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NZ623098B2 - Substituted benzylindazoles for use as bub1 kinase inhibitors in the treatment of hyperproliferative diseases. - Google Patents
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NZ623098B2 - Substituted benzylindazoles for use as bub1 kinase inhibitors in the treatment of hyperproliferative diseases. - Google Patents

Substituted benzylindazoles for use as bub1 kinase inhibitors in the treatment of hyperproliferative diseases. Download PDF

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Publication number
NZ623098B2
NZ623098B2 NZ623098A NZ62309812A NZ623098B2 NZ 623098 B2 NZ623098 B2 NZ 623098B2 NZ 623098 A NZ623098 A NZ 623098A NZ 62309812 A NZ62309812 A NZ 62309812A NZ 623098 B2 NZ623098 B2 NZ 623098B2
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New Zealand
Prior art keywords
jessb
annotation
indazolyl
methoxy
alkyl
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NZ623098A
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NZ623098A (en
Inventor
Hans Briem
Knut Eis
Jorg Fanghanel
Montalvan Amaury Ernesto Fernandez
Mark Jean Gnoth
Marion Hitchcock
Simon Holton
Philip Lienau
Anne Mengel
Stefan Prechtl
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Bayer Intellectual Property Gmbh
Bayer Pharma Aktiengesellschaft
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Priority claimed from PCT/EP2012/069562 external-priority patent/WO2013050438A1/en
Publication of NZ623098A publication Critical patent/NZ623098A/en
Publication of NZ623098B2 publication Critical patent/NZ623098B2/en

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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01H—NEW PLANTS OR NON-TRANSGENIC PROCESSES FOR OBTAINING THEM; PLANT REPRODUCTION BY TISSUE CULTURE TECHNIQUES
    • A01H6/00—Angiosperms, i.e. flowering plants, characterised by their botanic taxonomy
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    • A01H6/368—Vaccinium, e.g. cranberry, blueberry
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Abstract

Provided are pyrimidine substituted benzylindazoles of the general formula (I), wherein the variables are as defined in the specification. Examples of the compounds include 2-[1-(6-chloro-2-fluoro-3-methylbenzyl)-1H-indazol-3-yl]-5-methoxy-N-(pyridin-4-yl)pyrimidin-4-amine and 2-[1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1H-indazol-3-yl]-5-methoxy-N-(pyridin-4-yl)pyrimidin-4-amine. The compounds are inhibitors of Bub1 kinase. The compounds may be useful in the treatment of cancer. luorobenzyl)-4-methyl-1H-indazol-3-yl]-5-methoxy-N-(pyridin-4-yl)pyrimidin-4-amine. The compounds are inhibitors of Bub1 kinase. The compounds may be useful in the treatment of cancer.

Description

[Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb SUBSTITUTED BENZYLINDAZOLES FOR USE AS BUB1 KINASE INHIBITORS IN THE TREATMENT OF HYPERPROLIFERATIVE DISEASES Field of application of the invention The invention relates to substituted indazole compounds, a process for their production and the use thereof.
BACKGROUND OF THE INVENTION One of the most fundamental characteristics of cancer cells is their ability to sustain chronic proliferation whereas in normal tissues the entry into and progression through the cell divison cycle is tightly controlled to ensure a homeostasis of cell number and maintenance of normal tissue function. Loss of proliferation control was ized as one of the six hallmarks of cancer [Hanahan D and Weinberg RA, Cell 100, 57, 2000; Hanahan D and Weinberg RA, Cell 144, 646, 2011].
The eukaryotic cell division cycle (or cell cycle) ensures the duplication of the genome and its distribution to the daughter cells by passing through a nated and regulated sequence of events. The cell cycle is divided into four successive phases: 1. The G1 phase represents the time before the DNA replication, in which the cell grows and is sensitive to al stimuli. 2. In the S phase the cell replicates its DNA, and 3. in the G2 phase preparations are made for entry into mitosis. 4. In mitosis (M phase), the duplicated chromosomes get separated ted by a spindle device built from microtubules, and cell division into two daughter cells is completed.
