-5-methoxypyrimidin-4-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1 -carboxylate (140 mg, see Example 83.01 ) in 2-propanol (5.0 ml) in a microwave tube was added N-methylmethanamine (620 μΙ, 2.0 M in THF). The mixture was stirred at 100° C fo r 30 minutes in a microwave oven. The mixture was concentrated in vacuum. Aminophase-silicagel chromatography gave 135 mg of the title compound.
LC-MS (Method 2): R, = 1.31 min; MS (ESIpos): m/z = 574 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.278 (0.77), 1.295 (0.79), 1.376 (7.45), 1.394 (16.00), 2.518 (0.75), 2.522 (0.48), 3.197 (5.52), 3.377 (0.54), 8.324 (1.84).
Example 107.02.02
cyclopropyl(4-{(1R or 1S)-1 -[2-({6-[6-(dimethylamino)-5-methoxypyrimidin-4-yl]-1 H benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)methanone
Figure imgf000957_0001
To a stirred solution of 6-[6-(dimethylamino)-5-methoxypyrimidin-4-yl]-N-{4-[(1 R or 1 S)-1- (piperazin-1-yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride (90.0 mg, see Compound 107.02.01 ) in DMF (0.84 ml_) was added sodium bicarbonate (77.8 mg), cyclopropanecarboxylic acid (19 μΙ, 95 % purity) and HATU (94 mg). The mixture was stirred at r.t. for 16 h. Water was added, the mixture was stirred for 15 minutes and filtered. Preparative reverse phase HPLC (gradient of water and acetonitrile containing ammonia as additive) gave 50.0 mg of the title compound.
LC-MS (Method 2): F¾ = 1.11 min; MS (ESIpos): m/z = 542 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.656 (0.51 ), 0.663 (1.20), 0.667 (0.73), 0.676 (0.57), 0.682 (1.45), 0.686 (1.22), 0.691 (1.33), 0.698 (1.17), 0.703 (1.39), 0.710 (0.64), 1.298 (2.28), 1.315 (2.34), 1.935 (0.52), 2.327 (0.47), 2.518 (1.18), 2.523 (0.81 ), 3.197 (16.00), 3.371 (7.49), 3.450 (0.81 ), 3.466 (1.06), 3.676 (0.55), 6.941 (0.72), 6.954 (0.73), 8.251 (1.07), 8.264 (1.02), 8.322 (4.67).
Example 107.02.03
1 -(4-{(1 R or 1S)-1-[2-({6-[6-(dimethylamino)-5-methoxypyrimidin-4-yl]-1 H-benzim yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)-3,3,3-trifluoropropan-1-one
Figure imgf000958_0001
To a stirred solution of 6-[6-(dimethylamino)-5-methoxypyrimidin-4-yl]-N-{4-[(1 R or 1 S)-1 - (piperazin-1 -yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride (100 mg, see Compound 107.02.01 ) in DMF (2.9 mL) was added sodium bicarbonate (1 15 mg), 3,3,3- trifluoropropanoic acid (23 μΙ) and HATU (104 mg). The mixture was stirred at r.t. for 16 h. Water was added, the mixture was stirred for 15 minutes and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate), filtered and the solvent was removed in vacuum. Aminophase-silicagel chromatography gave a solid that was triturated with a mixture of dichloromethane and cyclohexane to give 45 mg of the title compound.
LC-MS (Method 2): Rt = 1.14 min; MS (ESIpos): m/z = 584 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.287 (2.69), 1.303 (2.69), 1.389 (12.44), 2.323 (0.69), 2.339 (0.68), 2.349 (0.63), 2.362 (0.55), 2.414 (0.75), 2.424 (0.80), 2.452 (0.50), 3.193 (16.00), 3.327 (7.92), 3.433 (1.44), 3.443 (1.12), 3.461 (1.39), 3.477 (1.87), 3.575 (0.51 ), 3.602 (1.44), 3.630 (1.36), 3.657 (0.44), 6.938 (0.87), 6.951 (0.89), 7.160 (0.99), 8.258 (1.14), 8.271 (1.11 ), 8.320 (3.88), 10.685 (0.49).
Example 107.02.04
(4-{(1 R or 1S)-1 -[2-({6-[6-(dimethylamino)-5-metho
yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)[1 -(trifluoromethyl)cyclopropyl]methanon
Figure imgf000959_0001
To a stirred solution of 6-[6-(dimethylamino)-5-methoxypyrimidin-4-yl]-N-{4-[(1 R or 1 S)-1 - (piperazin-1 -yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride (40.0 mg, see Compound 107.02.01 ) in DMF (0.4 mL) was added sodium bicarbonate (46.1 mg), 1- (trifluoromethyl)cyclopropanecarboxylic acid (15.9 mg) and HATU (41 .7 mg). The mixture was stirred at r.t. for 16 h. An excess of water was added and the mixture was stirred for 15 minutes. A solid precipitated and was collected by filtration. Aminophase-silicagel chromatography gave 20 mg of the title compound.
LC-MS (Method 2): Rt = 1.20 min; MS (ESIpos): m/z = 610 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.161 (0.77), 1.255 (0.46), 1.266 (0.96), 1.288 (1.74), 1.305 (1.60), 1.395 (16.00), 2.327 (0.46), 2.332 (0.41 ), 2.518 (1.52), 2.522 (0.99), 3.198 (12.27), 3.380 (1.06), 3.449 (0.41 ), 3.466 (0.41 ), 3.570 (0.51 ), 5.758 (0.74), 6.946 (0.46), 6.960 (0.47), 8.261 (0.59), 8.274 (0.56), 8.324 (4.03).
Example 108.01
tert-butyl 4-{[2-({6-[6-(cyclopropylamino)-5-methoxypyrimidin-4-yl]-1H-benzimidazol-2 yl}amino)pyridin-4-yl]methyl}piperazine-1-carboxylate
Figure imgf000960_0001
To a stirred solution of tert-butyl 4-[(2-{[6-(6-chloro-5-methoxypyrimidin-4-yl)-1 H-benzimidazol- 2-yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate (300 mg, see Compound 60.01 ) in 2- propanol (3.0 ml) in a microwave tube was added cyclopropanamine (190 μΙ). The mixture was stirred at 100° C for 1 h in a microwave oven. Furt her cyclopropanamine (95 μΙ) and the mixture was stirred at 100 Ό for 16 h. The mixture was concentrated in vacuum. Aminophase- silicagel chromatography gave 285 mg of the title compound.
LC-MS (Method 2): Rt = 1.20 min; MS (ESIpos): m/z = 572 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.609 (0.58), 0.615 (0.74), 0.624 (0.81 ), 0.712 (0.65), 0.719 (0.68), 0.730 (0.78), 1.394 (16.00), 2.346 (1.02), 2.358 (1.45), 2.369 (1.01 ), 2.518 (0.73), 2.522 (0.49), 3.428 (0.97), 3.498 (1.76), 5.758 (3.78), 6.916 (0.52), 6.929 (0.54), 7.170 (0.92), 7.310 (0.62), 7.320 (0.59), 8.256 (0.86), 8.268 (0.80), 8.307 (1.86).
Example 108.02
1 -(4-{[2-({6-[6-(cyclopropylamino)-5-methoxypyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1 -yl)-3,3,3-trifluoropropan-1-one
Figure imgf000961_0001
To a stirred solution of crude 6-[6-(cyclopropylamino)-5-methoxypyrimidin-4-yl]-N-[4-(piperazin- 1 -ylmethyl)pyridin-2-yl]-1 H-benzimidazol-2-amine hydrochloride (140 mg, see Compound 108.01 ) in DMF (4.9 ml_) was added sodium bicarbonate (154 mg), 3,3,3-trifluoropropanoic acid (22 μΙ) and HATU (113 mg). The mixture was stirred at r.t. for 3 h. Water was added, the mixture was stirred for 16 h. A saturated sodium chloride solution was added and the mixture was extracted with ethyl acetate. The organic phase was dried (sodium sulfate) and the solvent was removed in vacuum. Preparative reverse phase HPLC (gradient of water and acetonitrile containing ammonia as additive) gave 50.0 mg of the title compound.
LC-MS (Method 2): R, = 1.02 min; MS (ESIpos): m/z = 582 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.597 (1.37), 0.610 (4.04), 0.616 (5.07), 0.625 (6.22), 0.635 (2.09), 0.664 (0.71 ), 0.682 (0.40), 0.702 (2.02), 0.713 (4.64), 0.719 (4.92), 0.731 (5.70), 0.735 (3.85), 0.749 (1.50), 1.224 (0.54), 2.327 (0.45), 2.369 (3.03), 2.381 (4.59), 2.393 (3.47), 2.409 (3.01 ), 2.421 (4.29), 2.432 (3.42), 2.518 (1.60), 2.523 (1.14), 2.810 (0.51 ), 2.819 (1.38), 2.828 (1.72), 2.837 (2.92), 2.846 (2.89), 2.855 (1.83), 2.864 (1.34), 2.874 (0.47), 3.392 (1.18), 3.427 (9.18), 3.458 (3.28), 3.471 (4.16), 3.482 (3.71 ), 3.495 (3.80), 3.520 (14.20), 3.608 (1.98), 3.635 (5.49), 3.663 (5.16), 3.691 (1.63), 4.047 (2.97), 6.924 (3.48), 6.927 (3.34), 6.937 (3.49), 6.940 (3.40), 7.186 (6.01 ), 7.312 (4.55), 7.321 (4.43), 7.399 (0.62), 7.808 (0.69), 8.227 (0.72), 8.262 (5.77), 8.276 (5.37), 8.310 (16.00), 10.699 (0.58). Example 108.03
cyclopropyl(4-{[2-({6-[6-(cyclopropylamino)-5-methoxypyrimidin-4-yl]-1 H-benzimidazol- 2-yl}amino)pyridin-4-yl]methyl}piperazin-1 -yl)methanone
Figure imgf000962_0001
To a stirred solution of crude 6-[6-(cyclopropylamino)-5-methoxypyrimidin-4-yl]-N-[4-(piperazin- 1 -ylmethyl)pyridin-2-yl]-1 H-benzimidazol-2-amine hydrochloride (140 mg, see Compound 108.01 ) in DMF (1.2 mL) was added sodium bicarbonate (154 mg), cyclopropanecarboxylic acid (21 μΙ, 95 % purity) and HATU (1 13 mg). The mixture was stirred at r.t. for 16 h. Water was added, the mixture was stirred for 24 h. A saturated sodium chloride solution was added and the mixture was extracted with ethyl acetate. The organic phase was dried (sodium sulfate) and the solvent was removed in vacuum. Preparative reverse phase HPLC (gradient of water and acetonitrile containing ammonia as additive) gave 50.0 mg of the title compound.
LC-MS (Method 2): R, = 0.98 min; MS (ESIpos): m/z = 540 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.597 (0.69), 0.607 (1.57), 0.610 (1.96), 0.615 (2.43), 0.625 (3.04), 0.635 (1.05), 0.658 (0.52), 0.663 (0.61 ), 0.670 (1.36), 0.677 (2.83), 0.682 (1.94), 0.689 (1.45), 0.697 (3.39), 0.701 (2.71 ), 0.705 (2.19), 0.71 1 (4.85), 0.718 (5.09), 0.722 (4.11 ), 0.730 (4.28), 0.733 (2.25), 0.742 (0.66), 0.748 (0.78), 1.932 (0.70), 1.940 (0.75), 1.952 (1.24), 1.964 (0.70), 1.971 (0.65), 2.359 (1.37), 2.436 (1.38), 2.518 (0.58), 2.523 (0.42), 2.819 (0.61 ), 2.828 (0.78), 2.837 (1.26), 2.846 (1.25), 2.855 (0.82), 2.864 (0.57), 3.427 (16.00), 3.513 (6.31 ), 3.696 (1.30), 6.925 (1.79), 6.928 (1.75), 6.939 (1.79), 6.941 (1.79), 7.224 (1.46), 7.31 1 (2.00), 7.320 (1.93), 7.440 (0.52), 7.459 (0.55), 7.772 (0.86), 7.792 (0.77), 8.260 (2.85), 8.273 (2.69), 8.31 1 (8.63). Example 109.01.01
tert-butyl 4-({2-[(6-{6-[(cyclopropylmethyl)amino]-5-methoxypyrimidin-4-yl}-1 H- benzimidazol-2-yl)amino]pyridin-4-yl}methyl)piperazine-1 -carboxylate
Figure imgf000963_0001
To a stirred solution of tert-butyl 4-[(2-{[6-(6-chloro-5-methoxypyrimidin-4-yl)-1 H-benzimidazol- 2-yl]amino}pyridin-4-yl)methyl]piperazine-1-carboxylate (350 mg, see Compound 60.01 ) in 2- propanol (2.0 ml) in a microwave tube was added 1 -cyclopropylmethanamine (280 μΙ). The mixture was stirred at 100° C for 1.5 h in a microw ave oven. A half-saturated ammonium chloride solution was added and the reaction mixture was extracted with dichloromethane. The organic phase was dried (sodium sulfate) and the solvent was removed in vacuum. Silicagel chromatography gave a solid that was triturated with pentane to give 95 mg of the title compound.
LC-MS (Method 2): R, = 1.28 min; MS (ESIpos): m/z = 586 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppmj: 0.266 (0.80), 0.270 (0.75), 0.279 (0.86), 0.416 (0.70), 0.421 (0.69), 0.436 (0.74), 0.440 (0.67), 0.830 (0.69), 0.836 (0.45), 0.839 (0.42), 0.852 (0.55), 0.857 (1.01 ), 0.935 (0.47), 0.953 (0.49), 1.237 (0.49), 1.396 (16.00), 2.349 (0.86), 2.361 (1 .28), 2.373 (0.91 ), 2.518 (0.92), 2.523 (0.64), 3.271 (0.58), 3.287 (1.00), 3.302 (0.61 ), 3.331 (9.86), 3.352 (1.05), 3.500 (1.67), 6.920 (0.50), 6.933 (0.51 ), 7.172 (0.87), 7.328 (0.55), 8.241 (2.06), 8.259 (0.90), 8.272 (0.81 ).
Example 109.01.02
1 -[4-({2-[(6^6-[(cyclopropylmethyl)amino]-5-m
yl)amino]pyridin-4-yl}methyl)piperazin-1 -yl]-3,3,3-trifluoropropan-1-one
Figure imgf000964_0001
To a stirred solution of 6-{6-[(cyclopropylmethyl)amino]-5-methoxypyrimidin-4-yl}-N-[4- (piperazin-1 -ylmethyl)pyridin-2-yl]-1 H-benzimidazol-2-amine hydrochloride (90.0 mg, see Compound 109.01.01 ) in DMF (3.3 mL) was added sodium bicarbonate (102 mg), 3,3,3- trifluoropropanoic acid (20 μΙ) and HATU (92.0 mg). The mixture was stirred at r.t. for 65 h. Water was added, the mixture was stirred for 15 minutes and the mixture was extracted with ethyl acetate. The organic phase was dried (sodium sulfate) and the solvent was removed in vacuum. Silicagel chromatography gave a solid that was triturated with ethanol to give 30.0 mg of the title compound.
LC-MS (Method 2): R, = 1.12 min; MS (ESIpos): m/z = 596 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.255 (1.57), 0.267 (6.27), 0.271 (5.81 ), 0.279 (6.68), 0.292 (2.26), 0.407 (2.14), 0.416 (5.54), 0.421 (5.36), 0.427 (2.96), 0.432 (2.80), 0.436 (5.88), 0.441 (5.33), 0.452 (1.80), 1.122 (0.66), 1.142 (1.46), 1.154 (2.05), 1.166 (1.21 ), 1.171 (1.25), 1.396 (0.59), 2.373 (3.33), 2.385 (5.04), 2.397 (3.85), 2.414 (3.69), 2.425 (4.95), 2.437 (3.69), 2.518 (7.27), 2.523 (4.92), 3.271 (4.38), 3.287 (7.52), 3.303 (4.49), 3.483 (10.46), 3.512 (5.45), 3.525 (15.13), 3.611 (2.32), 3.638 (6.77), 3.666 (6.40), 3.693 (2.01 ), 6.931 (3.85), 6.944 (3.92), 7.186 (6.50), 7.312 (2.10), 7.327 (4.44), 7.342 (2.05), 7.378 (0.91 ), 7.398 (1.05), 7.552 (0.52), 7.747 (0.55), 7.823 (1.00), 7.842 (0.89), 8.000 (0.80), 8.241 (16.00), 8.267 (6.66), 8.280 (6.13), 10.696 (1.64), 12.189 (1.30), 12.213 (2.14). Example 109.01.03
cyclopropyl[4-({2-[(6-{6-[(cyclopropylmethyl)amino]-5-methoxypyrimidin
benzimidazol-2-yl)amino]pyridin-4-yl}methyl)piperazin-1-yl]methanone
Figure imgf000965_0001
To a stirred solution of crude 6-{6-[(cyclopropylmethyl)amino]-5-methoxypyrimidin-4-yl}-N-[4- (piperazin-1 -ylmethyl)pyridin-2-yl]-1 H-benzimidazol-2-amine hydrochloride (170 mg, see Compound 109.01.01 ) in DMF (1.3 ml_) was added sodium bicarbonate (125 mg), cyclopropanecarboxylic acid (31 μΙ, 95 % purity) and HATU (151 mg). The mixture was stirred at r.t. for 65 h. An excess of water was added and the mixture was stirred for 15 minutes. A solid precipitated and was collected by filtration. The solid was dissolved in ethyl acetate and the solution was filtered and concentrated in vacuum. Preparative reverse phase HPLC (gradient of water and acetonitrile containing ammonia as additive) gave 55.0 mg of the title compound.
LC-MS (Method 2): R, = 1.17 min; MS (ESIpos): m/z = 554 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.249 (1.58), 0.260 (6.60), 0.264 (6.06), 0.273 (7.18), 0.286 (2.31 ), 0.399 (2.02), 0.409 (5.61 ), 0.413 (5.33), 0.419 (3.03), 0.429 (5.98), 0.433 (5.38), 0.444 (1.75), 0.651 (1.09), 0.662 (2.97), 0.670 (5.79), 0.674 (4.49), 0.683 (3.36), 0.690 (6.72), 0.707 (6.01 ), 0.714 (6.69), 0.718 (7.32), 0.725 (4.00), 0.737 (1.07), 1.112 (0.51 ), 1.117 (0.71 ), 1.129 (1.33), 1.132 (1.36), 1.137 (1.40), 1.141 (1.17), 1.149 (2.15), 1.157 (1.18), 1.161 (1.31 ), 1.166 (1.34), 1.178 (0.66), 1.186 (0.48), 1.909 (0.72), 1.922 (1.51 ), 1.929 (1.74), 1.942 (2.69), 1.953 (1.61 ), 1.960 (1.44), 1.972 (0.67), 2.352 (3.50), 2.428 (3.51 ), 2.518 (0.96), 3.268 (4.48), 3.283 (7.82), 3.299 (4.65), 3.347 (1 1.60), 3.505 (15.47), 3.687 (3.30), 6.923 (4.21 ), 6.936 (4.30), 7.195 (6.46), 7.306 (2.18), 7.322 (4.56), 7.336 (2.17), 7.437 (0.69), 7.797 (1.16), 8.229 (0.63), 8.243 (16.00), 8.260 (6.74), 8.273 (6.17), 10.726 (0.62), 12.227 (0.57). Example 109.02.01
tert-butyl 4-[(1 R or 1S)-1 -{2-[(6-{6-[(cyclopropylmethyl)amino]-5-methoxypyrimidin-4-yl}- 1 H-benzimidazol-2-yl)amino]pyridin-4-yl}ethyl]piperazine-1-carboxylate
Figure imgf000966_0001
To a stirred solution of tert-butyl 4-[(1 R or S)-1 -(2-{[6-(6-chloro-5-methoxypyrimidin-4-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1-carboxylate (250 mg, see Example 83.01 ) in 2-propanol (10 ml) in a microwave tube was added 1 -cyclopropylmethanamine (190 μΙ). The mixture was stirred at 100° C for 1.5 h in a microwave oven. Further 1 - cyclopropylmethanamine (200 μΙ) was added and the mixture was stirred at 100° C for 2.5 h. The mixture was concentrated in vacuum. Silicagel chromatography followed by aminophase- silicagel chromatography gave 200 mg of the title compound.
LC-MS (Method 2): R, = 1.33 min; MS (ESIpos): m/z = 600 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.266 (0.91 ), 0.270 (0.84), 0.279 (0.96), 0.415 (0.80), 0.420 (0.77), 0.426 (0.41 ), 0.436 (0.84), 0.440 (0.75), 1.278 (1.76), 1.295 (1.75), 1.376 (16.00), 2.311 (0.47), 2.384 (0.48), 2.518 (0.55), 3.271 (0.71 ), 3.287 (1.24), 3.303 (1.07), 3.435 (0.51 ), 3.452 (0.62), 3.475 (1.22), 6.930 (0.55), 6.932 (0.55), 6.946 (0.56), 7.157 (0.98), 7.325 (0.65), 8.241 (2.32), 8.262 (1.01 ), 8.275 (0.92).
Example 109.02.02
cyclopropyl{4-[(1 R or 1S)-1 -{2-[(6-{6 (cyclopropylmethyl)amino]-5-methoxypyrimidin-4- yl}-1 H-benzimidazol-2-yl)amino]pyridin-4-yl}ethyl]piperazin-1-yl}methanone
Figure imgf000967_0001
To a stirred solution of crude 6-{6-[(cyclopropylmethyl)amino]-5-methoxypyrimidin-4-yl}-N-{4- [(1 R or 1 S)-1-(piperazin-1 -yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride (90.0 mg, see Compound 109.02.01 ) in DMF (0.75 ml_) was added sodium bicarbonate (68.5 mg), cyclopropanecarboxylic acid (17 μΙ, 95 % purity) and HATU (82.7 mg). The mixture was stirred at r.t. for 16 h. An excess of water was added and the mixture was stirred for 15 minutes. A solid precipitated and was collected by filtration. Preparative reverse phase HPLC (gradient of water and acetonitrile containing ammonia as additive) gave 50.0 mg of the title compound.
LC- S (Method 2): R, = 1.14 min; MS (ESIpos): m/z = 568 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.255 (1.69), 0.267 (6.34), 0.270 (5.88), 0.279 (6.79), 0.282 (6.29), 0.292 (2.44), 0.407 (2.21 ), 0.416 (5.60), 0.421 (5.51 ), 0.426 (3.07), 0.431 (2.90), 0.436 (6.01 ), 0.441 (5.41 ), 0.452 (1.90), 0.645 (0.86), 0.657 (2.72), 0.664 (6.36), 0.669 (4.00), 0.677 (3.20), 0.684 (7.78), 0.688 (6.55), 0.692 (7.37), 0.699 (6.36), 0.704 (7.37), 0.71 1 (3.59), 0.724 (0.91 ), 1.122 (0.69), 1.137 (1.38), 1.142 (1.54), 1.154 (2.29), 1.166 (1.30), 1.171 (1.30), 1.183 (0.67), 1 .296 (12.04), 1.312 (12.35), 1.405 (0.50), 1.422 (0.48), 1.904 (0.76), 1.917 (1.51 ), 1.924 (1.64), 1 .936 (2.75), 1.948 (1.58), 1.955 (1.45), 1.967 (0.67), 2.322 (2.03), 2.327 (2.38), 2.331 (1.92), 2.400 (2.12), 2.518 (10.34), 2.523 (7.35), 2.539 (8.52), 2.616 (0.45), 2.665 (0.95), 2.669 (1.34), 2.673 (0.97), 3.271 (4.50), 3.287 (7.70), 3.302 (4.78), 3.434 (1.64), 3.450 (5.66), 3.468 (10.18), 3.479 (10.05), 3.675 (2.98), 6.951 (3.83), 6.965 (3.98), 7.174 (6.77), 7.312 (2.10), 7.327 (4.50), 7.341 (2.18), 7.399 (0.86), 7.533 (0.45), 7.746 (0.48), 7.821 (0.86), 8.003 (0.58), 8.241 (16.00), 8.271 (6.90), 8.285 (6.42), 10.685 (1.04), 12.229 (1.47). Example 109.02.03
1 -{4-[(1R or 1S)-1-{2-[(6-{6-t(cyclopropylmethyl)amino]-5-methoxypyrimidin-4-yl}-1 H- benzimidazol-2-yl)amino]pyridin-4-yl}ethyl]piperazin-1 -yl}-3,3,3-trifluoropropan-1 -^
Figure imgf000968_0001
To a stirred solution of crude 6-{6-[(cyclopropylmethyl)amino]-5-metrioxypyrimidin-4-yl}-N-{4- [(1 R or 1 S)-1-(piperazin-1 -yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride (90.0 mg, see Compound 109.02.01 ) in DMF (2.3 ml_) was added sodium bicarbonate (68.5 mg), 3,3,3-trifluoropropanoic acid (18 μΙ) and HATU (82.7 mg). The mixture was stirred at r.t. for 16 h. An excess of water was added and the mixture was stirred for 15 minutes. A solid precipitated and was collected by filtration. Silicagel chromatography gave 35.0 mg of the title compound.
LC-MS (Method 2): F¾ = 1.17 min; MS (ESIpos): m/z = 610 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.255 (1.68), 0.267 (6.53), 0.279 (7.04), 0.292 (2.26), 0.407 (2.09), 0.417 (5.47), 0.421 (5.36), 0.427 (3.10), 0.436 (5.86), 0.441 (5.36), 0.452 (1.70), 1.066 (0.45), 1.154 (3.55), 1.172 (4.05), 1.189 (1.87), 1.229 (0.59), 1.294 (12.03), 1.310 (12.01 ), 1.394 (1.93), 1.987 (5.33), 2.331 (3.63), 2.345 (3.04), 2.369 (2.40), 2.430 (3.55), 2.669 (1.70), 2.728 (1.03), 2.888 (1.12), 3.271 (4.58), 3.287 (8.01 ), 3.303 (5.1 1 ), 3.438 (6.81 ), 3.451 (5.98), 3.474 (16.00), 3.565 (2.99), 3.580 (2.29), 3.608 (6.31 ), 3.635 (6.03), 3.662 (1.98), 3.999 (0.42), 4.017 (1.23), 4.035 (1.23), 4.053 (0.42), 5.758 (3.91 ), 6.944 (4.02), 6.957 (4.08), 7.165 (6.65), 7.316 (1.93), 7.331 (3.94), 7.346 (2.07), 7.398 (0.75), 7.821 (0.87), 8.242 (14.27), 8.271 (6.39), 8.285 (5.84), 10.678 (2.21 ), 12.222 (1.73). Example 110.01
tert-butyl 4-({2-[(6-{6-[(cyclopropylmethyl)(methyl)amino]-5-methoxypyrimidin benzimidazol-2-yl)amino]pyridin-4-yl}methyl)piperazine-1-carboxylate
Figure imgf000969_0001
To a stirred solution of tert-butyl 4-[(2-{[6-(6-chloro-5-methoxypyrimidin-4-yl)-1 H-benzimidazol- 2-yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate (350 mg, see Compound 60.01 ) in 2- propanol (2.0 ml) in a microwave tube was added 1 -cyclopropyl-N-methylmethanamine (270 mg). The mixture was stirred at 120° C for 15 minut es in a microwave oven. The mixture was concentrated in vacuum. Silicagel chromatography gave 340 mg of the title compound.
LC-MS (Method 2): R, = 1.42 min; MS (ESIpos): m/z = 600 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.267 (0.75), 0.271 (0.69), 0.280 (0.78), 0.283 (0.71 ), 0.469 (0.66), 0.473 (0.65), 0.489 (0.68), 0.493 (0.64), 1.066 (0.61 ), 1.070 (0.99), 1.088 (2.14), 1.105 (1.13), 1.395 (16.00), 2.347 (0.84), 2.359 (1.20), 2.371 (0.83), 2.518 (0.86), 2.522 (0.63), 3.242 (4.19), 3.353 (2.21 ), 3.371 (1.33), 3.388 (1.00), 3.499 (1.51 ), 3.547 (0.90), 3.565 (0.88), 6.917 (0.46), 6.920 (0.45), 6.930 (0.45), 8.250 (0.72), 8.264 (0.63), 8.325 (4.23).
Example 110.02
cyclopropyl[4-({2-[(6-{6-[(cyclopropylmethyl)(methyl)amino]-5-methoxypyrimid
1 H-benzimidazol-2-yl)amino]pyridin-4-yl}methyl)piperazin-1-yl]methanone
Figure imgf000970_0001
To a stirred solution of crude 6-{6-[(cyclopropylmethyl)(methyl)amino]-5-methoxypyrimidin-4- yl}-N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]-1 H-benzimidazol-2 -amine hydrochloride (130 mg, see Compound 110.01 ) in DMF (1.0 mL) was added sodium bicarbonate (93.6 mg), cyclopropanecarboxylic acid (23 μΙ, 95 % purity) and HATU (113 mg). The mixture was stirred at r.t. for 65 h. An excess of water was added and the mixture was stirred for 15 minutes. A solid precipitated and was collected by filtration. The solid was dissolved in ethyl acetate and the solution was filtered and concentrated in vacuum. Preparative reverse phase HPLC (gradient of water and acetonitrile containing ammonia as additive) gave 55.0 mg of the title compound.
LC-MS (Method 2): R, = 1.21 min; MS (ESIpos): m/z = 568 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.266 (1.42), 0.269 (1.34), 0.278 (1.54), 0.292 (0.50), 0.458 (0.46), 0.468 (1.24), 0.472 (1.23), 0.478 (0.65), 0.483 (0.62), 0.488 (1.30), 0.492 (1.24), 0.503 (0.42), 0.675 (0.62), 0.682 (1.45), 0.687 (0.90), 0.695 (0.70), 0.702 (1.72), 0.707 (1.34), 0.712 (1.51 ), 0.720 (1.47), 0.724 (1.76), 0.731 (0.83), 1.121 (0.47), 1.962 (0.64), 2.364 (0.70), 2.444 (0.72), 2.518 (0.83), 2.523 (0.56), 3.337 (16.00), 3.355 (6.48), 3.519 (3.33), 3.546 (1.85), 3.563 (1.78), 3.704 (0.67), 6.933 (0.91 ), 6.936 (0.91 ), 6.946 (0.93), 6.949 (0.92), 7.203 (0.74), 8.259 (1.46), 8.272 (1.38), 8.326 (5.80). Example 110.03
[4-({2-[(6-{6-[(cyclopropylmethyl)(methyl)amino]-5-methoxypyrimid
benzimidazol-2-yl)amino]pyridin-4-yl}methyl)piperazin-1 -yl][1 -
(trifluoromethyl)cyclopropyl]methanone
Figure imgf000971_0001
To a stirred solution of crude 6-{6-[(cyclopropylmethyl)(methyl)amino]-5-methoxypyrimidin-4- yl}-N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]-1 H-benzimidazol-2-amine hydrochloride (130 mg, see Compound 110.01) in DMF (1.0 mL) was added sodium bicarbonate (125 mg), 1- (trifluoromethyl)cyclopropanecarboxylic acid (42.9 mg) and HATU (113 mg). The mixture was stirred at r.t. for 65 h. An excess of water was added and the mixture was stirred for 15 minutes. A solid precipitated and was collected by filtration. The solid was dissolved in ethyl acetate and the solution was filtered and concentrated in vacuum. Preparative reverse phase HPLC (gradient of water and acetonitrile containing ammonia as additive) gave 75.0 mg of the title compound. LC-MS (Method 2): Rt = 1.29 min; MS (ESIpos): m/z = 636 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.256 (0.78), 0.267 (2.93), 0.271 (2.68), 0.280 (3.09), 0.293 (0.99), 0.459 (0.94), 0.469 (2.55), 0.473 (2.48), 0.479 (1.31 ), 0.484 (1.27), 0.489 (2.62), 0.493 (2.43), 0.504 (0.78), 1.105 (0.58), 1.1 10 (0.60), 1.122 (0.97), 1.135 (0.58), 1.142 (0.62), 1.182 (2.75), 1.237 (0.47), 1.275 (1.62), 1.287 (3.29), 1.307 (1.03), 2.423 (3.36), 2.518 (1.72), 2.523 (1.23), 2.539 (0.70), 3.242 (16.00), 3.358 (4.70), 3.522 (5.97), 3.547 (3.85), 3.565 (4.10), 3.596 (1.85), 6.929 (1.76), 6.945 (1.80), 7.181 (1.24), 7.392 (0.41 ), 7.744 (0.42), 8.193 (0.57), 8.259 (2.59), 8.272 (2.41), 8.326 (12.94), 10.708 (0.64), 12.253 (0.74). Example 110.04
1 -[4-({2-[(6-{6-[(cyclopropylmethyl)(methyl)amino]-5-methoxypyrimidin-4-yl}-1 H- benzimidazol-2-yl)amino]pyridin-4-yl}methyl)piperazin-1 -yl]-3,3,3-trifluoropropan-1 -one
Figure imgf000972_0001
To a stirred solution of crude 6-{6-[(cyclopropylmethyl)(metfiyl)amino]-5-methoxypyrimidin-4- yl}-N-t4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H-benzimidazol-2 -amine hydrochloride (130 mg, see Compound 1 10.01 ) in DMF (4.0 mL) was added sodium bicarbonate (125 mg), 3,3,3- trifluoropropanoic acid (25 μΙ) and HATU (113 mg). The mixture was stirred at r.t. for 65 h. An excess of water was added and the mixture was stirred for 15 minutes. A solid precipitated and was collected by filtration. The solid was dissolved in ethyl acetate and the solution was filtered and concentrated in vacuum. Preparative reverse phase HPLC (gradient of water and acetonitrile containing ammonia as additive) gave 50.0 mg of the title compound.
LC-MS (Method 2): R, = 1.24 min; MS (ESIpos): m/z = 610 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.250 (0.76), 0.262 (2.99), 0.265 (2.85), 0.274 (3.25), 0.287 (1.03), 0.454 (0.92), 0.464 (2.56), 0.468 (2.54), 0.474 (1.38), 0.479 (1.33), 0.484 (2.71 ), 0.488 (2.56), 0.499 (0.81 ), 1.099 (0.60), 1.104 (0.61 ), 1.1 17 (0.96), 1.125 (0.51 ), 1.129 (0.57), 1.134 (0.59), 2.368 (1.56), 2.380 (2.40), 2.392 (1.85), 2.407 (1.70), 2.420 (2.32), 2.431 (1.77), 2.518 (0.67), 2.523 (0.43), 3.237 (16.00), 3.458 (1.65), 3.470 (2.29), 3.481 (1.95), 3.497 (2.01 ), 3.516 (7.52), 3.542 (3.75), 3.559 (3.57), 3.608 (1.07), 3.635 (2.96), 3.662 (2.82), 3.690 (0.91 ), 4.046 (0.58), 6.924 (1.83), 6.925 (1.82), 6.939 (1.89), 7.187 (2.13), 8.258 (2.75), 8.271 (2.59), 8.328 (10.84), 10.725 (0.57). Example 111.01
tert-butyl 4-{(1R or 1S)-1-[2-({6-[6-(azetidin-1-yl)-5-methoxypyrimidin-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate
Figure imgf000973_0001
To a stirred solution of tert-butyl 4-[(1 R or S)-1-(2-{[6-(6-chloro-5-methoxypyrimidin-4-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1 -carboxylate (250 mg, see Example 83.01 ) in 2-propanol (3.0 ml) in a microwave tube was added azetidine (126 mg). The mixture was stirred at 100° C for 30 minutes. The mixture w as concentrated in vacuum. Silicagel chromatography gave 180 mg of the title compound.
LC-MS (Method 2): R, = 1.29 min; MS (ESIpos): m/z = 586 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.277 (1.73), 1.294 (1.73), 1.376 (16.00), 2.296 (0.41 ), 2.31 1 (0.55), 2.323 (0.50), 2.331 (0.64), 2.351 (0.64), 2.371 (0.70), 2.383 (0.55), 2.518 (0.87), 2.523 (0.60), 3.409 (1.22), 3.433 (0.52), 3.450 (0.46), 4.208 (0.88), 4.227 (1.47), 4.245 (0.85), 5.759 (4.15), 6.932 (0.54), 6.946 (0.55), 7.149 (0.52), 8.252 (0.88), 8.265 (0.75), 8.277 (2.92).
Example 111.02
(4-{(1 R or 1S)-1-[2-({6-[6-(azetidin-1-yl)-5-methoxypyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)(cyclopropyl)methanone
Figure imgf000974_0001
To a stirred solution of 6-[6-(azetidin-1-yl)-5-methoxypyrimidin-4-yl]-N-{4-[(1 R or 1 S)-1- (piperazin-1 -yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride (100 mg, see Compound 1 1 1.01 ) in DMF (2.0 mL) was added sodium bicarbonate (76.2 mg), cyclopropanecarboxylic acid (19 μΙ, 95 % purity) and HATU (92.0 mg). The mixture was stirred at r.t. for 16 h. Water was added, the mixture was stirred for 15 minutes and the mixture was filtered. The solution was directly used for preparative reverse phase HPLC purification. Preparative reverse phase HPLC (gradient of water and acetonitrile containing ammonia as additive) gave 40 mg of the title compound.
LC-MS (Method 2): R, = 1.1 1 min; MS (ESIpos): m/z = 554 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.641 (0.66), 0.653 (1.96), 0.660 (4.31 ), 0.665 (3.08), 0.673 (2.42), 0.679 (5.21 ), 0.684 (4.77), 0.689 (5.09), 0.696 (4.68), 0.701 (5.34), 0.708 (2.73), 0.720 (0.67), 1.288 (8.19), 1.305 (8.47), 1.895 (0.52), 1.908 (1.04), 1.914 (1.20), 1.927 (1.89), 1.939 (1.14), 1.946 (1.02), 1.958 (0.48), 2.309 (1.73), 2.327 (3.08), 2.347 (3.87), 2.367 (3.36), 2.385 (2.38), 2.444 (1.31 ), 2.61 1 (2.50), 3.402 (10.90), 3.425 (1.65), 3.442 (3.21 ), 3.459 (4.31 ), 3.668 (2.33), 4.205 (4.58), 4.224 (7.78), 4.242 (4.57), 6.947 (2.80), 6.960 (2.85), 7.166 (3.38), 7.388 (0.77), 7.397 (0.74), 7.685 (0.41 ), 7.792 (0.67), 8.247 (0.94), 8.260 (4.27), 8.276 (16.00), 8.281 (2.76), 10.709 (0.73), 12.263 (0.75). Example 111.03
1 -(4-{(1 R or 1S)-1-[2-({6-[6-(azetidin-1 -yl)-5-methoxypyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)-3,3,3-trifluoropropan-1 -one
Figure imgf000975_0001
To a stirred solution of 6-[6-(azetidin-1-yl)-5-methoxypyrimidin-4-yl]-N-{4-[(1 R or 1 S)-1- (piperazin-1 -yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2 -amine hydrochloride (100 mg, see Compound 1 1 1.01 ) in DMF (2.0 mL) was added sodium bicarbonate (76.2 mg), 3,3,3- trifluoropropanoic acid (20 μΙ) and HATU (92.0 mg). The mixture was stirred at r.t. for 16 h. Water was added, the mixture was stirred for 15 minutes and the mixture was filtered. The solution was directly used for preparative reverse phase HPLC purification. Preparative reverse phase HPLC (gradient of water and acetonitrile containing ammonia as additive) gave 40 mg of the title compound.
LC-MS (Method 2): Rt = 1.16 min; MS (ESIpos): m/z = 596 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.287 (5.08), 1.303 (5.19), 2.327 (2.64), 2.346 (3.39), 2.365 (2.69), 2.426 (1.69), 3.401 (16.00), 3.422 (2.80), 3.434 (3.50), 3.445 (2.77), 3.465 (3.33), 3.480 (3.91 ), 3.576 (1.00), 3.603 (2.63), 3.630 (2.49), 3.658 (0.86), 4.014 (0.64), 4.206 (2.96), 4.224 (4.97), 4.242 (2.95), 6.943 (1.83), 6.956 (1.86), 7.164 (3.03), 7.436 (0.76), 7.455 (0.85), 7.765 (1.22), 7.785 (1.12), 8.152 (0.55), 8.262 (2.62), 8.279 (7.81 ).
Example 112.01
tert-butyl 4-{(1 R or S)-1-[2-({6-[5-methoxy-6-(pyrrolidin-1 -yl)pyrimidin-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate
Figure imgf000976_0001
To a stirred solution of tert-butyl 4-[(1 R or S)-1 -(2-{[6-(6-chloro-5-methoxypyrimidin-4-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1 -carboxylate (250 mg, see Example 83.01 ) in 2-propanol (10 ml) in a microwave tube was added pyrrolidine (180 μΙ). The mixture was stirred at 100° C for 30 minutes. The mixture w as concentrated in vacuum. Silicagel chromatography gave 230 mg of the title compound.
LC-MS (Method 2): R, = 1.36 min; MS (ESIneg): m/z = 598 [M-H]- H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.814 (1.19), 0.831 (2.77), 0.836 (1.15), 0.840 (1.22), 0.852 (1.59), 0.858 (3.23), 0.870 (0.77), 0.875 (0.98), 0.936 (1.14), 0.953 (1.19), 1.238 (1.71 ), 1.244 (1.64), 1.279 (2.08), 1.296 (1.91 ), 1.377 (16.00), 1.395 (1.40), 1.902 (0.69), 1.919 (1.86), 1.935 (0.71 ), 2.31 1 (0.48), 2.323 (0.51 ), 2.327 (0.54), 2.385 (0.46), 2.518 (1.25), 2.523 (0.86), 3.435 (0.45), 3.452 (0.43), 3.657 (0.70), 3.673 (1.69), 3.688 (0.67), 5.759 (0.74), 6.932 (0.54), 6.945 (0.55), 7.154 (0.50), 8.253 (0.68), 8.266 (0.65), 8.276 (3.34).
Example 112.02
cyclopropyl(4-{(1 R or 1 S)-1 -[2-({6-[5-methoxy-6-(pyrrolidin-1 -yl)pyrimidin-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)methanone
Figure imgf000977_0001
To a stirred solution of 6-[5-methoxy-6-(pyrrolidin-1 -yl)pyrimidin-4-yl]-N-{4-[(1 R or 1 S)-1 - (piperazin-1 -yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride (120 mg, see compound 1 12.01 ) in D F (2.0 ml_) was added sodium bicarbonate (89.4 mg), cyclopropanecarboxylic acid (22 μΙ, 95 % purity) and HATU (108 mg). The mixture was stirred at r.t. for 16 h. Water was added, the mixture was stirred for 15 minutes and the mixture was filtered. The solution was directly used for preparative reverse phase HPLC purification. Preparative reverse phase HPLC (gradient of water and acetonitrile containing ammonia as additive) gave 40.0 mg of the title compound.