To ensure the extraordinary high fidelity required for an accurate distribution of the chromosomes to the daughter cells, the passage through the cell cycle is ly regulated and lled. The s that are ary for the progression [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb through the cycle must be activated at the correct time and are also turned off again as soon as the corresponding phase is passed. Corresponding control points kpoints") stop or delay the progression through the cell cycle if DNA damage is detected, or the DNA replication or the creation of the spindle device is not yet completed. The mitotic checkpoint (also known as spindle checkpoint or e assembly checkpoint) ls the accurate ment of mircrotubules of the spindle device to the kinetochors (the attachment site for microtubules) of the duplicated chromosomes. The mitotic checkpoint is active as long as ched kinetochores are present and generates a wait-signal to give the dividing cell the time to ensure that each kinetochore is attached to a spindle pole, and to correct attachment errors. Thus the mitotic checkpoint prevents a mitotic cell from completing cell division with unattached or erroneously attached chromosomes [Suijkerbuijk SJ and Kops GJ, Biochem. Biophys. Acta 1786, 24, 2008; hio A and Salmon ED, Nat. Rev. Mol. Cell. Biol. 8, 379, 2007]. Once all chores are attached with the mitotic spindle poles in a correct bipolar (amphitelic) fashion, the checkpoint is satisfied and the cell enters anaphase and proceeds through mitosis.
The mitotic checkpoint is established by a complex network of a number of essential proteins, including s of the MAD (mitotic arrest deficient, MAD 1-3) and Bub (Budding uninhibited by benzimidazole, Bub 1-3) families, Mps1 kinase, cdc20, as well as other components [reviewed in Bolanos-Garcia VM and Blundell TL, Trends Biochem. Sci. 36, 141, 2010], many of these being over-expressed in proliferating cells (e.g. cancer cells) and tissues [Yuan B et al., Clin. Cancer Res. 12, 405, 2006]. The major function of an unsatisfied c checkpoint is to keep the anaphase-promoting complex/cyclosome (APC/C) in an inactive state. As soon as the checkpoint gets satisfied the APC/C ubiquitin-ligase targets cyclin B and n for proteolytic degradation leading to separation of the paired chromosomes and exit from mitosis.
Inactive mutations of the Ser/Thr kinase Bub1 prevented the delay in ssion h mitosis upon treatment of cells of the yeast S. cerevisiae with microtubuledestabilizing drugs, which led to the identification of Bub1 as a mitotic checkpoint protein [Roberts BT et al., Mol. Cell Biol., 14, 8282, 1994]. A number of recent [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb publications provide evidence that Bub1 plays multiple roles during mitosis which, have been reviewed by Elowe [Elowe S, Mol. Cell. Biol. 31, 3085, 2011. In particular , Bub1 is one of the first mitotic oint proteins that binds to the kinetochores of duplicated chromosomes and probably acts as a scaffolding protein to constitute the mitotic checkpoint x. Furthermore, via orylation of histone H2A, Bub1 localizes the protein shugoshin to the centromeric region of the chromosomes to prevent premature segregation of the paired chromosomes [Kawashima et al. Science 327, 172, 2010]. In addition, together with a Thr-3 phosphorylated Histone H3 the shugoshin protein functions as a binding site for the chromosomal passenger complex which includes the ns survivin, borealin, INCENP and Aurora B. The chromosomal passenger complex is seen as a tension sensor within the mitotic checkpoint mechanism, which dissolves erroneously formed microtubule-kinetochor attachments such as syntelic (both sister kinetochors are attached to one spindle pole) or merotelic (one kinetochor is attached to two spindle poles) attachments [Watanabe Y, Cold Spring Harb. Symp. Quant.
Biol. 75, 419, 2010].
Incomplete mitotic checkpoint function has been linked with aneuploidy and tumourigenesis [Weaver BA and Cleveland DW, Cancer Res. 67, 10103, 2007; King RW, Biochim s Acta 1786, 4, 2008]. In st, complete inhibition of the c checkpoint has been recognised to result in severe chromosome missegregation and induction of apoptosis in tumour cells [Kops GJ et al., Nature Rev.