LC-MS (Method 2): R, = 1.19 min; MS (ESIpos): m/z = 568 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.630 (0.84), 0.642 (2.34), 0.649 (4.48), 0.662 (2.73), 0.669 (5.28), 0.683 (4.84), 0.690 (5.07), 0.694 (5.71 ), 0.701 (3.07), 0.714 (0.79), 1.031 (1.03), 1.048 (2.18), 1.066 (1.09), 1.277 (9.35), 1.293 (9.47), 1.903 (11.77), 1.910 (8.24), 1.919 (5.46), 1.941 (0.90), 2.298 (1.16), 2.322 (0.96), 2.327 (0.93), 2.380 (1.82), 2.425 (1.57), 2.605 (0.92), 3.322 (13.30), 3.393 (0.53), 3.412 (1.24), 3.428 (3.32), 3.445 (4.32), 3.460 (3.33), 3.661 (11.85), 6.934 (3.27), 6.948 (3.32), 7.168 (4.01 ), 7.380 (0.60), 7.392 (0.65), 7.691 (0.50), 7.752 (0.71 ), 8.196 (0.61 ), 8.255 (4.53), 8.269 (5.17), 8.272 (16.00), 10.720 (1.21 ), 12.259 (0.77).
Example 112.03
3,3,3-trifluoro-1 -(4-{(1 R or 1S)-1 -[2-({6-[5-methoxy-6-(pyrrolidin-1-yl)pyrimidin
benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)propan-1-one
Figure imgf000978_0001
To a stirred solution of 6-[5-methoxy-6-(pyrrolidin-1 -yl)pyrimidin-4-yl]-N-{4-[(1 R or 1 S)-1- (piperazin-1 -yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2 -amine hydrochloride (120 mg, see Compound 1 12.01 ) in DMF (2.0 mL) was added sodium bicarbonate (89.4 mg), 3,3,3- trifluoropropanoic acid (23 μΙ) and HATU (108 mg). The mixture was stirred at r.t. for 16 h. Water was added, the mixture was stirred for 15 minutes and the mixture was filtered. The solution was directly used for preparative reverse phase HPLC purification. Preparative reverse phase HPLC (gradient of water and acetonitrile containing ammonia as additive) gave 40.0 mg of the title compound.
LC-MS (Method 2): R, = 1.22 min; MS (ESIpos): m/z = 610 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.035 (1.37), 1.052 (2.69), 1.070 (1.43), 1.280 (6.63), 1.297 (6.77), 1.890 (2.99), 1.907 (7.86), 1.922 (3.31 ), 2.307 (0.78), 2.321 (1.40), 2.333 (1.74), 2.345 (1.62), 2.359 (1.35), 2.414 (2.01 ), 2.423 (1.79), 2.442 (1.28), 3.326 (16.00), 3.418 (3.12), 3.430 (4.73), 3.450 (3.59), 3.468 (4.27), 3.573 (1.26), 3.601 (3.47), 3.628 (3.53), 3.666 (7.28), 4.012 (0.60), 6.933 (2.35), 6.946 (2.37), 7.167 (3.70), 7.442 (0.45), 7.734 (0.77), 8.260 (3.51 ), 8.278 (1 1.47).
Example 113.01
tert-butyl 4-{(1 R or 1S)-1 -[2-({6-[6-(3,3-difluoroazetidin-1-yl)-5-methoxypyrimidin-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate
Figure imgf000979_0001
To a stirred solution of tert-butyl 4-[(1 R or S)-1 -(2-{[6-(6-chloro-5-methoxypyrimidin-4-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1 -carboxylate (225 mg, see Example 83.01 ) in 2-propanol (9.0 ml) in a microwave tube was added 3,3-difluoroazetidine hydrochloride (516 mg) and N,N-diisopropylethylamine (690 μΙ). The mixture was stirred at 90° C for 16 h. The mixture was concentrated in vacuum. Silicagel chromatography followed by aminophase-silicagel chromatography gave 160 mg of the title compound.
LC-MS (Method 2): R, = 1 .35 min; MS (ESIpos): m/z = 622 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (2.34), 1.172 (4.64), 1.190 (2.35), 1.278 (1.75), 1.295 (1.79), 1.377 (16.00), 1.987 (9.19), 2.297 (0.41 ), 2.310 (0.48), 2.322 (0.44), 2.327 (0.43), 2.385 (0.48), 2.396 (0.41 ), 2.518 (1.76), 2.523 (1.25), 3.437 (0.76), 3.454 (0.99), 3.469 (1.20), 3.999 (0.68), 4.017 (2.08), 4.035 (2.07), 4.053 (0.68), 4.590 (1.02), 4.622 (2.14), 4.653 (0.97), 6.938 (0.52), 6.951 (0.53), 7.149 (0.46), 8.258 (0.86), 8.271 (0.89), 8.404 (2.42).
Example 113.02
1-(4-{(1R or 1S)-1-[2-({6-[6-(3,3-dmuoroazetidin-1 -yl)-5-methoxypyrimidin-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)-3,3,3-trifluoropropan-1 -one
Figure imgf000980_0001
To a stirred solution of 6-t6-(3,3-difluoroazetidin-1 -yl)-5-methoxypyrimidin-4-yl]-N-{4-[(1 R or 1 S)-1 -(piperazin-1 -yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride (80.0 mg, see Compound 1 13.01 ) in DMF (1.5 ml_) was added sodium bicarbonate (57.5 mg), 3,3,3- trifluoropropanoic acid (15 μΙ) and HATU (69.4 mg). The mixture was stirred at r.t. for 3 h. An excess of water was added and the mixture was stirred for 15 minutes. A solid precipitated and was collected by filtration. Silicagel chromatography gave a solid that was triturated with pentane to give 50.0 mg of the title compound.
LC-MS (Method 2): R, = 1.19 min; MS (ESIpos): m/z = 632 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.839 (5.09), 0.857 (1 1.22), 0.874 (4.50), 1.232 (3.09), 1.237 (3.03), 1.253 (2.75), 1.270 (2.91 ), 1.295 (9.28), 1.311 (9.09), 1.377 (2.53), 1.395 (10.84), 2.327 (3.09), 2.331 (3.03), 2.433 (2.75), 2.523 (5.81 ), 2.669 (1.84), 3.439 (6.00), 3.460 (16.00), 3.580 (1.97), 3.608 (5.41 ), 3.635 (5.19), 3.662 (1.66), 4.591 (6.28), 4.623 (12.75), 4.653 (5.75), 6.953 (3.25), 6.965 (3.22), 7.165 (4.31 ), 7.433 (0.53), 7.823 (0.75), 8.270 (5.28), 8.283 (5.00), 8.406 (15.00), 10.730 (1.37), 12.298 (0.78).
Example 113.03
cyc!opropyl(4-{(1 R or 1 S)-1 -[2-({6-[6-(3,3-difluoroazetidin-1 -yl)-5-methoxypyrimidin-4-yl]- 1 H-benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)methanone
Figure imgf000981_0001
To a stirred solution of 6-[6-(3,3-difluoroazetidin-1 -yl)-5-methoxypyrimidin-4-yl]-N-{4-[(1 R or 1 S)-1-(piperazin-1-yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride (80.0 mg, see Compound 113.01 ) in DMF (1.5 mL) was added sodium bicarbonate (57.5 mg), cyclopropanecarboxylic acid (14 μΙ, 95 % purity) and HATU (69.4 mg). The mixture was stirred at r.t. for 3 h. Water was added, the mixture was stirred for 15 minutes and the mixture was filtered. The solution was directly used for preparative reverse phase HPLC purification. Preparative reverse phase HPLC (gradient of water and acetonitrile containing ammonia as additive) gave 40.0 mg of the title compound.
LC-MS (Method 2): F¾ = 1.16 min; MS (ESIpos): m/z = 590 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.653 (1 .04), 0.660 (2.29), 0.665 (1.47), 0.672 (1.17), 0.679 (2.77), 0.684 (2.30), 0.689 (2.50), 0.697 (2.36), 0.701 (2.73), 0.708 (1.32), 1.292 (4.51 ), 1.309 (4.60), 1.909 (0.57), 1.916 (0.62), 1.928 (1.01 ), 1.940 (0.58), 1.947 (0.53), 2.318 (0.49), 2.322 (0.52), 2.326 (0.52), 2.331 (0.43), 2.394 (0.77), 2.450 (0.61 ), 2.518 (0.72), 2.523 (0.45), 3.429 (0.69), 3.446 (1.95), 3.458 (16.00), 3.493 (0.65), 3.668 (1.10), 4.589 (2.68), 4.620 (5.66), 4.651 (2.48), 6.942 (1.47), 6.944 (1.47), 6.955 (1.49), 6.958 (1.50), 7.247 (0.62), 7.449 (0.56), 7.468 (0.61 ), 7.787 (0.83), 7.807 (0.74), 8.257 (2.41 ), 8.271 (2.27), 8.402 (9.17). Example 114.01
tert-butyl 4-{(1 R or 1S)-1 -[2-({6-[6-(cyclobutylamino)-5-methoxypyrimid
benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate
Figure imgf000982_0001
To a stirred solution of tert-butyl 4-[(1 R or S)-1-(2-{[6-(6-chloro-5-methoxypyrimidin-4-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1 -carboxylate (300 mg, see Example 83.01 ) in 2-propanol (10 ml) in a microwave tube was added cyclobutanamine (227 mg). The mixture was stirred at 90° C for 2 h. Further cyclo butanamine (1 15 mg) was added and the mixture was stirred at 90° C for 5 h. The mixture w as concentrated in vacuum. Silicagel chromatography gave 320 mg of the title compound that was used without further purification.
LC-MS (Method 2): Rt = 1.37 min; MS (ESIpos): m/z = 600 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.989 (0.40), 1.005 (0.43), 1.278 (1.52), 1.295 (1.41 ), 1.370 (5.88), 1.376 (13.86), 2.248 (0.46), 2.269 (0.52), 2.277 (0.45), 2.282 (0.44), 2.295 (0.43), 2.31 1 (0.43), 2.322 (0.42), 2.326 (0.43), 2.385 (0.44), 2.518 (1.14), 2.522 (0.75), 3.436 (0.53), 3.452 (0.81 ), 3.468 (0.82), 5.758 (16.00), 6.932 (0.40), 6.946 (0.41 ), 7.154 (0.69), 7.378 (0.41 ), 8.237 (1.77), 8.260 (0.73), 8.274 (0.69).
The Example compounds in the following table 11 were synthesized in analogy to the preparation of Example 1 17.02, followed by purification by preparative reverse phase HPLC or silicagel chromatography.
Table 11 :
Figure imgf000983_0001
Figure imgf000984_0001
Example 115.01
tert-butyl 4-{(1 R or 1S)-1 -[2-({6-[6-(azetidin-1-yl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate
Figure imgf000985_0001
To a stirred solution of tert-butyl 4-[(1 R or 1 S)-1 -(2-{[6-(6-chloropyrimidin-4-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1 -carboxylate (440 mg, see Example 85.01 ) in 2-propanol (6.0 ml) in a microwave tube was added azetidine (235 mg). The mixture was stirred at 90° C for 30 minutes. Upon cooling t o r.t. a solid precipitated, was collected by filtration and was washed with ethanol to give 130 mg of the title compound.
LC-MS (Method 2): Rt = 1.25 min; MS (ESIpos): m/z = 556 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.277 (1.72), 1.293 (1.76), 1.376 (16.00), 2.308 (0.46), 2.369 (0.63), 2.386 (0.93), 2.406 (0.70), 2.518 (1.32), 2.522 (0.92), 3.433 (0.44), 3.449 (0.43), 4.079 (1.20), 4.098 (1.95), 4.116 (1.18), 6.937 (0.45), 6.950 (0.46), 7.163 (0.85), 8.254 (0.98), 8.266 (0.95), 8.492 (1.56), 8.494 (1.66).
Example 115.02
1 -(4-{(1 R or 1S)-1 -[2-({6-[6-(azetidin-1 -yl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)-3,3,3-trifluoropropan-1-one
Figure imgf000985_0002
To a stirred solution of 6-[6-(azetidin-1 -yl)pyrimidin-4-yl]-N-{4-[(1 R or 1 S)-1 -(piperazin-1 - yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride (90.0 mg, see Compound 1 15.01 ) in DMF (1.9 ml_) was added sodium bicarbonate (72.3 mg), 3,3,3-trifluoropropanoic acid (19 μΙ) and HATU (87.2 mg). The mixture was stirred at r.t. for 16 h. An excess of water was added and the mixture was stirred for 15 minutes. A solid precipitated and was collected by filtration. Silicagel chromatography gave a solid that was triturated with ethanol to give 55.0 mg of the title compound.
LC-MS (Method 2): R, = 1.10 min; MS (ESIpos): m/z = 566 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.291 (14.31 ), 1.307 (14.45), 2.327 (4.38), 2.332 (3.76), 2.336 (3.34), 2.350 (3.86), 2.368 (5.17), 2.387 (4.86), 2.407 (4.72), 2.416 (4.21 ), 2.427 (4.72), 2.456 (2.17), 2.518 (10.00), 2.523 (6.52), 2.548 (0.72), 2.665 (1.48), 2.669 (2.07), 2.673 (1.48), 3.424 (3.76), 3.436 (6.76), 3.448 (4.97), 3.466 (6.93), 3.482 (8.97), 3.579 (2.66), 3.606 (7.62), 3.634 (7.14), 3.661 (2.24), 4.079 (9.93), 4.098 (16.00), 4.1 16 (9.52), 6.755 (2.24), 6.844 (1.41 ), 6.947 (3.28), 6.960 (3.34), 7.174 (6.41 ), 7.373 (1.24), 7.394 (1.38), 7.528 (0.79), 7.547 (0.83), 7.853 (2.21 ), 7.874 (1.41 ), 8.1 14 (1.38), 8.262 (7.93), 8.276 (8.07), 8.492 (13.03), 8.495 (13.86), 10.689 (1.24), 10.722 (1.97), 12.208 (1.66), 12.257 (2.48).
Example 115.03
(4-{(1 R or 1S)-1 -[2-({6-[6-(azetidin-1-yl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)(cyclopropyl)methanone
Figure imgf000986_0001
To a stirred solution of 6-[6-(azetidin-1 -yl)pyrimidin-4-yl]-N-{4-[(1 R or 1 S)-1 -(piperazin-1 - yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine trihydrochloride (60.0 mg, see Compound 1 15.01 ) in DMF (1.2 ml.) was added sodium bicarbonate (45.5 mg), cyclopropanecarboxylic acid (11 μΙ, 95 % purity) and HATU (54.9 mg). The mixture was stirred at r.t. for 16 h. Further sodium bicarbonate (45.5 mg), cyclopropanecarboxylic acid (11 μΙ, 95 % purity) and HATU (54.9 mg) were added and the mixture was stirred at r.t. for 24 h. Water was added, the mixture was stirred for 15 minutes and the mixture was filtered. The solution was directly used for preparative reverse phase HPLC purification. Preparative reverse phase HPLC (gradient of water and acetonitrile containing ammonia as additive) gave 10.0 mg of the title compound.
LC-MS (Method 2): R, = 1.03 min; MS (ESIpos): m/z = 524 [M+H]+
1H-NMR (500 MHz, DMSO-d6) δ [ppm]: 0.644 (1.40), 0.653 (3.45), 0.659 (6.53), 0.664 (5.24), 0.669 (3.49), 0.675 (7.33), 0.679 (3.66), 0.686 (4.45), 0.690 (6.54), 0.696 (7.02), 0.700 (7.79), 0.705 (4.58), 0.715 (1.21 ), 1.053 (0.42), 1.221 (0.45), 1.288 (14.84), 1.302 (15.06), 1.754 (0.77), 1.897 (0.93), 1.907 (1.84), 1.913 (2.01 ), 1.923 (3.19), 1.932 (1.84), 1.938 (1.71 ), 1.948 (0.81 ), 2.303 (1.36), 2.352 (2.23), 2.366 (4.82), 2.382 (6.73), 2.397 (5.27), 2.412 (2.69), 2.448 (1.53), 2.514 (1.28), 2.518 (1.22), 2.522 (0.98), 2.612 (0.45), 2.635 (0.43), 3.428 (1.47), 3.442 (4.50), 3.455 (5.86), 3.468 (3.94), 3.663 (3.26), 4.079 (10.01 ), 4.094 (16.00), 4.109 (9.56), 6.762 (0.75), 6.827 (0.47), 6.951 (3.96), 6.960 (3.97), 7.179 (7.1 1 ), 7.394 (0.58), 7.848 (2.06), 7.864 (1.89), 8.263 (8.19), 8.273 (7.77), 8.493 (13.25), 8.495 (13.53), 10.724 (1.18), 12.269 (0.83).
Example 116.01
tert-butyl 4-{(1 R or 1S)-1-[2-({6-[6-(3,3-difluoroazetidin-1 -yl)pyrimidin-4-yl]-1H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate
Figure imgf000987_0001
To a stirred solution of tert-butyl 4-[(1 R or 1 S)-1-(2-{[6-(6-chloropyrimidin-4-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1-carboxylate (270 mg, see Example 85.01 ) in 2-propanol (10 ml) in a microwave tube was added 3,3-difluoroazetidine hydrochloride (392 mg) and N,N-diisopropylethylamine (880 μΙ). The mixture was stirred at 90° C for 16 h. The mixture was concentrated in vacuum. Silicagel chromatography gave 270 mg of the title compound. LC-MS (Method 2): R, = 1.31 min; MS (ESIpos): m/z = 592 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.990 (1.50), 1.006 (1.45), 1.090 (0.52), 1.106 (0.50), 1.132 (0.48), 1.149 (0.49), 1.229 (0.46), 1.279 (1.69), 1.295 (1.66), 1.377 (16.00), 1.729 (0.46), 1.763 (0.45), 1.979 (0.58), 2.084 (0.42), 2.310 (0.43), 2.384 (0.41 ), 2.518 (0.72), 2.523 (0.48), 3.436 (0.42), 3.453 (0.41 ), 3.797 (0.41 ), 4.529 (1.04), 4.561 (2.23), 4.592 (0.97), 5.759 (2.60), 6.942 (0.41 ), 6.954 (0.41 ), 7.170 (0.68), 8.259 (0.89), 8.272 (0.84), 8.618 (1.61 ), 8.620 (1 .61 ).
Example 116.02
cyclopropyl(4-{(1 R or 1S)-1 -[2-({6-[6-(3,3-difluoroazetidin-1-yl)pyrimidin
benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)methanone
Figure imgf000988_0001
To a stirred solution of 6-[6-(3,3-difluoroazetidin-1-yl)pyrimidin-4-yl]-N-{4-[(1 R or 1 S)-1- (piperazin-1-yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine trihydrochloride (100 mg, see Compound 116.01 ) in DMF (2.1 mL) was added sodium bicarbonate (78.8 mg), cyclopropanecarboxylic acid (20 μΙ, 95 % purity) and HATU (95.2 mg). The mixture was stirred at r.t. for 3 h. An excess of water was added and the mixture was stirred for 15 minutes. A solid precipitated and was collected by filtration. Silicagel chromatography gave a solid that was triturated with cyclopentyl methyl ether to give 50.0 mg of the title compound.
LC-MS (Method 2): Rt = 1.10 min; MS (ESIpos): m/z = 560 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.644 (0.81 ), 0.656 (2.79), 0.663 (6.29), 0.683 (7.79), 0.687 (7.07), 0.691 (7.51 ), 0.699 (6.67), 0.703 (7.48), 0.710 (3.66), 0.723 (0.91 ), 1.294 (1 1.64), 1.31 1 (1 1.91 ), 1.903 (0.70), 1.915 (1.48), 1.922 (1.67), 1.934 (2.67), 1.946 (1.58), 1.953 (1.43), 1.966 (0.64), 2.322 (1.88), 2.326 (2.01 ), 2.395 (2.28), 2.616 (0.68), 2.668 (0.92), 2.673 (0.72), 3.144 (1.45), 3.434 (1.42), 3.450 (4.31 ), 3.467 (5.75), 3.674 (3.18), 4.530 (7.67), 4.561 (16.00), 4.592 (7.16), 6.960 (3.30), 6.972 (3.34), 7.032 (1.18), 7.134 (0.86), 7.186 (5.09), 7.415 (0.83), 7.554 (0.59), 7.884 (2.83), 7.903 (2.61 ), 8.164 (0.81 ), 8.268 (6.18), 8.281 (5.84), 8.330 (1.1 1 ), 8.618 (10.05), 8.621 (10.38), 10.739 (1.42), 12.245 (1.10), 12.304 (1.45).
Example 116.03
1-(4-{(1 R or 1S)-H2-({6 6-(3,3-difluoroazetidin-1 -yl)pyri
yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)-3,3,3-trifluoropropan-1-one
Figure imgf000989_0001
To a stirred solution of 6-[6-(3,3-difluoroazetidin-1 -yl)pyrimidin-4-yl]-N-{4-[(1 R or 1 S)-1 - (piperazin-1-yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride (100 mg, see Compound 1 16.01 ) in DMF (2.1 mL) was added sodium bicarbonate (78.8 mg), 3,3,3- trifluoropropanoic acid (21 μΙ) and HATU (95.2 mg). The mixture was stirred at r.t. for 3 h. An excess of water was added and the mixture was stirred for 15 minutes. A solid precipitated and was collected by filtration. Silicagel chromatography followed by aminophase-silicagel chromatography gave a solid that was triturated with a mixture of 2-propanol and cyclohexane to give 53,0 mg of the title compound.
LC-MS (Method 2): R, = 1.14 min; MS (ESIpos): m/z = 602 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.027 (0.71 ), 1.042 (0.71 ), 1.292 (5.91 ), 1.308 (6.02), 1.394 (16.00), 2.327 (1.71 ), 2.343 (1.69), 2.365 (1.35), 2.417 (1.81 ), 2.428 (2.1 1 ), 2.442 (1.67), 2.457 (1.42), 2.669 (0.51 ), 3.437 (3.34), 3.448 (2.54), 3.468 (3.52), 3.483 (4.27), 3.579 (1.1 1 ), 3.606 (3.10), 3.634 (2.96), 3.661 (0.97), 4.530 (3.85), 4.561 (7.84), 4.592 (3.66), 6.951 (1.61 ), 6.963 (1.62), 7.031 (0.96), 7.137 (0.73), 7.180 (2.33), 7.400 (0.56), 7.419 (0.61 ), 7.553 (0.42), 7.571 (0.44), 7.882 (1.37), 7.903 (1.24), 8.163 (0.68), 8.267 (2.92), 8.280 (2.77), 8.331 (0.91 ), 8.620 (4.81 ), 10.712 (0.63), 10.744 (0.81 ), 12.240 (0.80), 12.300 (1.03). Example 116.04
(4-{(1 R or 1S)-1-[2-({6-[6-(3,3-difluoroazetidin-1 -yl)py^^
yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)[1 -(trifluoromethyl)cyclopropyl]methanone
Figure imgf000990_0001
To a stirred solution of 6-[6-(3,3-difluoroazetidin-1-yl)pyrimidin-4-yl]-N-{4-[(1 R or 1 S)-1 - (piperazin-1 -yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride (80.0 mg, see Compound 116.01 ) in DMF (1.7 mL) was added sodium bicarbonate (63.1 mg), 1- (trifluoromethyl)cyclopropanecarboxylic acid (28.9 mg) and HATU (76.1 mg). The mixture was stirred at r.t. for 3 h. An excess of water was added and the mixture was stirred for 15 minutes. A solid precipitated and was collected by filtration. Preparative reverse phase HPLC (gradient of water and acetonitrile containing ammonia as additive) gave 55.0 mg of the title compound.
LC-MS (Method 2): Rt = 1.19 min; MS (ESIpos): m/z = 628 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.161 (5.70), 1.215 (0.89), 1.228 (0.54), 1.255 (3.26), 1.267 (7.13), 1.288 (12.83), 1.304 (1 1.49), 2.323 (1.40), 2.327 (2.16), 2.332 (1.99), 2.342 (1.99), 2.356 (2.40), 2.370 (2.79), 2.453 (2.85), 2.465 (2.61 ), 2.518 (4.58), 2.523 (3.15), 2.539 (9.98), 2.665 (0.84), 2.669 (1.23), 2.673 (0.89), 3.434 (0.89), 3.451 (2.85), 3.468 (2.83), 3.483 (0.97), 3.568 (3.93), 4.530 (7.51 ), 4.561 (16.00), 4.592 (6.80), 6.956 (2.55), 6.969 (2.61 ), 7.031 (1.60), 7.137 (1.14), 7.185 (4.08), 7.398 (0.89), 7.419 (0.95), 7.553 (0.67), 7.574 (0.69), 7.882 (2.18), 7.903 (1.92), 8.161 (1.10), 8.266 (6.1 1 ), 8.279 (5.79), 8.332 (1.51 ), 8.618 (1 1.90), 8.621 (1 1.88), 10.708 (0.89), 10.745 (1.17), 12.242 (1.17), 12.300 (1.58). Example 117.01
tert-butyl 4-{(1 R or 1S)-1 -[2-({6-[6-(pyrrolidin-1 -yl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate
Figure imgf000991_0001
To a stirred solution of tert-butyl 4-[(1 R or 1 S)-1-(2-{[6-(6-chloropyrimidin-4-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1 -carboxylate (300 mg, 561 pmol, see Example 85.01 ) in 2-propanol (10 ml) in a microwave tube was added pyrrolidine (280 μΙ). The mixture was stirred at 90° C for 2 h. The mixture w as concentrated in vacuum. Silicagel chromatography gave 250 mg of the title compound.
LC-MS (Method 2): R, = 1.31 min; MS (ESIpos): m/z = 570 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.814 (0.76), 0.830 (1.79), 0.835 (0.64), 0.849 (0.73), 0.852 (0.77), 0.858 (0.68), 0.935 (0.51 ), 0.952 (0.54), 1.237 (0.44), 1.278 (1.73), 1.295 (1.72), 1.377 (16.00), 1.394 (0.85), 1.971 (0.59), 2.310 (0.44), 2.383 (0.44), 2.518 (0.64), 2.523 (0.44), 3.434 (0.45), 3.450 (0.47), 3.513 (0.62), 6.936 (0.49), 6.949 (0.44), 7.165 (0.89), 8.255 (0.94), 8.268 (0.89), 8.499 (1.63), 8.501 (1.60).
Example 117.02
cyclopropyl(4-{(1 R or 1 S)-1 -[2-({6-[6-(pyrrolidin-1 -yl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)methanone
Figure imgf000992_0001
To a stirred solution of N-{4-[(1 R or 1 S)-1 -(piperazin-1 -yl)ethyl]pyridin-2-yl}-6-[6-(pyrrolidin-1- yl)pyrimidin-4-yl]-1 H-benzimidazol-2-amine hydrochloride (100 mg, see Compound 117.01 ) in DMF (2.3 mL) was added sodium bicarbonate (87.1 mg), cyclopropanecarboxylic acid (22 μΙ, 95 % purity) and HATU (105 mg). The mixture was stirred at r.t. for 16 h. An excess of water was added and the mixture was stirred for 15 minutes. A solid precipitated and was collected by filtration. Preparative reverse phase HPLC (gradient of water and acetonitrile containing ammonia as additive) gave 60.0 mg of the title compound.
LC-MS (Method 2): Rt = 1.1 1 min; MS (ESIpos): m/z = 538 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.642 (1.07), 0.653 (3.40), 0.661 (7.84), 0.666 (4.96), 0.674 (3.83), 0.681 (9.45), 0.686 (7.82), 0.690 (8.55), 0.698 (8.00), 0.702 (9.33), 0.709 (4.53), 0.722 (1.10), 1.069 (0.49), 1.225 (0.98), 1.291 (15.58), 1.307 (15.85), 1.409 (0.48), 1.897 (1.30), 1.909 (2.50), 1.917 (2.83), 1.929 (4.86), 1.934 (3.43), 1.941 (4.36), 1.948 (5.14), 1.960 (5.77), 2.318 (1.58), 2.323 (1.79), 2.327 (1.86), 2.332 (1.50), 2.390 (2.47), 2.450 (1.86), 2.518 (3.62), 2.523 (2.53), 2.540 (0.67), 2.665 (0.60), 2.669 (0.80), 2.674 (0.58), 3.428 (1.92), 3.444 (5.59), 3.461 (7.82), 3.477 (6.05), 3.509 (6.32), 3.669 (3.74), 6.868 (1.30), 6.920 (0.89), 6.952 (4.35), 6.964 (4.35), 7.183 (8.57), 7.403 (0.82), 7.544 (0.55), 7.865 (1.97), 8.137 (0.70), 8.264 (8.82), 8.277 (8.54), 8.299 (1.15), 8.499 (15.76), 8.502 (16.00), 10.710 (1.59), 12.216 (0.91 ), 12.257 (1.27). Example 117.03
3,3,3-trifluoro-1 -(4-{(1 R or 1S)-1 -[2-({6 6-(pyrrolidin-1-yl)pyrimidin-4-yl]-1 H-benzimidazol- 2-yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)propan-1 -one
Figure imgf000993_0001
To a stirred solution of N-{4-[(1 R or 1 S)-1 -(piperazin-1 -yl)ethyl]pyridin-2-yl}-6-[6-(pyrrolidin-1- yl)pyrimidin-4-yl]-1 H-benzimidazol-2-amine hydrochloride (100 mg, see Compound 1 17.01 ) in DMF (2.3 mL) was added sodium bicarbonate (87.1 mg), 3,3,3-trifluoropropanoic acid (23 μΙ) and HATU (105 mg). The mixture was stirred at r.t. for 16 h. An excess of water was added and the mixture was stirred for 15 minutes. A solid precipitated and was collected by filtration. Preparative reverse phase HPLC (gradient of water and acetonitrile containing ammonia as additive) gave 25.0 mg of the title compound.
LC-MS (Method 2): R, = 1.14 min; MS (ESIpos): m/z = 580 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.225 (0.69), 1.289 (15.12), 1.306 (15.29), 1.908 (0.87), 1.969 (5.59), 2.301 (0.81 ), 2.327 (3.36), 2.332 (2.84), 2.341 (3.28), 2.351 (3.08), 2.364 (2.67), 2.416 (3.51 ), 2.426 (3.77), 2.438 (2.86), 2.453 (2.20), 2.518 (3.32), 2.523 (2.30), 2.540 (2.86), 2.665 (0.56), 2.669 (0.80), 2.674 (0.55), 3.423 (4.20), 3.435 (7.28), 3.446 (5.80), 3.463 (7.71 ), 3.480 (1 1.72), 3.494 (8.33), 3.578 (3.1 1 ), 3.605 (7.94), 3.632 (7.36), 3.660 (2.35), 4.015 (1.68), 6.869 (1.34), 6.919 (0.97), 6.944 (4.34), 6.957 (4.23), 7.178 (8.19), 7.401 (0.85), 7.537 (0.57), 7.865 (2.03), 8.136 (0.74), 8.264 (8.47), 8.277 (8.22), 8.297 (1 .16), 8.499 (15.22), 8.502 (16.00), 10.710 (1.55), 12.214 (0.92), 12.251 (1.29).
The Example compounds in the following table 12 were synthesized in analogy to the preparation of Example 1 17.02, followed by purification by preparative reverse phase HPLC or silicagel chromatography.
Table 12:
Figure imgf000994_0001
Figure imgf000995_0001
Figure imgf000996_0001
Figure imgf000997_0001
Example 118.01
tert-butyl 4-{(1 R or 1S)-1 -[2-({6-[6-(morpholin-4-yl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate
Figure imgf000998_0001
To a stirred solution of tert-butyl 4-[(1 R or 1 S)-1 -(2-{[6-(6-chloropyrimidin-4-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1 -carboxylate (300 mg, see Example 85.01 ) in 2-propanol (10 ml) in a microwave tube was added morpholine (290 μΙ). The mixture was stirred at 90° C for 2 h. The mixture was conce ntrated in vacuum. Silicagel chromatography gave a solid that was triturated with warm ethanol to give 250 mg of the title compound.
LC-MS (Method 2): R, = 1.24 min; MS (ESIpos): m/z = 586 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.813 (1.12), 0.830 (2.39), 0.835 (0.97), 0.840 (0.56), 0.849 (1.05), 0.852 (1.17), 0.857 (1.41 ), 0.874 (0.40), 0.935 (0.83), 0.952 (0.90), 1.237 (0.76), 1.239 (0.71 ), 1.278 (1.85), 1.295 (1.78), 1.377 (16.00), 1.394 (1.23), 2.309 (0.45), 2.383 (0.44), 2.518 (0.70), 2.523 (0.48), 3.331 (11.92), 3.433 (0.41 ), 3.450 (0.40), 5.759 (1.90), 6.938 (0.41 ), 6.951 (0.41 ), 7.169 (0.91 ), 8.255 (0.91 ), 8.268 (0.86), 8.568 (1.56), 8.570 (1.53).
Example 118.02
cyclopropyl(4-{(1 R or 1S)-1 -[2-({6-[6-(morpholin-4-yl)pyrimidin-4-yl]- H-benzimidazol-2 yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)methanone
Figure imgf000999_0001
To a stirred solution of 6-[6-(morpholin-4-yl)pyrimidin-4-yl]-N-{4-[(1 R or 1 S)-1-(piperazin-1 - yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride (85.0 mg, see Compound 1 18.01 ) in DMF (1.9 ml.) was added sodium bicarbonate (72.0 mg), cyclopropanecarboxylic acid (18 μΙ, 95 % purity) and HATU (86.9 mg). The mixture was stirred at r.t. for 3 h. Water was added, the mixture was stirred for 15 minutes and the mixture was filtered. The solution was directly used for preparative reverse phase HPLC purification. Preparative reverse phase HPLC (gradient of water and acetonitrile containing ammonia as additive) gave 40.0 mg of the title compound.
LC-MS (Method 2): R, = 1.03 min; MS (ESIpos): m/z = 554 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.653 (0.81 ), 0.661 (1.79), 0.666 (1.14), 0.674 (0.93), 0.681 (2.17), 0.685 (1.82), 0.690 (1.97), 0.698 (1.79), 0.702 (2.10), 0.709 (1.01 ), 1.291 (3.48), 1.308 (3.48), 1.910 (0.45), 1.917 (0.48), 1.929 (0.79), 1.941 (0.44), 1.948 (0.40), 2.083 (1.44), 2.322 (0.43), 2.326 (0.45), 2.393 (0.57), 2.447 (0.42), 2.518 (0.89), 2.522 (0.60), 3.446 (1.16), 3.463 (1.55), 3.702 (16.00), 6.952 (1.01 ), 6.955 (1.02), 6.965 (1.03), 7.186 (1.94), 7.901 (0.97), 7.905 (0.97), 7.922 (0.87), 7.926 (0.87), 8.263 (1.97), 8.276 (1.86), 8.568 (3.21 ), 8.570 (3.27).
Example 118.03
3,3,3-trifluoro-1-(4-{(1 R or 1 S)-1 -[2-({6-[6-(morpholin-4-yl)pyrimidin-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)propan-1 -one
Figure imgf001000_0001
To a stirred solution of 6-[6-(morpholin-4-yl)pyrimidin-4-yl]-N-{4-[(1 R or 1 S)-1-(piperazin-1- yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine trihydrochloride (85.0 mg, see Compound 1 18.01 ) in DMF (1.9 ml.) was added sodium bicarbonate (72.0 mg), 3,3,3-trifluoropropanoic acid (19 μΙ) and HATU (86.9 mg). The mixture was stirred at r.t. for 3 h. Water was added, the mixture was stirred for 15 minutes and the mixture was filtered. The solution was directly used for preparative reverse phase HPLC purification. Preparative reverse phase HPLC (gradient of water and acetonitrile containing ammonia as additive) gave 40 mg of the title compound.
LC-MS (Method 2): R, = 1.08 min; MS (ESIpos): m/z = 596 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.036 (5.01 ), 1.054 (9.81 ), 1.071 (5.08), 1.285 (14.20), 1.302 (14.48), 1.334 (0.47), 2.081 (0.78), 2.310 (1.65), 2.323 (2.98), 2.337 (3.61 ), 2.347 (3.33), 2.361 (2.85), 2.412 (3.72), 2.435 (3.16), 2.449 (2.41 ), 2.522 (1.23), 3.352 (16.00), 3.433 (8.05), 3.442 (6.71 ), 3.459 (6.68), 3.476 (9.33), 3.490 (4.87), 3.576 (2.61 ), 3.603 (7.36), 3.631 (7.02), 3.658 (2.58), 4.014 (1.54), 4.352 (0.53), 4.364 (0.90), 4.376 (0.51 ), 6.943 (4.42), 6.956 (4.42), 7.183 (8.34), 7.278 (1.17), 7.345 (0.48), 7.41 1 (0.66), 7.535 (0.53), 7.905 (4.14), 7.908 (4.17), 7.926 (3.71 ), 7.929 (3.76), 8.212 (0.58), 8.262 (8.01 ), 8.276 (7.51 ), 8.333 (0.72), 8.571 (13.14), 10.732 (1.35), 12.252 (1.00).
Example 118.04
(4-{(1 R or 1S)-1 -[2-({6^6-(morpholin-4-y!)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)[1 -(trifluoromethyl)cyclopropyl]methanone
Figure imgf001001_0001
To a stirred solution of 6-[6-(morpholin-4-yl)pyrimidin-4-yl]-N-{4-[(1 R or 1 S)-1-(piperazin-1- yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine trihydroc loride (60.0 mg, see Compound 1 18.01 ) in DMF (1.3 ml_) was added sodium bicarbonate (50.8 mg), 1- (trifluoromethyl)cyclopropanecarboxylic acid (23.3 mg) and HATU (61.4 mg). The mixture was stirred at r.t. for 65 h. Water was added, the mixture was stirred for 15 minutes and the mixture was filtered. The solution was directly used for preparative reverse phase HPLC purification. Preparative reverse phase HPLC (gradient of water and acetonitrile containing ammonia as additive) gave 40.0 mg of the title compound.
LC-MS (Method 2): R, = 1.14 min; MS (ESIpos): m/z = 622 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.159 (1.63), 1.254 (0.94), 1.266 (2.03), 1.289 (3.41 ), 1.305 (3.28), 2.327 (0.59), 2.332 (0.54), 2.341 (0.55), 2.356 (0.67), 2.370 (0.78), 2.453 (0.82), 2.466 (0.76), 2.518 (1.36), 2.523 (0.97), 3.447 (0.93), 3.463 (0.90), 3.569 (1.12), 3.702 (16.00), 6.941 (1.01 ), 6.944 (1.02), 6.955 (1.03), 6.958 (1.05), 7.261 (0.48), 7.285 (1.16), 7.891 (1.07), 7.896 (1.05), 7.912 (0.94), 7.917 (0.97), 8.253 (2.03), 8.267 (1.99), 8.565 (3.20), 8.567 (3.29).
Example 119.01
tert-butyl 4-{(1 R or 1S)-1 -[2-({6-[6-(2,2,2 rifluoroethoxy)pyrimidin-4-yl]-1 H-benzimidazol- 2-yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate
Figure imgf001002_0001
To a stirred solution of 2,2,2-trifluoroethanol (748 mg) in 1 ,4-dioxane (4.0 ml) was added sodium hydride (196 mg, 55 % w/w in oil) and the mixture was stirred for 10 minutes. A solution of tert-butyl 4-[(1 R or 1 S)-1-(2-{[6-(6-chloropyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazine-1-carboxylate (400 mg, see Example 85.01 ) in 1 ,4- dioxane (2.0 ml) was added and the mixture was stirred at r.t. for 1 h and at 60 "C for 2 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with half-saturated sodium chloride solution, dried (sodium sulfate), filtered and the solvent was removed in vacuum. Silicagel chromatography followed by aminophase-silicagel chromatography gave 250 mg of the title compound.
LC-MS (Method 2): R, = 1.46 min; MS (ESIpos): m/z = 599 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.278 (1.66), 1.295 (1.67), 1.307 (0.42), 1.369 (5.29), 1.375 (16.00), 2.295 (0.43), 2.309 (0.51 ), 2.322 (0.42), 2.383 (0.49), 2.396 (0.41 ), 2.518 (0.48), 5.107 (0.41 ), 5.130 (1.18), 5.152 (1.09), 5.758 (4.36), 7.167 (0.48), 8.269 (0.73), 8.283 (0.67), 8.863 (1.56), 8.865 (1.57).
The Example compounds in the following table 13 were synthesized in analogy to the preparation of Example 1 17.02, followed by purification by preparative reverse phase HPLC or silicagel chromatography.
Table 13:
Figure imgf001003_0001
Figure imgf001004_0001
Figure imgf001005_0001
Figure imgf001006_0001
Example 120.01
tert-butyl 4-{(1 R or 1S)-1 -[2-({6-[1 -(cyclopropylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate
Figure imgf001007_0001
tert-Butyl 4-[(1 R or 1 S)-1 -{2-[({2-amino-4-[1 -(cyclopropylmethyl)-3,5-dimethyl-1 H-pyrazol-4- yl]phenyl}carbamothioyl)amino]pyridin-4-yl}ethyl]piperazine-1 -carboxylate (240 mg, 397 pmol; see Compund 120.02) and EDCI (76.1 mg, 397 pmol) were stirred in dichloromethane (7.2 ml) under argon overnight at rt. The mixture was concentrated under reduced pressure and the crude mixture was purified by flash chromatography on silica gel to give 47 mg (19 % yield) of the title compound.
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.353 (0.49), 0.366 (0.48), 0.519 (0.42), 1.035 (3.70), 1.052 (8.44), 1.070 (4.28), 1.266 (1.62), 1.282 (1.83), 1.294 (0.90), 1.319 (0.44), 1.372 (16.00), 1.376 (8.97), 2.126 (0.54), 2.147 (0.80), 2.228 (0.61 ), 2.247 (1.10), 2.265 (0.48), 2.280 (0.59), 2.292 (0.83), 2.323 (0.67), 2.327 (0.79), 2.331 (0.62), 2.337 (0.48), 2.359 (0.48), 2.372 (0.48), 2.387 (0.51 ), 2.398 (0.73), 2.518 (1.97), 2.523 (1.41 ), 2.665 (0.42), 2.669 (0.56), 2.673 (0.41 ), 3.404 (0.60), 3.417 (0.68), 3.422 (1.84), 3.435 (1.89), 3.440 (1.97), 3.452 (1.73), 3.457 (0.95), 3.469 (0.63), 3.878 (0.48), 3.895 (0.48), 4.344 (1.15), 4.356 (2.21 ), 4.369 (1.06), 6.999 (0.57), 7.003 (0.56), 7.013 (0.57), 7.016 (0.56), 8.212 (0.75), 8.225 (0.72).
Example 120.02
1-(4-{(1 R or 1S)-1-[2-({6-[1 -(cyclopropylmethyl)-3,5-dimethyl-1 H-pyrazol-4-yI]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)-3,3,3-trifluoropropan-1 -one
Figure imgf001008_0001
6-[1-(cyclopropylmethyl)-3,5-dimethyl-1 H-pyrazol-4-yl]-N-{4-[(1 R or 1 S)-1 -(piperazin-1 - yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride (56.0 mg; see Compound 120.03), 3,3,3-trifluoropropanoic acid (26 μΙ), NaHC03 (48.7 mg) and HATU (1 10 mg) were stirred in DMF (740 μΙ) overnight at rt. The crude mixture was purified without work up by preparative HPLC to give 4 mg (90 % purity) of the title compound.
LC-MS (method 2): Rt = 1.19 min; MS (ESIpos): m/z = 851 [M+H]+
1 H-NMR (400MHz, DMSO-d6): δ [ppm]= 0.36 (dd, 2H), 0.47 - 0.54 (m, 2H), 1.18 - 1.25 (m, 1 H), 1.30 (d, 3H), 2.15 (br s, 3H), 2.25 (br s, 3H), 2.33 - 2.39 (m, 2H), 2.40 - 2.46 (m, 2H), 3.42 - 3.50 (m, 5H), 3.62 (q, 2H), 3.89 (d, 2H), 6.85 - 6.95 (m, 2H), 7.12 - 7.52 (m, 3H), 8.26 (d, 1 H), 10.55 (br d, 1 H), 12.05 (br d, 1 H).
Example 121.01
tert-butyl 4-{(1 R or 1S)-1-[2-({6-[1-(cyclopropylmethyl)-1 H-pyrazol-4-yl]-7-fluoro-1H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate
Figure imgf001009_0001
tert-butyl 4-[(1 R or 1 S)-1-{2-[({2-amino-4-[1-(cyclopropylmethyl)-1 H-pyrazol-4-yl]-3- fluorophenyl}carbamothioyl)amino]pyridin-4-yl}ethyl]piperazine-1 -carboxylate (1.30 g; see Compound 121.02) and EDCI (419 mg) were stirred in dichloromethane (39 ml) under argon overnight at rt. The mixture was then concentrated under reduced pressure and the crude mixture was purified by flash chromatography on silica gel to give 728 mg (90 % purity) of the title compound.
LC-MS (method 2): R, = 1.37 min; MS (ESIpos): m/z = 561 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm]= 0.37 - 0.44 (m, 2H), 0.51 - 0.58 (m, 2H), 1.20 - 1.33 (m, 4H), 1.38 (s, 9H), 2.24 - 2.44 (m, 4H), 3.33 (s, 4H), 3.44 (q, 1 H), 4.01 (d, 2H), 6.94 (d, 1 H), 7.1 1 (br s, 1 H), 7.22 - 7.35 (m, 2H), 7.83 (s, 1 H), 8.12 (d, 1 H), 8.25 (s, 1 H), 10.77 (br s, 1 H), 12.28 (br s, 1 H).
Example 121.02
1 -(4-{(1 R or 1 S)-1 -[2-({6-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-7-fluoro-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)-3,3,3-trifluoropropan-1 -one
Figure imgf001010_0001
6-[1 -(cyclopropylmethyl)-1 H-pyrazol-4-yl]-7-fluoro-N-{4-[(1 R or 1 S)-1 -(piperazin-1 - yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride (100 mg; see Compound 121.03), 3,3,3-trifluoropropanoic acid (46 μΙ), NaHC03 (88.4 mg) and HATU (200 mg) were stirred in DMF (2.0 ml) overnight at rt. The crude mixture was purified without work up by preparative HPLC to give 51 mg (95 % purity) of the title compound.
LC-MS (method 2): R, = 1.20 min; MS (ESIpos): m/z = 571 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm]= 0.37 - 0.43 (m, 2H), 0.52 - 0.59 (m, 2H), 1.21 - 1.34 (m, 4H), 2.28 - 2.47 (m, 4H), 3.39 - 3.53 (m, 5H), 3.62 (d, 2H), 4.01 (d, 2H), 6.92 - 6.99 (m, 1 H), 7.11 (s, 1 H), 7.31 (s, 2H), 7.83 (s, 1 H), 8.12 (d, 1 H), 8.27 (d, 1 H), 10.79 (s, 1 H), 12.27 (s, 1 H).
Example 121.03
cyclopropyl(4-{(1R or 1S)-1-[2-({6-[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]-7-fluoro-1H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)methanone
Figure imgf001011_0001
6-[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]-7-fluoro-N-{4-[(1R or 1S)-1-(piperazin-1- yl)ethyl]pyridin-2-yl}-1H-benzimidazol-2-amine hydrochloride (100 mg; see Compound 121.03), cyclopropanecarboxylic acid (42 μΙ), NaHC03 (88.4 mg) and HATU (200 mg) were stirred in DMF (2.0 ml) overnight at rt. The crude mixture was purified without work up by preparative HPLC to give 21.7 mg (92 % purity) of the title compound.
LC-MS (method 2): F¾ = 1.16 min; MS (ESIpos): m/z = 529 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm]= 0.36 - 0.43 (m, 2H), 0.52 - 0.58 (m, 2H), 0.63 - 0.73 (m, 4H), 1.21 - 1.34 (m, 4H), 1.90 - 1.98 (m, 1H), 2.24 - 2.43 (m, 4H), 3.41 - 3.54 (m, 3H), 3.68 (brs, 2H), 4.01 (d, 2H), 6.93-6.99 (m, 1H), 7.12 (s, 1H), 7.23-7.35 (m, 2H), 7.83 (s, 1H), 8.12 (d, 1H), 8.27 (d, 1H), 10.79 (s, 1H), 12.28 (brs, 1H).
Example 122.01
tert-butyl 4-{(1 R or 1S)-1 -[2-({7-chloro-6-[1-(cyclopropylmethyl)-1 H-pyrazol-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate
Figure imgf001012_0001
tert-butyl 4-[(1 R or 1 S)-1 -{2-[({2-amino-3-chloro-4-[1-(cyclopropylmethyl)-1 H-pyrazol-4- yl]phenyl}carbamothioyl)amino]pyridin-4-yl}ethyl]piperazine-1 -carboxylate (1.10 g, see Compound 122.02) and EDCI (345 mg) were stirred in dichloromethane (32 ml) under argon overnight at rt. The mixture was concentrated under reduced pressure and purified by flash chromatography on silica gel to give 554 mg (91 % purity) of the title compound.
LC-MS (method 2): F¾ = 1.40 min; MS (ESIpos): m/z = 577 [M+H]+
1 H-NMR (400MHz, DMSO-d6): δ [ppm]= 0.37 - 0.43 (m, 2H), 0.52 - 0.58 (m, 2H), 1.25 - 1.31 (m, 4H), 1.38 (s, 9H), 2.25 - 2.44 (m, 4H), 3.33 (s, 4H), 3.44 (q, H), 4.02 (d, 2H), 6.92 - 6.98 (m, 1 H), 7.07 (s, 1 H), 7.20 (d, 1 H), 7.41 - 7.47 (m, 1 H), 7.78 (s, 1 H), 8.13 (s, 1 H), 8.27 (d, 1 H), 10.96 (s, 1 H), 12.30 (s, 1 H).
Example 122.02
1 -(4-{(1 R or 1S)-1-[2-({7-chloro-6-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)-3,3,3-trifluoropropan-1 -one
Figure imgf001013_0001
7-chloro-6-[1-(cyclopropylmethyl)-1 H-pyrazol-4-yl]-N-{4-[(1 R or 1 S)-1 -(piperazin-1 - yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride (100 mg; see Compound 122.03), 3,3,3-trifluoropropanoic acid (45 μΙ), NaHCC>3 (86.0 mg) and HATU (195 mg) were stirred in DMF (2.0 ml) overnight at rt. The crude mixture was purified without work up by preparative HPLC to give 22.0 mg (95 % purity) of the title compound.
LC-MS (method 2): R, = 1.23 min; MS (ESIpos): m/z = 587 [M+H]+
1 H-NMR (400MHz, DMSO-d6): δ [ppm]= 0.37 - 0.43 (m, 2H), 0.52 - 0.58 (m, 2H), 1.22 - 1.34 (m, 4H), 2.29 - 2.46 (m, 4H), 3.40 - 3.51 (m, 5H), 3.62 (q, 2H), 4.02 (d, 2H), 6.94 - 6.98 (m, 1 H), 7.08 (s, 1 H), 7.19 (d, 1 H), 7.44 (d, 1 H), 7.78 (s, 1 H), 8.13 (s, 1 H), 8.28 (d, 1 H), 10.98 (s, 1 H), 12.30 (s, 1 H).
Example 122.03
(4-{(1R or 1S)-1-[2-({7-chloro-6-[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]-1H-benzimidazol- 2-yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)(cyclopropyl)methanone
Figure imgf001014_0001
7-chloro-6-[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]-N-{4-[(1R or 1S)-1-(piperazin-1- yl)ethyl]pyridin-2-yl}-1H-benzimidazol-2-amine hydrochloride (100 mg; see Compound 122.03), cyclopropanecarboxylic acid (41 μΙ), NaHC03 (86.0 mg) and HATU (195 mg) were stirred in DMF (2.0 ml) overnight at rt. The crude mixture was purified without work up by preparative HPLC to give 44.1 mg (90 % purity) of the title compound.
LC-MS (method 2): Rt = 1.20 min; MS (ESIpos): m/z = 545 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm]= 0.37 - 0.43 (m, 2H), 0.52 - 0.59 (m, 2H), 0.64 - 0.73 (m, 4H), 1.22 - 1.35 (m, 4H), 1.88 - 1.98 (m, 1 H), 2.25 - 2.45 (m, 4H), 3.41 - 3.53 (m, 3H), 3.68 (brs, 2H), 4.02 (d, 2H), 6.94-7.00 (m, 1H), 7.09 (brs, 1H), 7.19 (d, 1H), 7.44 (d, 1H), 7.78 (s, 1H), 8.13 (s, 1H), 8.25-8.31 (m, 1H), 10.98 (s, 1H), 12.31 (s, 1H).
Example 123.01
tert-butyl 4-[(1R or 1S)-1-(2-{[6-(1-methyl-1H-pyrazol-5-yl)-1H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazine-1-carboxylate
Figure imgf001014_0002
tert-butyl 4-{(1R or 1S)-1-[2-({[2-amino-4-(1-methyl-1H-pyrazol-5- yl)phenyl]carbamothioyl}amino)pyridin-4-yl]ethyl}piperazine-1-carboxylate (466 mg; see Compound 123.02) and EDCI (167 mg) were stirred in dichloromethane (16 ml) under argon overnight at rt. The mixture was concentrated under reduced pressure and purified by flash chromatography on silica gel to give 21 1 mg (83 % purity) of the title compound.
LC-MS (method 2): R, = 1.24 min; MS (ESIpos): m/z = 503 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.20 - 1.32 (m, 4H), 1.38 (s, 9H), 2.25 - 2.44 (m, 4H), 3.33 (s, 4H), 3.44 (q, 1 H), 3.86 (s, 3H), 6.33 (d, 1 H), 6.94 (dd, 1 H), 7.17 (br s, 2H), 7.44 (d, 2H), 7.52 - 7.66 (m, 1 H), 8.27 (d, 1 H), 10.66 (br s, 1 H), 12.18 - 12.30 (m, 1 H), 12.24 (br s, 1 H).
Example 123.02
3,3,3-trifluoro-1 -{4-[(1 R or 1 S)-1 -(2-{[6-(1 -methyl-1 H-pyrazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}propan-1 -one
Figure imgf001015_0001
6-(1 -Methyl-1 H-pyrazol-5-yl)-N-{4-[(1 R or 1 S)-1 -(piperazin- -yl)ethyl]pyridin-2-yl}-1 h- benzimidazol-2-amine hydrochloride (75.0 mg; see Compound 123.03), 3,3,3- trifluoropropanoic acid (39 μΙ), NaHC03 (73.8 mg) and HATU (167 mg) were stirred in DMF (2.0 ml) overnight at rt. The crude mixture was purified without work up by preparative HPLC to give 7.50 mg (90 % purity) of the title compound.
LC-MS (method 2): R, = 1.04 min; MS (ESIpos): m/z = 513 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.30 (d, 3H), 2.31 - 2.39 (m, 2H), 2.43 (dt, 2H), 3.44 (br t, 2H), 3.47 (br d, 3H), 3.62 (q, 2H), 3.86 (s, 3H), 6.33 (d, 1 H), 6.95 (dd, 1 H), 7.18 (s, 2H), 7.44 (d, 2H), 7.53 - 7.65 (m, 1 H), 8.28 (d, 1 H), 10.69 (br s, 1 H), 12.23 (br s, 1 H).
Example 123.03
cyclopropyl{4-[(1 R or 1 S)-1 -(2-{[6-(1 -methyl-1 H-pyrazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}methanone
Figure imgf001016_0001
6-(1-methyl-1 H-pyrazol-5-yl)-N-{4-[(1 R or 1 S)-1 -(piperazin-1-yl)ethyl]pyridin-2-yl}-1 H- benzimidazol-2-amine hydrochloride (75.0 mg; see Compound 123.03), cyclopropanecarboxylic acid (35 μΙ), NaHC03 (73.8 mg) and HATU (167 mg) were stirred in DMF (2.0 ml) overnight at rt. The crude mixture was purified without work up by preparative HPLC to give 9.00 mg (90 % purity) of the title compound.
LC-MS (method 2): Rt = 1.01 min; MS (ESIpos): m/z = 471 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm]= 0.63 - 0.74 (m, 4H), 1 .30 (d, 3H), 1.88 - 1.99 (m, 1 H), 2.25 - 2.46 (m, 4H), 3.41 - 3.54 (m, 3H), 3.60 - 3.74 (m, 2H), 3.86 (s, 3H), 6.33 (s, 1 H), 6.96 (dd, 1 H), 7.10 - 7.22 (m, 2H), 7.37 - 7.48 (m, 2H), 7.54 - 7.66 (m, 1 H), 8.28 (d, 1 H), 10.67 (br d, 1 H), 12.23 (br d, 1 H).
Example 124.02
3,3,3-trifluoro-1 -{4-[(2-{[6-(1 H-pyrazol-5-yl)-1 H-benzimidazol-2-yl]amino}pyrid
yl)methyl]piperazin-1 -yl}propan-1-one
Figure imgf001016_0002
Crude N-[4-(piperazin-1-ylmethyl)pyridin-2-yl]-6-(1 H-pyrazol-5-yl)-1 H-benzimidazol-2-amine hydrochloride (35.0 mg; see compound 124.04), 3,3,3-trifluoropropanoic acid (19 μΙ), NaHCOa (36.5 mg) and HATU (82.5 mg) were stirred in DMF (550 μΙ) for 2h at rt. The mixture was diluted with water and stirred for 1 h at rt. The aqueous phase was extracted three times with DCM. The organic layer was filtered (silicone filter) and concentrated under reduced pressure. The crude mixture was purified without work up by preparative HPLC to give 6.00 mg (95 % purity) of the title compound.
LC-MS (Method 2): R, = 0.95 min; MS (ESIpos): m/z = 485 [M+H]+
1 H-NMR (400MHz, DMSO-d6): δ [ppm]= 2.40 (dt, 4H), 3.16 (s, 2H), 3.42 - 3.55 (m, 6H), 3.65 (q, 2H), 6.55 - 6.67 (m, 1 H), 6.92 (dd, 1 H), 7.18 - 7.55 (m, 3H), 7.57 - 7.79 (m, 1 H), 8.26 (d, 1 H), 10.65 (br s, 1 H), 12.18 (br s, 1 H).
Example 125.01
tert-butyl 4-[(5-bromo-2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate
Figure imgf001017_0001
tert-Butyl 4-{f2-({[2-amino-4-(3-methyl-1 ,2,4-oxadiazol-5-yl)phenyl]carbamothioyl}amino)-5- bromopyridin-4-yl]methyl}piperazine-1 -carboxylate (1 16 mg, see compound 125.04) was stirred with EDCI (73.7 mg) in dichloromethane (4.0 ml) under argon overnight at rt. The mixture was diluted with water and extracted three times with DCM. The organic layer was filtered, dried over a silicone filter and concentrated under reduced pressure. The compound was used without further purification.
LC-MS (Method 2): Rt = 1.59 min; MS (ESIpos): m/z = 541 [M+H]+
Example 125.02
1 -{4-[(5-bromo-2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2-yl]amino}pyridin- 4-yl)methyl]piperazin-1 -yl}-3,3,3-trifluoropropan-1 -one
Figure imgf001018_0001
N-[5-Bromo-4-(piperazin-1 -ylmethyl)pyridin-2-yl]-6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H- benzimidazol-2-amine hydrochloride (110 mg; see compound 125.05), 3,3,3-trifluoropropanoic acid (50 μΙ), NaHCOs (95.8 mg) and HATU (217 mg) were stirred in DMF (1.5 ml) for 2h at rt. The mixture was diluted with water stirred for 1 h at rt. The reaction mixture was extracted three times with DCM. The organic layer was dried (silicone filter) and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica gel to give 5 mg of the title compound.
LC-MS (Method 2): Rt = 1.20 min; MS (ESIpos): m/z = 579 [M+H]+
1 H-NMR (400MHz, DMSO-d6): δ [ppm]= 2.40 (s, 3H), 3.58 (s, 6H), 3.68 (d, 2H), 7.45 - 7.60 (m, 1.5H), 7.66 (d, 0.5H), 7.74 - 7.89 (m, 1 H), 8.02 (s, 0.5H), 8.21 (s, 0.5H), 8.34 - 8.43 (m, 1 H), 10.94 - 1 1.08 (m, 1 H), 12.22 - 12.33 (m, 1 H).
Example 126.02
1-(4-{[2-({6-[5-(cyclobutylmethyl)-1 ,3,4-oxadiazol-2-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1 -yl)-3,3,3-trifluoropropan-1 -one
Figure imgf001018_0002
6-[5-(Cyclobutylmethyl)-1 ,3,4-oxadiazol-2-yl]-N-[4-(piperazin-1 -ylmethyl)pyridin-2-yl]-1 H- benzimidazol-2-amine (7.00 mg; see compound 126.03), 3,3,3-trifluoropropanoic acid (4.2 μΙ, 47 pmol), NaHC03 (7.94 mg) and HATU (18.0 mg) were stirred in DMF (89 μΙ) overnight at rt. The mixture was concentrated and purified by preparative thin layer chromatography to give 2.00 mg (95 % purity) of the title compound.
LC-MS (method 2): Rt = 1.17 min; MS (ESIpos): m/z = 555 [M+H]+
1 H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.77 - 1.95 (m, 4H), 2.07 - 2.19 (m, 2H), 2.40 (dt, 4H), 2.72 - 2.82 (m, 1 H), 3.03 (d, 2H), 3.42 - 3.55 (m, 6H), 3.65 (q, 2H), 6.97 (br d, 1 H), 7.19 (s, 1 H), 7.47 (br d, 1 H), 7.62 - 7.71 (m, 1 H), 7.84 - 8.15 (m, 1 H), 8.29 (d, 1 H), 10.80 - 10.91 (m, 1 H), 12.43 (br s, 1 H).
The compounds shown in table 14 below were prepared according to the following general procedure :
Compound 01.04 (1 eq.) and the respective heteroaryl halide (1 .3 eq) were solubilised in DME and aqueous Na2CC>3 (2.5 eq, 2M) was added. The mixture was sparged with argon and 1 ,1 '-bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (0.1 eq) was added. The reaction mixture was stirred at 150°C for 2 hours (if the reaction was not complete, 1.3 eq. of heteroaryl halide as well as 0.1 eq. of catalyst were added and the reaction was stirred between 2 and 20 additional hours at 150Ό). The reaction mixture was then filtered through silicone filter and concentrated under reduced pressure. The crude mixture was purified without work up by preparative HPLC to the desired compound.
Table 14:
Figure imgf001020_0001
Figure imgf001021_0001
Figure imgf001022_0001
Figure imgf001023_0001
Figure imgf001024_0001
Figure imgf001025_0001
Figure imgf001026_0001
Example 145.01.01
Tert-butyl 4-[(2-{[6-(6-chloropyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl )methyl]pi perazi n e- 1 -ca rboxylate
Figure imgf001027_0001
Tert-butyl 4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazine-1-carboxylate (500 mg; see Compound 01.04), 4,6- dichloropyrimidine (418 mg), Na2C03 (1.4 ml, 2.0 M) were solubilised in a mixture of 1 ,4- dioxane (15 ml) and water (1.5 ml) and the reaction mixture was sparged with argon for 5 min. The 1 ,1 '-bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (76.4 mg) was added and the mixture was stirred 5 h at 120 The mixture was diluted with water and extracted three times with EtOAc. The combined organic layer were washed with brine, dried over a silicone filter and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica gel to give 286 mg (71 % purity) of the title compound.
LC-MS (method 2): R, = 1.32 min; MS (ESIneg): m/z = 519 [M-H]-
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.805 (0.50), 0.814 (1.49), 0.822 (0.56), 0.831 (3.56), 0.836 (2.02), 0.841 (0.67), 0.851 (1.58), 0.853 (2.39), 0.858 (1.79), 0.869 (0.66), 0.875 (0.48), 0.936 (0.92), 0.953 (1.06), 1.066 (1.70), 1.237 (1.03), 1.274 (0.44), 1.299 (4.92), 1.395 (16.00), 1 .987 (0.48), 2.332 (0.60), 2.359 (1.23), 2.518 (2.69), 2.522 (1.73), 2.673 (0.48), 3.349 (1.1 1 ), 3.490 (0.63), 3.507 (1.01 ), 7.180 (0.41 ), 8.271 (0.40), 8.283 (0.50), 9.009 (0.56).
Example 145.01.02
tert-butyl 4-[(2-{[6-(6-chloro-5-fluoropyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin yl)methyl]piperazine-1 -carboxylate
Figure imgf001028_0001
tert-butyl 4-[(2-{[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazine-1-carboxylate (500 mg, see Compound 01.04), 4,6- dichloro-5-fluoropyrimidine (469 mg), aqueous Na2C03 (1.4 ml, 2.0 M) and 1 , 1 '- bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (76.4 mg) were stirred in a sealed tube in a mixture of 1 ,4-dioxane (10 ml) and water (2.0 ml) overnight at 1 10 . The mixture was then filtered over a silicon e filter and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica gel to give 556 mg (60 % purity) of the title compound.
LC-MS (method 2): R, = 1.36 min; MS (ESIpos): m/z = 537 [M-H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.065 (16.00), 1.155 (1.74), 1.299 (1.42), 1.393 (2.88), 1.414 (1.32), 2.539 (0.70), 3.334 (0.76), 3.937 (0.68), 8.097 (0.85).
The Example compounds shown in table 15 below were prepared as follows:
The respective chloride (example 145.01.01 or 145.01.02) was solubilised in dioxane and the respective amine (4 to 6 eq) was added. In some cases K2CO3 or DIPEA (4 eq.) was used. The reaction mixture was stirred 16 hours at reflux. The reaction mixture was then filtered, concentrated under reduced pressure and purified by standard reversed-phase preparative HPLC.
or
The respective chloride (example 145.01.01 or 145.01.02) was solubilised in dioxane and the respective alcohol (2 to 6 eq) and NaH (6 eq.) was added. The reaction was stirred 1 to 3 hours at rt. The reaction was stopped by the addition of water, and the aqueous phase was extracted three times with DCM. The organic phase was dried (silicone filter), concentrated under reduced pressure and purified by standard reversed-phase preparative HPLC. Table 15:
Figure imgf001029_0001
Figure imgf001030_0001
Figure imgf001031_0001
Figure imgf001032_0001
Figure imgf001033_0001
Figure imgf001034_0001
Figure imgf001035_0001
Figure imgf001036_0001
Figure imgf001037_0001
Figure imgf001038_0001
LC-MS (Method 2): Rt = 1 .28 min; MS (ESIpos): m/z = 548 [M+H]+
The Example compounds shown below in table 16 were prepared according to the following general procedure :
The respective amine (1 eq.; see Compounds 130.01 to 163.01 , respectively; Table 3), 3,3,3- trifluoropropionic acid (1.5 eq), NaHCC (6 eq.) and HATU (1.5 eq.) were solublised in DMF and the reaction mixture was stirred at rt between 2 and 48 hours. The crude mixture was directly purified by preparative HPLC without workup to give the respective title compound.
Table 16:
Figure imgf001039_0001
Figure imgf001040_0001
Figure imgf001041_0001
Figure imgf001042_0001
Figure imgf001043_0001
1H), 12.20 (brs, 1H).
Figure imgf001044_0001
Figure imgf001045_0001
Figure imgf001046_0001
Figure imgf001047_0001
Figure imgf001048_0001
Figure imgf001049_0001
Figure imgf001050_0001
(brd, 1H), 8.44 (s, 1H), 10.72 (brs, 1H), 12.23 (brs, 1H).
Figure imgf001051_0001
Figure imgf001052_0001
Figure imgf001053_0001
Figure imgf001054_0001
Figure imgf001055_0001
Figure imgf001056_0001
The Example compounds shown below in table 17 were prepared according to the following general procedure: The respective amine (1 eq.; see Compounds 130.01 to 163.01 , respectively; Table 3), cyclopropanecarboxylic acid (1.5 eq), NaHCC (6 eq.) and HATU (1.5 eq.) were solublised in DMF and the reaction mixture was stirred at rt between 2 and 48 hours. The crude mixture was directly purified by preparative HPLC without workup to give the respective title compounds.
Table 17:
Figure imgf001057_0001
Figure imgf001058_0001
Figure imgf001059_0001
Figure imgf001060_0001
Figure imgf001061_0001
Figure imgf001062_0001
Figure imgf001063_0001
Figure imgf001064_0001
Figure imgf001065_0001
Figure imgf001066_0001
Figure imgf001067_0001
Figure imgf001068_0001
Figure imgf001069_0001
Figure imgf001070_0001
Figure imgf001071_0001
The Example compounds in the following table 18 were synthesised according to the preparations, and from starting materials (SM), as specified for the respective Examples in their table entries below.
Table 18:
Figure imgf001072_0001
Figure imgf001073_0001
Figure imgf001074_0001
Figure imgf001075_0001
Figure imgf001076_0001
Figure imgf001077_0001
Figure imgf001078_0001
Figure imgf001079_0001
Figure imgf001080_0001
Figure imgf001081_0001
The Example compounds in the following table 19 were synthesized in analogy to the preparation of Example 1 17.02, followed by purification by preparative reverse phase HPLC or silicagel chromatography.
Table 19:
Figure imgf001082_0001
Figure imgf001083_0001
SM: Compound 164.01 and cyclopropanecarboxylic acid
Figure imgf001084_0001
Figure imgf001085_0001
Figure imgf001086_0001
SM: Compound 165.01 and 3,3,3-trifluoropropanoic acid
Figure imgf001087_0001
Figure imgf001088_0001
Figure imgf001089_0001
SM: Compound 166.01 and cyclopropanecarboxylic acid
Figure imgf001090_0001
Figure imgf001091_0001
Figure imgf001092_0001
Figure imgf001093_0001
Figure imgf001094_0001
Figure imgf001095_0001
Structure
lUPAC-Name
Example LC-MS (method): Retention time; Mass found
1H-NMR
Starting materials (SM):
Example
168.03
cyclopropyl{4-[(2-{[6-(furo[3,2-d]pyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1-yl}methanone
LC-MS (Method 2): R, = 0.97 min; MS (ESIpos): m/z = 495 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.655 (0.88), 0.667 (2.24), 0.674 (4.47), 0.680 (3.15), 0.687 (2.42), 0.694 (5.21 ), 0.699 (2.70), 0.705 (3.00), 0.710 (4.37), 0.717 (4.75), 0.722 (5.29), 0.729 (2.79), 0.741 (0.73), 1.916 (0.58), 1.928 (1.20), 1.936 (1.26), 1.948 (2.05), 1.960 (1.18), 1.967 (1.06), 1.979 (0.48), 2.327 (0.53), 2.360 (2.26), 2.436 (2.25), 2.518 (0.77), 2.523 (0.51 ), 2.539 (3.10), 3.496 (2.62), 3.520 (10.35), 3.694 (2.12), 6.953 (2.82), 6.956 (2.81 ), 6.966 (2.88), 6.969 (2.89), 7.228 (3.83), 7.278 (10.05), 7.284 (10.17), 7.587 (0.79), 7.603 (0.82), 8.286 (6.33), 8.299 (5.19), 8.621 (10.93), 8.627 (10.75), 8.636 (0.58), 8.659 (0.65), 9.047 (16.00).
SM: Compound 168.01 and cyclopropanecarboxylic acid
Figure imgf001097_0001
Figure imgf001098_0001
SM: Compound 169.01 and cyclopropanecarboxylic acid
Figure imgf001099_0001
Figure imgf001100_0001
Structure
lUPAC-Name
Example LC-MS (method): Retention time; Mass found
1H-NMR
Starting materials (SM):
Example |_j C H 3
171.03
(4-{(1 R or 1 S)-1 -[2-({6-[1 -(cyclobutylmethyl)-l H-pyrazol-4-yl]-7-fluoro-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1- yl)(cyclopropyl)methanone
LC-MS (Method 2): R, = 1.25 min; MS (ESIpos): m/z = 543.3 [M+H]+ Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.639 (1.18), 0.651 (3.68), 0.659 (7.90), 0.671 (4.13), 0.678 (9.28), 0.684 (6.84), 0.690 (8.36), 0.697 (8.40), 0.702 (9.69), 0.709 (4.77), 0.721 (1.19), 1.282 (15.81 ), 1.299 (16.00), 1.743 (0.44), 1.749 (0.53), 1.767 (2.57), 1.788 (3.99), 1.795 (2.54), 1.807 (6.01 ), 1.819 (7.16), 1.823 (6.10), 1.828 (8.54), 1.847 (3.06), 1.854 (3.54), 1.869 (1.71 ), 1.876 (2.43), 1.892 (1.87), 1.904 (2.22), 1.91 1 (2.35), 1.923 (3.73), 1.935 (2.31 ), 1.942 (2.10), 1.955 (2.15), 1.960 (2.33), 1.974 (3.31 ), 1.982 (4.50), 1.992 (4.15), 2.003 (4.36), 2.021 (1.91 ), 2.033 (0.48), 2.302 (1.75), 2.322 (1.47), 2.327 (1.52), 2.331 (1.42), 2.384 (2.72), 2.437 (2.17), 2.518 (1.96), 2.523 (1.35), 2.539 (0.96), 2.609 (0.93), 2.669 (0.46), 2.744 (0.97), 2.762 (2.34), 2.780 (3.10), 2.799 (2.58), 2.818 (1.16), 3.421 (1.54), 3.437 (4.69), 3.454 (6.68), 3.468 (4.77), 3.661 (4.11 ), 4.158 (13.02), 4.176 (12.81 ), 6.947 (5.17), 6.959 (5.25), 7.1 12 (6.43), 7.241 (1.73), 7.260 (3.53), 7.277 (3.37), 7.303 (6.95), 7.324 (3.19), 7.826 (10.39), 8.059 (8.30), 8.262 (6.34), 8.275 (6.09), 10.800 (5.01 ), 12.278 (4.74).
SM: Compound 171.01 and cyclopropanecarboxylic acid
Figure imgf001102_0001
Figure imgf001103_0001
Figure imgf001104_0001
Figure imgf001105_0001
Figure imgf001106_0001
Figure imgf001107_0001
Example 174.01
tert-butyl 4-{(1 R or 1S)-1-[2-({6-[6-(difluoromethyl)pyrimidin-4-yl]-1H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazine-1-carboxylate
Figure imgf001108_0001
Tert-butyl 4-[(1 R or 1 S)-1 -{2-[({2-amino-4-[6-(difluoromethyl)pyrimidin-4- yl]phenyl}carbamothioyl)amino]pyridin-4-yl}ethyl]piperazine-1-carboxylate (300 mg, see Compound 174.01.02) was solubilized in dichloromethane (6.6 ml) and DIC (240 μΙ, 1.5 mmol) was added. The reaction mixture was stirred overnight under inert atmosphere. The crude residue was purified, without further workup, by flash chromatography on silica gel to give 228 mg (90 % purity) of the title compound.
LC-MS (Method 2): R, = 1.35 min; MS (ESIpos): m/z = 551 [M+H]+
1 H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.29 (d, 3H), 1.34 - 1.42 (m, 9H), 2.23 - 2.34 (m, 2H), 2.35 - 2.44 (m, 2H), 3.33 (s, 4H), 3.45 (q, 1 H), 6.86 - 7.21 (m, 3H), 7.38 - 7.69 (m, 1 H), 7.98 - 8.23 (m, 2H), 8.26 - 8.53 (m, 2H), 9.29 (s, 1 H), 10.83 (br s, 1 H), 12.39 (br s, 1 H).
Example 175.01
tert-butyl 4-[(2^[6-(2-chlorothiophen-3-yl)-1 H^enzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1-carboxylate
Figure imgf001109_0001
tert-Butyl 4-{[2-({[4-amino-6-(2-chlorothiophen-3-yl)pyridin-3-yl]carb^
yl]methyl}piperazine-1-carboxylate (630 mg, see Compound 107.01.02) and EDCI (216 mg) were stirred in dichloromethane (15 ml) under inert atmosphere over the weekend at rt. The mixture was concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel to give 160 mg of the title compound.
LC-MS (Method 2): Rt = 1.44 min; MS (ESIpos): m/z = 525 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.395 (16.00), 1.415 (1.94), 2.323 (0.56), 2.327 (0.68), 2.332 (0.68), 2.337 (0.69), 2.347 (1.16), 2.359 (1.40), 2.371 (1.01 ), 2.518 (1.71 ), 2.523 (1.21 ), 2.669 (0.44), 3.498 (1.76), 5.759 (5.93), 6.918 (0.50), 6.931 (0.50), 7.229 (0.42), 7.234 (0.54), 7.248 (0.61 ), 7.530 (0.56), 7.543 (0.47), 7.552 (0.41 ), 8.255 (0.67), 8.268 (0.63).
Example 176.01
tert-butyl 4-[(2-{[6-(morpholin-4-yl)-1H-benzimidazol-2-yl]amino}pyridin-4
yl)methyl]piperazine-1-carboxylate
Figure imgf001110_0001
Tert-butyl 4-{[2-({[2-amino-4-(morpholin-4-yl)phenyl]carbamothioyl}amino)pyridin-4- yl]methyl}piperazine-1 -carboxylate (380 mg, see Compound 176.01.03) and EDCI (138 mg) were stirred in dichloromethane (13 ml) under inert atmosphere overnight at rt. The mixture was concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel to give 43.0 mg (95 % purity) of the title compound.
LC-MS (Method 2): R, = 1.19 min; MS (ESIpos): m/z = 494 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.39 (s, 9H), 2.33 - 2.37 (m, 4H), 3.00 - 3.07 (m, 4H), 3.33 - 3.37 (m, 4H), 3.48 (s, 2H), 3.73 - 3.79 (m, 4H), 6.74 (br s, 1 H), 6.85 - 7.10 (m, 2H), 7.14 (br s, 1 H), 7.18 - 7.37 (m, 1 H), 8.21 (d, 1 H), 10.36 - 10.54 (m, 1 H), 1 1.84 (br s, 1 H).
The Example compounds shown in table 20 below were prepared according to the following general procedure :
Compound 01.04 (1 eq.) and the respective heteroaryl halide (1.3 eq) were solubilised in DME and an aqueous solution of Na2CC>3 (2.5 eq, 2M) was added. The mixture was sparged with argon and 1 , 1 '-bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (0.1 eq) was added. The reaction mixture was stirred at Ι δΟ for 2 hours (if the reaction was not complete, 1.3 eq. of heteroaryl halide as well as 0.1 eq. of catalyst were added and the reaction mixture was stirred between 2 and 20 additional hours at Ι δΟ ). The reaction mixture was then filtered through silicone filter and concentrated under reduced pressure. The crude mixture was purified without work up by preparative HPLC to the desired compound.
Table 20:
Figure imgf001111_0001
Figure imgf001112_0001
Figure imgf001113_0001
Figure imgf001114_0001
Figure imgf001115_0001
Figure imgf001116_0001
Figure imgf001117_0001
The Example compounds shown in table 21 below were prepared as follows:
The respective chloride (example 145.01.01 or 145.01.02, if not specified otherwise in the table below) was solubilised in dioxane and the respective amine (4 to 6 eq) was added. In some cases K2CO3 or DIPEA (4 eq.) was used. The reaction mixture was stirred 16 hours at reflux. The reaction mixture was then filtered, concentrated under reduced pressure and purified by preparative HPLC.
or
The respective chloride (example 145.01.01 or 145.01.02, if not specified otherwise in the table below) was solubilised in dioxane and the respective alcohol (2 to 6 eq) and NaH (6 eq.) was added. The reaction mixture was stirred 1 to 3 hours at rt. The reaction was stopped by the addition of water and the aqueous phase was extracted three times with DCM. The organic phase was dried (silicone filter), concentrated under reduced pressure and purified by preparative HPLC.
Table 21 :
Figure imgf001118_0001
Figure imgf001119_0001
Figure imgf001120_0001
Figure imgf001121_0001
Figure imgf001122_0001
Example 198.01
tert-butyl 4-{[2-({6-[6-(3,6-dihydro-2H^yran-4-yl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate
Figure imgf001123_0001
Tert-butyl 4-[(2-{[6-(6-chloropyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1-carboxylate (150 mgsee Example 145.01.01 ), 4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (181 mg), an aqueous solution of a2CC>3 (430 μΙ, 2.0 M) and 1 ,1 '-bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (23.5 mg, 28.8 pmol) were stirred in 1 ,4-dioxane (3.0 ml) / water (600 μΙ) for 3h at 1 10 TJ. The mixture was then concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel to give 30.1 mg (97 % purity) of the title compound.
LC-MS (Method 2): Rt = 1.24 min; MS (ESIpos): m/z = 569 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.40 (s, 9H), 2.36 (br t, 4H), 2.62 (br s, 2H), 3.35 - 3.42 (m, 4H), 3.51 (s, 2H), 3.86 (t, 2H), 4.34 (br d, 2H), 6.95 (br s, 1 H), 7.19 (s, 2H), 7.41 - 7.62 (m, 1 H), 7.99 - 8.14 (m, 2H), 8.27 (d, 1 H), 8.29 - 8.46 (m, 1 H), 9.10 (d, 1 H), 10.70 - 10.85 (m, 1 H), 12.33 (br s, 1 H).
Example 199.01
tert-butyl 4-{[2-({6-[6-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1-carboxylate
Figure imgf001123_0002
Tert-butyl 4 [2-({6-[6-(3,6-dihydro-2H-pyran-4-yl)pyrimidin-4-yl]-1H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1-carboxylate (30.1 mg) was solubilised in ethanol (2.0 ml), and the reaction vessel was purged three times with argon. Pd/C (1.68 g, 10 % purity) was added to the mixture, and the vessel was purged three times with argon and three times with hydrogen gas. The reaction mixture was stirred under hydrogen atmosphere at rt overnight. The reaction mixture was filtered through Celite® and concentrated under reduced pressure. The crude title compound (27 mg) was used without further purification.
LC-MS (Method 2): R, = 1.20 min; MS (ESIpos): m/z = 571 [M+H]+
1H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.40 (s, 9H), 1.85 (br d, 4H), 2.36 (br t, 4H), 2.94 - 3.05 (m, 1H), 3.34-3.40 (m, 4H), 3.40-3.55 (m, 4H), 3.95-4.04 (m, 2H), 6.94 (brd, 1H), 7.20 (s, 1H), 7.38-7.65 (m, 1H), 7.98 (brd, 2H), 8.21 -8.45 (m, 2H), 9.08 (d, 1H), 10.78 (brd, 1H), 12.35 (d, 1H).
The Example compounds shown below in table 22 were prepared according to the following general procedure :
The respective amine (1 eq.; see Compounds 174.01 to 198.01 , respectively; Table 6), 3,3,3- trifluoropropionic acid (1.5 eq), NaHCC (6 eq.) and HATU (1.5 eq.) were solublised in DMF and the reaction mixture was stirred at rt between 2 and 48 hours. The crude mixture was directly purified by preparative HPLC without workup to give the respective title compound.
Table 22:
Figure imgf001125_0001
Figure imgf001126_0001
Figure imgf001127_0001
Figure imgf001128_0001
Figure imgf001129_0001
Figure imgf001130_0001
Figure imgf001131_0001
Figure imgf001132_0001
Figure imgf001133_0001
Figure imgf001134_0001
Figure imgf001135_0001
The Example compounds shown below in table 23 were prepared according to the following general procedure : The respective amine (1 eq.; see Compounds 174.01 to 198.01 , respectively; Table 6), cyclopropanecarboxylic acid (1.5 eq), NaHCC (6 eq.) and HATU (1.5 eq.) were solublised in DMF and the reaction mixture was stirred at rt between 2 and 48 hours. The crude mixture was directly purified by preparative HPLC without workup to give the respective title compounds.
Table 23:
Figure imgf001136_0001
Figure imgf001137_0001
Figure imgf001138_0001
Figure imgf001139_0001
Figure imgf001140_0001
Figure imgf001141_0001
Figure imgf001142_0001
Figure imgf001143_0001
Example 197.04
{4-[(1R or 1S)-1-{2-[(6-{6-[(cyclopropylmethyl)(methyl)amino]pyrimidin
benzimidazol-2-yl)amino]pyridin-4-yl}ethyl]piperazin-1-yl}[1-
(trifluoromethyl)cyclopropyl]methanone
Figure imgf001143_0002
A mixture of 6-{6-[(cyclopropylmethyl)(methyl)amino]pyrimidin-4-yl}-N-{4-[(1 or 1S)-1- (piperazin-1-yl)ethyl]pyridin-2-yl}-1 H-benzimidazol-2-amine hydrochloride (1 15 mg), 1- (trifluoromethyl)cyclopropanecarboxylic acid (89.6 mg), solid NaHCOa (97.7 mg) and HATU (221 mg) was stirred in DMF (1.2 ml) overnight at rt. The crude mixture was purified without work up by preparative HPLC to give 35.3 mg (95 % purity) of the title compound.