Cancer 5, 773, 2005; Schmidt M and Medema RH, Cell Cycle 5, 159, 2006; t M and Bastians H, Drug Res. Updates 10, 162, 2007]. Thus, mitotic checkpoint abrogation through pharmacological inhibition of components of the mitotic checkpoint, such as Bub1 kinase, represents a new approach for the treatment of erative disorders, including solid tumours such as carcinomas, sarcomas, leukaemias and id ancies or other disorders, associated with rolled cellular proliferation.
The present invention relates to chemical nds that inhibit Bub1 kinase.
[Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb Established anti-mitotic drugs such as vinca alkaloids, taxanes or epothilones activate the mitotic checkpoint, ng a mitotic arrest either by stabilising or destabilising microtubule dynamics. This arrest prevents separation of the duplicated chromosomes to form the two daughter cells. Prolonged arrest in mitosis forces a cell either into c exit without cytokinesis (mitotic slippage or adaption) or into mitotic catastrophe leading to cell death [Rieder CL and Maiato H, Dev. Cell 7, 637, 2004]. In contrast, inhibitors of Bub1 prevent the establishment and/or functionality of the mitotic checkpoint, which finally results in severe chromosomal regation , induction of apoptosis and cell death.
These findings suggest that Bub1 inhibitors should be of therapeutic value for the treatment of proliferative disorders associated with enhanced uncontrolled proliferative ar processes such as, for example, cancer, inflammation, arthritis, viral diseases, cardiovascular diseases, or fungal diseases in a warm-blooded animal such as man.
Due to the fact that especially cancer disease as being expressed by uncontrolled proliferative cellular processes in tissues of ent organs of the human- or animal body still is not considered to be a controlled disease in that ient drug therapies already exist, there is a strong need to provide further new therapeutically useful drugs, preferably ting new targets and ing new therapeutic options.
Description of the invention Therefore, inhibitors of Bub1 represent le compounds that should ment therapeutic options either as single agents or in combination with other drugs.
In accordance with a first aspect, the invention relates to compounds of formula (I) [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb (R4) N (R8) R6 (I) in which R1 is hydrogen, halogen, 1-3C-alkyl, R2/R3 are independently from each other hydrogen, n, cyano, hydroxy 1-6C-haloalkyl, 1-6C-haloalkoxy, 1-6C-alkoxy, R4 is independently hydrogen, hydroxy, n, cyano, NO2, 1-6C-alkyl, 2-6C- alkenyl, 2-6C-alkynyl, 1-6C-haloalkyl, 1-6C-hydroxyalkyl, 1-6C-alkoxy, -O-(2-6Calkylen)-O-C(O)-(1-6C-alkyl), 1-6C-haloalkoxy, -C(O)OR9, -(1-6C- alkylen)-C(O)OR9, -C(O)-(1-6C-alkyl), -C(O)NR10R11, 3-7C-cycloalkyl, -S-(1- 6C-haloalkyl), SF5, -(3-7C-cycloalkyl), -SO2NR10R11, NR10R11, heteroaryl which optionally is tuted independently one or more times with cyano, 1-4C-alkyl, 1-6C-haloalkyl, 1-6C-haloalkoxy, 9, C(O)NR10R11, whereby two of R2, R3 (R4)n, when positioned ortho to each other, may form together with the two carbon atoms to which they are attached, a heterocyclic -, 6- or 7-membered ring containing 1 or 2 heteroatoms selected from O or N, and optionally containing an onal double bond and/or optionally tuted by an oxo (=O) group and/or an 1-4C-alkyl group, n 0 - 3 R6 is (a) hydrogen; (b) hydroxy; (c) cyano; (d) 