LC-MS (Method 2): R, = 1.29 min; MS (ESIpos): m/z = 620 [M+H]+ 1 H-NMR (400MHz, DMSO-d6): δ [ppm]= 0.26 - 0.54 (m, 4H), 1.01 - 1.20 (m, 3H), 1.22 - 1.35 (m, 5H), 2.29 - 2.47 (m, 4H), 3.17 (s, 3H), 3.42 - 3.50 (m, 1H), 3.51 - 3.66 (m, 6H), 6.96 (d, 1H), 7.08 (br s, 1H), 7.18 (s, 1H), 7.38 - 7.52 (m, 1H), 7.88 (dd, 1H), 8.14 - 8.34 (m, 2H), 8.52 (d, 1H), 10.72 (brs, 1H), 12.26 (brs, 1H).
EXPERIMENTAL SECTION - BIOLOGICAL ASSAYS & BIOLOGICAL DATA PART Abbreviations:
The following table 24 lists the abbreviations used herein, in particular in the Biological Assys & Biological Data part of the Experimental Section:
Table 24:
Figure imgf001145_0001
ΙΚΚα inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase alpha
ΙΚΚβ inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta
ΙΚΚε inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase epsilon
IL-6 interleukin 6 (interferon, beta 2)
IRF interferon regulatory factor
Kras v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog
Luc2 Firefly Luciferase 2
MgCI2 Magnesiumchloride
μΜ micromolar
mM millimolar
NF-kB nuclear factor of kappa light polypeptide gene enhancer in B-cells
Ni-NTA Nitrilotriacetic acid
nM nanomolar
nm nanometer
ON over night
Pea prostate cancer
polylC Polyinosinic:polycytidylic acid
Poly
(l:C)_HMW Polyinosinic:polycytidylic acid, high molecular weight
pSer phospho-serine
v-ral simian leukemia viral oncogene homolog B (ras related; GTP binding
RalB protein)
RANTES chemokine (C-C motif) ligand 5
TBK1 TANK-binding kinase 1
TR-FRET Time-resolved-Fluorescence Resonance Energy Transfer
v/v volume by volume
Examples were tested in selected biological assays one or more times. When tested more than once, data are reported as either average values or as median values, wherein • the average value, also referred to as the arithmetic mean value, represents the sum of the values obtained divided by the number of times tested, and
• the median value represents the middle number of the group of values when ranked in ascending or descending order. If the number of values in the data set is odd, the median is the middle value. If the number of values in the data set is even, the median is the arithmetic mean of the two middle values.
Examples were synthesized one or more times. When synthesized more than once, data from biological assays represent average values or median values calculated utilizing data sets obtained from testing of one or more synthetic batch.
The in vitro activity of the compounds of the present invention can be demonstrated in the following assays:
In vitro assay 1 : TBK1 low ATP kinase assay
TBK1 -inhibitory activity of compounds of the present invention at a low ATP concentration after pre-incubation of enzyme and test compounds was quantified employing the TR-FRET- based TBK1 assay as described in the following paragraphs.
Recombinant full-length N-terminally His-tagged human TBK1 , expressed in insect cells and purified by Ni-NTA affinity chromatography, was purchased from Life Technologies (Cat. No PR5618B) and used as enzyme. As substrate for the kinase reaction biotinylated peptide biotin-Ahx-GDEDFSSFAEPG (C-terminus in amide form) was used which can be purchased e.g. from the company Biosyntan (Berlin-Buch, Germany).
For the assay 50 nl of a 100-fold concentrated solution of the test compound in DMSO was pipetted into either a black low volume 384well microtiter plate or a black 1536well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), 2 μΙ of a solution of TBK1 in aqueous assay buffer [50 mM HEPES pH 7.0, 10 mM MgCI2, 1.0 mM dithiothreitol, 0.05 % (w/v) bovine serum albumine, 0.01 % (v/v) Nonidet-P40 (Sigma), protease inhibitor mixture ("Complete w/o EDTA" from Roche, 1 tablet per 5 ml)] were added and the mixture was incubated for 15 min at 22*C to allow pre-binding of the test compounds to the enzyme before the start of the kinase reaction. Then the kinase reaction was started by the addition of 3 μΙ of a solution of adenosine-tri-phosphate (ATP, 16.7 μΜ => final cone, in the 5 μΙ assay volume is 10 μΜ) and substrate (1.67 μΜ => final cone, in the 5 μΙ assay volume is 1 μΜ) in assay buffer and the resulting mixture was incubated for a reaction time of 30 min at 22 . The concentration of TBK1 was adjusted depending of the activity of the enzyme lot and was chosen appropriate to have the assay in the linear range, a typical concentration is 0.03 Mg/ml. The reaction was stopped by the addition of 3 μΙ of a solution of TR-FRET detection reagents (0.33 μΜ streptavidine-XL665 [Cisbio Bioassays, Codolet, France], 2.5 nM anti-phosho-Serine anti-body [Merck Millipore, "STK antibody", cat. # 35-002] and 1.25 nM LANCE EU-W1024 labeled anti- mouse IgG anti-body [Perkin-Elmer, product no. AD0077]) in an aqueous EDTA-solution (167 mM EDTA, 0.13 % (w/v) bovine serum albumin in 100 mM HEPES/NaOH pH 7.5).
The resulting mixture was incubated 1 h at 22'C to allow the formation of complex between the phosphorylated biotinylated peptide and the detection reagents. Subsequently the amount of phosphorylated substrate was evaluated by measurement of the resonance energy transfer from the Eu-chelate to the streptavidine-XL. Therefore, the fluorescence emissions at 620 nm and 665 nm after excitation at 350 nm was measured in a TR-FRET reader, e.g. a Pherastar (BMG Labtechnologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665 nm and at 622 nm was taken as the measure for the amount of phosphorylated substrate. The data were normalised (enzyme reaction without inhibitor = 0 % inhibition, all other assay components but no enzyme = 100 % inhibition). Usually the test compounds were tested on the same microtiterplate in 1 1 different concentrations in the range of 20 μΜ to 0.07 nM (20 μΜ, 5.7 μΜ, 1.6 μΜ, 0.47 μΜ, 0.13 μΜ, 38 nM, 1 1 nM, 3.1 nM, 0.9 nM, 0.25 nM and 0.07 nM, the dilution series prepared separately before the assay on the level of the l OOfold concentrated solutions in DMSO by serial dilutions, exact concentrations may vary depending pipettors used)) in duplicate values for each concentration and IC50 values were calculated using Genedata Screener™ software.
In vitro assay 2: TBK1 high ATP kinase assay
TBK1 -inhibitory activity of compounds of the present invention at a high ATP concentration after pre-incubation of enzyme and test compounds was quantified employing the TR-FRET- based TBK1 assay as described in the following paragraphs.
Recombinant full-length N-terminally His-tagged human TBK1 , expressed in insect cells and purified by Ni-NTA affinity chromatography, was purchased from Life Technologies (Cat. No PR5618B) and used as enzyme. As substrate for the kinase reaction biotinylated peptide biotin-Ahx-GDEDFSSFAEPG (C-terminus in amide form) was used which can be purchased e.g. from the company Biosyntan (Berlin-Buch, Germany).
For the assay 50 nl of a 100-fold concentrated solution of the test compound in DMSO was pipetted into either a black low volume 384well microtiter plate or a black 1536well microtiter plate (both Greiner Bio-One, Frickenhausen, Germany), 2 μΙ of a solution of TBK1 in aqueous assay buffer [50 mM HEPES pH 7.0, 10 mM MgCI2, 1.0 mM dithiothreitol, 0.05 % (w/v) bovine serum albumine, 0.01 % (v/v) Nonidet-P40 (Sigma), protease inhibitor mixture ("Complete w/o EDTA" from Roche, 1 tablet per 5 ml)] were added and the mixture was incubated for 15 min at 22'C to allow pre-binding of the test compounds to the enzyme before the start of the kinase reaction. Then the kinase reaction was started by the addition of 3 μΙ of a solution of adenosine-tri-phosphate (ATP, 1.67 mM => final cone, in the 5 μΙ assay volume is 1 mM) and substrate (1.67 μΜ => final cone, in the 5 μΙ assay volume is 1 μΜ) in assay buffer and the resulting mixture was incubated for a reaction time of 30 min at 22 . The concentration of TBK1 was adjusted depending of the activity of the enzyme lot and was chosen appropriate to have the assay in the linear range, typical concentrations were in the range of 0.002-0.004 g/ml. The reaction was stopped by the addition of 3 μΙ of a solution of TR-FRET detection reagents (0.33 μΜ streptavidine-XL665 [Cisbio Bioassays, Codolet, France], 2.5 nM anti- phosho-Serine anti-body [Merck Millipore, "STK antibody", cat. # 35-002] and 1.25 nM LANCE EU-W1024 labeled anti-mouse IgG anti-body [Perkin-Elmer, product no. AD0077]) in an aqueous EDTA-solution (100 mM EDTA, 0.13 % (w/v) bovine serum albumin in 100 mM HEPES/NaOH pH 7.5).
The resulting mixture was incubated 1 h at 22"C to allow the formation of complex between the phosphorylated biotinylated peptide and the detection reagents. Subsequently the amount of phosphorylated substrate was evaluated by measurement of the resonance energy transfer from the Eu-chelate to the streptavidine-XL. Therefore, the fluorescence emissions at 620 nm and 665 nm after excitation at 350 nm was measured in a TR-FRET reader, e.g. a Pherastar (BMG Labtechnologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665 nm and at 622 nm was taken as the measure for the amount of phosphorylated substrate. The data were normalized (enzyme reaction without inhibitor = 0 % inhibition, all other assay components but no enzyme = 100 % inhibition). Usually the test compounds were tested on the same microtiterplate in 1 1 different concentrations in the range of 20 μΜ to 0.07 nM (20 μΜ, 5.7 μΜ, 1.6 μΜ, 0.47 μΜ, 0.13 μΜ, 38 nM, 11 nM, 3.1 nM, 0.9 nM, 0.25 nM and 0.07 nM, the dilution series prepared separately before the assay on the level of the l OOfold concentrated solutions in DMSO by serial dilutions, exact concentrations may vary depending pipettors used) in duplicate values for each concentration and IC50 values were calculated using Genedata Screener™ software.
In vitro assay 3: CDK9/CycT1 high ATP kinase assay
CDK9/CycT1 -inhibitory activity of compounds of the present invention at a high ATP concentration after preincubation of enzyme and test compounds was quantified employing the CDK9/CycT1 TR-FRET assay as described in the following paragraphs.
Recombinant full-length His-tagged human CDK9 and CycT1 , expressed in insect cells and purified by Ni-NTA affinity chromatography, were purchased from Life Technologies (Cat. No PV4131 ). As substrate for the kinase reaction biotinylated peptide biotin-Ttds- YISPLKSPYKISEG (C-terminus in amide form) was used which can be purchased e.g. form the company JERINI peptide technologies (Berlin, Germany).
For the assay 50 nl of a 100fold concentrated solution of the test compound in DMSO was pipetted into either a black low volume 384well microtiter plate or a black 1536well microtiter plate (both Greiner Bio-One, Frickenhausen, Germany), 2 μΙ of a solution of CDK9/CycT1 in aqueous assay buffer [50 mM Tris/HCI pH 8.0, 10 mM MgCI2, 1.0 mM dithiothreitol, 0.1 mM sodium ortho-vanadate, 0.01 % (v/v) Nonidet-P40 (Sigma)] were added and the mixture was incubated for 15 min at 22Ό to allow pre-binding o f the test compounds to the enzyme before the start of the kinase reaction. Then the kinase reaction was started by the addition of 3 μΙ of a solution of adenosine-tri-phosphate (ATP, 3.3 mM => final cone, in the 5 μΙ assay volume is 2 mM) and substrate (1.67 μΜ => final cone, in the 5 μΙ assay volume is 1 μΜ) in assay buffer and the resulting mixture was incubated for a reaction time of 25 min at 22Ό. The concentration of CDK9/CycT1 was adjusted depending of the activity of the enzyme lot and was chosen appropriate to have the assay in the linear range, typical concentrations were in the range of 0.5 pg/ml. The reaction was stopped by the addition of 3 μΙ of a solution of TR- FRET detection reagents (0.33 μΜ streptavidine-XL665 [Cisbio Bioassays, Codolet, France] and 1.67 nM anti-RB(pSer807/pSer811 )-anti-body from BD Pharmingen [# 558389] and 2 nM LANCE EU-W1024 labeled anti-mouse IgG anti-body [Perkin-Elmer, product no. AD0077]) in an aqueous EDTA-solution (167 mM EDTA, 0.2 % (w/v) bovine serum albumin in 100 mM HEPES pH 7.5).
The resulting mixture was incubated 1 h at 22Ό to allow the formation of complex between the phosphorylated biotinyiated peptide and the detection reagents. Subsequently the amount of phosphorylated substrate was evaluated by measurement of the resonance energy transfer from the Eu-chelate to the streptavidine-XL. Therefore, the fluorescence emissions at 620 nm and 665 nm after excitation at 350 nm was measured in a TR-FRET reader, e.g. a Pherastar (BMG Labtechnologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665 nm and at 622 nm was taken as the measure for the amount of phosphorylated substrate. The data were normalised (enzyme reaction without inhibitor = 0 % inhibition, all other assay components but no enzyme = 100 % inhibition). Usually the test compounds were tested on the same microtiterplate in 1 1 different concentrations in the range of 20 μΜ to 0.07 nM (20 μΜ, 5.7 μΜ, 1.6 μΜ, 0.47 μΜ, 0.13 μΜ, 38 nM, 1 1 nM, 3.1 nM, 0.9 nM, 0.25 nM and 0.07 nM, the dilution series prepared separately before the assay on the level of the 100fold concentrated solutions in DMSO by serial dilutions, exact concentrations may vary depending pipettors used) in duplicate values for each concentration and IC50 values were calculated using Genedata Screener™ software. In vitro assay 4: ΙΚΚε low ATP kinase assay
ΙΚΚε -inhibitory activity of compounds of the present invention at a low ATP concentration after preincubation of enzyme and test compounds was quantified employing the TR-FRET-based ΙΚΚε assay as described in the following paragraphs.
A recombinant fusion protein of GST (N-terminally) and full-length human ΙΚΚε, expressed in insect cells and purified by glutathione affinity chromatography, was purchased from Life Technologies (Cat. No PV4876) and used as enzyme. As substrate for the kinase reaction biotinylated peptide biotin-Ahx-GDEDFSSFAEPG (C-terminus in amide form) was used which can be purchased e.g. from the company Biosyntan (Berlin-Buch, Germany).
For the assay 50 nl of a 100fold concentrated solution of the test compound in DMSO was pipetted into either a black low volume 384well microtiter plate or a black 1536well microtiter plate (both Greiner Bio-One, Frickenhausen, Germany), 2 μΙ of a solution of ΙΚΚε in aqueous assay buffer [50 mM HEPES pH 7.0, 10 mM MgCI2, 1.0 mM dithiothreitol, 0.05 % (w/v) bovine serum albumin, 0.01 % (v/v) Nonidet-P40 (Sigma), protease inhibitor mixture ("Complete w/o EDTA" from Roche, 1 tablet per 5 ml)] were added and the mixture was incubated for 15 min at 22Ό to allow pre-binding of the test compounds to the enzyme before the start of the kinase reaction. Then the kinase reaction was started by the addition of 3 μΙ of a solution of adenosine-tri-phosphate (ATP, 16.7 μΜ => final cone, in the 5 μΙ assay volume is 10 μΜ) and substrate (1.67 μΜ => final cone, in the 5 μΙ assay volume is 1 μΜ) in assay buffer and the resulting mixture was incubated for a reaction time of 30 min at 22"C. The concentration of ΙΚΚε was adjusted depending of the activity of the enzyme lot and was chosen appropriate to have the assay in the linear range, a typical concentration is 0.01 pg/ml. The reaction was stopped by the addition of 3 μΙ of a solution of TR-FRET detection reagents (0.33 μΜ streptavidine-XL665 [Cisbio Bioassays, Codolet, France], 2.5 nM anti-phosho-Serine antibody [Merck Millipore, "STK antibody", cat. # 35-002] and 1.25 nM LANCE EU-W1024 labeled anti- mouse IgG antibody [Perkin-Elmer, product no. AD0077]) in an aqueous EDTA-solution (167 mM EDTA, 0.13 % (w/v) bovine serum albumin in 100 mM HEPES/NaOH pH 7.5). The resulting mixture was incubated 1 h at 22 to allow the formation of complex between the phosphorylated biotinylated peptide and the detection reagents. Subsequently the amount of phosphorylated substrate was evaluated by measurement of the resonance energy transfer from the Eu-chelate to the streptavidine-XL. Therefore, the fluorescence emissions at 620 nm and 665 nm after excitation at 350 nm was measured in a TR-FRET reader, e.g. a Pherastar (BMG Labtechnologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665 nm and at 622 nm was taken as the measure for the amount of phosphorylated substrate. The data were normalised (enzyme reaction without inhibitor = 0 % inhibition, all other assay components but no enzyme = 100 % inhibition). Usually the test compounds were tested on the same microtiterplate in 1 1 different concentrations in the range of 20 μΜ to 0.07 nM (20 μΜ, 5.7 μΜ, 1.6 μΜ, 0.47 μΜ, 0.13 μΜ, 38 ηΜ, 1 1 ηΜ, 3.1 ηΜ, 0.9 ηΜ, 0.25 nM and 0.07 nM, the dilution series prepared separately before the assay on the level of the lOOfold concentrated solutions in DMSO by serial dilutions, exact concentrations may vary depending pipettors used) in duplicate values for each concentration and IC50 values were calculated using Genedata Screener™ software.
In vitro assay 5: Assay for the detection of lkke TBK1 inhibition in MDA-MB231 cells ΤΒΚ1/ΙΚΚε kinases are involved in the regulation of the Toll-like receptor 3 dependent innate immune response pathway. Stimulation of TLR3 by poly-l:C activates ΤΒΚ1/ΙΚΚε which in turn phosphorylate the transcription factor IRF3. IRF3 translocates into the cell nucleus and activates the transcription of interferon regulated genes (e.g., IFN-beta, RANTES). The cellular assay for the determination of inhibition of ΙΚΚε and TBK1 was performed in MDA-MB231 cells (ATCC, Manassas, USA) that stably express an ISRE-Luciferase reporter responsive for IRF3. The promoter sequence was based on the pISRE-TA-Luc vector (available from Clontech) containing five copies of the ISRE enhancer element, located upstream of the minimal TA promoter. The coding sequence of optimized firefly luciferase Iuc2 (Promega) was placed downstream of the ISRE-TA element. The final reporter plSRE-TA-luc2 containing a Hygromycin resistance gene was integrated into a lentiviral expression system that was used to generate the stable reporter cells. The coding sequence of the ISRE promoter and luciferase gene is as follows:
ISRE-TA-luc2 sequence
1843 AATAGTAGACATAATAGCAACAGACATACAAACTAAAGAATTAC»AAAACAAATTACAAA
1903 AATTCAAAATTTTATCGATACTAGTTCTTACGCGTGGTACCGAGCTCTTACGCGTGCTAG
1963 CGAAACTGAAACTGAAACTGAAACTGAAACTGAAACTGAAACTGAAACTGAAACTGAAAC
2023 TAGATCTGGGTATATAATGGAAGCTTGGCATTCCGGTACTGTTGGTAAAGCCACCATGGA
2083 AGATGCCAAAAACATTAAGAAGGGCCCAGCGCCATTCTACCCACTCGAAGACGGGACCGC
2143 CGGCGAGCAGCTGCACAAAGCCATGAAGCGCTACGCCCTGGTGCCCGGCACCATCGCCTT
2203 TACCGACGCACATATCGAGGTGGACATTACCTACGCCGAGTACTTCGAGATGAGCGTTCG
2263 GCTGGCAGAAGCTATGAAGCGCTATGGGCTGAATACAAACCATCGGATCGTGGTGTGCAG
2323 CGAGAATAGCTTGCAGTTCTTCATGCCCGTGTTGGGTGCCCTGTTCATCGGTGTGGCTGT
2383 GGCCCCAGCTAACGACATCTACAACGAGCGCGAGCTGCTGAACAGCATGGGCATCAGCCA
2443 GCCCACCGTCGTATTCGTGAGCAAGAAAGGGCTGCAAAAGATCCTCAACGTGCAAAAGAA
2503 GCTACCGATCATACAAAAGATCATCATCATGGATAGCAAGACCGACTACCAGGGCTTCCA
2563 AAGCATGTACACCTTCGTGACTTCCCATTTGCCACCCGGCTTCAACGAGTACGACTTCGT
2623 GCCCGAGAGCTTCGACCGGGACAAAACCATCGCCCTGATCATGAACAGTAGTGGCAGTAC
2683 CGGATTGCCCAAGGGCGTAGCCCTACCGCACCGCACCGCTTGTGTCCGATTCAGTCATGC
2743 CCGCGACCCCATCTTCGGCAACCAGATCATCCCCGACACCGCTATCCTCAGCGTGGTGCC
2803 ATTTCACCACGGCTTCGGCATGTTCACCACGCTGGGCTACTTGATCTGCGGCTTTCGGGT 2863 CGTGCTCATGTACCGCTTCGAGGAGGAGCTATTCTTGCGCAGCTTGCAAGACTATAAGAT
2923 TCAATCTGCCCTGCTGGTGCCCACACTATTTAGCTTCTTCGCTAAGAGCACTCTCATCGA
2983 CAAGTACGACCTAAGCAACTTGCACGAGATCGCCAGCGGCGGGGCGCCGCTCAGCAAGGA
3043 GGTAGGTGAGGCCGTGGCCAAACGCTTCCACCTACCAGGCATCCGCCAGGGCTACGGCCT
3103 GACAGAAACAACCAGCGCCATTCTGATCACCCCCGAAGGGGACGACAAGCCTGGCGCAGT
3163 AGGCAAGGTGGTGCCCTTCTTCGAGGCTAAGGTGGTGGACTTGGACACCGGTAAGACACT
3223 GGGTGTGAACCAGCGCGGCGAGCTGTGCGTCCGTGGCCCCATGATCATGAGCGGCTACGT
3283 TAACAACCCCGAGGCTACAAACGCTCTCATCGACAAGGACGGCTGGCTGCACAGCGGCGA
3343 CATCGCCTACTGGGACGAGGACGAGCACTTCTTCATCGTGGACCGGCTGAAGAGCCTGAT
3 03 CAAATACAAGGGCTACCAGGTAGCCCCAGCCGAACTGGAGAGCATCCTGCTGCAACACCC
3463 CAACATCTTCGACGCCGGGGTCGCCGGCCTGCCCGACGACGATGCCGGCGAGCTGCCCGC
3523 CGCAGTCGTCGTGCTGGAACACGGTAAAACCATGACCGAGAAGGAGATCGTGGACTATGT
3583 GGCCAGCCAGGTTACAACCGCCAAGAAGCTGCGCGGTGGTGTTGTGTTCGTGGACGAGGT
3643 GCCTAAAGGACTGACCGGCAAGTTGGACGCCCGCAAGATCCGCGAGATTCTCATTAAGGC
3703 CAAGAAGGGCGGCAAGATCGCCGTGTAATAATTCTAGAACGAAGCGGCCGCAGGGTTTAA
ISRE-TA 1945 -2040
Luc2 2078 - 373 0 ( 1652bp ) The ISRE-luc2-MDA-MB231 cells were cultured in DMEM/ Ham's F12 (Gibco # 21041 ) supplemented with 10% fetal calf serum (typically but not exclusively used: FCS Gold Gibco- No. 10500-064), 2 mM L-glutamine (Gibco-No. 35050-038), 150 g/ml Hygromycin B, cryopreserved in 90% FCS + 10% dimethylsulphoxide (DMSO) and stored as frozen aliquots of typically 5-10 million cells/vial at -Ι δΟ ) or b elow until further use.
For the assay, sufficient cells were rapidly thawed in a 37 water bath and pipetted into pre- warmed assay medium (DMEM/ Ham 's F12, 10% FCS, 2 mM L-glutamine, 1% Penicillin/Streptomycin (Biochrom AG; # A2213)). The cells were centrifuged for 5 min at 180 x g. The supernatant was removed and the cell pellet was resuspended in fresh medium to give a suspension of 2.4 million cells / ml. Poly (l:C)_HMW (InvivoGen, # tlrl-pic) was diluted in assay medium to 0.2 mg/L and subsequently mixed with the cell suspension in 1 :1 ratio.
Fifty nl of a 100-fold concentrated solution of the test compound in DMSO were transferred into a white microtiter test plate (384 or 1536, Greiner Bio-One, Frickenhausen, Germany). For this, either a Hummingbird liquid handler (Digilab, MA, USA) or an Echo acoustic system (Labcyte, CA, USA) was used. Five μΙ of a freshly prepared cell suspension was added to the wells of a test plate and incubated at 37Ό in a 5% CO 2 atmosphere. The inhibitor control cell suspension was added to empty wells at the side of the test plate. After completion of the incubation for 20-24 hours, 2.5 μΙ of Steady-Glo® Luciferase detection solution (Promega), prepared as recommended by the supplier, were added to all wells. The test plate was incubated at 20*0 for 30 min before measurement of the luminescence in a microplate reader (typically Pherastar by BMG, Germany, or ViewLux by Perkin-Elmer, USA). Data were normalized (cells without inhibitor = 0% inhibition, cells with reference inhibitor = 100% inhibition). Compounds were tested in duplicates at up to 1 1 concentrations (for example 20 μΜ, 5.7 μΜ, 1.6 μΜ, 0.47 μΜ, 0.13 μΜ, 38 nM, 1 1 nM, 3.1 nM, 0.89 nM, 0.25 nM and 0.073 nM). Dilution series were made prior to the assay in a 100fold concentrated form by serial dilution. IC50 values were calculated by 4-Parameter fitting using a commercial software package (Genedata Screener, Switzerland).
To prepare the inhibitor control cell suspension, a part of prepared the cell suspension mixture was supplemented with 10 μΜ of a reference inhibitor, for the generation of above mentioned 100% inhibition reference for data normalization.
In vitro assay 6: Counterassay for the detection of off-target inhibition in MDA-MB231 cells
The cellular assay for the determination of off-target inhibition for ΙΚΚε and TBK1 was performed in DA-MB231 (ATCC, Manassas, USA) cells that stably express a constitutively active CMV-Luciferase reporter. Selective ΙΚΚε / TBK1 inhibitors are inactive, whereas inhibition of the firefly luciferase assay indicates off-target inhibition, e.g. transcriptional or translational inhibition, toxicity or inhibition of the luciferase activity. The coding sequence of the CMV promoter and luciferase gene is as follows:
1 CTCGAGATCCGGCCATTAGCCATATTATTCATTGGTTATATAGCATAAATCAATATTGGC
61 TATTGGCCATTGCATACGTTGTATCCATATCATAATATGTACATTTATATTGGCTCATGT
121 CCAACATTACCGCCATGTTGACATTGATTATTGACTAGTTATTAATAGTAATCAATTACG
181 GGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGC
241 CCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCC
301 ATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACT
361 GCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAAT
421 GACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACT
481 TGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTAC
5 1 ATCAATGGGCGTGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGAC
601 GTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAAC
661 TCCGCCCCATTGACGCAAATGGGCGGTAGGCATGTACGGTGGGAGGTCTATATAAGCAGA
721 GCTCGTTTAGTGAACCGTCAGATCGCCTGGAGACGCCATCCACGCTGTTTTGACCTCCAT
781 AGAAGACACCGGGACCGATCCAGCCTCCGCGGCCCCAAGCTTGGCAATCCGGTACTGTTG
841 GTAAAGCCACCATGGAAGATGCCAAAAACATTAAGAAGGGCCCAGCGCCATTCTACCCAC
901 TCGAAGACGGGACCGCCGGCGAGCAGCTGCACAAAGCCATGAAGCGCTACGCCCTGGTGC
961 CCGGCACCATCGCCTTTACCGACGCACATATCGAGGTGGACATTACCTACGCCGAGTACT
1021 TCGAGATGAGCGTTCGGCTGGCAGAAGCTATGAAGCGCTATGGGCTGAATACAAACCATC
1081 GGATCGTGGTGTGCAGCGAGAATAGCTTGCAGTTCTTCATGCCCGTGTTGGGTGCCCTGT
1141 TCATCGGTGTGGCTGTGGCCCCAGCTAACGACATCTACAACGAGCGCGAGCTGCTGAACA
1201 GCATGGGCATCAGCCAGCCCACCGTCGTATTCGTGAGCAAGAAAGGGCTGCAAAAGATCC
1261 TCAACGTGCAAAAGAAGCTACCGATCATACAAAAGATCATCATCATGGATAGCAAGACCG
1321 ACTACCAGGGCTTCCAAAGCATGTACACCTTCGTGACTTCCCATTTGCCACCCGGCTTCA
1381 ACGAGTACGACTTCGTGCCCGAGAGCTTCGACCGGGACAAAACCATCGCCCTGATCATGA
1441 ACAGTAGTGGCAGTACCGGATTGCCCAAGGGCGTAGCCCTACCGCACCGCACCGCTTGTG
1501 TCCGATTCAGTCATGCCCGCGACCCCATCTTCGGCAACCAGATCATCCCCGACACCGCTA 1561 TCCTCAGCGTGGTGCCATTTCACCACGGCTTCGGCATGTTCACCACGCTGGGCTACTTGA
1621 TCTGCGGCTTTCGGGTCGTGCTCATGTACCGCTTCGAGGAGGAGCTATTCTTGCGCAGCT
1681 TGCAAGACTATAAGATTCAATCTGCCCTGCTGGTGCCCACACTATTTAGCTTCTTCGCTA
1741 AGAGCACTCTCATCGACAAGTACGACCTAAGCAACTTGCACGAGATCGCCAGCGGCGGGG
1801 CGCCGCTCAGCAAGGAGGTAGGTGAGGCCGTGGCCAAACGCTTCCACCTACCAGGCATCC
1861 GCCAGGGCTACGGCCTGACAGAAACAACCAGCGCCATTCTGATCACCCCCGAAGGGGACG
1921 ACAAGCCTGGCGCAGTAGGCAAGGTGGTGCCCTTCTTCGAGGCTAAGGTGGTGGACTTGG
1981 ACACCGGTAAGACACTGGGTGTGAACCAGCGCGGCGAGCTGTGCGTCCGTGGCCCCATGA
2041 TCATGAGCGGCTACGTTAACAACCCCGAGGCTACAAACGCTCTCATCGACAAGGACGGCT
2101 GGCTGCACAGCGGCGACATCGCCTACTGGGACGAGGACGAGCACTTCTTCATCGTGGACC
2161 GGCTGAAGAGCCTGATCAAATACAAGGGCTACCAGGTAGCCCCAGCCGAACTGGAGAGCA
2221 TCCTGCTGCAACACCCCAACATCTTCGACGCCGGGGTCGCCGGCCTGCCCGACGACGATG
2281 CCGGCGAGCTGCCCGCCGCAGTCGTCGTGCTGGAACACGGTAAAACCATGACCGAGAAGG
2341 AGATCGTGGACTATGTGGCCAGCCAGGTTACAACCGCCAAGAAGCTGCGCGGTGGTGTTG
2401 TGTTCGTGGACGAGGTGCCTAAAGGACTGACCGGCAAGTTGGACGCCCGCAAGATCCGCG
2461 AGATTCTCATTAAGGCCAAGAAGGGCGGCAAGATCGCCGTGTAATAATTCTAGAACGAAG
2521 CGGCCGCAGGGTTTAAACACGGTCGACGGTACCGCGGGCCCAACATCGATAAAATAAAAG
2581 ATTTTATTTAGTCTCCAGAAAAAGGGGGGAATGAAAGACCCCACCTGTAGGTTTGGCAAG
2641 CTAGCTTAAGTAACGCCATTTTGCAAGGCATGGAAAAATACATAACTGAGAATAGAGAAG
2701 TTCAGATCAAGGTCAGGAACAGATGGAACAGCTGAATATGGGCCAAACAGGATATCTGTG
C V promoter 1-813
Luc2 852-2504 (1652bp)
The CMV-luc2-MDA-MB231 cell were cultured in DMEIW Ham's F12 (Gibco # 21041 ) supplemented with 10% fetal calf serum (typically but not exclusively used: FCS Gold Gibco- No. 10500-064), 150 pg/ml Hygromycin B, cryopreserved in 90% culture medium + 10% dimethylsulfoxide (DMSO) and stored as frozen aliquots of typically 5-10 million cells/vial at - 150Ό or below until further use.
For the assay, sufficient cells were rapidly thawed in a 37Ό water bath and pipetted into pre- warmed assay medium (DMEIW Ham's F12, 10% FCS, 2 mM L-glutamine, 1% Penicillin/Streptomycin (Biochrom AG; # A2213)). The cells were centrifuged for 5 min at 180 x g. The supernatant was removed and the cell pellet was resuspended in fresh medium to give a suspension of 0.3 million cells / ml. Poly (l:C)_HMW (InvivoGen, # tlrl-pic) was diluted in assay medium to 0.2 mg/L and subsequently mixed with the cell suspension in 1 : 1 ratio.
To prepare the inhibitor control cell suspension, a part of prepared the cell suspension mixture was supplemented with 5 μΜ of Actinomycin D (Sigma A1410).
Fifty nl of a 100-fold concentrated solution of the test compound in DMSO were transferred into a white microtiter test plate (384 or 1536, Greiner Bio-One, Frickenhausen, Germany). For this, either a Hummingbird liquid handler (Digilab, MA, USA) or an Echo acoustic system (Labcyte, CA, USA) was used. Five μΙ of a freshly prepared cell suspension was added to the wells of a test plate and incubated at 37Ό in a 5% CO 2 atmosphere. The inhibitor control cell suspension was added to empty wells at the side of the test plate. After completion of the incubation for 20-24 hours, 2.5 μΙ of Steady-Glo® Luciferase detection solution (Promega), prepared as recommended by the supplier, were added to all wells. The test plate was incubated at 20Ό for 30 min before measurement of the luminescence in a microplate reader (typically Pherastar by BMG, Germany, or ViewLux by Perkin-Elmer, USA). Data were normalized (cells without inhibitor = 0% inhibition, cells with reference inhibitor = 100% inhibition). Compounds were tested in duplicates at up to 1 1 concentrations (for example 20 μΜ, 5.7 μ , 1.6 μΜ, 0.47 μΜ, 0.13 μΜ, 38 ηΜ, 1 1 ηΜ, 3.1 ηΜ, 0.89 ηΜ, 0.25 ηΜ and 0.073 ηΜ). Dilution series were made prior to the assay in a l OOfold concentrated form by serial dilution. IC50 values were calculated by 4-Parameter fitting using a commercial software package (Genedata Screener, Switzerland).
In vitro assay 7: plRF3 cell based mechanistic assay
ΙΚΚε and TBK1 are highly homologous serine/threonine kinases which are in involved in innate anti-viral immunity and which phosphorylates Interferon regulatory factor 3. plRF3 (Ser 386) is measured in an HTRF assay (CisBio, Codolet, France). This assay is designed for the quantitative determination of phosphoSer(385/386) of human IRF3 protein. pSer(385/386) IRF3 is measured in a sandwich assay format using 2 different specific antibodies, one labelled with Cryptate (donor) and the second with d2 (acceptor). The two conjugates bind to the phosphorylated IRF3 present in the sample, thereby generating FRET. The intensity of the signal obtained is proportional to the number of antigen-antibody complexes formed and therefore the fluorescence is proportional to the concentration of the pSer(385/386) IRF3. Protocol:
The cellular assay for the determination of inhibition of ΙΚΚε and TBK1 was performed in MDA- MB231 cells (ATCC, Manassas, USA) that stably overexpress human IRF3 (human interferon regulatory factor 3 (IRF3; NM_001571 )) under the control of the CMV promoter. The coding sequence for human IRF3 (from cDNA clone pCMV6-XL4-IRF3, Origene, Rockville, MD; USA) was cloned into a lentiviral expression system containing a Hygromycin resistance gene. Derived lentiviral particles were used to generate the stable reporter cells. The clone MDA MB 231 mlRF3 #12 was selected for the assays.
The coding sequence of the CMV promoter and IRF3 gene is as follows:
ACTAGTATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTAC
GTATTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGA
TAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTG TTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACG
CAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTCGTTTAGTGAAC
CGTCAGATCGCCTGGAGACGCCATCCACGCTGTTTTGACCTCCATAGAAGATTCTAGAGC
TAGCGCTCAACTTTGTATAGAAAAGTTGACTAGTCCAGTGTGGTGGAATTCTGCAGATAT
CAACAAGTTTGTACAAAAAAGCAGGCTGCCACCATGGGAACCCCAAAGCCACGGATCCTG CCCTGGCTGGTGTCGCAGCTGGACCTGGGGCAACTGGAGGGCGTGGCCTGGGTGAACAAG AGCCGCACGCGCTTCCGCATCCCTTGGAAGCACGGCCTACGGCAGGATGCACAGCAGGAG
GATTTCGGAATCTTCCAGGCCTGGGCCGAGGCCACTGGTGCATATGTTCCCGGGAGGGAT AAGCCAGACCTGCCAACCTGGAAGAGGAATTTCCGCTCTGCCCTCAACCGCAAAGAAGGG TTGCGTTTAGCAGAGGACCGGAGCAAGGACCCTCACGACCCACATAAAATCTACGAGTTT GTGAACTCAGGAGTTGGGGACTTTTCCCAGCCAGACACCTCTCCGGACACCAATGGTGGA GGCAGTACTTCTGATACCCAGGAAGACATTCTGGATGAGTTACTGGGTAACATGGTGTTG GCCCCACTCCCAGATCCGGGACCCCCAAGCCTGGCTGTAGCCCCTGAGCCCTGCCCTCAG CCCCTGCGGAGCCCCAGCTTGGACAATCCCACTCCCTTCCCAAACCTGGGGCCCTCTGAG AACCCACTGAAGCGGCTGTTGGTGCCGGGGGAAGAGTGGGAGTTCGAGGTGACAGCCTTC TACCGGGGCCGCCAAGTCTTCCAGCAGACCATCTCCTGCCCGGAGGGCCTGCGGCTGGTG GGGTCCGAAGTGGGAGACAGGACGCTGCCTGGATGGCCAGTCACACTGCCAGACCCTGGC ATGTCCCTGACAGACAGGGGAGTGATGAGCTACGTGAGGCATGTGCTGAGCTGCCTGGGT GGGGGACTGGCTCTCTGGCGGGCCGGGCAGTGGCTCTGGGCCCAGCGGCTGGGGCACTGC CACACATACTGGGCAGTGAGCGAGGAGCTGCTCCCCAACAGCGGGCATGGGCCTGATGGC GAGGTCCCCAAGGACAAGGAAGGAGGCGTGTTTGACCTGGGGCCCTTCATTGTAGATCTG ATTACCTTCACGGAAGGAAGCGGACGCTCACCACGCTATGCCCTCTGGTTCTGTGTGGGG GAGTCATGGCCCCAGGACCAGCCGTGGACCAAGAGGCTCGTGATGGTCAAGGTTGTGCCC ACGTGCCTCAGGGCCTTGGTAGAAATGGCCCGGGTAGGGGGTGCCTCCTCCCTGGAGAAT ACTGTGGACCTGCACATTTCCAACAGCCACCCACTCTCCCTCACCTCCGACCAGTACAAG GCCTACCTGCAGGACTTGGTGGAGGGCATGGATTTCCAGGGCCCTGGGGAGAGCTGA
MDA MB 231 mlRF3 #12 cells were plated in 384well plates at 10.000 cells/well in 30 μΙ DMEM / Ham's F12 + 10% FCS per well. After ON incubation at 37 /5% C02, the medium was exchanged for phenol red-free medium. Compounds were added by HP Dispenser with compounds diluted in DMSO, maximal compound concentration was30 μΜ, then 1 :3 dilution steps, i.e. 30 μΜ, 10 μΜ, 3.3, μΜ etc, were applied using a HP D300 digital dispenser (Tecan, Germany). Normalization was done with DMSO to a final concentration of 0.6% per well. The cells were incubated for 1 h in an incubator, then poly IC was added to stimulate the cells (100 μΜ poly IC were diluted in 1000 μΙ OptiMEM (Gibco); in parallel 300 μΙ Lipofectamine 2000 (Life Technologies) were diluted in 1000 μΙ OptiMEM. Both solutions were mixed and incubated for 20 min at room temperature, then 3 μΙ per well (= 0,15μg/30μl (5pg/ml) PolylC/Lipofectamine2000) were added. The cells were incubated for another hour in an incubator, then the plate was assayed according to the manufacturer (Cisbio Bioassays, Codolet, France, item # 6FRF3PEH, IRF3 phospho-S385/386 kit): the medium was removed, then 18 μΙ of supplemented Lysis buffer #2 (1.9 ml Lysis buffer #2 (4x), + 58 μΙ Blocking Reagent, included in Kit (100x), +3.84 ml ultrapure water) were added. 16 μΙ of the lysate were transferred into a 384well small volume white plate (Greiner Bio-One, Germany), the antibodies (included in the kit) were added and the plate was sealed with foil and incubated for 3 h at room temperature. Finally the measurement was done in a Pherastar (BMG, Germany) with 2 wavelengths (665 nm und 620 nm). IC5o values were calculated by 4-Parameter fitting using a commercial software package (Genedata Screener, Switzerland). In vitro assay 8: ACHN Anti proliferation assay
Tissue cultured ACHN human kidney renal cell adenocarcinoma cells (ATCC, Manassas, USA) were plated at 300 cells/well in 50 μΙ Earle's MEM (Biochrom; # FG 0325, with stable glutamine and 10% FCS, typically but not exclusively used: FCS Gold Gibco-No. 10500-064) in 384well microtiter plates (Corning 3707 white/clear bottom, Corning, Germany). All plates were incubated ON in an incubator at 37 , 5% CO 2. The next day one plate was measured for time zero determination (using CTG solution, see below). The rest of the plates were treated with test compounds by a HP D300 digital dispenser (Tecan, Germany) with a starting concentration of 30 μΜ and subsequent 1 :3 dilution steps. The plates were incubated at 37Ό for 96h. Thereafter the plates were measured by addition of 40 ul/well CTG solution (Promega Cell Titer Glo solution (catalog number G755B and G756B)), incubation for 30 min on a shaker (Heidolph Titramax 1000, Heidolph, Germany) in the dark and afterwards luminescence was measured in a VICTOR V (Perkin Elmer). IC50 values were calculated by 4-Parameter fitting using a commercial software package (Genedata Screener, Switzerland).
In vitro assay 9: Calu-1 Antiproliferation assay
Tissue cultured Calu-1 human lung epidermoid carcinoma cells (CLS Cell Lines Services, Eppelheim, Germany) were plated at 870 cells/well in 50 μΙ McCoy's 5A (Biochrom; # F 1015 and 10% FCS, typically but not exclusively used: FCS Gold Gibco-No. 10500-064) in 384well microtiter plates (Corning 3707 white/clear bottom, Corning, Germany). All plates were incubated ON in an incubator at 37 , 5% CO 2. The next day one plate was measured for time zero determination (using CTG solution, see below). The rest of the plates were treated with test compounds by a HP D300 digital dispenser (Tecan, Germany) with a starting concentration of 30 μΜ and subsequent 1 :3 dilution steps. The plates were incubated at 37 for 96h. Thereafter the plates were measured by addition of 40 ul/well CTG solution (Promega Cell Titer Glo solution (catalog number G755B and G756B)), incubation for 30 min on a shaker (Heidolph Titramax 1000, Heidolph, Germany) in the dark and afterwards luminescence was measured in a VICTOR V (Perkin Elmer). IC50 values were calculated by 4-Parameter fitting using a commercial software package (Genedata Screener, Switzerland). Table 25: TBK1 low ATP kinase assay: IC50 values of examples in in vitro assay 1
Figure imgf001159_0001
Example 07.01 2.24E-7
Example 07.02 2.77E-7
Example 07.03 3.84E-7
Example 07.04 4.44E-7
Example 08.01 6.24E-7
Example 09.01 2.51 E-7
Example 09.02 2.97E-7
Example 09.03 3.24E-7
Example 09.04 3.52E-7
Example 10.01 2.26E-6
Example 1 1.01 3.61 E-6
> 2.00 E-5
> 2.00 E-5
Example 12.01
1.00 E-5 8.12 E-6
Example 12.02 9.24E-7
Example 12.03 5.35E-7
Example 13.01 1.25E-6
Example 13.02 1.66E-7
Example 13.03 1.90E-7
Example 14.01 1.95E-7
Example 14.02 2.83E-7
Example 14.03 5.50E-7
Example 15.01 3.39E-7
Example 15.02 4.01 E-7
Example 15.03 3.81 E-6
Example 16.01.01 2.30E-7
Example 16.01.02 1 -09E-7 Example 16.01.03 1.15E-7
Example 16.01.04 6.70E-8
Example 16.01.05 1.46E-7
Example 16.01.06 2.08E-7
Example 16.02.01 2.26E-6
Example 16.02.02 3.35E-7
Example 16.02.03 2.27E-7
Example 16.02.04 2.68E-7
Example 16.02.05 4.05E-7
Example 16.03.01 1.25E-7
Example 16.03.02 6.31 E-8
Example 16.03.03 6.70E-8
Example 16.03.04 5.46E-8
Example 16.03.05 8.47E-8
> 2.00 E-5
> 2.00 E-5
Example 16.04.01
1.40 E-6 2.61 E-6
Example 16.04.02 4.96E-7
Example 16.04.03 3.78E-7
Example 16.04.04 4.97E-7
Example 16.04.05 4.91 E-7
Example 16.05.01 8.25E-8
Example 16.05.02 3.30E-8
Example 16.05.03 4.31 E-8
Example 16.06.01. A Not determined
Example 16.06.02.A 1.05E-7
Example 16.06.02.B 1.72E-8 Example 16.06.03.A 1.38E-8
Example 17.01 9.78E-8
Example 17.02 6.49E-8
Example 17.03 5.65E-8
Example 17.04 1.02E-7
Example 17.05 3.82E-8
Example 17.06 6.13E-8
Example 17.07 1.02E-7
Example 18.01 7.24E-8
Example 18.02 1.54E-7
Example 19.01 4.14E-7
Example 20.01 6.85E-7
Example 21.01 1.93E-7
Example 22.01 4.81 E-7
Example 22.02 7.79E-7
Example 23.01.01 3.34E-8
Example 23.01.02 2.21 E-8
Example 23.02.01 2.04E-8
Example 23.02.02 1.36E-8
Example 23.03.01 1.61 E-7
Example 23.04.01 3.44E-9
Example 23.04.02 2.42E-9
Example 23.04.03 2.47E-9
Example 23.05.01. A 2.05E-9
Example 23.05.01. B 1.24E-8
Example 23.05.02.A 8.23E-9
Example 23.05.02.B 1.86E-9 Example 23.05.03.A 2.99E-9
Example 23.05.03.B 1.45E-8
Example 24.01.01 3.54E-8
Example 24.01.02 3.99E-8
Example 24.01.03 4.32E-8
Example 24.01.04 4.44E-8
Example 24.02.01 4.58E-8
Example 24.02.02 6.31 E-8
Example 24.03.01 4.78E-7
Example 24.04.01 9.19E-9
Example 24.04.02 1.61 E-8
Example 24.04.03 1.24E-8
Example 24.04.04 1.44E-8
Example 24.05.01. A 4.54E-8
Example 24.05.01. B 6.62E-9
Example 24.05.02.A 1.10E-8
Example 24.05.02.B 5.51 E-8
Example 24.05.03.A 4.54E-8
Example 24.05.03.B 1.38E-8
Example 24.05.04.A 6.67E-9
Example 24.05.04.B 3.39E-8
Example 25.01.01 1.74E-7
Example 25.01.02 2.18E-7
Example 25.01.03 9.67E-8
Example 25.01.04 7.90E-8
Example 25.01.05 6.45E-8
Example 25.02.01 3.46E-7 Example 26.01.01 3.57E-8
Example 26.01.02 8.58E-9
Example 26.01.03 1.30E-8
Example 26.01.04 1.16E-8
Example 26.01.05 1.41 E-8
Example 26.02.01 4.68E-9
Example 26.03.01. A 2.98E-9
Example 26.03.01. B 1.95E-8
Example 27.01 1.64E-7
Example 27.02 2.20E-7
Example 27.03 2.03E-7
Example 27.04 1.97E-7
Example 28.01 1.1 1 E-7
Example 29.01.01 Not determined
Example 29.01.02 3.47E-9
Example 29.02.01. A 9.23E-8
Example 29.02.01. B 8.64E-9
Example 30.01.01 1.50E-8
Example 30.01.02 1.85E-8
Example 30.01.03 1.69E-8
Example 30.01.04 1.23E-8
Example 30.02.01 4.46E-9
Example 30.02.02 7.86E-9
Example 30.02.03 3.73E-9
Example 30.02.04 9.35E-9
Example 30.03.01. A 1.80E-8
Example 30.03.01. B 2.15E-9 Example 30.03.02.A 4.15E-9
Example 30.03.02.B 2.75E-8
Example 30.03.03.A 3.06E-9
Example 30.03.03.B 1 .40E-8
Example 31.01 8.68E-8
Example 31.02 7.70E-8
Example 32.01 9.51 E-7
Example 32.02 1.17E-6
Example 32.03 5.19E-6
Example 33.01 3.54E-6
Example 33.02 1.59E-6
Example 33.03 1.50E-6
Example 33.04 2.12E-6
Example 34.01.01 5.06E-8
Example 34.02.01 1 .24E-8
Example 34.02.02 9.10E-9
Example 34.03.01. A 1.21 E-8
Example 34.03.01. B 5.01 E-8
Example 34.03.02.A 4.64E-8
Example 34.03.02.B 7.22E-9
Example 35.01.01 1.89E-8
Example 35.01.02 1.80E-8
Example 35.01.03 5.91 E-8
Example 35.01.04 2.69E-8
Example 35.01.05 4.80E-8
Example 35.01.06 4.79E-8
Example 35.01.07 7.73E-8 Example 35.01.08 2.43E-8
Example 35.01.09 4.06E-8
Example 35.01.10 3.50E-8
Example 35.01.1 1 2.86E-8
Example 35.01.12 3.24E-8
Example 35.01.13 6.09E-8
Example 35.01.14 2.28E-8
Example 35.01.15 3.80E-8
Example 35.01.16 4.59E-8
Example 35.01.17 3.92E-8
Example 35.01.18 4.18E-8
Example 35.02.01 7.67E-9
Example 35.02.02 1.15E-8
Example 35.02.03 6.29E-9
Example 35.02.04 1.04E-8
Example 35.03.01. A 3.85E-9
Example 35.03.01. B 3.00E-8
Example 35.03.02.A 8.33E-9
Example 35.03.02.B 3.28E-8
Example 35.03.03.A 5.62E-9
Example 35.03.03.B 3.17E-8
Example 35.03.04.A 8.38E-9
Example 35.03.04.B 3.45E-8
Example 36.01 Not determined
Example 36.02 1.96E-9
Example 36.03 2.13E-9
Example 36.04 2.50E-9 Example 37.01 5.53E-8
Example 37.02 6.25E-8
Example 37.03 5.27E-8
Example 37.04 7.39E-8
Example 38.01 Not determined
Example 38.02 5.04E-8
Example 38.03 5.58E-8
Example 39.01.01 Not determined
Example 39.01.02 5.89E-9
Example 39.01.03 5.35E-9
Example 39.02.01 8.61 E-9
Example 39.02.02 1.80E-9
Example 39.02.03 1.66E-9
Example 40.01 1.13E-6
Example 40.02 1.27E-6
Example 40.03 9.88E-7
Example 40.04 1.39E-6
Example 41.01 Not determined
Example 41.02 6.81 E-7
Example 41.03 7.70E-7
Example 42.01 5.77E-7
Example 42.02 3.97E-7
Example 43.01 2.62E-7
Example 43.02 1.84E-6
Example 43.03 6.96E-7
Example 44.01 9.40E-8
Example 44.02 6.68E-8 Example 44.03 8.58E-8
Example 45.01.01 3.23E-7
Example 45.01.02 3.97E-7
Example 45.01.03 2.05E-7
Example 45.02.01 1.24E-7
Example 45.02.02 3.80E-7
Example 45.03.01 3.79E-6
Example 45.03.02 1.33E-6
Example 45.04.01 2.24E-6
Example 45.05.01 1.43E-6
Example 45.05.02 1 -02E-6
Example 45.05.03 8.40E-7
Example 46.01 3.25E-8
Example 46.02 7.22E-8
Example 47.01 3.94E-7
Example 47.02 5.04E-7
Example 48.01 1.93E-7
Example 49.01 2.17E-7
Example 50.01 4.99E-7
Example 50.02 3.33E-7
Example 50.03 6.45E-7
Example 51.01 1.48E-7
Example 51.02 2.70E-7
Example 51 .03 1.13E-7
Example 51 .04 2.03E-7
Example 52.01 6.47E-8
Example 52.02 3.69E-8 Example 53.01 1.32E-7
Example 53.02 1.21 E-7
Example 54.01 2.43E-7
Example 54.02 2.29E-7
Example 55.01 4.05E-9
Example 55.02 1.06E-9
Example 55.03 5.64E-10
Example 56.01 1.65E-8
Example 56.02 2.63E-9
Example 57.01 7.83E-9
Example 58.01.01 1.28E-8
Example 58.01.02 9.81 E-9
Example 58.01.03 6.44E-9
Example 59.01.01 1.42E-8
Example 59.01.02 1.88E-9
Example 59.01.03 2.59E-9
Example 59.02.01 7.56E-9
Example 59.02.02 6.71 E-9
Example 60.01 4.30E-8
Example 61.01.01 1.97E-8
Example 61.01.02 2.30E-8
Example 62.01.01 5.73E-8
Example 62.01.02 9.54E-9
Example 62.01.03 3.38E-9
Example 62.01.04 5.19E-9
Example 63.01.01 3.64E-8
Example 64.01.01 2.17E-7 Example 64.01.02 3.37E-8
Example 64.01.03 4.70E-8
Example 65.01.01 2.55E-7
Example 65.01.02 5.84E-8
Example 66.01.01 3.33E-8
Example 66.01.02 3.30E-8
Example 55.01.01 5.5E-9
Example 55.01.02 4.8E-9
Example 55.02.01 7.2E-10
Example 55.02.02 1.3E-9
Example 55.03.01 6.1 E-10
Example 55.03.02 6.6E-10
Example 67.01 4.6E-8
Example 67.02 2.9E-9
Example 67.03 2.0E-9
Example 68.01 2.6E-8
Example 68.02 1.5E-9
Example 69.01 1.2E-8
Example 69.02 6.4E-10
Example 70.01 8.8E-10
Example 70.02 7.3E-10
Example 71.01 1.0E-7
Example 71.02 7.1 E-9
Example 72.01 8.0E-7
Example 72.02 2.5E-7
Example 72.03 1.0E-7
Example 73.01 6.7E-8 Example 74.01 1.2E-7
Example 74.02 1.9E-8
Example 75.01 2.0E-8
Example 75.02 1.4E-9
Example 75.03 8.8E-10
Example 76.01 3.2E-9
Example 76.02 9.4E-9
Example 77.01 9.2E-9
Example 78.01 2.2E-8
Example 78.02 1.5E-8
Example 79.01 8.3E-9
Example 79.02 4.8E-9
Example 79.03 3.3E-9
Example 80.01 3.3E-8
Example 80.02 4.5E-9
Example 80.03 2.9E-9
Example 81.01 1.3E-8
Example 82.01 3.6E-9
Example 83.01 1.4E-8
Example 83.02 1.0E-8
Example 83.03 2.2E-9
Example 83.04 1.5E-9
Example 83.05 2.9E-9
Example 84.01 1.1 E-9
Example 84.02 7.0E-10
Example 84.03 1.7E-9
Example 85.01 5.7E-9 Example 85.02 1.4E-8
Example 85.03 1.8E-9
Example 86.01 1.1 E-8
Example 86.02 2.1 E-9
Example 86.03 1.5E-9
Example 87.01 2.3E-9
Example 87.02 2.0E-9
Example 88.01 1.1 E-5
Example 88.02 8.6E-7
Example 88.03 9.9E-7
Example 89.01 6.1 E-7
Example 89.02 4.5E-7
Example 89.03 3.2E-7
Example 90.01 5.7E-9
Example 90.02 1.1 E-8
Example 91.01 1.7E-8
Example 91 .02 1.2E-8
Example 91.03 1.3E-8
Example 92.01 8.8E-8
Example 92.02 4.5E-7
Example 93.01 2.3E-9
Example 94.01 7.2E-9
Example 95.01 6.6E-9
Example 95.02 9.5E-9
Example 96.01 4.6E-8
Example 96.02 2.2E-8
Example 97.01 2.1 E-8 Example 97.02 1.8E-8
Example 97.03 2.9E-8
Example 98.01 1.0E-7
Example 98.02 4.4E-8
Example 98.03 7.6E-8
Example 99.01 3.3E-8
Compound 95.01 3.9E-8
Example 100.03 2.0E-9
Example 100.01 1.5E-9
Example 101.01 6.8E-7
Example 101.02 6.8E-7
Example 101.03 6.9E-7
Example 101.04 3.0E-6
Example 101.05 7.8E-7
Example 101.06 9.9E-7
Example 101.07 1.7E-7
Example 101.08 > 2.0E-5
Example 101.09 4.6E-7
Example 101.10 1.8E-7
Example 101.1 1 > 2.0E-5
Example 101.12 4.5E-7
Example 101.13 3.6E-7
Example 101.14 4.3E-7
Example 101.15 2.1 E-7
Example 101.16 1.9E-7
Example 101.17 1.5E-7
Example 101.18 1.5E-6 Example 101.19 3.4E-7
Example 101.20 5.6E-7
Example 101.21 > 5.7 E-5
Example 101.22 Not determined
Example 101.23 2.8E-7
Example 101.24 1.6E-7
Example 101.26 3.1 E-7
Example 101.27 3.5E-7
Example 101.28 2.1 E-7
Example 101.29 4.5E-7
Example 101.30 5.6E-7
Example 101.31 5.1 E-7
Example 102.01 7.1 E-7
Example 103.01 3.6E-7
Example 104.01 2.6E-6
Example 105.01 2.7E-7
Example 106.01 1.5E-6
Compound 60.01 1.1 E-7
Example 107.01.01 5.2E-8
Example 107.01.02 1.6E-8
Example 107.01.03 1.3E-8
Example 107.02.01 2.1 E-8
Example 107.02.02 5.9E-9
Example 107.02.03 5.4E-9
Example 107.02.04 5.2E-9
Example 108.01 3.5E-8
Example 108.02 8.2E-9 Example 108.03 8.9E-9
Example 109.01.01 9.2E-9
Example 109.01.02 5.4E-9
Example 109.01.03 8.7E-9
Example 109.02.01 8.0E-9
Example 109.02.02 2.0E-9
Example 109.02.03 2.4E-9
Example 110.01 Not determined
Example 110.02 3.0E-8
Example 110.03 5.2E-8
Example 110.04 6.2E-8
Example 111.01 2.6E-9
Example 111.02 1.0E-9
Example 111.03 1.4E-9
Example 112.01 8.2E-9
Example 112.02 1.3E-9
Example 1 2.03 1.4E-9
Example 113.01 6.1E-9
Example 113.02 1.6E-9
Example 113.03 1.1 E-9
Example 114.01 6.1 E-8
Example 115.01 1.4E-9
Example 115.02 7.6E-10
Example 1 5.03 6.2E-10
Example 116.02 7.6E-10
Example 116.03 1.3E-9
Example 116.04 1.0E-9 Example 1 17.01 2.0E-9
Example 1 17.02 3.3E-10
Example 1 17.03 4.9E-10
Example 1 18.01 7.9E-9
Example 1 18.02 3.3E-9
Example 1 18.03 1.4E-9
Example 1 18.04 2.6E-9
Example 1 19.01 Not determined
Example 120.02 1.7E-8
Example 121.01 1.1 E-8
Example 121.02 2.5E-9
Example 121.03 1.6E-9
Example 122.01 9.3E-9
Example 122.02 1.2E-9
Example 122.03 1.1 E-9
Example 123.01 3.6E-8
Example 123.02 3.5E-8
Example 123.03 2.6E-8
Example 124.02 1.0E-7
Example 125.02 6.5E-7
Example 126.02 3.9E-9
Example 130.01 8.9E-7
Example 130.02 1.9E-7
Example 130.03 2.5E-7
Example 131.01 1.4E-7
Example 131.02 6.2E-8
Example 131.03 3.2E-8 Example 132.01 1.8E-7
Example 132.02 1.9E-7
Example 132.03 2.6E-7
Example 133.01 2.8E-7
Example 133.02 1.4E-7
Example 134.01 5.7E-8
Example 134.02 1.1 E-8
Example 134.03 1.9E-8
Example 135.01 7.1 E-8
Example 135.02 2.3E-8
Example 135.03 3.0E-8
Example 136.01 5.3E-8
Example 136.02 3.8E-8
Example 136.03 2.1 E-8
Example 137.01 1.3E-8
Example 137.02 5.8E-9
Example 137.03 2.0E-8
Example 138.01 5.8E-9
Example 138.02 4.1 E-9
Example 138.03 4.3E-9
Example 139.01 5.5E-8
Example 139.02 1.5E-8
Example 139.03 9.7E-9
Example 140.01 1.3E-8
Example 140.02 5.4E-7
Example 140.03 2.9E-7
Example 141.01 4.3E-8 Example 141.02 1.9E-8
Example 141.03 1.3E-8
Example 142.01 7.5E-9
Example 142.02 6.6E-9
Example 142.03 3.0E-9
Example 143.01 1.8E-8
Example 143.02 8.2E-9
Example 143.03 4.8E-9
Example 144.01 5.1 E-7
Example 144.02 3.5E-7
Example 144.03 4.4E-7
Example 145.01 1.3E-8
Example 145.02 2.9E-9
Example 145.03 2.1 E-9
Example 146.01 1.4E-8
Example 146.02 9.8E-9
Example 147.01 Not determined
Example 147.02 1.8E-9
Example 148.01 2.5E-8
Example 148.02 6.5E-9
Example 148.03 4.8E-9
Example 149.01 4.7E-9
Example 149.02 2.0E-9
Example 149.03 2.3E-9
Example 150.01 1.5E-8
Example 150.02 9.6E-9
Example 150.03 5.4E-9 Example 151.02 2.1 E-9
Example 151.03 1.0E-9
Example 152.02 4.8E-10
Example 152.03 9.6E-10
Example 153.01 1.4E-8
Example 153.02 5.9E-9
Example 153.03 5.0E-9
Example 154.01 4.2E-9
Example 154.02 3.3E-9
Example 154.03 1.4E-9
Example 155.01 3.6E-8
Example 155.02 1.5E-8
Example 155.03 1.7E-8
Example 156.01 3.8E-8
Example 156.02 9.3E-9
Example 156.03 1.9E-8
Example 157.01 2.5E-8
Example 157.02 8.9E-9
Example 157.03 7.6E-9
Example 158.01 1.6E-7
Example 158.02 2.1 E-8
Example 158.03 1.3E-8
Example 159.01 3.1 E-7
Example 159.02 1.5E-8
Example 160.01 6.4E-8
Example 160.02 1.3E-8
Example 160.03 8.5E-9 Example 161.01 Not determined
Example 161.02 7.7E-9
Example 161.03 6.7E-9
Example 162.02 2.0E-8
Example 163.02 1.9E-8
Example 163.03 1.8E-8
Example 04.07 1.00E-8
Example 04.08 1.38E-8
Example 04.09 2.85E-8
Example 04.10 2.83E-8
Example 16.06.04 2.17E-8
Example 16.06.05 1.81 E-8
Example 16.06.06 7.30E-8
Example 1 14.02 8.27E-9
Example 1 4.03 8.07E-9
Example 1 17.04 8.19E-10
Example 1 17.05 4.73E-10
Example 1 17.06 8.60E-10
Example 1 17.07 2.70E-9
Example 19.02 6.69E-9
Example 1 19.03 5.93E-9
Example 1 19.04 1.09E-8
Example 1 19.05 6.35E-9
Example 164.01 5.48E-9
Example 164.02 9.43E-10
Example 164.03 5.58E-10
Example 164.04 8.32E-10 Example 164.05 5.66E-10
Example 165.01 Not determined
Example 165.02 1.71 E-9
Example 165.03 1.79E-9
Example 166.01 3.00E-7
Example 166.02 2.05E-8
Example 166.03 2.1 1 E-8
Example 166.04 5.42E-8
Example 166.05 3.42E-8
Example 167.01 2.22E-7
Example 167.02 3.50E-8
Example 167.03 4.13E-8
Example 167.04 2.37E-8
Example 168.01 Not determined
Example 168.02 4.18E-9
Example 168.03 7.12E-9
Example 169.01 Not determined
Example 169.02 1.16E-8
Example 169.03 1.66E-8
Example 170.01 Not determined
Example 170.02 5.21 E-9
Example 171.01 Not determined
Example 171.02 5.95E-9
Example 171.03 2.85E-9
Example 172.01 3.98E-8
Example 172.02 1.21 E-8
Example 172.03 1.50E-8 Example 172.04 2.09E-8
Example 173.01 3.96E-7
Example 173.02 7.71 E-8
Example 173.03 5.06E-8
Example 173.04 1.49E-7
Example 174.01 1.1 1 E-8
Example 174.02 3.63 E-9
Example 174.03 3.26 E-9
Example 175.01 Not determined
Example 175.02 3.53 E-7
Example 175.03 2.23 E-7
Example 176.01 Not determined
Example 176.02 3.58 E-6
Example 177.01 2.27 E-7
Example 177.02 7.45 E-8
Example 178.01 8.90 E-7
Example 178.02 4.02 E-7
Example 179.01 3.01 E-6
Example 179.02 1.14 E-6
Example 179.03 1.26 E-6
Example 180.01 5.76 E-7
Example 180.02 5.56 E-7
Example 180.03 3.64 E-7
Example 181.01 7.91 E-7
Example 181.02 1 .52 E-7
Example 181.03 3.62 E-7
Example 182.01 2.75 E-7 Example 182.02 1.10 E-7
Example 182.03 1.36 E-7
Example 183.01 7.28 E-6
Example 183.02 2.10 E-6
Example 183.03 2.24 E-6
Example 184.01 Not determined
Example 184.02 2.01 E-7
Example 184.03 2.16 E-7
Example 185.01 2.12 E-7
Example 186.01 5.91 E-8
Example 187.01 Not determined
Example 188.01 Not determined
Example 189.01 Not determined
Example 189.02 2.86 E-8
Example 190.01 Not determined
Example 190.02 8.68 E-7
Example 191.01 Not determined
Example 191.02 9.53 E-8
Example 191.03 9.48 E-8
Example 192.01 Not determined
Example 192.02 1 .83 E-8
Example 192.03 8.30 E-9
Example 193.01 4.21 E-8
Example 193.02 3.46 E-8
Example 193.03 1.78 E-8
Example 194.01 Not determined
Example 194.02 4.59 E-8 Example 194.03 4.94 E-8
Example 195.01 1.05 E-7
Example 195.02 3.37 E-8
Example 195.03 3.41 E-8
Example 196.01 1.53 E-6
Example 196.02 1.83 E-6
Example 196.03 1.42 E-6
Example 197.01 Not determined
Example 198.01 4.38 E-8
Example 199.01 Not determined
Example 199.02 4.19 E-8
Example 197.04 6.46 E-9

Claims

A compound of general formula (I):
Figure imgf001185_0001
(I),
in which :
R1 represents a group selected from
pyrazolyl, imidazolyl, oxadiazolyl, triazolyl, isoxazolyl, thienyl, pyridin-2-yl, pyridin-4-yl, pyrimidinyl, triazinyl and pyrazinyl, said group being optionally substituted with one R6 group, and said group being, additionally, optionally substituted one or two times, differently or identically, with a R7 group,
or
R1 represents a group selected from
Figure imgf001185_0002
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group,
in which "*" represents the point of attachment to the rest of the molecule,
or
R1 represents a group selected from pyridine-3-yl or pyridazin-3-yl, optionally substituted with one R8 group; represents a group selected from
Figure imgf001186_0001
in which "*" represents the point of attachment to the rest of the molecule;
R3 represents a hydrogen atom or a halogen atom or a group selected from Ci-C4-alkyl and Ci-C6-alkoxy;
R4 represents a hydrogen atom or a halogen atom or a group selected from Ci-C4-alkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy and Ci-C4-haloalkoxy;
R5 represents a hydrogen atom or a halogen atom or a group selected from Ci-C4-alkyl, Ci-C4-haloalkyl and C3-C6-cycloalkyl; represents a hydrogen atom or a group selected from Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-Ce-hydroxyalkyl, (Ci-C3-alkoxy)-(Ci-C3-alkyl)-, C3-C6-cycloalkyl and (C3-C6- cycloalkyl)-(Ci-C3-alkyl)-,
said C3-C6-cycloalkyl and said (C3-C6-cycloalkyl)-(Ci-C3-alkyl)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or with a group selected from Ci-C3-alkyl and Ci- C3-haloalkyl;
represents a halogen atom or a group selected from hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-hydroxyalkyl, (Ci-C3-alkoxy)-(Ci-C3-alkyl)-, (Ci-C3-haloalkoxy)-(Ci-C3-alkyl)-, C2-C6-alkenyl, C2-C6-alkynyl, C3-C8-cycloalkyl, C4-C8- cycloalkenyl, (C3-C8-cycloalkyl)-(Ci-C3-alkyl)-, (phenyl)-Ci-C3-alkyl-, 4- to 7-membered heterocycloalkyi, 5- to 7-membered heterocycloalkenyl, heterospirocycloalkyi, phenyl, heteroaryl, -CN, -(CH2)x-N(R11)R11a, -C(=0)R13, -C(=0)-OR13, -C(=0)-N(R11)R 1a, -N(R11)R11a, -N(R16)-C(=0)-R13, -N(R16)-S(=0)2-R13, -N(R16)-C(=0)-N(R11)R11a, -N(R16)- C(=0)-OR13, Ci-C6-alkoxy, Ci-C6-haloalkoxy, C3-C8-cycloalkoxy-, (C3-C8-cycloalkyl)- (Ci-C3-alkoxy)-, phenyloxy-, heteroaryloxy-, -0-(CH2)x-phenyl, -0-(CH2)x-heteroaryl, -0-C(=0)-R13, -0-C(=0)-N(R11)R11a, Ci-C6-alkylsulfanyl, Ci-Ce-haloalkylsulfanyl, - S(=0)-R13, -S(=0)2-R13, -S(=0)2-N(R1 )R 1a and -S(=0)(=NR17)R13,
said C3-C8-cycloalkyl, said (C3-C8-cycloalkyl)-(Ci-C3-alkyl)- and said (C3-C8- cycloalkyl)-(Ci-C3-alkoxy)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or with a group selected from Ci-C3-alkyl and Ci-C3-haloalkyl,
said 4- to 7-membered heterocycloalkyi, said 5- to 7-membered heterocycloalkenyl and said heterospirocycloalkyi group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or with a group selected from oxo, Ci-C3-alkyl and Ci-C3- haloalkyl, and
said heteroaryl group and said phenyl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from -CN, Ci-C3-alkyl, trifluoromethyl, Ci-C3-alkoxy and trifluoromethoxy; and R7, or two R7 groups, when being attached to adjacent ring atoms of the group R1, together form a group selected from:
-(O-CHz-O)-, -(0-(CH2)2-0)-, -(0-(CH2)2)-, -(CH2-0-CH2)-, -(NR 6-(CH2)2-0)-, -(NR16-(CH2)3-0)-, -(S-(CH2)2)-, -(0-(CH2)3)-, -((CH2)3)-, -((CH2)4)-, -(0-CH=CH)-, -(S-CH=CH)-; R8 represents a hydrogen atom or a group selected from methyl, ethyl, methoxy, ethoxy and dimethylamino;
R9 represents a hydrogen atom or a -CN or Ci-C3-alkyl group;
R10 represents a group selected from -C(=0)R12, -C(=0)OR13, -C(=0)N(R14)R14a, -S(=0)2R15, -S(=0)2N(R14)R14a, 5- to 6-membered heteroaryl and phenyl,
said 5- to 6-membered heteroaryl group and said phenyl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from -CN, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy and Ci- C3-haloalkoxy;
R11 and R11a, independently from each other, represent a hydrogen atom or a group selected from Ci-C4-alkyl, Ci-C4-haloalkyl, C3-C6-cycloalkyl, Ci-C6-hydroxyalkyl, (Ci-C3-alkoxy)- (Ci-C3-alkyl)-, (C3-C6-cycloalkyl)-(Ci-C3-alkyl)- and benzyl,
or
R11 and R11a, together with the nitrogen atom they are attached to, represent a 4- to 7- membered heterocycloalkyi group, said group being optionally substituted one or two times, identically or differently, with a halogen atom, or a group selected from hydroxy, oxo, -CN, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy, -C(=0)R18, -C(=0)OR18 and -S(=0)2R18;
R12 represents a hydrogen atom or a group selected from Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-Ce-hydroxyalkyl, (Ci-C3-alkoxy)-(Ci-C3-alkyl)-, C3-C6-cycloalkyl, (C3-C6-cycloalkyl)- (Ci-C3-alkyl)-, C2-C6-alkenyl, C2-C6-alkynyl, 4- to 7-membered heterocycloalkyi, 5- to 7-membered heterocycloalkenyl, 5- to 6-membered heteroaryl and phenyl,
said 5- to 6-membered heteroaryl group and said phenyl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from -CN, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy and Ci-C3-haloalkoxy,
said C3-C6-cycloalkyl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from -CN, Ci- C3-alkyl and Ci-C3-haloalkyl;
R 3 represents a group selected from Ci-C4-alkyl and benzyl;
R14 and R14a, independently from each other, represent a hydrogen atom or a group selected from Ci-C4-alkyl, Ci-C4-haloalkyl, C3-C6-cycloalkyl and benzyl, or
R14 and R14a, together with the nitrogen atom they are attached to, represent a 4- to 7- membered heterocycloalkyi group, said group being optionally substituted one or two times, identically or differently, with a halogen atom or a group selected from hydroxyl, -CN, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy, Ci-C3-haloalkoxy and (Ci-C3-alkoxy)-
(Ci-C3-alkyl)-;
R15 represents a group selected from Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-hydroxyalkyl, (Ci- C3-alkoxy)-(Ci-C6-alkyl)-, (Ci-C3-alkoxy)-(C2-C3-alkoxy)-(Ci-C6-alkyl)-, C3-C6-cycloalkyl, (C3-C6-cycloalkyl)-(Ci-C3-alkyl)-, 4- to 7-membered heterocycloalkyi, 5- to 6-membered heteroaryl and phenyl,
said 5- to 6-membered heteroaryl group and said phenyl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from -CN, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy and Ci-C3-haloalkoxy;
R16 represents a hydrogen atom or a group selected from Ci-C4-alkyl and benzyl;
R17 represents a hydrogen atom or a group selected from -CN, -C(=0)OR13, Ci-C4-alkyl and benzyl;
R18 represents a Ci-C3-alkyl group;
x represents an integer selected from 1 , 2, 3 and 4,
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
2. The compound according to claim 1 , wherein
R1 represents a group selected from
Figure imgf001190_0001
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group,
or
R1 represents a group selected from
Figure imgf001190_0002
in which "*" represents the point of attachment to the rest of the molecule;
R2 represents a group selected from
Figure imgf001191_0001
in which "*" represents the point of attachment to the rest of the molecule;
R3 represents a hydrogen atom or a halogen atom or a group selected from Ci-C4-alkyl and Ci-C4-alkoxy;
R4 represents a hydrogen atom or a group selected from Ci-C3-alkyl and Ci-C3-fluoroalkyl; R5 represents a hydrogen atom or a bromine atom;
R6 represents a hydrogen atom or a group selected from Ci-C6-alkyl, Ci-C4-fluoroalkyl, Ci-C4-hydroxyalkyl, (Ci-C2-alkoxy)-(Ci-C3-alkyl)-, C3-C5-cycloalkyl and (C3-C5-cycloalkyl)-(methyl)-,
said C3-C5-cycloalkyl and said (C3-C5-cycloalkyl)-(methyl)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or with a group selected from methyl and trifluoromethyl;
R7 represents a halogen atom or a group selected from hydroxy, Ci-C6-alkyl, C1-C4- fluoroalkyl, Ci-C4-hydroxyalkyl, (Ci-C2-alkoxy)-(Ci-C3-alkyl)-, (Ci-C2-fluoroalkoxy)-(Ci- C3-alkyl)-, C3-C4-cycloalkyl, (C3-C4-cycloalkyl)-(methyl)-, (phenyl)-(Ci-C3-alkyl)-, 4- to 7- membered heterocycloalkyl, heterospirocycloalkyl, 5-to 6-membered heteroaryl, -CN, -
(CH2)x-N(R11)R11a, -C(=0)R13, -C(=0)-N(R 1)R 1a, -N(R11)R 1a, Ci-C6-alkoxy, C1-C4- fluoroalkoxy, (C3-C4-cycloalkyl)-(methoxy)-, Ci-C4-alkylsulfanyl, S(=0)-R13 and -S(=0)2- R13,
said C3-C4-cycloalkyl, said (C3-C4-cycloalkyl)-(methyl)- and said (C3-C4- cycloalkyl)-(methoxy)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom or with a group selected from methyl and trifluoromethyl,
said 4- to 7-membered heterocycloalkyi and said heterospirocycloalkyl group being optionally substituted one, two or three times, identically or differently, with a fluorine atom or with a group selected from oxo, methyl and trifluoromethyl, and said 5- to 6-membered heteroaryl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from methyl, trifluoromethyl and methoxy;
or
R6 and R7, or two R7 groups, when being attached to adjacent ring atoms of the group R1, together form a group selected from:
-(O-CHz-O)-, -(0-(CH2)2-0)-, -(0-(CH2)2)-, -(CH2-0-CH2)-, -(NR16-(CH2)2-0)-, -((CH2)3)-, -((CH2)4)-, -(0-CH=CH)-, -(S-CH=CH)-;
R8 represents a hydrogen atom or a group selected from methoxy and ethoxy;
R9 represents a hydrogen atom or a methyl or ethyl group;
R10 represents a group selected from -C(=0)R12, -C(=0)OR13, -C(=0)N(R14)R14a, -S(=0)2R15, -S(=0)2N(R14)R14a, 5- to 6-membered heteroaryl and phenyl,
said 5- to 6-membered heteroaryl group and said phenyl group being optionally substituted one or two times, identically or differently, with a fluorine atom, chlorine atom or bromine atom, or a group selected from -CN, methyl, trifluoromethyl and methoxy;
R11 and R11a, independently from each other, represent a hydrogen atom or a group selected from Ci-C4-alkyl, Ci-C4-fluoroalkyl, C3-C4-cycloalkyl, Ci-C4-hydroxyalkyl, (Ci-C2-alkoxy)- (Ci-C3-alkyl)-, (C3-C4-cycloalkyl)-(methyl)- and benzyl,
or
R11 and R11a, together with the nitrogen atom they are attached to, represent a 4- to 6- membered heterocycloalkyi group, said group being optionally substituted one or two times, identically or differently, with a fluorine atom, or a group selected from hydroxy, oxo, -CN, methyl, trifluoromethyl and methoxy;
R12 represents a hydrogen atom or a group selected from Ci-C4-alkyl, Ci-C4-fluoroalkyl, Ci-C4-hydroxyalkyl, (Ci-C2-alkoxy)-(Ci-C3-alkyl)-, C3-C6-cycloalkyl, (C3-C6-cycloalkyl)- (Ci-C2-alkyl)-, C2-C4-alkenyl, 5- to 6-membered heteroaryl and phenyl, said 5- to 6-membered heteroaryl group and said phenyl group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or a group selected from methyl, trifluormethyl and methoxy, said C3-C6-cycloalkyl group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or a group selected from -CN, methyl and trifluoromethyl;
R13 represents a group selected from Ci-C4-alkyl and benzyl;
R14 and R14a, independently from each other, represent a hydrogen atom or a group selected from Ci-C3-alkyl, trifluoromethyl and cyclopropyl,
or
R14 and R14a, together with the nitrogen atom they are attached to, represent a 4- to 7- membered heterocycloalkyi group, said group being optionally substituted one or two times, identically or differently, with a group selected from Ci-C3-alkyl, Ci-C3-fluoroalkyl, Ci-C3-alkoxy, trifluoromethoxy and (Ci-C2-alkoxy)-(Ci-C2-alkyl)-;
R15 represents a group selected from Ci-C4-alkyl, Ci-C4-fluoroalkyl, (Ci-C2-alkoxy)-(Ci-C3- alkyl)-, (Ci-C2-alkoxy)-(ethoxy)-(Ci-C3-alkyl)-, C3-C6-cycloalkyl, (C3-C6-cycloalkyl)-(Ci- C2-alkyl)- and 4- to 7-membered heterocycloalkyi;
R16 represents a hydrogen atom or a Ci-C3-alkyl group;
x represents an integer selected from 1 and 2,
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
The compound according to claim 1 or 2, wherein
represents a group selected from
Figure imgf001194_0001
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group,
or
R1 represents a group selected from
Figure imgf001194_0002
in which "*" represents the point of attachment to the rest of the molecule; represents a group selected from
Figure imgf001194_0003
in which "*" represents the point of attachment to the rest of the molecule; R3 represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom or a group selected from methyl, ethoxy and iso-butoxy;
R4 represents a hydrogen atom or a group selected from methyl and trifluoromethyl;
R5 represents a hydrogen atom;
R6 represents a hydrogen atom or a group selected from Ci-C6-alkyl, Ci-C4-fluoroalkyl, Ci-C4-hydroxyalkyl, (methoxy)-(Ci-C3-alkyl)-, C3-Cs-cycloalkyl and (C3-C5-cycloalkyl)-(methyl)-,
said C3-C5-cycloalkyl and said (C3-C5-cycloalkyl)-(methyl)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or with a methyl group;
R7 represents a halogen atom or a group selected from Ci-C6-alkyl, Ci-C4-fluoroalkyl, Ci- C4-hydroxyalkyl, (Ci-C2-alkoxy)-(Ci-C3-alkyl)-, C3-C4-cycloalkyl, (C3-C4-cycloalkyl)- (methyl)-, (phenyl)-(Ci-C3-alkyl)-, 4- to 7-membered heterocycloalkyl, heterospirocycloalkyl, -CN, -(CH2)x-N(R11 )R11a, -C(=0)R13, -C(=0)-N(R11)R11a, -N(R11 )R11a, Ci-C6-alkoxy, Ci-C4-fluoroalkoxy and (C3-C4-cycloalkyl)-(methoxy)-,
said C3-C4-cycloalkyl, said (C3-C4-cycloalkyl)-(methyl)- and said (C3-C4- cycloalkyl)-(methoxy)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom or with a group selected from methyl and trifluoromethyl, and
said 4- to 7-membered heterocycloalkyl and said heterospirocycloalkyl group being optionally substituted one, two or three times, identically or differently, with a fluorine atom or with a group selected from methyl and trifluoromethyl, or
R6 and R7, or two R7 groups, when being attached to adjacent ring atoms of the group R1 , together form a group selected from -(0-CH=CH)- and -(NR16-(CH2)2-0)-;
R8 represents a hydrogen atom or a methoxy group;
R9 represents a hydrogen atom or a methyl group;
R10 represents a group selected from -C(=0)R12, -C(=0)N(R14)R14a, -S(=0)2R15 and -S(=0)2N(R14)R14a;
R11 and R11a, independently from each other, represent a hydrogen atom or a group selected from Ci-C3-alkyl, Ci-C3-fluoroalkyl, C3-C4-cycloalkyl, Ci-C3-hydroxyalkyl, (Ci-C2-alkoxy)- (Ci-C3-alkyl)-, (C3-C4-cycloalkyl)-(methyl)- and benzyl,
or R11 and R11a, together with the nitrogen atom they are attached to, represent a 4- to 6- membered heterocycloalkyl group, said group being optionally substituted one or two times, identically or differently, with a fluorine atom or a group selected from methyl and trifluoromethyl;
R12 represents a group selected from Ci-C4-alkyl, Ci-C3-fluoroalkyl, Ci-C3-hydroxyalkyl, (methoxy)-(Ci-C3-alkyl)-, C3-C4-cycloalkyl, (cyclopropyl)-(methyl)- and allyl,
said C3-C4-cycloalkyl group being optionally substituted one, two or three times, identically or differently, with a fluorine atom or a group selected from methyl and trifluoromethyl;
R13 represents a Ci-C3-alkyl group;
R14 and R14a, independently from each other, represent a hydrogen atom or a group selected from methyl and ethyl,
or
R14 and R14a, together with the nitrogen atom they are attached to, represent a 5- to 6- membered heterocycloalkyl group selected from pyrrolidinyl, piperidinyl and morpholinyl, said group being optionally substituted one or two times, identically or differently, with a group selected from methyl, methoxy and (methoxy)-(methyl)-;
R15 represents a group selected from ethyl, 3,3,3-trifluoropropyl, (3-methoxy)-(propyl)-, (2'- methoxy)-(2-ethoxy)-(ethyl)-, cyclopropyl, cyclohexyl and tetrahydropyranyl;
R16 represents a hydrogen atom or a Ci-C2-alkyl group;
x represents an integer 1 ,
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
The compound according to claim 1 , 2 or 3, wherein
represents a group selected from
Figure imgf001197_0001
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group;
R2 represents a group
Figure imgf001197_0002
in which "*" represents the point of attachment to the rest of the molecule;
represents a hydrogen atom, a fluorine atom or a chlorine atom;
represents a hydrogen atom or a methyl group;
represents a hydrogen atom;
represents a group selected from methyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl and (C3-C5-cycloalkyl)-(methyl)-,
said (C3-C5-cycloalkyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom, a chlorine atom or with a methyl group;
represents a group selected from Ci-C3-alkyl, difluoromethyl, trifluoromethyl, (methoxy)-(methyl)-, cyclopropyl, -NR11R11a, d-C3-alkoxy, Ci-C3-fluoroalkoxy, (C3-C4- cycloalkyl)-(methoxy)- and [1-(trifluoromethyl)cyclopropyl]-(methoxy)-; R6 and R7, or two R7 groups, when being attached to adjacent ring atoms of the group R1, together form a group selected from -(0-CH=CH)- and -(NR16-(CH2)2-0)-;
R9 represents a hydrogen atom or a methyl group;
R10 represents a group selected from -C(=0)R12, -C(=0)N(R14)R14a, -S(=0)2R15 and -S(=0)2N(R14)R14a;
R11 and R11a, independently from each other, represent a hydrogen atom or a group selected from Ci-C3-alkyl, 2,2,2-trifluoroethyl, C3-C4-cycloalkyl, (Ci-C2-alkoxy)-(Ci-C3-alkyl)- and (C3-C4-cycloalkyl)-(methyl)-,
or
R11 and R11a, together with the nitrogen atom they are attached to, represent a 4- to 6- membered heterocycloalkyl group, said group being optionally substituted one or two times with a fluorine atom or a trifluoromethyl group;
R12 represents a group selected from Ci-C2-fluoroalkyl, C3-C4-cycloalkyl, 2-hydroxyprop-2- yl, (2-methoxy)-(prop-2-yl)-, (l -trifluoromethyl)-(cyclopropyl)-, 2,2-difluorocyclopropyl, 2,2-difluoro-1 -methylcyclopropyl and (cyclopropyl)-(methyl)-;
R14 and R 4a, independently from each other, represent a group selected from methyl and ethyl,
or
R14 and R14a, together with the nitrogen atom they are attached to, represent a 5- to 6- membered heterocycloalkyl group selected from pyrrolidinyl, piperidinyl and morpholinyl, said group being optionally substituted one or two times, identically or differently, with a group selected from methyl, methoxy and (methoxy)-(methyl)-;
R15 represents a group selected from ethyl, 3,3,3-trifluoropropyl, (3-methoxy)-(propyl)-, (2'- methoxy)-(2-ethoxy)-(ethyl)-, cyclopropyl, cyclohexyl and tetrahydropyranyl;
R16 represents a hydrogen atom or a methyl group,
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. The compound according to claim 1 , 2, 3 or 4, wherein
represents a group selected from
Figure imgf001199_0001
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group; represents a group
Figure imgf001199_0002
in which "*" represents the point of attachment to the rest of the molecule;
R3 represents a hydrogen atom, a fluorine atom or a chlorine atom;
R4 represents a hydrogen atom;
R5 represents a hydrogen atom;
R6 represents a group selected from methyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, (cyclopropyl)-(methyl)-, (2,2-difluorocyclopropyl)-(methyl)-, (2,2-dichlorocyclopropyl)-
(methyl)-, (2,2-dimethylcyclopropyl)-(methyl)-, (2-methylcyclopropyl)-(methyI)-, (1 -methylcyclopropyl)-(methyl)-, (1 -chlorocyclopropyl)-(methyl)-, (cyclobutyl)-(methyl)-, 3,3-difluorocyclobutyl-(methyl)- and (cyclopentyl)-methyl)-;
R7 represents a group selected from Ci-C3-alkyl, trifluoromethyl, (methoxy)-(methyl)-, cyclopropyl,
_NRi iRi ia Ci-C3-alkoxy, Ci-C3-fluoroalkoxy and (C3-C4-cycloalkyl)-(methoxy)-;
R9 represents a hydrogen atom or a methyl group;
R10 represents a -C(=0)R12 group;
R11 and R11a, independently from each other, represent a hydrogen atom or a group selected from Ci-C3-alkyl, 2,2,2-trifluoroethyl, C3-C4-cycloalkyl, (Ci-C2-alkoxy)-(Ci-C3-alkyl)- and
(C3-C4-cycloalkyl)-(methyl)-, or
R11 and R11a, together with the nitrogen atom they are attached to, represent a 4- to 6- membered heterocycloalkyi group, said group being optionally substituted one or two times with a fluorine atom or a trifluoromethyl group;
R12 represents a group selected from Ci-C2-fluoroalkyl, C3-C4-cycloalkyl, 2-hydroxyprop-2- yl, (2-methoxy)-(prop-2-yl)-, (l -trifluoromethyl)-(cyclopropyl)-, 2,2-difluorocyclopropyl, 2,2-difluoro-1 -methylcyclopropyl and (cyclopropyl)-(methyl)-,
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
The compound according to claim 1 , 2, 3, 4 or 5, wherein
represents a group selected from
Figure imgf001200_0001
in which "*" represents the point of attachment to the rest of the molecule,
the ring of said group being, besides R6, optionally substituted further one or two times, differently or identically, with a R7 group; represents a group
Figure imgf001200_0002
in which "*" represents the point of attachment to the rest of the molecule;
R3 represents a hydrogen atom;
R4 represents a hydrogen atom;
R5 represents a hydrogen atom;
R6 represents a group selected from methyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, (cyclopropyl)-(methyl)-, (2,2-difluorocyclopropyl)-(methyl)-, (2,2-dichlorocyclopropyl)- (methyl)-, (2,2-dimethylcyclopropyl)-(methyl)-, (2-methylcyclopropyl)-(methyl)-, (l -methylcyclopropyl)-(methyl)-, (l-chlorocyclopropyl)-(methyl)-, (cyclobutyl)-(methyl)-, 3,3-difluorocyclobutyl-(methyl)- and (cyclopentyl)-methyl)-;
R7 represents a group selected from methyl, trifluoromethyl, (methoxy)-(methyl)-, ethylamino, isopropylamino, (cyclopropyl)-(methyl)-amino-, cyclopropylamino, cyclobutylamino, dimethylamino, azetidin-1 -yl, 3,3-difluoroazetidin-1 -yl, 3- trifluoromethylazetidin-1 -yl, pyrrolidin-1 -yl, piperidin-1-yl, morpholinyl, methoxy, ethoxy, iso-propoxy, 2,2,2-trifluoroethoxy, 2,2-difluoropropoxy and (cyclopropyl )-(methoxy)-;
R9 represents a hydrogen atom or a methyl group;
R10 represents a -C(=0)R12 group;
R12 represents a group selected from 2,2,2-trifluoroethyl, cyclopropyl, (1 -trifluoromethyl)- (cyclopropyl)-, 2,2-difluorocyclopropyl and 2,2-difluoro-1 -methylcyclopropyl, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
7. The compound according to claim 1 , 2, 3, 4 or 5, wherein
R1 represents a group
Figure imgf001201_0001
in which "*" represents the point of attachment to the rest of the molecule;
represents a group
Figure imgf001201_0002
in which "*" represents the point of attachment to the rest of the molecule;
R3 represents a hydrogen atom, a fluorine atom or a chlorine atom;
R4 represents a hydrogen atom;
R5 represents a hydrogen atom; R6 represents a group selected from methyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, (cyclopropyl)-(methyl)-, (2,2-difluorocyclopropyl)-(methyl)-, (2,2-dichlorocyclopropyl)- (methyl)-, (2,2-dimethylcyclopropyl)-(methyl)-, (2-methylcyclopropyl)-(methyl)-, (l -methylcyclopropyl)-(methyl)-, (l-chlorocyclopropyl)-(methyl)-, (cyclobutyl)-(methyl)-, 3,3-difluorocyclobutyl-(methyl)- and (cyclopentyl)-methyl)-;
R9 represents a methyl group;
R10 represents a -C(=0)R12 group;
R12 represents a group selected from 2,2,2-trifluoroethyl, cyclopropyl, (1 -trifluoromethyl)- (cyclopropyl)-, cyclobutyl and (cyclopropyl)-(methyl)-,
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
The compound according to claim 1 , 2, 3, 4, 5 or 6, wherein
represents a group selected from
Figure imgf001202_0001
in which "*" represents the point of attachment to the rest of the molecule,
said group being optionally substituted one or two times, differently or identically, with R7 group;
represents a group
Figure imgf001202_0002
in which "*" represents the point of attachment to the rest of the molecule;
represents a hydrogen atom;
represents a hydrogen atom;
represents a hydrogen atom;
represents a group selected from methyl, (methoxy)-(methyl)-, ethylamino, isopropylamino, (cyclopropyl)-(methyl)-amino-, cyclopropylamino, cyclobutylamino, dimethylamino, azetidin-1-yl, 3,3-difluoroazetidin-1 -yl, 3-trifluoromethylazetidin-1-yl, pyrrolidin-1 -yl, piperidin-1-yl, morpholinyl, methoxy, ethoxy, iso-propoxy, 2,2,2- trifluoroethoxy, 2,2-difluoropropoxy and (cyclopropyl)-(methoxy)-;
R9 represents a methyl group;
R10 represents a -C(=0)R12 group;
R 2 represents a group selected from 2,2,2-trifluoroethyl, cyclopropyl, (1 -trifluoromethyl)- (cyclopropyl)-, 2,2-difluorocyclopropyl and 2,2-difluoro-1 -methylcyclopropyl, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
9. The compound according to claim 1 , which is selected from the group consisting of:
tert-butyl 4-[(2-{[6-(2-methylpyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate; cyclopropyl{4-[(2-{[6-(2-methylpyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone;
3,3,3-trifluoro-1 -{4-[(2-{[6-(2-methylpyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}propan-1 -one;
2-cyclopropyl-1 -{4-[(2-{[6-(2-methylpyridin-4-yl)- H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}ethanone; cyclobutyl{4-[(2-{[6-(2-methylpyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone; tert-butyl 4-[(2-{[6-(2-methoxypyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate; cyclopropyl{4-[(2-{[6-(2-methoxypyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone;
3,3,3-trifluoro-1-{4-[(2-{[6-(2-methoxypyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}propan-1-one; cyclobutyl{4-[(2-{[6-(2-methoxypyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1-yl}methanone;
2-cyclopropyl-1-{4-[(2-{[6-(2-methoxypyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4 yl)methyl]piperazin-1 -yl}ethanone; cyclopropyl{4-[(2-{[6-(5-fluoro-2-methoxypyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyrid 4-yl)methyl]piperazin-1 -yl}methanone;
3,3,3-trifluoro-1-{4-[(2-{[6-(5-fluoro-2-methoxypyridin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}propan-1-one; cyclobutyl{4-[(2-{[6-(5-fluoro-2-met oxypyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin yl)methyl]piperazin-1-yl}methanone;
2-cyclopropyl-1-{4-[(2-{[6-(5-fluoro-2-methoxypyridin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}ethanone; tert-butyl 4-[(2-{[6-(3-methoxypyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate;
3,3,3-trifluoro-1-{4-[(2-{[6-(3-methoxypyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4 yl)methyl]piperazin-1 -yl}propan-1-one; cyclopropyl{4-[(2-{[6-(3-methoxypyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone; cyclobutyl{4-[(2-{[6-(3-methoxypyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)met yl]piperazin-1 -yl}methanone;
2-cyclopropyl-1-{4-[(2 [6-(3-methoxypyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4 yl)methyl]piperazin-1 -yl}ethanone;
1-{4-[(2 [6-(3-methoxypyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}-2,2-dimethylpropan-1 -one;
3,3,3-trifluoro-1-(4-{[2-({6-[3-(2,2,2-trifluoroethoxy)pyridin-4-yl]-1 H-benzimidazoi-2- yl}amino)pyridin-4-yl]methyl}piperazin-1-yl)propan-1 -one;
3,3,3-trifluoro-1-(4-{[2-({6-[3-(propan-2-yloxy)pyridin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1 -yl)propan-1-one; cyclopropyl(4 [2-({6-[3-(propan-2-yloxy)pyridin-4-yl]-1 H-benzimidazol-2-yl}amino)pyridin 4-yl]methyl}piperazin-1 -yl)methanone;
2-cyclopropyl-1 -(4-{[2-({6-[3-(propan-2-yloxy)pyridin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1-yl)ethanone; cyclopropyl{4-[(2 [6-(5-methoxy-2-methylpyridin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}methanone;
3,3,3-trifluoro-1-{4-[(2-{[6-(5-methoxy-2-methylpyridin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}propan-1-one; cyclobutyl{4-[(2-{[6-(5-methoxy-2-methylpyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin- 4-yl)methyl]piperazin-1 -yl}methanone;
2-cyclopropyl-1 -{4-[(2-{[6-(5-methoxy-2-methylpyridin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}ethanone;
4-{2-[(4-{[4-(cyclopropylcarbonyl)piperazin-1 -yl]methyl}pyridin-2-yl)amino]-1 H- benzimidazol-6-yl}-5-methoxy-N,N-dimethylpyridine-2-carboxamide;
1 4-[(2 [6-(5-ethoxy-2-methylpyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}-3,3,3-trifluoropropan-1 -one; cyclopropyl{4-[(2-{[6-(5-ethoxy-2-methylpyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin- 4-yl)methyl]piperazin-1-yl}methanone;
2-cyclopropyl-1-{4-[(2-{[6-(5-ethoxy-2-met ylpyridin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}ethanone; cyclobutyl{4-[(2-{[6-(5-ethoxy-2-methylpyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone; cyclopropyl{4-[(2-{[6-(2-methoxy-3-methylpyridin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}methanone; cyclopropyl(4-{[2-({6-[3-methyl-2-(propan-2-yloxy)pyridin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]met yl}piperazin-1-yl)methanone; tert-butyl 4-[(2-{[6-(6-methylpyridin-2-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate; cyclopropyl{4-[(2-{[6-(6-methylpyridin-2-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone; 2-cyclopropyl-1 -{4-[(2-{[6-(6-methylpyridin^
yl)methyl]piperazin-1 -yl}ethanone; tert-butyl 4-[(2-{[6-(6-methoxypyridin-3-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate; cyclopropyl{4-[(2-{[6-(6-methoxypyridin-3-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone;
3 , 3 , 3-trif I uoro- 1 -{4-[(2-{[6-(6-m eth oxypyri^ ^
yl)methyl]piperazin-1 -yl}propan-1-one; cyclobutyl{4-[(2-{[6-(4-methoxypyridin-3-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone;
2-cyclopropyl-1 -{4-[(2-{[6-(4-methoxypyridin-3-yl)-1 H-benzimidazol-2-yl]amino}pyridin yl)methyl]piperazin-1 -yl}ethanone; cyclopropyl{4-[(2-{[6-(4-methoxypyridin-3-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone;
3,3,3-trifluoro-1-{4-[(2-{[6-(2-methoxypyridin-3-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}propan-1-one;
2-cyclopropyl-1 -{4-[(2-{[6-(2-methoxypyridin-^
yl)methyl]piperazin-1 -yl}ethanone; cyclopropyl{4-[(2-{[6-(2-methoxypyridin-3-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone; tert-butyl 4-[(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate;
3,3,3-trifluoro-1-{4-[(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}propan-1 -one;
2-cyclopropyl-1-{4-[(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}ethanone; cyclopropyl{4-[(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2-yl]amino}pyridin- 4-yl)methyl]piperazin-1 -yl}methanone; cyclobutyl{4-[(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone;
2,2-dimethyl-1 -{4-[(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}propan-1 -one; tert-butyl (2R,5S)-2,5-dimethyl-4-[(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol- 2-yl]amino}pyridin-4-yl)methyl]piperazine-1-carboxylate;
1 -{(2R,5S)-2,5-dimethyl-4-[(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}-3,3,3-trifluoropropan-1-one;
2-cyclopropyl-1-{(2R,5S)-2,5-dimethyl-4-[(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H- benzimidazol-2-yi]amino}pyridin-4-yl)methyl]piperazin-1-yl}ethanone; cyclopropyl{(2R,5S)-2,5-dimethyl-4-[(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}methanone; cyclobutyl{(2R,5S)-2,5-dimethyl-4-[(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimid 2-yl]aiTiino}pyridin-4-yl)methyl]piperaziri-1 -yl}methanone; tert-butyl (3R)-3-methyl-4-[(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate;
3,3,3-trifluoro-1-{(3R)-3-methyl-4-[(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benz^ 2-yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}propan-1 -one;
2-cyclopropyl-1 -{(3R)-3-methyl-4-[(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol- 2-yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}ethanone; cyclopropyl{(3R)-3-methyl-4-[(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1-yl}methanone; cyclobutyl{(3R)-3-methyl-4-[(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1-yl}methanone; tert-butyl 3,3-dimethyl-4-[(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazine-1-carboxylate;
1 -{3,3-dimethyl-4-[(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}-3,3,3-trifluoropropan-1-one;
2-cyclopropyl-1 -{3,3-dimethyl-4-[(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}ethanone; cyclopropyl{3,3-dimethyl-4-[(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1-yl}methanone; cyclobutyl{3,3-dimethyl-4-[(2-{[6-(3-met yl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}methanone;
(rac)-tert-butyl 4-[1-(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]am i no}pyridin-4-yl )ethyl]pi perazine- 1 -carboxylate;
(rac)-3,3,3-trifluoro-1-{4-[1-(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimi yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}propan-1 -one;
(rac)-cyclopropyl{4-[1-(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}methanone; tert-butyl 4-[(1 R or 1 S)-1-(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazine-1-carboxylate (single stereoisomer A) ;
3,3,3-trifluoro-1-{4-[(1 R)-1 -(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}propan-1 -one;
3,3,3-trifluoro-1-{4-[(1 S)-1 -(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}propan-1 -one; cyclopropyl{4-[(1 R or 1 S)-1 -(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}methanone (single stereoisomer A) ; tert-butyl 4-[(2-{[6-(3-cyclopropyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate;
1 -{4-[(2-{[6-(3-cyclopropyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yI)methyl]piperazin-1-yl}-3,3,3-trifluoropropan-1 -one;
2-cyclopropyl-1-{4-[(2-{[6-(3-cyclopropyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1-yl}ethanone;
1 -{4-[(2-{[6-(3-cyclopropyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}but-3-en-1 -one; cyclopropyl{4-[(2-{[6-(3-cyclopropyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)met yl]piperazin-1 -yl}methanone; cyclobutyl{4-[(2-{[6-(3-cyclopropyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}methanone;
N-(4-{[4-(2-chlorophenyl)piperazin-1-yl]methyl}pyridin-2-yl)-6-(3-cyclopropyl-1 ,2,4- oxadiazol-5-yl)-1 H-benzimidazol-2-amine;
3,3,3-trifluoro-1-(4-{[2-({6-[3-(2-methylpropyl)-1 ,2,4-oxadiazol-5-yl]-1 H-benzim
yl}amino)pyridin-4-yl]methyl}piperazin-1 -yl)propan-1-one; cyclopropyl(4-{[2-({6-[3-(2-methylpropyl)-1 ,2,4-oxadiazol-5-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1-yl)methanone;
{4-[(2-{[6-(3-cyclopentyl-1 ,2^-oxadiazol-5-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}(cyclopropyl)methanone;
(4-{[2-({6-[3-(butan-2-yl)-1 ,2,4-oxadiazol-5-yl]-1 H-benzimidazol-2-yl}amino)pyridin-4- yl]methyl}piperazin-1 -yl)(cyclopropyl)methanone;
{4-[(2 [6-(3-benzyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}(cyclopropyl)methanone;
N-(4-{[4-(2-chlorophenyl)piperazin-1 -yl]methyl}pyridin-2-yl)-6-(5-cyclopropyl-1 ,2,4- oxadiazol-3-yl)-1 H-benzimidazol-2 -amine;
N-(4-{[4-(2-chlorophenyl)piperazin-1-yl]methyl}pyridin-2-yl)-6-[5-(2,2-dimethylpropyl)-1 ,2,4- oxadiazol-3-yl]-1 H-benzimidazol-2 -amine;
2-cyclopropyl-1 -{4-[(2-{[6-(pyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}ethanone; cyclopropyl{4-[(2-{[6-(pyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone;
3,3,3-trifluoro-1-{4-[(2-methyl-6-{[6-(pyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}propan-1 -one; cyclopropyl{4-[(2-methyl-6-{[6-(pyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone; cyclopropyl(4-{[2-{[6-(pyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}-6- (trifluoromethyl)pyridin-4-yl]methyl}piperazin-1 -yl)methanone;
(rac)-cyclobutyl{4-[1 -(2-{[6-(pyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)ethyl]piperazin-1 -yl}methanone; (rac)-cyclopropyl{4-[1-(2-{[6-(pyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)ethyl]piperazin-1 -yl}methanone;
(rac)-3 ,3-trifluoro-1 -{4-[1 -(2-{[6-(pyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)ethyl]piperazin-1 -yl}propan-1 -one; cyclopropyl{4-[(1 R)-1 -(2-{[6-(pyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)ethyl]piperazin-1 -yl}methanone; cyclopropyl{4-[(1 S)-1-(2 [6-(pyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4^ yl)ethyl]piperazin-1-yl}methanone;
3,3,3-trifluoro-1-{4-[(1 R)-1-(2-{[6-(pyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}py^^ yl)ethyl]piperazin-1 -yl}propan-1 -one;
3,3,3-trifluoro-1-{4-[(1 S)-1-(2-{[6-(pyrimidin-4-yI)-1 H-benzimidazol-2-yl]amino}^^^ yl)ethyl]piperazin-1 -yl}propan-1-one; cyclobutyl{4-[(1 R)-1 -(2-{[6-(pyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)ethyl]piperazin-1-yl}methanone; cyclobutyl{4-[(1 S)-1-(2-{[6-(pyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)ethyl]piperazin-1 -yl}methanone;
3,3,3-trifluoro-1-{4-[(2-{[6-(2-methylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}propan-1-one; cyclobutyl{4-[(2-{[6-(2-methylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone; cyclopropyl{4-[(2-{[6-(2-methylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone;
2-cyclopropyl-1-{4-[(2-{[6-(2-methylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}ethanone; cyclopropyl{4-[(2-methyl-6-{[6-(2-methylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}methanone;
3,3,3-trifluoro-1 -{4-[(2-methyl-6-{[6-(2-methylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}propan-1 -one; cyclopropyl(4-{[2-{[6-(2-methylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}-6- (trifluoromethyl)pyridin-4-yl]methyl}piperazin-1 -yl)methanone;
(rac)-cyclopropyl{4-[1 -(2-{[6-(2-methylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin- 4-yl)ethyl]piperazin-1 -yl}methanone;
(rac)-cyclobutyl{4-[1 -(2 [6-(2-methylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin yl)ethyl]piperazin-1-yl}methanone;
(rac)-3,3,3-trifluora-1-{4-[1 -(2-{[6-(2-methylpyrimidin-4-yl)-1 H-benzim
yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}propan-1 -one;
(rac)-2-cyclopropyl-1-{4-[1 -(2 [6-(2-methylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}ethanone;
3,3,3-trifluoro-1-{4-[(1 R)-1 -(2-{[6-(2-methylpyrimidin-4-yl)-1 H-benzimida^^
yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}propan-1 -one;
3,3,3-trifluoro-1-{4-[(1 S)-1 -(2-{[6-(2-methylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}propan-1 -one; cyclobutyl{4-[(1 R)-1-(2-{[6-(2-methylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)ethyl]piperazin-1 -yl}methanone; cyclobutyl{4-[(1 S)-1-(2-{[6-(2-methylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyn yl)ethyl]piperazin-1 -yl}methanone;
2-cyclopropyl-1 -{4-[(1 R)-1 -(2-{[6-(2-methylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}ethanone;
2-cyclopropyl-1-{4-[(1 S)-1 -(2-{[6-(2-methylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}ethanone ; cyclopropyl{4-[(1 R)-1 -(2-{[6-(2-methylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin- 4-yl)ethyl]piperazin-1 -yl}methanone ; cyclopropyl{4-[(1 S)-1-(2-{[6-(2-methylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyrid 4-yl)ethyl]piperazin-1 -yl}methanone ; tert-butyl 4-[(2-{[6-(2-methoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate; cyclobutyl{4-[(2-{[6-(2-methoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone; 2-cyclopropyl-1-{4-[(2-{[6-(2-methoxypyrimi
yl)methyl]piperazin-1 -yl}ethanone;
3,3,3-trifluoro-1-{4-[(2-{[6-(2-methoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyri yl)methyl]piperazin-1 -yl}propan-1-one; cyclopropyl{4-[(2-{[6-(2-methoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone; cyclopropyl(4-{[2-{[6-(2-methoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}-6- (trifluoromethyl)pyridin-4-yl]methyl}piperazin-1 -yl)methanone; tert-butyl 4-[(2-{[6-(2-ethoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate; cyclopropyl{4-[(2-{[6-(2-et oxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone;
1 - {4-[(2-{[6-(2-ethoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}-3,3,3-trifluoropropan-1 -one; cyclobutyl{4-[(2-{[6-(2-ethoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone;
2- cyclopropyl-1 -{4-[(2-{[6-(2-ethoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)met yl]piperazin-1 -yl}ethanone;
(rac)-1-{4-[1 -(2-{[6-(2-ethoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)ethyl]piperazin-1 -yl}-3,3,3-trifluoropropan-1 -one;
1 -{4-[(1 R)-1 -(2-{[6-(2-ethoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)ethyl]piperazin-1 -yl}-3,3,3-trifluoropropan-1 -one;
1 - {4-[(1 S)-1 -(2-{[6-(2-ethoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)ethyl]piperazin-1 -yl}-3,3,3-trifluoropropan-1-one; cyclopropyl(4-{[2-({6-[2-(trifluoromet yl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1-yl)methanone; cyclobutyl(4-{[2-({6-[2-(trifluoromethyl)pyrimidin-4-yl]-1 H-benzimidazol-2-yl}amino)pyridin- 4-yl]methyl}piperazin-1-yl)methanone;
2- cyclopropyl-1 -(4-{[2-({6-[2-(trifluoromethyl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1-yl)ethanone;
3,3,3-trifluoro-1 -(4-{[2-({6-[2-(trifluoromethyl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1 -yl)propan-1 -one; tert-butyl 4-[(2-{[6-(2-ethylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate;
(rac)-3,3,3-trifluoro-1-(4-{1 -[2-({6-[6-(trifluoromethyl)pyrimidin-4-yl]-1 H-benzimidazo yl}amino)pyridin-4-yl]et yl}piperazin-1 -yl)propan-1 -one;
(rac)-cyclopropyl(4-{1-[2-({6-[6-(trifluoromethyl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)methanone;
3,3,3-trifluoro-1-(4-{(1 R)-1 -[2-({6-[6-(trifluoromethyl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)propan-1 -one ;
3,3,3-trifluoro-1-(4-{(1 S)-1-[2-({6-[6-(trifluoromethyl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)propan-1 -one;
3,3,3-trifluoro-1-{4-[(2-{[6-(6-met ylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]ami
yl)methyl]piperazin-1 -yl}propan-1-one; cyclobutyl{4-[(2-{[6-(6-methylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone;
2-cyclopropyl-1 -{4-[(2-{[6-(6-methylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1-yl}ethanone; cyclopropyl{4-[(2-{[6-(6-methylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1-yl}methanone;
(rac)-3,3,3-trifluoro-1-{4-[1 -(2-{[6-(6-methylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}propan-1 -one;
(rac)-cyclobutyl{4-[1 -(2-{[6-(6-methylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)ethyl]piperazin-1 -yl}methanone;
(rac)-cyclopropyl{4-[1 -(2-{[6-(6-methylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin- 4-yl)ethyl]piperazin-1-yl}methanone;
(rac)-2-cyclopropyl-1-{4-[1 -(2-{[6-(6-methylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}ethanone; 3,3,3-trifluoro-1-{4-[(1 R)-1 -(2-{[6-(6-met ylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}propan-1-one;
3,3,3-trifluoro-1-{4-[(1 S)-1 -(2-{[6-(6-methylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}propan-1 -one; cyclobutyl{4-[(1 R)-1 -(2-{[6-(6-methylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]am
yl)ethyl]piperazin-1 -yl}methanone; cyclobutyl{4-[(1 S)-1 -(2-{[6-(6-methylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]am
yl)ethyl]piperazin-1 -yl}methanone; cyclopropyl{4-[(1 R)-1-(2-{[6-(6-methylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin 4-yl)ethyl]piperazin-1 -yl}methanone; cyclopropyl{4-[(1 S)-1-(2-{[6-(6-methylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin- 4-yl)ethyl]piperazin-1 -yl}methanone;
1 -{4-[(2-{[6-(2,6-dimethylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridi
yl)methyl]piperazin-1 -yl}-3,3,3-trifluoropropan-1 -one; cyclopropyl{4-[(2-{[6-(2,6-dimethylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1-yl}methanone; cyclopropyl{4-[(2-{[6-(5,6-dimethylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone;
1 -{4-[(2-{[6-(5,6-dimethylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}-3,3,3-trifluoropropan-1 -one;
1-{4-[(2-{[6-(5,6-dimethylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}ethanone; tert-butyl 4-[(2-{[6-(2,5-dimethylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate;
1 -{4-[(2-{[6-(2,5-dimethylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}-3,3,3-trifluoropropan-1 -one; cyclopropyl{4-[(2-{[6-(2,5-dimethylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone; cyclobutyl{4-[(2-{[6-(2,5-dimethylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone; tert-butyl 4-[(2 [6-(6-methoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate;
(rac)-3,3,3-trifluoro-1-{4-[1-(2 [6-(6-methoxypyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}propan-1 -one;
(rac)-cyclopropyl{4-t1-(2-{[6-(6-methoxypyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}methanone;
3,3,3-trifluoro-1-{4-[(1 R)-1-(2 [6-(6-methoxypyrimidin-4-yl)-1 H-benzimi
yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}propan-1 -one (single stereoisomer A) ;
3,3,3-trifluoro-1-{4-[(1 S)-1-(2-{[6-(6-methoxypyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}propan-1-one ; cyclopropyl{4-[(1 R)-1-(2-{[6-(6-methoxypyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}methanone; cyclopropyl{4-[(1 S)-1-(2-{[6-(6-methoxypyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}methanone;
3,3,3-trifluoro-1-{4-[(2-{[6-(5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyri yl)methyl]piperazin-1 -yl}propan-1 -one; cyclopropyl{4-[(2-{[6-(5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone;
4-[(2-{[6-(5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4-yI)methyl]-N,^ dimethylpiperazine-1 -carboxamide;
N,N-diethyl-4-[(2-{[6-(5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxamide;
{4-[(2-{[6-(5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}(pyrrolidin-1 -yl)methanone;
{4-[(2-{[6-(5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}(piperidin-1 -yl)methanone;
{4-[(2-{[6-(5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}(morpholin-4-yl)methanone; N-(4-{[4-(ethylsulfonyl)piperazin-1-yl]met^
benzimidazol-2-amine;
6-(5-methoxypyrimidin-4-yl)-N-[4-({4-[(3,3,3-trifluoropropyl)sulfonyl]piperazin-1 - yl}methyl)pyridin-2-yl]-1 H-benzimidazol-2-amine;
N-[4-({4-[(3-methoxypropyl)sulfonyl]piperazin-1-yl}methyl)pyridin-2-yl]-6-(5- methoxypyrimidin-4-yl)-1 H-benzimidazol-2-amine;
N-{4-[(4-{[2-(2-methoxyethoxy)ethyl]sulfonyl}piperazin-1 -yl)methyl]pyridin-2-yl}-6-(5- methoxypyrimidin-4-yl)-1 H-benzimidazol-2-amine;
N-(4-{[4-(cyclopropylsulfonyl)piperazin-1 -yl]methyl}pyridin-2-yl)-6-(5-methoxypyrimidin-4- yl)-1 H-benzimidazol-2-amine;
N-(4-{[4-(cyclohexylsulfonyl)piperazin-1 -yl]methyl}pyridin-2-yl)-6-(5-methoxypyrimidin-4- yl)-1 H-benzimidazol-2-amine;
6-(5-rnethoxypyrimidin-4-yl)-N-(4-{[4-(tetrahydro-2H-pyran-4-ylsulfonyl)piperazin-1 - yl]methyl}pyridin-2-yl)-1 H-benzimidazol-2-amine;
4-[(2 [6-(5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4-yl)methyl]-N,N dimethylpiperazine-1 -sulfonamide;
N-{4-[(4-{[4-(methoxymethyl)piperidin-1-yl]sulfo^
methoxypyrimidin-4-yl)-1 H-benzimidazol-2-amine;
N-[4-({4-[(4-methoxypiperidin-1 -yl)sulfonyl]piperazin-1 -yl}methyl)pyridin-2-yl]-6-(5 methoxypyrimidin-4-yl)-1 H-benzimidazol-2-amine;
N-[4-({4-[(2,6-dimethylmorpholin-4-yl)sulfonyl]piperazin-1 -yl}methyl)pyridin-2-yl]-6-(5- methoxypyrimidin-4-yl)-1 H-benzimidazol-2-amine;
(rac)-3,3,3-trifluoro-1 -{4-[1-(2 [6-(5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}propan-1 -one;
(rac)-2-cyclopropyl- 1 -{4-[1 -(2-{[6-(5-methoxypyrim idin-4-yl)- 1 H-benzim idazol-2- yl]amino}pyridin-4-yl)et yl]piperazin-1-yl}ethanone;
(rac)-cyclopropyl{4-[1 -(2-{[6-(5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}methanone;
(rac)-cyclobutyl{4-[1 -(2-{[6-(5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin- 4-yl)ethyl]piperazin-1 -yl}methanone;
3,3,3-trifluoro-1 -{4-[(1 R)-1 -(2-{[6-(5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}propan-1 -one ;
3,3,3-trifluoro-1 -{4-[(1 S)-1 -(2 [6-(5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}propan-1 -one ;
2-cyclopropyl-1 -{4-[(1 R)-1 -(2-{[6-(5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}ethanone;
2-cyclopropyl-1 -{4-[(1 S)-1 -(2-{[6-(5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}ethanone; cyclopropyl{4-[(1 R)-1 -(2-{[6-(5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}methanone ; cyclopropyl{4-[(1 S)-1 -(2-{[6-(5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}methanone ; cyclobutyl{4-[(1 R)-1-(2-{[6-(5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin 4-yl)ethyl]piperazin-1 -yl}methanone) ; cyclobutyl{4-[( 1 S)-1-(2-{[6-(5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin- 4-yl)ethyl]piperazin-1 -yl}methanone (single stereoisomer B) ; tert-butyl 4-{(1 R or 1 S)-1-[2-({6-[5-(propan-2-yloxy)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate (single stereoisomer A) ;
3,3,3-trifluoro-1-(4-{(1 R or 1S)-1 -[2-({6-[5-(propan-2-yloxy)pyrimidin-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)propan-1-one (single stereoisomer A) ; cyclopropyl(4-{(1 R or 1 S)-1 -[2-({6-[5-(propan-2-yloxy)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)methanone (single stereoisomer A) ; cyclobutyl(4-{(1 R or 1 S)-1 -[2-({6-[5-(propan-2-yloxy)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)methanone (single stereoisomer A) ;
3,3,3-trifluoro-1-{4-[(2-{[6-(1-methyM
4-yl)methyl]piperazin-1-yl}propan-1 -one;
2-cyclopropyl-1 -{4-[(2-{[6-(1-methyl-1 H-pyrazol-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin- 4-yl)methyl]piperazin-1 -yl}ethanone; cyclopropyl{4-[(2-{[6-(1 -methyl-1 H-pyrazol-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone; cyclobutyl{4-[(2-{[6-(1 -methyl-1 H-pyrazol-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone; tert-butyl 4-[(2-{[6-(1 -ethyl-1 H-pyrazol-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate;
1 -{4-[(2-{[6-(1 -ethyl-1 H-pyrazol-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}-3,3,3-trifluoropropan-1 -one; cyclopropyl{4-[(2-{[6-(1 -ethyl-1 H-pyrazol-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone; tert-butyl 4-{[2-({6-[1 -(cyclopropylmethyl)-1 H-pyrazol-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1-carboxylate;
1 - (4-{[2-({6-[1-(cyclopropylmethyl)-1 H-pyrazol-4-yl]-1 H-benzimidazol-2-yl}amino)pyridin-4- yl]methyl}piperazin-1 -yl)-3,3,3-trifluoropropan-1-one; cyclopropyl(4-{[2-({6-[1-(cyclopropylmethyl)-1 H-pyrazol-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1 -yl)methanone; tert-butyl 4-{(1 R or 1 S)-1-[2-({6-[1-(cyclopropylmethyl)-1 H-pyrazol-4-yl]- H-benzimidazol-
2- yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate (single stereoisomer A) ;
1 -(4-{(1 R or 1 S)-1 -[2-({6-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)-3,3,3-trifluoropropan-1 -one (single stereoisomer A) ; cyclopropyl(4-{(1 R or 1 S)-1 -[2-({6-[1 -(cyclopropylmethyl)-l H-pyrazol-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)methanone (single stereoisomer A) ;
3,3,3-trifluoro-1 -{4-[(2-{[6-(1 -methyl-1 H-pyrazol-3-yl)-1 H-benzimidazol-2-yl]amino}pyridin- 4-yl)methyl]piperazin-1-yl}propan-1-one;
2-cyclopropyl-1 -{4-[(2-{[6-(1 -methyl-1 H-pyrazol-3-yl)-1 H-benzimidazol-2-yl]amino}pyridin- 4-yl)methyl]piperazin-1 -yl}ethanone; cyclopropyl{4-[(2-{[6-(1 -methyl-1 H-pyrazol-3-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone; cyclobutyl{4-[(24[6-(1-methyl-1 H-pyrazol-3-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone; tert-butyl 4-[(2-{[6-(1 -methyl-1 H-1 ,2,4-triazol-5-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1-carboxylate;
3,3,3-trifluoro-1-{4-[(2-{[6-(1 -methyl-1 H-1 , 2,4-triazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}propan-1 -one; cyclopropyl{4-[(2-{[6-(1 -methyl-1 H-1 ,2,4-triazol-5-yl)-1 H-benzimidazol-2-yl]amino}pyridin- 4-yl)methyl]piperazin-1 -yl}methanone; tert-butyl 4-{[2-({6-[1 -methyl-3-(2-methylpropyl)-1 H-1 ,2,4-triazol-5-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate;
3,3,3-trifluoro-1-(4-{[2-({6-[1 -methyl-3-(2-methylpropyl)-1 H-1 ,2,4-triazol-5-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]methyl}piperazin-1 -yl)propan-1-one; cyclopropyl{4-[(2-{[6-(1 H-imidazol-2-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone; cyclopropyl{4-[(2-{[6-(4-methyl-1 H-imidazol-2-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1-yl}methanone; cyclopropyl{4-[(2-{[6-(4-cyclopropyl-1 H-imidazol-2-yl)-1 H-benzimidazol-2-yl]amino}pyridin- 4-yl)methyl]piperazin-1 -yl}methanone;
1 - (cyclopropylmethyl)-4-{2-[(4-{[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]methyl}pyridin-2- yl)amino]-1 H-benzimidazol-6-yl}pyridin-2(1 H)-one;
4-{2-[(4-{[4-(cyclopropylcarbonyl)piperazin-1 -yl]methyl}pyridin-2-yl)amino]-1 H- benzimidazol-6-yl}-1-(cyclopropylmethyl)pyridin-2(1 H)-one;
4-{2-[(4-{[4-(cyclobutylcarbonyl)piperazin-1-yl]methyl}pyridin-2-yl)amino]-1 H-benzimidazol- 6-yl}-1 -(cyclopropylmethyl)pyridin-2(1 H)-one;
3,3,3-trifluoro-1-{4-[(2-{[6-(pyrimidin-5-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}propan-1-one;
2- cyclopropyl-1 -{4-[(2-{[6-(pyrimidin-5-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1-yl}ethanone; cyclopropyl{4-[(2 [6-(pyrimidin-5-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone;
1 - {4-[(2-{[6-(2-chloropyrimidin-5-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1-yl}-3,3,3-trifluoropropan-1 -one;
{4-[(2-{[6-(2-chloropyrimidin-5-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}(cyclopropyl)methanone;
3 , 3, 3-trif luoro- 1 -{4-[(2-{[6-(2-methyl pyrim ^
yl)methyl]piperazin-1 -yl}propan-1 -one; cyclopropyl{4-[(2-{[6-(2-methylpyrimidin-5-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone; cyclopropyl{4-[(2-{[6-(2-cyclopropylpyrimidin-5-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone;
3,3,3-trifluoro-1-(4-{[2-({6-[2-(methylsulfanyl)pyrimidin-5-yl]-1 H-benzim idazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1 -yl)propan-1-one;
2- cyclopropyl-1-(4-{[2-({6-[2-(methylsulfanyl)pyrimidin-5-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1-yl)ethanone; cyclopropyl(4-{[2-({6-[2-(methylsulfanyl)pyrimidin-5-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1-yl)methanone; cyclopropyl{4-[(2-{[6-(3-methoxypyridazin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone;
{4-[(2-{[6-(6-chloro-3-methoxypyridazin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}(cyclopropyl)methanone; cyclopropyl{4-[(2-{[6-(6-methoxypyridazin-3-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone; cyclopropyl{4-[(2-{[6-(5-methoxypyridazin-3-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone; cyclopropyl{4-[(2-{[6-(6-methoxypyrazin-2-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone; cyclopropyl{4-[(2-{[6-(2-methoxypyridin-4-yl)-7-(2-methylpropoxy)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}methanone;
3,3,3-trifluoro-1-{4-[(2-{[6-(3-methoxypyridin-4-yl)-7-(2-methylpropoxy)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}propan-1 -one; cyclopropyl{4-[(2-{[6-(3-methoxypyridin-4-yl)-7-(2-methylpropoxy)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}methanone; cyclobutyl{4-[(2-{[6-(3-methoxypyridin-4-yl)-7-(2-methylpropoxy)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}methanone;
1 - {4-[(2-{[7-ethoxy-6-(3-methoxypyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}-3,3,3-trifluoropropan-1-one;
2- cyclopropyl-1 -{4-[(2-{[7-ethoxy-6-(3-methoxypyridin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}ethanone; cyclopropyI{4-[(2-{[7-ethoxy-6-(3-methoxypyridin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}methanone; cyclobutyl{4-[(2-{[7-ethoxy-6-(3-methoxypyridin-4-yl)-1 H-benzimidazol-2-y!]amino}pyridin- 4-yl)methyl]piperazin-1 -yl}methanone;
1 -{4-[(2-{[6-(1-ethyl-1 H-pyrazol-4-yl)-7-(2-methylpropoxy)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}-3,3,3-trifluoropropan-1 -one; cyclopropyl{4-[(2-{[6-( 1 -ethyl- 1 H-pyrazol-4-yl )-7-(2-methyl propoxy)- 1 H-benzi m idazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}methanone;
1 -{4-[(2-{[7-ethoxy-6-(1 -ethyl-1 H-pyrazol-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}-3,3,3-trifluoropropan-1 -one; cyclopropyl{4-[(2-{[7-ethoxy-6-(1 -ethyl-1 H-pyrazol-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}methanone;
3,3,3-trifluoro-1-{4-[(2-{[7-methyl-6-(3-methyl-1 ,2^-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}propan-1 -one; cyclopropyl{4-[(2-{[7-methyl-6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}methanone; tert-butyl 4-[(1R or 1S)-1-(2-{[6-(1-{[(1RS)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)- 1 H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1-carboxylate;
tert-butyl 4-[(1R or 1S)-1-(2-{[6-(1-{[(1R)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)- 1H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1-carboxylate;
tert-butyl 4-[(1R or 1S)-1-(2-{[6-(1-{[(1S)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-
1H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1-carboxylate;
1 -{4-[(1 R or 1 S)-1 -(2-{[6-(1 -{[(1 RS)-2,2-difluorocyclopropyl]methyl}-1 H-pyrazol-4-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}-3,3,3-trifluoropropan-1-on
1-{4-[(1Ror 1S)-1-(2-{[6-(1-{[(1R)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-1H- benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}-3,3,3-trifluoropropan-1 -one;
1 -{4-[(1 R or 1 S)-1 -(2-{[6-(1 -{[(1 S)-2,2-difluorocyclopropyl]methyl}-1 H-pyrazol-4-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}-3,3,3-trifluoro
cyclopropyl{4-[(1 R or 1 S)-1-(2-{[6-(1-{[(1 RS)-2,2-difluorocyclopropyl]methyl}-1 H-pyrazol-4- yl)-1H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}methan
cyclopropyl{4-[(1R or 1S)-1-(2-{[6-(1-{[(1R)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4- yl)-1H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}methanon
cyclopropyl{4-[(1 R or 1 S)-1 -(2-{[6-(1 -{[(1 S)-2,2-difluorocyclopropyl]methyl}-1 H-pyrazol-4- yl)-1H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}methanone;
tert-butyl 4-[(1R or 1S)-1-(2-{[6-(1-{[(1RS,2RS)-2-methylcyclopropyl]met yl}-1H-pyrazol-4- yl)-1 H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1 -carboxylate;
3,3,3-trifluoro-1-{4-[(1Ror 1S)-1-(2-{[6-(1-{[(1RS,2RS)-2-methylcyclopropyl]methyl}-1H- pyrazol-4-yl)-1H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}propan-1-on tert-butyl 4-[(1R or 1S)-1-(2-{[6-(1H-pyrazol-4-yl)-1H-benzimidazol-2-yl]amino}pyridin-4- yl)ethyl]piperazine-1 -carboxylate;
cyclobutyl(4-{[2-({6-[1-(2,2,2-trifluoroethyl)-1 H-pyrazol-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1-yl)methanone;
3,3,3-trifluoro-1-(4-{[2-({6-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]-1H-benzir^
yl}amino)pyridin-4-yl]methyl}piperazin-1-yl)propan-1-one;
cyclopropyl(4-{[2-({6-[1 -(2,2,2-trifluoroethyl)-1 H-pyrazol-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1-yl)methanone;
tert-butyl 4-{(1R or 1S)-1-[2-({6-[1-(cyclobutylmethyl)-1H-pyrazol-4-yl]-1H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate (Single Stereoisomer A); 1 -(4-{(1 R or 1 S)-1 -[2-({6-[1 -(cyclobutylmethyl)-l H-pyrazol-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)-3,3,3-trifluoropropan-1-one (Single Stereoisomer A);
(4-{(1 R or 1 S)-1-[2-({6-[1 -(cyclobutylmethyl)-1 H-pyrazol-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)(cyclopropyl)methanone (Single Stereoisomer A);
1- (4-{[2-({6-[1-(cyclobutylmethyl)-1 H-pyrazol-4-yl]-1 H-benzimidazol-2-yl}amino)pyridin-4- yl]methyl}piperazin-1 -yl)-3,3,3-trifluoropropan-1-one;
(4-{[2-({6-[1-(cyclobutylmet yl)-1 H-pyrazol-4-yl]-1 H-benzimidazol-2-yl}amino)pyridin-4- yl]methyl}piperazin-1 -yl)(cyclopropyl)methanone;
1 -{4-[(2-{[6-(6-chloro-5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}-3,3,3-trifluoropropan-1-one;
3,3,3-trifluoro-1 -{4-[(2-{[6-(5-methoxy-6-methylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}propan-1 -one;
cyclopropyl{4-[(2-{[6-(5-methoxy-6-methylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}methanone;
tert-butyl 4-{[2-({6-[2-(cyclopropylmethoxy)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate;
cyclobutyl(4-{[2-({6-[2-(cyclopropylmethoxy)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1-yl)methanone;
1 -(4-{[2-({6-[2-(cyclopropylmethoxy)pyrimidin-4-yl]-1 H-benzimidazol-2-yl}amino)pyridin-4- yl]methyl}piperazin-1-yl)-3,3,3-trifluoropropan-1-one;
cyclopropyl(4-{[2-({6-t2-(cyclopropylmethoxy)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1 -yl)methanone;
tert-butyl 4-[(2-{[6-(2-chloro-5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin- 4-yl)methyl]piperazine-1-carboxylate;
tert-butyl 4-{[2-({6-[2-(cyclopropylmethoxy)-5-methoxypyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate;
cyclopropyl(4-{[2-({6-[2-(cyclopropylmethoxy)-5-methoxypyrimidin-4-yl]-1 H-benzimidazol-
2- yl}amino)pyridin-4-yl]methyl}piperazin-1-yl)methanone;
1 -(4-{[2-({6-[2-(cyclopropylmethoxy)-5-methoxypyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1-yl)-3,3,3-trifluoropropan-1 -one;
tert-butyl 4-{[2-({6-[6-(cyclopropylmethoxy)-5-methoxypyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate; 1-(4-{[2-({6-[6-(cyclopropylmethoxy)-5-met oxypyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1-yl)-3,3,3-trifluoropropan-1-one;
tert-butyl 4-[(2-{[6-(5-methyl-1 ,3,4-oxadiazol-2-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate;
cyclopropyl{4-[(2-{[6-(5-methyl-1 ,3,4-oxadiazol-2-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone;
3,3,3-trifluoro-1-{4-[(2-{[6-(5-methyl-1 ,3^-oxadiazol-2-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}propan-1 -one;
tert-butyl 4-[(1 R or 1 S)-1-(2-{[6-(1-{[(1 RS)-2,2-dimethylcyclopropyl]methyl}-1 H-pyrazol-4- yl)-1 H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1 -carboxylate;
1 -{4-[(1 R or 1 S)-1 -(2-{[6-(1 -{[(1 RS)-2,2-dimethylcyclopropyl]methyl}-1 H-pyrazol-4-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}-3,3,3-trifluoropropan-1-o cyclopropyl{4-[(1 R or 1 S)-1-(2-{[6-(1-{[(1 RS)-2,2-dimethylcyclopropyl]methyl}-1 H-pyrazol- 4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}methanone;
tert-butyl 4-[(1 R or 1 S)-1-{2-[(6-{1 -[(1-methylcyclopropyl)methyl]-1 H-pyrazol-4-yl}-1 H- benzimidazol-2-yl)amino]pyridin-4-yl}ethyl]piperazine-1 -carboxylate;
3,3,3-trifluoro-1-{4-[(1 R or 1 S)-1 -{2-[(6-{1-[(1-methylcyclopropyl)methyl]-1 H-pyrazol-4-yl}- 1 H-benzimidazol-2-yl)amino]pyridin-4-yl}ethyl]piperazin-1 -yl}propan-1-on
tert-butyl 4-[(1 R or 1 S)-1-{2-[(6-{1-[(1-chlorocyclopropyl)methyl]-1 H-pyrazol-4-yl}-1 H- benzimidazol-2-yl)amino]pyridin-4-yl}ethyl]piperazine-1-carboxylate;
1 -{4-[(1 R or 1 S)-1 -{2-[(6-{1 -[(1 -chlorocyclopropyl)methyl]-1 H-pyrazol-4-yl}-1 H- benzimidazol-2-yl)amino]pyridin-4-yl}ethyl
1 -{4-[(1 R or 1 S)-1-(2-{[7-chloro-6-(1-{[(1 RS)-2,2-difluorocyclopropyl]methyl}-1 H-pyrazol-4- yl)-1 H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}-3,3,3^
one;
{4-[(1 R or 1 S)-1 -(2-{[7-chloro-6-(1 -{[(1 RS)-2,2-difluorocyclopropyl]methyl}-1 H-pyrazol-4- yl)-1 H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}(cyclopropyl)methanone; tert-butyl 4-{(1 R or 1 S)-1-[2-({6-[1-(cyclopentylmethyl)-1 H-pyrazol-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate;
1 -(4-{(1 R or 1 S)-1-[2-({6-[1 -(cyclopentylmethyl)-1 H-pyrazol-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)-3,3,3-trifluoropropan-1-one;
tert-butyl 4-{(1 R or 1 S)-1-[2-({6-[1-(propan-2-yl)-1 H-pyrazol-5-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate; 3,3,3-trifluoro-1-(4-{(1 R or 1 S)-1 -[2-({6-[1-(propan-2-yl)-1 H-pyrazol-5-yl]-1 H-benzimidazol- 2-yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)propan-1 -one;
cyclopropyl(4-{(1 R or 1 S)-1 -[2-({6-[1 -(propan-2-yl)-1 H-pyrazol-5-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)methanone;
1 -{4-[(1 R or 1S)-1 -(2-{[6-(1 ,4-dimethyl-1 H-pyrazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}-3,3,3-trifluoropropan-1-one;
tert-butyl 4-[(1 R or 1 S)-1-{2-[(6-{1-[(1 RS)-1-cyclopropylethyl]-1 H-pyrazol-4-yl}-1 H- benzimidazol-2-yl)amino]pyridin-4-yl}ethyl]piperazine-1-carboxylate;
1 -{4-[(1 R or 1 S)-1 -{2-[(6-{1 -[(1 RS)-1 -cyclopropylethyl]-1 H-pyrazol-4-yl}-1 H-benzimidazol- 2-yl)amino]pyridin-4-yl}ethyl]piperazin-1-yl}-3,3,3-trifluoropropan-1 -one;
tert-butyl 4-{(1 R or 1 S)-1-[2-({7-c loro-6-[1-(cyclobutylmethyl)-1 H-pyrazol-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate;
1- (4-{(1 R or 1 S)-1-[2-({7-chloro-6-[1 -(cyclobutylmethyl)-1 H^yrazol-4-yl]-1 H-benzimidazol-
2- yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)-3,3,3-trifluoropropan-1 -one;
(4-{(1 R or 1 S)-1-[2-({7-chloro-6-[1-(cyclobutylmethyl)-1 H^yrazol-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)(cyclopropyl)methanone;
1 -{4-[(2-{[6-(6-cyclopropylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}-3,3,3-trifluoropropan-1 -one;
cyclopropyl{4-[(2-{[6-(6-cyclopropylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridi yl)methyl]piperazin-1 -yl}methanone;
6-{2-[(4-{[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]methyl}pyridin-2-yl)amino]-1 H benzimidazol-6-yl}pyrimidine-4-carbonitrile;
3,3,3-trifluoro-1 -(4-{[2-({6-[6-(propan-2-yl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}arnino)pyridin-4-yl]methyl}piperazin-1-yl)propan-1 -one;
cyclopropyl(4-{[2-({6-[6-(propan-2-yl)pyrimidin-4-yl]-1 H-benzimidazol-2-yl}amino)pyridin yl]methyl}piperazin-1 -yl)methanone;
3,3,3-trifluoro-1 -(4-{[2-({6-[6-(methoxymethyl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1 -yl)propan-1 -one;
cyclopropyl(4-{[2-({6-[6-(rnethoxymethyl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1 -yl)methanone;
(4-{[2-({6-[6-(methoxymethyl)pyrimidin-4-yl]-1 H-benzimidazol-2-yl}amino)pyridin-4- yl]methyl}piperazin-1 -yl)[1 -(trifluoromethyl)cyclopropyl]methanone; tert-butyl 4-{[2-({6-[6-(cyclopropylmethoxy)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate;
1 -(4-{[2-({6-[6-(cyclopropylmethoxy)pyrimidin-4-yl]-1 H-benzimidazol-2-yl}amino)pyrid yl]methyl}piperazin-1 -yl)-3,3,3-trifluoropropan-1 -one;
cyclopropyl(4-{[2-({6-[6-(cyclopropylmethoxy)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1-yl)methanone;
tert-butyl 4-({2-[(6-{6-[(2-hydroxyethyl)amino]pyrimidin-4-yl}-1 H-benzimidazol-2- yl)amino]pyridin-4-yl}methyl)piperazine-1 -carboxylate;
tert-butyl 4-{[2-({6-[6-(cyclopropylamino)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate;
tert-butyl 4-[(1 R or 1 S)-1 -(2-{[6-(6-chloro-5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazine-1 -carboxylate;
tert-butyl 4-[(1 R or 1 S)-1-(2-{[6-(5-methoxy-6-methylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazine-1-carboxylate;
3,3,3-trifluoro-1 -{4-[(1 R or 1 S)-1 -(2-{[6-(5-methoxy-6-methylpyrimidin-4-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}propan-1 -one;
cyclopropyl{4-[(1 R or 1 S)-1 -(2-{[6-(5-methoxy-6-methylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}methanone;
{4-[(1 R or 1 S)-1-(2-{[6-(5-methoxy-6-methylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}[1-(trifluoromethyl)cyclopropyl]methanone tert-butyl 4-{(1 R or 1 S)-1-[2-({6-[6-(methoxymethyl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate;
3,3,3-trifluoro-1-(4-{(1 R or 1 S)-1 -[2-({6-[6-(methoxymethyl)pyrimidin-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)propan-1 -one;
cyclopropyl(4-{(1 R or 1 S)-1-[2-({6-[6-(methoxymethyl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)methanone;
tert-butyl 4-[(1 R or 1 S)-1 -(2-{[6-(6-chloropyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazine-1-carboxylate;
tert-butyl 4-{(1 R or 1 S)-1-[2-({6-[6-(cyclopropylmethoxy)pyrimidin-4-yl]-1 H-benzirnidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate;
1 -(4-{(1 R or 1 S)-1-[2-({6-[6-(cyclopropylmethoxy)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)-3,3,3-trifluoropropan-1-one; tert-butyl 4-[(1 R or 1 S)-1-(2-{[6-(1-{[(1 RS)-2,2-difluorocyclopropyl]methyl}-1 H-pyrazol-4-yl)- 7-fluoro-1 H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1-carboxylate;
1 -{4-[(1 R or 1 S)-1 -(2-{[6-(1 -{[(1 RS)-2,2-difluorocyclopropyl]methyl}-1 H-pyrazol-4-yl)-7- fluoro-1 H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}-3,3,3-trffl
one;
cyclopropyl{4-[(1 R or 1 S)-1 -(2-{[6-(1-{[(1 RS)-2,2-difluorocyclopropyl]methyl}-1 H-pyrazol-4- yl)-7-fluoro-1 H-benzimidazol-2-yl]amino}pyridin-4-yl)et yl]piperazin-1-yl}meth
1 - (4-{(1 R or 1 S)-1-[2-({6-[1-(2,2-difluoroethyl)-1 H-pyrazol-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)-3,3,3-trifluoropropan-1-one;
cyclopropyl(4-{(1 R or 1 S)-1 -[2-({6-[1-(2,2-difluoroethyl)-1 H-pyrazol-4-yl]-1 H-benzimidazol-
2- yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)methanone;
tert-butyl 4-{(1 R or 1 S)-1-[2-({5-[1 -methyl-3-(trifluoromethyl)-1 H-pyrazol-5-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1-carboxylate;
3,3,3-trifluoro-1 -(4-{(1 R or 1 S)-1 -[2-({6-[1 -methyl-3-(trifluoromethyl)-1 H-pyrazol-5-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)propan-1 -one;
cyclopropyl(4-{(1 R or 1 S)-1-[2-({6-[1-methyl-3-(trifluoromethyl)-1 H-pyrazol-5-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)methanone;
tert-butyl 4-[(1 R or 1 S)-1-(2-{[6-(1 ,3-dimethyl-1 H-pyrazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazine-1-carboxylate;
1-{4-[(1 R or 1 S)-1 -(2-{[6-(1 ,3-dimethyl-1 H-pyrazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}-3,3,3-trifluoropropan-1-one;
cyclopropyl{4-[(1 R or 1 S)-1-(2-{[6-(1 ,3-dimethyl-1 H-pyrazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)et yl]piperazin-1 -yl}methanone;
tert-butyl 4-({2-[(6-{6-[(3-methoxypropyl)amino]pyrimidin-4-yl}-1 H-benzimidazol-2- yl)amino]pyridin-4-yl}methyl)piperazine-1 -carboxylate;
3,3,3-trifluoro-1 -[4-({2-[(6-{6-[(3-methoxypropyl)amino]pyrimidin-4-yl}-1 H-benzimidazol-2- yl)amino]pyridin-4-yl}methyl)piperazin-1-yl]propan-1 -one;
tert-butyl 4-[(2-{[6-(6-ethylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate;
1 -{4-[(2-{[6-(6-ethylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}-3,3,3-trifluoropropan-1 -one;
cyclopropyl{4-[(2-{[6-(6-ethylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone; tert-butyl 4-{[2-({6-[6-(3,5-dimethyl-1 ,2-oxazol-4-yl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate;
1 -(4-{[2-({6-[6-(3,5-dimethyl-1 ,2-oxazol-4-yl)pyri^^
yl}amino)pyridin-4-yl]methyl}piperazin-1-yl)-3,3,3-trifluoropropan-1 -one;
3,3,3-trifluoro-1-(4-{[2-({6-[6-(pyrrolidin-1 -yl)pyrimidin-4-yl]-1 H-benz^
yl}amino)pyridin-4-yl]methyl}piperazin-1 -yl)propan-1 -one;
3,3,3-trifluoro-1 -(4-{[2-({6-[6-(morpholin-4-yl)pyrimidin-4-yl]-1 H-benzi
yl}amino)pyridin-4-yl]methyl}piperazin-1-yl)propan-1 -one;
3,3,3-trifluoro-1-(4-{[2-({6-[6-(methylsulfanyl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1-yl)propan-1 -one;
cyclopropyl(4-{[2-({6-[6-(methylsulfanyl)pyrimidin-4-yl]-1 H-benzimidazol-2-yl}amino)pyri 4-yl]methyl}piperazin-1-yl)methanone;
tert-butyl 4-{[2-({6-[6-(2-hydroxypropan-2-yl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate;
3,3,3-trifluoro-1 -(4-{[2-({6-[6-(2-hydroxypropan-2-yl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1-yl)propan-1 -one;
(rac)-tert-butyl 4-({2-[(6-{6-[1-hydroxyethyl]pyrimidin-4-yl}-1 H-benzimidazol-2- yl)amino]pyridin-4-yl}methyl)piperazine-1 -carboxylate;
(rac)-3,3,3-trifluoro-1-[4-({2-[(6-{6-[1 -hydroxyethyl]pyrimidin-4-yl}-1 H-benzimidazol-2- yl)amino]pyridin-4-yl}methyl)piperazin-1-yl]propan-1 -one;
1 -{4-[(2-{[6-(6-acetylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}-3,3,3-trifluoropropan-1 -one;
tert-butyl 4-[(1 R or 1 S)-1-(2-{[7-chloro-6-(6-methylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazine-1-carboxylate;
1 -{4-[(1 R or 1 S)-1-(2-{[7-chloro-6-(6-methylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}-3,3,3-trifluoropropan-1-one;
{4-[(1 R or 1 S)-1-(2-{[7-chloro-6-(6-methylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}(cyclopropyl)methanone;
1-(4-{(1 R or 1 S)-1 -[2-({7-chloro-6-[6-(methoxymethyl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)-3,3,3-trifluoropropan-1-one;
1-(4-{(1 R or 1 S)-1-[2-({6-[6-(dimethylamino)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)-3,3,3-trifluoropropan-1-one; cyclopropyl(4-{(1 R or 1 S)-1 -[2-({6-[6-(dirnethylamino)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)methanone;
4- [(2^[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4 yl)methyl]piperazine-1-carbaldehyde;
N-(4 [4-(2-fluorophenyl)piperazin-1 -yl]methyl}pyridin-2-yl)-6-(3-methyl-1 ,2,4-oxadiazol-5- yl)-1 H-benzimidazol-2-amine;
6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-N-(4-{[4-(3-methylphenyl)piperazin-1-yl]methyl}pyridin yl)-1 H-benzimidazol-2-amine;
6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-N-{4-[(4-phenylpiperazin-1 -yl)methyl]pyridin-2-yl}-1 H- benzimidazol-2-amine;
6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-N-(4-{[4-(pyrimidin-2-yl)piperazin-1-yl]methyl}pyridin yl)-1 H-benzimidazol-2-amine;
1 - {4-[(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2-yl]amino}pyri^
yl)methyl]piperazin-1-yl}ethanone;
N-(4-{[4-(2-methoxyphenyl)piperazin-1 -yl]methyl}pyridin-2-yl)-6-(3-methyl-1 ,2,4-oxadiazol-
5- yl)-1 H-benzimidazol-2-amine;
6- (3-methyl-1 ,2^-oxadiazol-5-yl)-N-[4-({4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1 - yl}methyl)pyridin-2-yl]-1 H-benzimidazol-2-amine;
N-(4 [4-(3-fluorophenyl)piperazin-1 -yl]methyl}pyridin-2-yl)-6-(3-methyl-1 ,2,4-oxadiazol-5- yl)-1 H-benzimidazol-2-amine;{4-[(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1-yl}(phenyl)methanone;
N-(4-{[4-(2,4-difluorophenyl)piperazin-1-yl]m^
5- yl)-1 H-benzimidazol-2-amine;
6- (3-methyl-1 ,2,4-oxadiazol-5-yl)-N-(44[4-(pyridin-4-yl)piperazin-1 -yl]methyl}pyridin-2-y^ 1 H-benzimidazol-2-amine;
6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-N-(4 [4-(pyrazin-2-yl)piperazin-1 -yl]methyl}pyridin-2-yl)- 1 H-benzimidazol-2-amine;
furan-2-yl{4-[(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2-yl]amino}pyridin yl)methyl]piperazin-1 -yl}methanone;
6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-N-(4-{[4-(pyridin-2-yl)piperazin-1 -yl]methyl}pyridin-2^ 1 H-benzimidazol-2-amine;
2- hydroxy-2-methyl-1 -{4-[(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}propan-1 -one; N-(4-{[4-(3-methoxypyridin-2-yl)piperazin-1 -yl]methyl}pyridin-2-yl)-6-(3-methyl-1 ,2,4- oxadiazol-5-yl)-1 H-benzimidazol-2-amine;
4 4-[(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)met yl]piperazin-1 -yl}benzonitrile;
6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-N-(4-{[4-(6-methylpyridin-2-yl)piperazin-1 - yl]methyl}pyridin-2-yl)-1 H-benzimidazol-2-amine;
4-[(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxamide;
N-(4-{[4-(3,4-difluorophenyl)piperazin-1-yl]methyl}pyridin-2-yl)-6-(3-methyl-1 ,2,4-oxadiazol- 5-yl)-1 H-benzimidazol-2-amine;
2 4 (2 [6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}pyridine-3-carbonitrile;
N-(4-{[4-(3,5-dic loropyridin-4-yl)piperazin-1 -yl]methyl}pyridin-2-yl)-6-(3-methyl-1 ,2,4- oxadiazol-5-yl)-1 H-benzimidazol-2-amine;
{4-[(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}(thiophen-2-yl)methanone;
{4-[(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}(pyridin-3-yl)methanone;
6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-N-(4-{[4-(1 ,3,5-triazin-2-yl)piperazin-1 -yl]methyl}pyridin- 2-yl)-1 H-benzimidazol-2-amine;
1 4-[(2-{[6-(3-methyl-1 ,2^-oxadiazol-5-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4^ yl)methyl]piperazin-1 -yl}propan-1 -one;
N-(4-{[4-(6-chloropyrazin-2-yl)piperazin-1 -yl]methyl}pyridin-2-yl)-6-(3-methyl-1 ,2,4- oxadiazol-5-yl)-1 H-benzimidazol-2-amine;
6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-N-(4-{[4-(4-methylpyridin-2-yl)piperazin-1 - yl]methyl}pyridin-2-yl)-1 H-benzimidazol-2-amine;
{4-[(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}(pyrrolidin-1 -yl)methanone;
cyclopropyl{4-[(2 [6-(2,6-dimethylpyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone;
4 2-[(4 [4-(cyclopropylcarbonyl)piperazin-1 -yl]methyl}pyridin-2-yl)amino]-1 H- benzimidazol-6-yl}pyridine-3-carbonitrile; 3,3,3-trifluoro-1-{4-[(2-{[6-(2-methyl^
yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}propan-1 -one;
3,3,3-trifluoro-1-{4-[(2-{[6-(thieno[2,3-d]pyrimidin-4-yl)-1 H-benzimidazol^
4-yl)methyl]piperazin-1-yl}propan-1-one;
3,3,3-trifluoro-1-(4-{[2-({6-[3-(trifluoromethyl)pyridin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1-yl)propan-1 -one;
tert-butyl 4-{[2-({6-[6-(dimethylamino)-5-methoxypyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate;
cyclopropyl(4-{[2-({6-[6-(dimethylamino)-5-methoxypyrimidin-4-yl]-1 H-benzimi yl}amino)pyridin-4-yl]methyl}piperazin-1-yl)methanone;
1 -(4-{[2-({6-[6-(dimethylamino)-5-methoxypyrimidin-4-yl]-1 H-benzimidazol^
yl}amino)pyridin-4-yl]methyl}piperazin-1-yl)-3,3,3-trifluoropropan-1 -one;
tert-butyl 4-{(1 R or 1 S)-1-[2-({6-[6-(dimethylamino)-5-methoxypyrimidin-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate;
cyclopropyl(4-{(1 R or 1 S)-1 -[2-({6-[6-(dimethylamino)-5-methoxypyrimidin-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)methanone;
1 -(4-{(1 R or 1 S)-1 -[2-({6-[6-(dimethylamino)-5-methoxypyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)-3,3,3-trifluoropropan-1-one;
(4-{(1 R or 1 S)-1-[2-({6-[6-(dimethylamino)-5-methoxypyrimidin-4-yl]-1 H-benzim yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)[1-(trifluoromethyl)cyclopropyl]methanon tert-butyl 4-{[2-({6-[6-(cyclopropylamino)-5-methoxypyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate;
1-(4-{[2-({6-[6-(cyclopropylamino)-5-methoxypyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1-yl)-3,3,3-trifluoropropan-1 -one;
cyclopropyl(4-{[2-({6-[6-(cyclopropylamino)-5-meth^
yl}amino)pyridin-4-yl]methyl}piperazin-1-yl)methanone;
tert-butyl 4-({2-[(6-{6-[(cyclopropylmethyl)amino]-5-met oxypyrimidin-4-yl}-1 H- benzimidazol-2-yl)amino]pyridin-4-yl}methyl)piperazine-1 -carboxylate;
1 -[4-({2-[(6-{6-[(cyclopropylmet yl)amino]-5-methoxypyrimidin-4-yl}-1 H-benzimidazol-2- yl)amino]pyridin-4-yl}methyl)piperazin-1-yl]-3,3,3-trifluoropropan-1 -one;
cyclopropyl[4-({2-[(6-{6-[(cyclopropylmethyl)amino]-5-methoxypyrimidin-4-yl}-1 H- benzimidazol-2-yl)amino]pyridin-4-yl}methyl)piperazin-1-yl]methanone; tert-butyl 4-[(1 R or 1 S)-1-{2-[(6 6-[(cyclopropylmethyl)amino]-5-methoxypyrimidin-4-yl}- 1 H-benzimidazol-2-yl)amino]pyridin-4-yl}ethyl]piperazine-1 -carboxylate;
cyclopropyl{4-[(1 R or 1 S)-1 -{2-[(6 6-[(cyclopropylmethyl)amino]-5-methoxypyrimidin-4-yl}- 1 H-benzimidazol-2-yl)amino]pyridin-4-yl}ethyl]piperazin-1-yl}methanone;
1 -{4-[(1 R or 1 S)-1 -{2-[(6-{6-[(cyclopropylmethyl)amino]-5-met oxypyrimidin-4-yl}-1 H- benzimidazol-2-yl)amino]pyridin-4-yl}ethyl]piperazin-1 -yl}-3,3,34rifluoropropan tert-butyl 4-({2-[(6-{6-[(cyclopropylmethyl)(methyl)amino]-5-methoxypyrimidin-4-yl}-1 H- benzimidazol-2-yl)arnino]pyridin-4-yl}met yl)piperazine-1 -carboxylate;
cyclopropyl[4-({2-[(6-{6-[(cyclopropylmethyl)(methyl)amino]-5-methoxypyrimidin-4-yl}-1 H benzimidazol-2-yl)amino]pyridin-4-yl}methyl)piperazin-1-yl]methanon
[4-({2-[(6-{6-[(cyclopropylmethyl)(methyl)amino]-5-methoxypyrimidin-4-yl}-1 H- benzimidazol-2-yl)amino]pyridin-4-yl}methyl)piperazin-1 -yl][1 -
(trifluoromethyl)cyclopropyl]methanone;
1 -[4-({2-[(6-{6-[(cyclopropylmethyl)(methyl)amino]-5-methoxypyrimidin-4-yl}-1 H- benzimidazol-2-yl)amino]pyridin-4-yl}methyl)pip^
tert-butyl 4-{(1 R or 1 S)-1-[2-({6-[6-(azetidin-1 -yl)-5-methoxypyrimidin-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1-carboxylate;
(4-{(1 R or 1 S)-1-[2-({6-[6-(azetidin-1-yl)-5-methoxypyrimid^
yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)(cyclopropyl)methanone;
1 -(4-{(1 R or 1 S)-1 -[2-({6-[6-(azetidin-1-yl)-5-methoxypyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)-3,3,3-trifluoropropan-1 -one;
tert-butyl 4-{(1 R or S)-1 -[2-({6-[5-methoxy-6-(pyrrolidin-1-yl)pyrimidin-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]et yl}piperazine-1-carboxylate;
cyclopropyl(4-{(1 R or 1 S)-1 -[2-({6-[5-methoxy-6-(pyrrolidin-1 -yl)pyrimidin-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)methanone;
3,3,3-trifluoro-1-(4-{(1 R or 1 S)-1 -[2-({6-[5-methoxy-6-(pyrrolidin-1 -yl)pyrimidin-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)propan-1 -one;
tert-butyl 4-{(1 R or 1 S)-1-[2-({6-[6-(3,3-difluoroazetidin-1 -yl)-5-methoxypyrimidin-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate;
1-(4-{(1 R or 1 S)-1-t2-({6-[6-(3,3-difluoroazetidin-1 -yl)-5-methoxypyrimidin-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)-3,3,3-trifluorop
cyclopropyl(4-{(1 R or 1 S)-1-[2-({6-[6-(3,3-difluoroazetidin-1 -yl)-5-methoxypyrimidin-4-yl]- 1 H-benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)methanone; tert-butyl 4-{(1R or 1S)-1-[2-({6-[6-(cyclobutylamino)-5-methoxypyrimidin-4-yl]-1H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1-carboxylate;
tert-butyl 4-{(1R or 1S)-1-[2-({6-[6-(azetidin-1-yl)pyrimidin-4-yl]-1H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazine-1-carboxylate;
1-(4-{(1R or 1S)-1-[2-({6-[6-(azetidin-1-yl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)-3,3,3-trifluoropropan-1-one;
(4-{(1 R or 1S)-1-[2-({6-[6-(azetidin-1-yl)pyrimidin-4-yl]-1 H-benzimidazol-2-yl}amino)pyridin- 4-yl]ethyl}piperazin-1-yl)(cyclopropyl)methanone;
tert-butyl 4-{(1R or 1S)-1-[2-({6-[6-(3,3-difluoroazetidin-1-yl)pyrimidin-4-yl]-1H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate;
cyclopropyl(4-{(1 R or 1S)-1-[2-({6-[6-(3,3-difluoroazetidin-1-yl)pyrimidin-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)methanone;
1- (4-{(1Ror 1S)-1-[2-({6-[6-(3,3-difluoroazetidin-1-yl)pyrimidin-4-yl]-1H-ben
yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)-3,3,3-trifluoropropan-1-one;
(4-{(1R or 1S)-1-[2-({6-[6-(3,3-difluoroazetidin-1-yl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)t1-(trifluoromethyl)cyclopropyl]methano tert-butyl 4-{(1R or 1S)-1-[2-({6-[6-(pyrrolidin-1-yl)pyrimidin-4-yl]-1H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate;
cyclopropyl(4-{(1 R or 1S)-1-[2-({6-[6-(pyrrolidin-1-yl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)methanone;
3,3,3-trifluoro-1-(4-{(1Ror 1S)-1-[2-({6-[6-(pyrrolidin-1-yl)pyrimidin-4-yl]-1 H-benzimidazol-
2- yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)propan-1-one;
tert-butyl 4-{(1R or 1S)-1-[2-({6-[6-(morpholin-4-yl)pyrimidin-4-yl]-1H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate;
cyclopropyl(4-{(1R or 1S)-1-[2-({6-[6-(morpholin-4-yl)pyrimidin-4-yl]-1H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)methanone;
3,3,3-trifluoro-1-(4-{(1R or 1S)-1-[2-({6-[6-(morpholin-4-yl)pyrimidin-4-yl]-1 H-benzimidazol- 2-yl}arnino)pyridin-4-yl]et yl}piperazin-1-yl)propan-1-one;
(4-{(1 R or 1 S)-1 -[2-({6-[6-(morpholin-4-yl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)[1-(trifluoromethyl)cydopropyl]methan tert-butyl 4-{(1R or 1S)-1-[2-({6-[6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl]-1H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate; tert-butyl 4-{(1R or 1S)-1-[2-({6-[1-(cyclopropylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl]-1H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1-carboxylate;
1-(4-{(1Ror 1S)-1-[2-({6-[1-(cyclopropylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl]-1H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)-3,3,3 rifluoropropan-1-on tert-butyl 4-{(1R or 1S)-1-[2-({6-[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]-7-fluoro-1H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1-carboxylate;
1- (4-{(1 R or 1S)-1-[2-({6-[1-(cyclopropylmethyl)-1 H-pyrazol-4-yl]-7-fluoro-1 H-benzimidazol-
2- yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)-3,3,3-trifluoropropan-1-one;
cyclopropyl(4-{(1R or 1S)-1-[2-({6-[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]-7-fluoro-1H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)methanone;
tert-butyl 4-{(1R or 1S)-1-[2-({7-chloro-6-[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]-1H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1-carboxylate;
1- (4-{(1Ror 1S)-1-[2-({7-chloro-6-[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]-1H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)-3,3,3-trifluoropropan-1-one; (4-{(1R or 1S)-1-[2-({7-chloro-6-[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]-1H-benzimidazol-
2- yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)(cyclopropyl)methanone;
tert-butyl 4-[(1R or 1S)-1-(2-{[6-(1-methyl-1H-pyrazol-5-yl)-1H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazine-1-carboxylate;
3,3,3-trifluoro-1-{4-[(1Ror 1S)-1-(2-{[6-(1-methyl-1H-pyrazol-5-yl)-1H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}propan-1-one;
cyclopropyl{4-[(1R or 1S)-1-(2-{[6-(1-methyl-1H-pyrazol-5-yl)-1H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}rrietrianone;
3,3,3-trifluoro-1-{4-[(2-{[6-(1H-pyrazol-5-yl)-1H-benzimidazol-2-yl]amino}pyn
yl)methyl]piperazin-1-yl}propan-1-one;
tert-butyl 4-[(5-bromo-2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazine-1-carboxylate;
1 -{4-[(5-bromo-2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}-3,3,3-trifluoropropan-1 -one;
1 -(4-{[2-({6-[5-(cyclobutylmethyl)-1 ,3,4-oxadiazol-2-yl]-1 H-benzimidazol-2-yl}amino)pyridin- 4-yl]methyl}piperazin-1-yl)-3,3,3-trifluoropropan-1-one;
tert-butyl 4-[(2-{[6-(3-chloro-2-methylpyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1-carboxylate; tert-butyl 4-[(2-{[6-(5-fluoro-2-methylpyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate;
tert-butyl 4-[(2-{[6-(3-chloro-5-fluoropyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate;
tert-butyl 4-[(2-{[6-(3-cyanopyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate;
tert-butyl 4-{[2-({6-[2-(morpholin-4-yl)pyridin-4-yl]-1 H-benzimidazol-2-yl}amino)pyridin-4- yl]methyl}piperazine-1 -carboxylate;
tert-butyl 4-{[2-({6-[2-(dimethylamino)pyridin-4-yl]-1 H-benzimidazol-2-yl}amino)pyridin-4- yl]methyl}piperazine-1 -carboxylate;
tert-butyl 4-[(2-{[6-(2-cyano-6-methylpyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate;
tert-butyl 4-[(2-{[6-(2-fluoropyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate;
tert-butyl 4-[(2-{[6-(2-aminopyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate;
tert-butyl 4-{[2-({6-[2-(difluoromethyl)pyridin-4-yl]-1 H-benzimidazol-2-yl}amino)pyridin-4- yl]methyl}piperazine-1 -carboxylate;
tert-butyl 4-[(2-{[6-(5-bromopyrazin-2-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate;
tert-butyl 4-({2-[(6-{6-[(cyclopropylmethyl)(methyl)amino]pyrimidin-4-yl}-1 H-benzimidazol- 2-yl)amino]pyridin-4-yl}methyl)piperazine-1 -carboxylate;
tert-butyl 4-({2-[(6-{6-[(cyclopropylmethyl)amino]pyrimidin-4-yl}-1 H-benzimidazol-2- yl)amino]pyridin-4-yl}methyl)piperazine-1 -carboxylate;
tert-butyl 4-{[2-({6-[6-(dimethylamino)pyrimidin-4-yl]-1 H-benzimidazol-2-yl}amino)pyrW yl]methyl}piperazine-1 -carboxylate;
Tert-butyl 4-[(2-{[6-(6-chloropyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate;
tert-butyl 4-[(2-{[6-(6-chloro-5-fluoropyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate;
tert-butyl 4-{[2-({6-[5-(dimethylamino)pyrazin-2-yl]-1 H-benzimidazol-2-yl}amino)pyridin-4- yl]methyl}piperazine-1 -carboxylate; tert-butyl 4-{[2-({6-[6-(piperidin-1 -yl)pyrimidin-4-yl]-1 H-benzimidazol-2-yl}amino)pyridin-4- yl]methyl}piperazine-1 -carboxylate;
tert-butyl 4-({2-[(6-{6-[methyl(2,2,2-trifluoroethyl)amino]pyrimidin-4-yl}-1 H-benzimi yl)amino]pyridin-4-yl}methyl)piperazine-1 -carboxylate;
tert-butyl 4-{[2-({6-[6-(azetidin-1 -yl)pyrimidin-4-yl]-1 H-benzimidazol-2-yl}amino)pyridin-4- yl]methyl}piperazine-1 -carboxylate;
tert-butyl 4-({2-[(6-{6-[ethyl(methyl)amino]pyrimidin-4-yl}-1 H-benzimidazol-2- yl)amino]pyridin-4-yl}methyl)piperazine-1-carboxylate;
tert-butyl 4-{[2-({6-[6-(ethylamino)pyrimidin-4-yl]-1 H-benzimidazol-2-yl}amino)pyridin yl]methyl}piperazine-1 -carboxylate;
tert-butyl 4-{[2-({6-[6-(methylamino)pyrimidin-4-yl]-1 H-benzimidazol-2-yl}amino)pyridin yl]methyl}piperazine-1 -carboxylate;
tert-butyl 4-{[2-({6-[6-(cyclopropylamino)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate;
tert-butyl 4-{[2-({6-[6-(cyclobutylamino)pyrimidin-4-yl]-1 H-benzimidazol-2-yl}amino)pyridin-
4-yl]methyl}piperazine-1 -carboxylate;
tert-butyl 4-({2-[(6-{6-[methyl(propan-2-yl)amino]pyrimidin-4-yl}-1 H-benzimidazol-2- yl)amino]pyridin-4-yl}methyl)piperazine-1 -carboxylate ;
tert-butyl 4-{[2-({6-[6-(propan-2-ylamino)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate;
tert-butyl 4-{[2-({6-[6-(diethylamino)pyrimidin-4-yl]-1 H-benzimidazol-2-yl}amino)pyridm yl]methyl}piperazine-1 -carboxylate;
tert-butyl 4-({2-[(6-{6-[cyclobutyl(methyl)amino]pyrimidin-4-yl}-1 H-benzimidazol-2- yl)amino]pyridin-4-yl}methyl)piperazine-1 -carboxylate;
tert-butyl 4-({2-[(6-{6-[cyclopropyl(methyl)amino]pyrimidin-4-yl}-1 H-benzimidazol-2- yl)amino]pyridin-4-yl}methyl)piperazine-1 -carboxylate;
tert-butyl 4-[(2-{[6-(6-{[1 -(trifluoromethyl)cyclopropyl]methoxy}pyrimidin-4-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate;
tert-butyl 4-{[2-({6-[6-(cyclobutylmethoxy)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate;
tert-butyl 4-{[2-({6-[6-(propan-2-yloxy)pyrimidin-4-yl]-1 H-benzimidazol-2-yl}amino)pyridin-4- yl]methyl}piperazine-1 -carboxylate; tert-butyi 4-[(2 [6-(6-ethoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1-carboxylate;
tert-butyl 4 [2-({6-[6-(dimethylamino)-5-fluoropyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate;
1 -{4-[(2-{[6-(3-chloro-2-methylpyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}-3,3,3-trifluoropropan-1-one;
3,3,3-trifluoro-1 -{4-[(2-{t6-(5-fluoro-2-methylpyridin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}propan-1 -one;
1-{4-[(2-{[6-(3-chloro-5-fluoropyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}-3,3,3-trifluoropropan-1-one;
4-{2-[(4-{[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]methyl}pyridin-2-yl)amino]-1 H- benzimidazol-6-yl}pyridine-3-carbonitrile;
3,3,3-trifluoro-1-(4-{[2-({6-[2-(morpholin-4-yl)pyridin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1-yl)propan-1 -one;
1-(4-{[2-({6-[2-(dimethylamino)pyridin-4-yl]-1 H^^
yl]methyl}piperazin-1 -yl)-3,3,3-trifluoropropan-1 -one;
6-methyl-4-{2-[(4-{[4-(3,3,3-trifluoropropanoyl)piperazin-1 -yl]methyl}pyridin-2-yl)amino]-1 H- benzimidazol-6-yl}pyridine-2-carbonitrile;
3,3,3-trifluoro-1-{4-[(2-{[6-(2-fluoropyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}propan-1-one;
1-{4-[(2-{[6-(2-aminopyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}-3,3,3-trifluoropropan-1 -one;
1 -(4-{[2-({6-[2-(difluoromethyl)pyridin-4-yl]-1 H-benzimidazol-2-yl}amino)pyridin-4- yl]methyl}piperazin-1 -yl)-3,3,3-trifluoropropan-1 -one;
1 -{4-[(2-{[6-(5-chloropyrazin-2-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}-3,3,3-trifluoropropan-1 -one ;
1-[4-({2-[(6-{6-[(cyclopropylmethyl)(met yl)amino]pyrimidin-4-yl}-1 H-benzimidazol-2- yl)amino]pyridin-4-yl}methyl)piperazin-1 -yl]-3,3,3-trifluoropropan-1 -one;
1 -[4-({2-[(6-{6-[(cyclopropylmethyl)amino]pyrimidin-4-yl}-1 H-benzimidazol-2- yl)amino]pyridin-4-yl}melhyl)piperazin-1 -yl]-3,3,3-trifluoropropan-1-one;
1 -(4-{[2-({6-[6-(dimethylamino)pyrimidin-4-yl]-1 H-benzimidazol-2-yl}amino)pyridin-4- yl]methyl}piperazin-1 -yl)-3,3,3-trifluoropropan-1 -one; 1 -(4^[2-({6-[5-(dimethylamino)pyrazin-2-yl]-1 H-benzimidazol-2-yl}amino)
yl]methyl}piperazin-1 -yl)-3,3,3-trifluoropropan-1 -one;
3,3,3-trifluoro-1-(4-{[2-({6-[6-(piperidin-1 -yl)pyrimidin-4-yl]-1 H-benzim
yl}amino)pyridin-4-yl]methyl}piperazin-1-yl)propan-1 -one;
3,3,3-trifluoro-1-[4-({2-[(6-{6-[methyl(2,2,2-trifluoroethyl)amino]pyrimidin-4-yl}-^ benzimidazol-2-yl)amino]pyridin-4-yl}methyl)piperazin-1-yl]propan-1 -one;
1 -(4-{[2-({6-[6-(azetidin-1 -yl)pyrimidin-4-yl]-1 H-benzimidazol-2-yl}amin
yl]methyl}piperazin-1-yl)-3,3,3-trifluoropropan-1 -one;
1 -[4-({2-[(6-{6-[ethyl(methyl)amino]pyrimidin-4-yl}-1 H-benzimidazol-2-yl)amin
yl}methyl)piperazin-1 -yl]-3,3,3-trifluoropropan-1 -one;
1 -(4-{[2-({6-[6-(ethylamino)pyrimidin-4-yl]-1 H-benzimidazol-2-yl}amino)pyridin-4- yl]methyl}piperazin-1 -yl)-3,3,3-trifluoropropan-1 -one;
3,3,3-trifluoro-1-(4-{[2-({6-[6-(methylamino)pyrimidin-4-yl]-1 H-benzimidaz
yl}amino)pyridin-4-yl]methyl}piperazin-1-yl)propan-1 -one;
1 -(4-{[2-({6-[6-(cyclopropylamino)pyrimidin-^^
yl]methyl}piperazin-1 -yl)-3,3,3-trifluoropropan-1-one;
1 -(4-{[2-({6-[6-(cyclobutylamino)pyrimidin-4-yl]-1 H-benzimidazol-2-yl}amino)pyridin-4- yl]methyl}piperazin-1 -yl)-3,3,3-trifluoropropan-1 -one;
3,3,3-trifluoro-1 -[4-({2-[(6-{6-[methyl(propan-2-yl)amino]pyrimidin-4-yl}-1 H-benzimidazol-2- yI)amino]pyridin-4-yl}methyl)piperazin-1-yl]propan-1 -one;
3,3,3-trifluoro-1 -(4-{[2-({6-[6-(propan-2-ylamino)pyhmidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]met yl}piperazin-1 -yl)propan-1 -one;
1 -(4-{[2-({6-[6-(diethylamino)pyrimidin-4-yl]-1 H-benzimidazol-2-yl}amino)pyridin-4- yl]methyl}piperazin-1 -yl)-3,3,3-trifluoropropan-1-one;
1 -[4-({2-[(6-{6-[cyclobutyl(methyl)amino]pyrimidin-4-yl}-1 H-benzimidazol-2- yl)amino]pyridin-4-yl}methyl)piperazin-1 -yl]-3,3,3-trifluoropropan-1 -one;
1 -[4-({2-[(6-{6-[cyclopropyl(methyl)amino]pyrimidin-4-yl}-1 H-benzimidazol-2- yl)amino]pyridin-4-yl}methyl)piperazin-1-yl]-3,3,3-trifluoropropan-1-one;
3,3,3-trifluoro-1 -{4-[(2-{[6-(6-{[1-(trifluoromet yl)cyclopropyl]methoxy}pyhmidin-4-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}propan-1 -one;
1 -(4-{[2-({6-[6-(cyclobutylmethoxy)pyrimidin-4-yl]-1 H-benzimidazol-2-yl}amino)pyridin-4- yl]methyl}piperazin-1 -yl)-3,3,3-trifluoropropan-1-one; 3,3,3-trifluoro-1-(4 [2-({6-[6-(propan-2-yloxy)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1-yl)propan-1 -one;
1-{4-[(2-{[6-(6-ethoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}-3,3,3-trifluoropropan-1 -one;
1 -(4-{[2-({6-[6-(dimethylamino)-5-fluoro^
4-yl]methyl}piperazin-1-yl)-3,3,3-trifluoropropan-1 -one;
3,3,3-trifluoro-1-{4-[(2-{[6-(6-methoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]ami yl)methyl]piperazin-1 -yl}propan-1-one;
{4-[(2-{[6-(3-chloro-2-methylpyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}(cyclopropyl)methanone;
cyclopropyl{4-[(2-{[6-(5-fluoro-2-methylpyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone;
{4-[(2-{[6-(3-chloro-5-fluoropyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}(cyclopropyl)methanone;
cyclopropyl(4-{[2-({6-[2-(morp olin-4-yl)pyridin-4-yl]-1 H-benzimidazol-2-yl}amino)pyridin yl]methyl}piperazin-1 -yl)methanone;
cyclopropyl(4-{[2-({6-[2-(dimethylamino)pyridin-4-yl]-1 H-benzimidazol-2-yl}amino)pyridi yl]methyl}piperazin-1 -yl)methanone;
4-{2-[(4-{[4-(cyclopropylcarbonyl)piperazin-1 -yl]methyl}pyridin-2-yl)amino]-1 H- benzimidazol-6-yl}-6-methylpyridine-2-carbonitrile;
cyclopropyl{4-[(2-{[6-(2-fluoropyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone;
{4-[(2-{[6-(2-aminopyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4-yl)methyl]pi 1 -yl}(cyclopropyl)methanone;
cyclopropyl(4-{[2-({6-[2-(difluoromethyl)pyridin-4-yl]-1 H-benzimidazol-2-yl}amino)pyridin yl]methyl}piperazin-1 -yl)methanone;
{4-[(2-{[6-(5-chloropyrazin-2-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4-yl)methyl]piperazin 1 -yl}(cyclopropyl)methanone;
cyclopropyl[4-({2-[(6-{6-[(cyclopropylmethyl)(methyl)amino]pyrimidin-4-yl}-1 H- benzimidazol-2-yl)amino]pyridin-4-yl}methyl)piperazin-1 -yl]methanone;
cyclopropyl[4-({2-[(6-{6-[(cyclopropylmethyl)amino]pyrimidin-4-yl}-1 H-benzimidazol-2- yl)amino]pyridin-4-yl}methyl)piperazin-1-yl]methanone; cyclopropyl(4-{[2-({6-[6-(dimethylamino)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1 -yl)methanone;
cyclopropyl(4 [2-({6-[5-(dimethylamino)pyrazin-2-yl]-1 H-benzimidazol-2-yl}amino)pyridin^ 4-yl]methyl}piperazin-1 -yl)methanone;
cyclopropyl(4-{[2-({6-[6-(piperidin-1-yl)pyrimidin-4-yl]-1 H-benzimidazol-2-yl}amino)pyri 4-yl]methyl}piperazin-1-yl)methanone;
cyclopropyl[4-({2-[(6-{6-[ethyl(methyl)amino]pyrimidin-4-yl}-1 H-benzimidazol-2- yl)amino]pyridin-4-yl}methyl)piperazin-1 -yl]methanone;
cyclopropyl(4-{[2-({6-[6-(ethylamino)pyrimidin-4-yl]-1 H-benzimidazol-2-yl}amino)pyridi yl]methyl}piperazin-1-yl)methanone;
cyclopropyl(4-{[2-({6-[6-(methylamino)pyrimi
4-yl]methyl}piperazin-1-yl)methanone;
cyclopropyl(4-{[2-({6-[6-(cyclopropylamino)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1 -yl)methanone;
(4-{[2-({6-[6-(cyclobutylamino)pyrimidin-4-yl]-1 H-benzimidazol-2-yl}amino)pyridin-4- yl]methyl}piperazin-1 -yl)(cyclopropyl)methanone;
cyclopropyl[4-({2-[(6-{6-[methyl(propan-2-yl)amino]pyrimidin-4-yl}-1 H-benzimidazol-2- yl)amino]pyridin-4-yl}methyl)piperazin-1-yl]methanone;
cyclopropyl(4-{[2-({6-[6-(propan-2-ylamino)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1-yl)methanone;
cyclopropyl(4-{[2-({6-[6-(diethylamino)pyrimidin-4-yl]-1 H-benzimidazol-2-yl}amino)pyridi 4-yl]methyl}piperazin-1 -yl)methanone;
[4-({2-[(6-{6-[cyclobutyl(methyl)amino]pyrimidin^-yl}-1 H-benzimidazol-2-yl)amino]pyri 4-yl}methyl)piperazin-1 -yl](cyclopropyl)methanone;
cyclopropyl[4-({2-[(6-{6-[cyclopropyl(methyl)amino]pyrimidin-4-yl}-1 H-benzimidazol-2- yl)amino]pyridin-4-yl}methyl)piperazin-1 -yl]methanone;
cyclopropyl{4-[(2-{[6-(6-{[1 -(trifluoromethyl)cyclopropyl]methoxy}pyrimidin-4-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)methyl]piperazin-1-yl}methanone;
cyclopropyl(4-{[2-({6-[6-(propan-2-yloxy)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1-yl)methanone;
cyclopropyl{4-[(2-{[6-(6-ethoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone; cyclopropyl{4-[(2-{[6-(6-methoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone;
{4-[(2 [6-(3-methoxypyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}[1 -(trifluoromethyl)cyclopropyl]methanone;
((1 RS)-2,2-difluorocyclopropyl){4-[(2-{[6-(3-methoxypyridin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1-yl}methanone;
2-hydroxy-1-{4-[(2-{[6-(3-methoxypyridin-4-yl)-1 H-benzimidazol-2 -yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}-2-methylpropan-1 -one;
2-methoxy-1 -{4-[(2-{[6-(3-methoxypyridin-4-yl)-1 H-benzimidazol-2-yi]amino}pyridin-4- yl)methyl]piperazin-1 -yl}-2-methylpropan-1 -one;
{4-[(1 R or 1 S)-1-(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2-yl]amino}pyridin- 4-yl)ethyl]piperazin-1 -yl}[1 -(trifluoromethyl)cyclopropyl]methanone;
((1 RS)-2,2-difluorocyclopropyl){4-[(1 R or 1 S)-1 -(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}methanone;
2-hydroxy-2-methyl-1 -{4-[(1 R or 1 S)-1-(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}propan-1 -one;
(4-{(1 R or 1 S)-1-[2-({6-[6-(dimethylamino)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)[1 -(trifluoromethyl)cyclopropyl]methanon
1 -(4-{(1 R or 1 S)-1 -[2-({6-[6-(cyclobutylamino)-5-methoxypyrimidin-4-yl]-1 H-benzimidazol- 2-yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)-3,3,3-trifluoropropan-1 -one;
(4-{(1 R or 1 S)-1 -[2-({6-[6-(cyclobutylamino)-5-methoxypyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)(cyclopropyl)methanone;
(4-{(1 R or 1 S)-1-[2-({6-[6-(pyrrolidin-1-yl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)[1-(trifluoromethyl)cyclopropyl]meth
((1 RS)-2,2-difluorocyclopropyl)(4-{(1 R or 1 S)-1-[2-({6-[6-(pyrrolidin-1 -yl)pyrimidin-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)methanone;
[(1 RS)-2,2-difluoro-1-methylcyclopropyl](4-{(1 R or S)-1-[2-({6-[6-(pyrrolidin-1 -yl)pyrimidin- 4-yl]-1 H-benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)methanone;
2-hydroxy-2-methyl-1 -(4-{(1 R or 1 S)-1 -[2-({6-[6-(pyrrolidin-1 -yl)pyrimidin-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)propan-1 -one;
3,3,3-trifluoro-1-(4-{(1 R)-1-[2-({6-[6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl]-1 ^
2-yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)propan-1 -one; cyclopropyl(4-{(1 R or 1 S)-1-[2-({6-[6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)rrietrianone;
(4-{(1 R or 1 S)-1-[2-({6-[6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)[1 -(trifluoromethyl)cyclopropyl]methan
((1 RS)-2,2-difluorocyclopropyl)(4-{(1 R or 1S)-1 -[2-({6-[6-(2,2,2-trifluoroethoxy)pyrimidin-4^ yl]-1 H-benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)methanon
tert-butyl 4-[(1 R or 1 S)-1 -{2-[(6-{6-[3-(trifluoromethyl)azetidin-1 -yl]pyrimidin-4-yl}-1 H- benzimidazol-2-yl)amino]pyridin-4-yl}ethyl]piperazine-1 -carboxylate;
tert-butyl 4-{(1 R or 1 S)-1 -[2-({6-[6-(2,2-difluoropropoxy)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate;
tert-butyl 4-{(1 R or 1 S)-1 -[2-({6-[6-(2,2,3,3,3-pentafluoropropoxy)pyrimidin-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate;
tert-butyl 4-[(2-{[6-(6-ethoxy-5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin 4-yl)methyl]piperazine-1 -carboxylate;
tert-butyl 4-[(2-{[6-(furo[3,2-d]pyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate;
tert-butyl 4-[(1 R or 1 S)-1 -{2-[(6-{1-[(3,3-difluorocyclobutyl)methyl]-1 H-pyrazol-4-yl}-1 H- benzimidazol-2-yl)amino]pyridin-4-yl}ethyl]piperazine-1 -carboxylate;
tert-butyl 4-[(1 R or 1S)-1-(2-{[6-(1 -{[(1 RS)-2,2-dichlorocyclopropyl]methyl}-1 H-pyrazol-4- yl)-1 H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1 -carboxylate;
tert-butyl 4-{(1 R or 1 S)-1 -[2-({6-[1 -(cyclobutylmethyl)-1 H-pyrazol-4-yl]-7-fluoro-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate;
tert-butyl 4-[(1 R or 1 S)-1-(2-{[7-fluoro-6-(6-methylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazine-1 -carboxylate;
tert-butyl 4-{(1 R or 1 S)-1-[2-({7-fluoro-6-[6-(trmuoromethyl)pyrimidin-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate;
3,3,3-trifluoro-1 -{4-[(1 R or 1 S)-1 -{2-[(6-{6-[3-(trifluoromethyl)azetidin-1 -yl]pyrimidin-4-yl}- 1 H-benzimidazol-2-yl)amino]pyridin-4-yl}ethyl]piperazin-1-yl}propan-1-one;
cyclopropyl{4-[(1 R or 1 S)-1 -{2-[(6-{6-[3-(trifluoromethyl)azetidin-1 -yl]pyrimidin-4-yl}-1 H- benzimidazol-2-yl)amino]pyridin-4-yl}ethyl]piperazin-1 -yl}methanone;
{4-[(1 R or 1 S)-1 -{2-[(6-{6-[3-(trifluoromethyl)azetidin-1 -yl]pyrimidin-4-yl}-1 H-benzimidazol- 2-yl)amino]pyridin-4-yl}ethyl]piperazin-1 -yl}[1 -(trifluoromethyl)cyclopropyl]methanone; ((1 RS)-2,2-difluorocyclopropyl){4-[(1 R or 1 S)-1 -{2-[(6-{6-[3-(trifluoromethyl)azetidin-1 - yl]pyrimidin-4-yl}-1 H-benzimidazol-2-yl)amino]pyridin-4-yl}ethyl]piperazi
1 - (4-{(1 R or 1 S)-1-[2-({6-[6-(2)2-difluoropropoxy)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)-3,3,3-trifluoropropan-1-one;
cyclopropyl(4-{(1 R or 1 S)-1-[2-({6-[6-(2,2-difluoropropoxy)pyrimidin-4-yl]-1 H-benzimidazol-
2- yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)methanone;
3,3,3-trifluoro-1 -(4-{(1 R or 1 S)-1-[2-({6-[6-(2,2,3,3,3-pentafluoropropoxy)pyrimidin-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)propan-1 -one;
cyclopropyl(4-{(1 R or 1 S)-1 -[2-({6-[6-(2,2,3,3,3-pentafiuoropropoxy)pyrimidin-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)methanone;
(4-{(1 R or 1 S)-1 -[2-({6-[6-(2,2,3,3,3-pentafluoropropoxy)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)[1-(trifluoromethyl)cyclopropyl]methanone;
((1 RS)-2,2-difluorocyclopropyl)(4-{(1 R or 1 S)-1 -[2-({6-[6-(2,2,3,3,3- pentafluoropropoxy)pyrimidin-4-yl]-1 H-benzimidazol-2-yl}amino)pyridin-4- yl]ethyl}piperazin-1 -yl)methanone;
1 -{4-[(2-{[6-(6-et oxy-5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}-3,3,3-trifluoropropan-1 -one;
cyclopropyl{4-[(2-{[6-(6-ethoxy-5-methoxypyrimidin-4-yl)-1 H-benzirnidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}methanone;
{4-[(2-{[6-(6-ethoxy-5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}[1 -(trifluoromethyl)cyclopropyl]metrianone;
3,3,3-trifluoro-1-{4-[(2-{[6-(furo[3,2-d]pyrimidin-4-yl)-1 H-benzimidazol-2-y^
yl)methyl]piperazin-1 -yl}propan-1-one;
cyclopropyl{4-[(2-{[6-(furo[3,2-d]pyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yljmethanone;
1 -{4-[(1 R or 1 S)-1 -{2-[(6-{1 -[(3,3-difluorocyclobutyl)methyl]-1 H-pyrazol-4-yl}-1 H- benzimidazol-2-yl)amino]pyridin-4-yl}ethyl]piperazin-1-yl}-3,3,3-trifluoropropan
cyclopropyl{4-[(1 R or 1 S)-1 -{2-[(6-{1 -[(3,3-difluorocyclobutyl)methyl]-1 H-pyrazol-4-yl}-1 H- benzimidazol-2-yl)amino]pyridin-4-yl}ethyl]piperazin-1-yl}methanone;
1-{4-[(1 R or 1 S)-1-(2-{[6-(1-{[(1 RS)-2,2-dichlorocyclopropyl]methyl}-1 H-pyrazol-4-yl)-1 H- benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]pi
1- (4-{(1 R or 1 S)-1-[2-({6-[1-(cyclobutylmethyl)-1 H^yrazol-4-yl]-7-fluoro-1 H-benzimidazol-
2- yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)-3,3,3-trifluoropropan-1 -one; (4-{(1 R or 1S)-1-[2-({6-[1-(cyclobutylmethyl)-1 H-pyrazol-4-yl]-7-fluoro-1 H-benzimidazol-2- yl}amino)pyridin^-yl]ethyl}piperazin-1-yl)(cyclopropyl)methanone;
3,3,3-trifluoro-1 -{4-[(1 R or 1 S)-1-(2-{[7-fluoro-6-(6-methylpyrirnidin-4-yl)-1 H-benzimidazol- 2-yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}propan-1 -one;
cyclopropyl{4-[(1 R or 1S)-1-(2-{[7-fluoro-6-(6-methylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1 -yl}methanorie;
{4-[(1 R or 1 S)-1 -(2-{[7-fluoro-6-(6-methylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazin-1-yl}[1-(trifluoromethyl)cyclopropyl]methanon
3,3,3-trifluoro-1 -(4-{(1 R or 1 S)-1 -[2-({7-fluoro-6-[6-(trifluoromethyl)pyrimidin-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)propan-1 -one;
cyclopropyl(4-{(1 R or 1 S)-1 -[2-({7-fluoro-6-[6-(trifluoromethyl)pyrimidin-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)methanone;
(4-{(1 R or 1 S)-1-[2-({7-fluoro-6-[6-(trifluoromethyl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)[1-(trifluoromethyl)cyclopropyl]methanone;
tert-butyl 4-{(1 R or 1 S)-1 -[2-({6-[6-(difluoromethyl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate;
tert-butyl 4-[(2-{[6-(2-chlorothiop en-3-yl)-1 H-benzimidazol-2 -yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate;
tert-butyl 4-[(2-{[6-(morpholin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate;
tert-butyl 4-{[2-({6-[2-(pyrrolidin-1 -yl)pyrimidin-4-yl]-1 H-benzimidazol-2-yl}amino)pyridin-4- yl]methyl}piperazine-1 -carboxylate;
tert-butyl 4-{[2-({6-[2-(dimethylamino)-6-methylpyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate;
tert-butyl 4-{[2-({6-[5-chloro-6-(dimethylamino)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate;
tert-butyl 4-[(2-{[6-(pyrimidin-2-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate;
tert-butyl 4-{[2-({6-[4-(dimethylamino)pyrimidin-2-yl]-1 H-benzimidazol-2-yl}arnino)pyridin-4- yl]methyl}piperazine-1 -carboxylate;
tert-butyl 4-[(2-{[6-(5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate; tert-butyl 4-{[2-({6-[5-methyl-6-(trifluoromethyl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate;
tert-butyl 4-[(2-{[6-(5-methylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate;
tert-butyl 4-[(2-{[6-(6-chloro-2-methoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-
4-yl)methyl]piperazine-1 -carboxylate;
tert-butyl 4-[(2-{[6-(6-chloro-2-methylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4^ yl)methyl]piperazine-1 -carboxylate;
tert-butyl 4-[(2-{[6-(6-chloro-5-fluoropyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate;
tert-butyl 4-[(2-{[6-(3-chloropyrazin-2-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate;
tert-butyl 4-{[2-({6-[6-(dimethylamino)-2-methoxypyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate;
tert-butyl 4-{[2-({6-[6-(dimethylamino)-2-methylpyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate;
tert-butyl 4-({2-[(6-{6-[(cyclobutylmethyl)amino]-5-fluoropyrimidin-4-yl}-1 H-benzimidazol-2- yl)amino]pyridin-4-yl}methyl)piperazine-1 -carboxylate;
tert-butyl 4-{[2-({6-[6-(cyclopropylamino)-5-fluoropyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate;
tert-butyl 4-{[2-({6-[5-fluoro-6-(propan-2-ylamino)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate;
tert-butyl 4-{[2-({6-[6-(cyclobutylamino)-5-fluoropyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate;
tert-butyl 4-({2-[(6-{6-[(cyclopropylmethyl)amino]-5-fluoropyrimidin-4-yl}-1 H-benzimidazol-
2-yl)amino]pyridin-4-yl}methyl)piperazine-1 -carboxylate;
tert-butyl 4-{[2-({6-[3-(dimethylamino)pyrazin-2-yl]-1 H-benzimidazol-2-yl}amino)pyridin-4- yl]methyl}piperazine-1 -carboxylate;
tert-butyl 4-[(1 R or 1 S)-1 -{2-[(6-{6-[(cyclopropylmethyl)(methyl)amino]pyrimidin-4-yl}-1 H- benzimidazol-2-yl)amino]pyridin-4-yl}ethyl]piperazine-1 -carboxylate;
tert-butyl 4-{[2-({6-[6-(3,6-dihydro-2H-pyran-4-yl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate; tert-butyl 4 [2-({6-[6-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate;
1 -(4-{(1 R or 1 S)-1-[2-({6-[6-(difluoromethyl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]et yl}piperazin-1-yl)-3,3,3-trifluoropropan-1 -one;
1 -{4-[(2-{[6-(2-chlorothiophen-3-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}-3,3,3-trifluoropropan-1 -one;
3,3,3-trifluoro-1 4-[(2-{[6-(6-methoxy-2-methylpyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazin-1 -yl}propan-1 -one;
3,3,3-trifluoro-1 -(4-{[2-({6-[2-(pyrrolidin-1 -yl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1-yl)propan-1 -one;
1 -(4-{[2-({6-[2-(dimethylamino)-6-methylpyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1 -yl)-3,3,3-trifluoropropan-1-one;
1 -(4-{[2-({6-[5-chloro-6-(dimethylamino)py^
4-yl]methyl}piperazin-1-yl)-3,3,3-trifluoropropan-1 -one;
3,3,3-trifluoro-1-{4-[(2-{[6-(pyrimidin-2-yl)-1 H-benzimidazol-2-yl]amino}pyr^
yl)methyl]piperazin-1 -yl}propan-1-one;
1 -(4-{[2-({6-[4-(dimethylamino)pyrimidin-2-yl]-1 H-benzimidazol-2-yl}amino)pyridin-4- yl]methyl}piperazin-1 -yl)-3,3,3-trifluoropropan-1 -one;
1-{4-[(2-{[6-(5J-dihydrofuro[3^-d]pyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}-3,3,3-trifluoropropan-1 -one;
3,3,3-trifluoro-1-(4-{[2-({6-[5-methyl-6-(trifluoromethyl)pyrimidin-4-yl]-1 H-benzim yl}amino)pyridin-4-yl]methyl}piperazin-1-yl)propan-1 -one;
3,3,3-trifluoro-1-{4-[(2-{[6-(5-methylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}propan-1 -one;
1 -(4-{[2-({6-[6-(dimethylamino)-2-methoxypyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1 -yl)-3,3,3-trifluoropropan-1 -one;
1-(4-{[2-({6-[6-(dimethylamino)-2-methylpyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1 -yl)-3,3,3-trifluoropropan-1 -one;
1-[4-({2-[(6-{6-[(cyclobutylmethyl)amino]-5-fluoropyrimidin-4-yl}-1 H-benzimidazol-2- yl)amino]pyridin-4-yl}methyl)piperazin-1-yl]-3,3,3-trifluoropropan-1 -one;
1 -(4-{[2-({6-[6-(cyclopropylamino)-5-fluoropyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1-yl)-3,3,3-trifluoropropan-1 -one; 3 , 3 , 3-trif I uoro- 1 -(4-{[2-({6- [5-fl u oro-6-(pro
yl}amino)pyridin-4-yl]methyl}piperazin-1-yl)propan-1 -one;
1 -(4^[2-({6-[6-(cyclobutylamino)-5-fluoropyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1-yl)-3,3,3-trifluoropropan-1 -one;
1 -t4-({2-[(6-{6-[(cyclopropylmethyl)amino]-5-fluoropyrimidin-4-yl}-1 H-benzimidazol-2- yl)amino]pyridin-4-yl}met yl)piperazin-1-yl]-3,3,3-trifluoropropan-1 -one;
1-(4-{[2-({6-[3-(dimethylamino)pyrazin-2-ylH
yl]methyl}piperazin-1 -yl)-3,3,3-trifluoropropan-1 -one;
3 , 3 , 3-trif I uoro- 1 -(4-{[2-({6- [6-(tetraty^
yl}amino)pyridin-4-yl]methyl}piperazin-1-yl)propan-1 -one;
cyclopropyl(4-{(1 R or 1 S)-1-[2-({6-[6-(difluoromethyl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazin-1 -yl)methanone;
{4-[(2-{[6-(2-chlorothiophen-3-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1-yl}(cyclopropyl)methanone;
(4-{[2-({6-[5-chloro-6-(dimethylamino)pyrimidin-4-yl]-1 H-benzimidazol-2-yl}amino)pyridin-
4-yl]methyl}piperazin-1-yl)(cyclopropyl)methanone;
cyclopropyl{4-[(2-{[6-(pyrimidin-2-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazin-1 -yl}methanone;
cyclopropyl(4-{[2-({6-[4-(dimethylamino)pyrimidin-2-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1-yl)methanone;
cyclopropyl{4-[(2-{[6-(5 -dihydrofuro[3,4-d]pyrimidin-4-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)met yl]piperazin-1 -yl}methanone;
cyclopropyl(4-{[2-({6-[5-methyl-6-(trifluoromethyl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-ylJmethyl}piperazin-1 -yl)methanone;
cyclopropyl{4-[(2-{[6-(5-methylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4 yl)methyl]piperazin-1 -yl}methanone;
[4-({2-[(6-{6-[(cyclobutylmethyl)amino]-5-fluoropyrimidin-4-yl}-1 H-benzimidazol-2- yl)amino]pyridin-4-yl}methyl)piperazin-1-yl](cyclopropyl)methanone;
cyclopropyl(4-{[2-({6-[6-(cyclopropylamino)-5-fluoropyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1-yl)methanone;
cyclopropyl(4-{[2-({6-[5-fluoro-6-(propan-2-ylamino)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazin-1 -yl)methanone; (4-{[2-({6-[6-(cyclobutylamino)-5-fluoropyrimidin-4-yl]-1 H-benzimidazol-2-yl}am
4-yl]methyl}piperazin-1 -yl)(cyclopropyl)methanone;
cyclopropyl[4-({2-[(6-{6-[(cyclopropylmethyl)amino]-5-fluoropyrimidin-4-yl}-1 H- benzimidazol-2-yl)amino]pyridin-4-yl}methyl)piperazin-1 -yl]methanone;
cyclopropyl(4-{[2-({6-[3-(dimethylamino)pyrazin-2-yl]-1 H-benzimidazol-2-yl}amino) 4-yl]methyl}piperazin-1-yl)methanone;
{4-[(1 R or 1 S)-1-{2-[(6-{6-[(cyclopropylmethyl)(methyl)amino]pyrimidin-4-yl}-1 H- benzimidazol-2-yl)amino]pyridin-4-yl}ethyl]piperazin-1 -yl}[1-
(trifluoromethyl)cyclopropyl]methanone;
tert-butyl 4-[(2-{[6-(5-fluoro-2-methoxypyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate;
tert-butyl 4-{[2-({6-[3-(2,2,2-trifluoroethoxy)pyridin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate;
tert-butyl 4-{[2-({6-t3-(propan-2-yloxy)pyridin-4-yl]-1 H-benzimidazol-2-yl}amino)pyridin-4- yl]methyl}piperazine-1 -carboxylate;
tert-butyl 4-[(2-{[6-(5-methoxy-2-methylpyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate;
tert-butyl 4-[(2-{[6-(5-ethoxy-2-methylpyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate;
tert-butyl 4-[(2-{[6-(4-methoxypyridin-3-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate;
tert-butyl 4-[(2-{[6-(2-methoxypyridin-3-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate;
tert-butyl (3R)-3-methyl-4-[(2-{[6-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate;
tert-butyl 4-{[2-({6-[3-(2-methylpropyl)-1 ,2,4-oxadiazol-5-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate;
tert-butyl 4-[(2-{[6-(pyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridiri-4- yl)methyl]piperazine-1 -carboxylate;
tert-butyl 4-[(2-methyl-6-{[6-(pyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate;
(rac)-tert-butyl 4-[1-(2-{[6-(pyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)ethyl]piperazine-1 -carboxylate; tert-butyl 4-[(2-{[6-(2-methylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- y I )m ethyl] piperazine- 1 -ca rboxyl ate ;
tert-butyl 4-[(2-methyl-6-{[6-(2-methylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridi yl)methyl]piperazine-1 -carboxylate;
(rac)-tert-butyl 4-[1-(2-{[6-(2-methylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)ethyl]piperazine-1 -carboxylate;
(rac)-tert-butyl 4-[-1-(2-{[6-(2-ethoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)ethyl]piperazine-1-carboxylate;
tert-butyl 4-{[2-({6-[2-(trifluoromethyl)pyrimidin-4-yl]-1 H-benzimidazol-2-yl}amino)pyn yl]methyl}piperazine-1 -carboxylate; i
(rac)-tert-butyl 4-{1 -[2-({6-[6-(trifluoromethyl)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate;
tert-butyl 4-[(2-{[6-(6-methylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate;
(rac)-tert-butyl 4-[1-(2-{[6-(6-methylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)ethyl]piperazine-1 -carboxylate;
tert-butyl 4-[(2-{[6-(2,6-dimethylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1-carboxylate;
tert-butyl 4-[(2-{[6-(5,6-dimethylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate;
(rac)-tert-butyl 4-[1-(2-{[6-(6-methoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)ethyl]piperazine-1 -carboxylate;
tert-butyl 4-[(2-{[6-(5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate;
(rac)-tert-butyl 4-[1-(2-{[6-(5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl )ethyl]piperazi ne- 1 -carboxylate;
tert-butyl 4-[(2-{[6-(1 -methyl-1 H-pyrazol-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate;
tert-butyl 4-[(2-{[6-(1 -methyl-1 H-pyrazol-3-yl)-1 H-benzimidazoI-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate;
tert-butyl 4-{[2-({6-[1 -(cyclopropylmethyl)-2-oxo-1 ,2-dihydropyridin-4-yl]-1 H-benzimidazol- 2-yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate; tert-butyl 4-[(2-{[6-(pyrimidin-5-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1-carboxylate;
tert-butyl 4-[(2-{[6-(2-chloropyrimidin-5-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate;
tert-butyl 4-[(2-{[6-(2-methylpyrimidin-5-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate;
tert-butyl 4-[(2-{[6-(2-cyclopropylpyrimidin-5-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl )m ethyl] pi perazine- 1 -ca rboxyl ate;
tert-butyl 4-{[2-({6-[2-(methylsulfanyl)pyrimidin-5-yl]-1 H-benzimidazol-2-yl}amino)pyridm yl]methyl}piperazine-1 -carboxylate;
tert-butyl 4-[(2-{[6-(3-methoxypyridin-4-yl)-7-(2-methylpropoxy)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate;
tert-butyl 4-[(2-{[7-ethoxy-6-(3-methoxypyridin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate;
tert-butyl 4-[(2-{[6-(1 -ethyl-1 H-pyrazol-4-yl)-7-(2-methylpropoxy)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate;
tert-butyl 4-[(2-{[7-ethoxy-6-(1 -ethyl-1 H-pyrazol·4-yl)-1 H-benzimidazol-2-yl]amino}pyridin- 4-yl)methyl]piperazine-1 -carboxylate;
tert-butyl 4-[(2-{[7-methyl-6-(3-methyl-1 ,2,4-oxadiazo!-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)methyl]piperazine-1 -carboxylate,
tert-butyl 4-{[2-({6-[1 -(2,2,2-trifluoroethyl)-1 H-pyrazol-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate;
tert-butyl 4-{[2-({6-[1 -(cyclobutylmethyl)-1 H-pyrazol-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]methyl}piperazine-1 -carboxylate;
tert-butyl 4-[(2-{[6-(6-chloro-5-methoxypyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-
4-yl)methyl]piperazine-1 -carboxylate;
tert-butyl 4-[(2-{[6-(5-methoxy-6-methylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyri^ 4-yl)methyl]piperazine-1 -carboxylate, and
tert-butyl 4-[(2-{[6-(2-chloropyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate;
tert-butyl 4-[(1 R or 1 S)-1-(2-{[7-chloro-6-(1-{[(1 S)-2,2-difluorocyclopropyl]methyl}-1 H- pyrazol-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4-yl)ethyl]piperazine-1 -carboxylate; tert-butyl 4-[(1 R or 1 S)-1 -(2-{[6-(1 ,4-dimethyl-1 H-pyrazol-5-yl)-1 H-benzimidazol-2- yl]amino}pyridin-4-yl)ethyl]piperazine-1 -carboxylate;
tert-butyl 4-[(2-{[6-(6-cyclopropylpyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate;
tert-butyl 4-[(2-{[6-(6-cyanopyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate;
tert-butyl 4-{[2-({6-[6-(propan-2-yl)pyrimidin-4-yl]-1 H-benzimidazol-2-yl}amino)pyridin-4- yl]methyl}piperazine-1 -carboxylate;
tert-butyl 4-{[2-({6-[6-(methoxymethyl)pyrimidin-4-yl]-1 H-benzimidazol-2-yl}amino)pyridin- 4-yl]methyl}piperazine-1 -carboxylate;
tert-butyl 4-[(2-{[6-(6-chloropyrimidin-4-yl)-1 H-benzimidazol-2-yl]amino}pyridin-4- yl)methyl]piperazine-1 -carboxylate;
tert-butyl 4-{(1 R or 1 S)-1 -[2-({6-[1-(2,2-difluoroethyl)-1 H-pyrazol-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate;
tert-butyl 4-{[2-({6-[6-(pyrrolidin-1-yl)pyrimidin-4-yl]-1 H-benzimidazol-2-yl}amino)pyridin yl]methyl}piperazine-1 -carboxylate;
tert-butyl 4-{[2-({6-[6-(morpholin-4-yl)pyrimidin-4-yl]-1 H-benzimidazol-2-yl}amino)pyrid yl]methyl}piperazine-1 -carboxylate;
tert-butyl 4-{[2-({6-[6-(methylsulfanyl)pyrimidin-4-yl]-1 H-benzimidazol-2-yl}amino)pyridin-4 yl]methyl}piperazine-1 -carboxylate;
tert-butyl 4-{(1 R or 1 S)-1-[2-({7-chloro-6-[6-(methoxymethyl)pyrimidin-4-yl]-1 H- benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate;
tert-butyl 4-{(1 R or 1 S)-1-[2-({6-[6-(dimethylamino)pyrimidin-4-yl]-1 H-benzimidazol-2- yl}amino)pyridin-4-yl]ethyl}piperazine-1 -carboxylate;
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
A method of preparing a compound of general formula (I) according to any one of claims 1 to 9, said method comprising the step of allowing an intermediate compound of general formula (XL) or a salt thereof:
Figure imgf001252_0001
(XL),
in which R1, R3, R4, R5 and R9 are as defined for the compound of general formula (I) according to any one of claims 1 to 9, and in which "#" indicates that the piperazine ring can be either unsubstituted or bridged, or substituted with one or two methyl groups, according to the definition of R2 in general formula (I) according to any one of claims 1 to 9,
to react with one reagent selected from the group (RG) consisting of R12-C(=0)OH, R12- C(=0)-LG7, R130-C(=0)-LG7, R14a(R14)N-C(=0)-LG7, R14a(R14)N-S(=0)2-LG7 and R15- S(=0)2-LG7, in which R12, R13, R14, R14a and R15 are as defined for the^compounds of general formula (I) according to any one of claims 1 to 9, and in which LG7 represents a leaving group,
thereby giving a compound of general formula (I) :
Figure imgf001252_0002
(I).
in which R1, R2, R3, R4 and R5 are as defined for the compound of general formula (I) according to any one of claims 1 to 9.
1 1. A compound of general formula (I) according to any one of claims 1 to 9 for use in the treatment or prophylaxis of a disease.
12. A pharmaceutical composition comprising a compound of general formula (I) according to any one of claims 1 to 9 and one or more pharmaceutically acceptable excipients.
13. A pharmaceutical combination comprising:
• one or more first active ingredients, in particular compounds of general formula (I) according to any one of claims 1 to 9, and
one or more further active ingredients, in particular anticancer agents.
14. Use of a compound of general formula (I) according to any one of claims 1 to 9 for the treatment or prophylaxis of a disease. 15. Use of a compound of general formula (I) according to any one of claims 1 to 9 for the preparation of a medicament for the treatment or prophylaxis of a disease.
16. Use according to claim 11 , 14 or 15, wherein the disease is a hyperproliferative or an inflammatory disorder, such as a cancer, for example.
17. A compound of general formula (XL):
Figure imgf001253_0001
(XL),
in which R1, R3, R4, R5 and R9 are as defined for the compound of general formula (I) according to any one of claims 1 to 9, and in which "#" indicates that the piperazine ring can be either unsubstituted or bridged, or substituted with one or two methyl groups, according to the definition of R2 in general formula (I) according to any one of claims 1 to 9.
18. Use of a compound of general formula (XL)
Figure imgf001253_0002
(XL),
in which R1, R3, R4, R5 and R9 are as defined for the compound of general formula (I) according to any one of claims 1 to 9, and in which "#" indicates that the piperazine ring can be either unsubstituted or bridged, or substituted with one or two methyl groups, according to the definition of R2 in general formula (I) according to any one of claims 1 to 9,
for the preparation of a compound of general formula (I) according to any one of claims 1 to 9.
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