1-6C-alkoxy optionally substituted independently one or more times with (d1) OH, [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb (d2) –O-(1-6C-alkyl) (d3) C(O)OR9, (d4) C(O)NR10R11, (d5) NR10R11, (d6) –S-(1-6C-alkyl), (d7) –S(O)-(1-6C-alkyl), (d8) –SO2-(1-6C-alkyl) (d9) SO2NR10R11, (d10) cyclyl, which is optionally substituted with 9, or oxo (=O), (d11) heteroaryl, which is optionally substituted independently one or more times with cyano, lkyl, 1-6C-haloalkyl, aloalkoxy, C(O)OR9, C(O)NR10R11, alkylen)-O-(1-6C-alkyl), (e) SO2NR10R11, (f) 3-7C-cycloalkoxy, (g) 1-6C-haloalkoxy, (h) COOR9, (i) -C(O)NR10R11, (j) -O-heteroaryl opt. subst. with CN * O O H (k) O , whereby the * is the point of attachment, (l) –O-(2-6C-alkylen)-O-(1-6C-alkyl) which is optionally substituted with hydroxy , NH(CO)OR9, R7 is (a) hydrogen, (b)1-6C-alkyl, which is optionally substituted with heteroaryl (c) 1-6C-haloalkyl, (d) 1-6C-hydroxyalkyl, C H 2 (e) O , whereby the * is the point of attachment, (f) -C(O)-(1-6C-alkyl) [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb (g) –C(O)-(1-6C-alkylen)-O-(1-6C-alkyl) (h) –C(O)-(1-6C-alkylen)-O-(2-6C-alkylen)-O-(1-6C-alkyl) (i) –C(O)-heterocyclyl, (j) benzyl whereby the phenyl ring is opt. subst with 1-5 substituents independently selected from the group consisting of hydrogen, halogen, 1-4C-alkyl, aloalkyl, 1-4C-alkoxy, 1-4C-haloalkoxy, cyano, C(O)OR9, (k) aryl optionally, R6 and R7 er with the nitrogen atom to which R7 is attached form a 6-membered ring which may n one further heteroatom ed from the group consisting of O, S, N, and which is optionally substituted by (1-6C-alkyl)-OH, (1-6C-alkyl)-NR10R11, R8 is hydrogen, halogen, hydroxy, cyano, 1-6C-alkyl, 1-6C-hydroxyalkyl, 1-6C- haloalkyl, 1-6C-haloalkoxy, C(O)OR9, C(O)NR10R11, m is 0-4 R9 is (a) hydrogen, (b) 1-6C-alkyl which optionally is substituted with hydroxy, R10, R11 are independently from each other hydrogen, 1-4C-alkyl, 1-4C- hydroxyalkyl, 1-4C-alkoxy, -(CO)-(1-6C-alkyl), CHO, COOR9, or together with the nitrogen atom to which they are attached form a 4 membered heterocyclic ring optionally containing one r heteroatom selected from the group consisting of O, S or N, and which is optionally substituted with 1-2 fluorine atoms or COOR9, or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer. ing to a further aspect of the invention, the invention relates to compounds of formula (I) wherein R1 is hydrogen, n, 1-3C-alkyl, [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb R2/R3 are independently from each other hydrogen, halogen, cyano, 1-6C- kyl, 1-6C-haloalkoxy, R4 is independently hydrogen, halogen, cyano, 1-6C-alkyl, 2-6C-alkenyl, 1-6C- haloalkyl, 1-6C-hydroxyalkyl, lkoxy, 1-6C-haloalkoxy, R9, -(1- 6C-alkylen)-C(O)OR9, -C(O)-(1-6C-alkyl), -C(O)NR10R11, 3-7C-cycloalkyl, - S-(1-6C-haloalkyl), SF5, -SO2NH-(3cycloalkyl), -SO2NR10R11, heteroaryl which optionally is substituted independently one or more times with cyano, lkyl, 1-6C-haloalkyl, 1-6C-haloalkoxy, C(O)OR9, C(O)NR10R11, whereby two of R2, R3 (R4)n, when positioned ortho to each other, may form together with the two carbon atoms to which they are attached, a heterocyclic -, 6- or 7-membered ring containing 1 or 2 heteroatoms selected from O or N, and optionally an additional double bond and/or a yl group and/or an 1-4C-alkyl group, n 0 - 3 R6 is (a) hydrogen; (b) hydroxy; (c) cyano; (d) 1-6C-alkoxy opt. subst. with (d1) 1-2 OH, (d2) NR10R11, (d3) SO2NR10R11, (d4) heterocyclyl, (d5) heteroaryl, which is optionally substituted independently one or more times with cyano, 1-4Calkyl, 1-6C-haloalkyl, 1-6C-haloalkoxy, C(O)OR9, C(O)NR10R11, (e) SO2NR10R11, (f) 3-7C-cycloalkoxy, (g) aloalkoxy, (h) -C(O)NR10R11, ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb [Annotation] jessb ed set by jessb (i) -O-heteroaryl opt. subst. with CN * O O H (j) O , whereby the * is the point of attachment, R7 is (a) hydrogen, (b)1-6C-alkyl, which is optionally substituted with heteroaryl (c) 1-6C-haloalkyl, (d) 1-6C-hydroxyalkyl, C H 2 (e) O , whereby the * is the point of attachment, (f) -C(O)-(1-6C-alkyl) (g) (1-6C-alkylen)-O-(1-6C-alkyl) (h) –C(O)-(1-6C-alkylen)-O-(1-6C-alkylen)-O-(1-6C-alkyl) (i) –C(O)-heterocyclyl, (j) benzyl whereby the phenyl ring is opt. subst with 1-5 substituents independently selected from the group consisting of hydrogen, halogen, 1-4Calkyl, 1-4C-haloalkyl, 1-4C-alkoxy, 1-4C-haloalkoxy, cyano, (k) heteroaryl optionally R6 and R7 together with the nitrogen atom to which they are attached form a 6-membered ring which may contain one further heteroatom selected from the group consisting of O, S, N, and which is optionally substituted by hydroxy-(1-6alkyl), R8 is hydrogen, halogen, cyano, 1-6C-haloalkyl, 1-6C-haloalkoxy, C(O)OR9, C(O)NR10R11, m is 0-4 R9 is (a) en, (b) 1-6C-alkyl which optionally may be substituted with hydroxy, [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb R10, R11 are independently from each other hydrogen, 1-4C-alkyl, 1-4C- hydroxyalkyl, 1-4C-alkoxy, or er with the nitrogen atom to which they are attached form a 5 membered heterocyclic ring optionally containing one further atom selected from the group consisting of O, S or N, or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.
Another aspect of the invention are compounds of formula (I) according to claim 1, wherein R1 is hydrogen, n, 1-3C-alkyl, R2/R3 are ndently from each other hydrogen, halogen, cyano, hydroxy, 1-3C-haloalkyl, 1-3C-haloalkoxy, lkoxy, R4 is independently en, hydroxy, n, cyano, NO2, 1-3C-alkyl, 2-3C- l, 2-3C-alkynyl, 1-3C-haloalkyl, 1-3C-hydroxyalkyl, 1-3C-alkoxy, -O-(2-3C-alkylen)-O-C(O)-(1-3C-alkyl), 1-3C-haloalkoxy, -C(O)OR9, -(1-3C- alkylen)-C(O)OR9, -C(O)-(1-3C-alkyl), -C(O)NR10R11, 3-7C-cycloalkyl, -S-(1- 3C-haloalkyl), SF5, -SO2NH-(3-7C-cycloalkyl), -SO2NR10R11, NR10R11, heteroaryl which optionally is substituted independently one or more times with cyano, lkyl, 1-3C-haloalkyl, 1-3C-haloalkoxy, C(O)OR9, C(O)NR10R11, whereby two of R2, R3 (R4)n, when positioned ortho to each other, may form together with the two carbon atoms to which they are attached, a heterocyclic -, 6- or 7-membered ring containing 1 or 2 heteroatoms ed from O or N, and optionally containing an additional double bond and/or optionally substituted by an oxo (=O) group and/or an 1-3C-alkyl group, n 0 - 3 R6 is (a) hydrogen; (b) hydroxy; (c) cyano; (d) 1-6C-alkoxy optionally substituted independently one or more times with (d1) OH, (d2) –O-(1-3C-alkyl) [Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb (d3) C(O)OR9, (d4) C(O)NR10R11, (d5) 1, (d6) –S-(1-3C-alkyl), (d7) –S(O)-(1-3C-alkyl), (d8) –SO2-(1-3C-alkyl) (d9) SO2NR10R11, (d10) heterocyclyl, which is optionally substituted with C(O)OR9, or oxo (=O), (d11) heteroaryl, which is optionally substituted independently one or more times with cyano, 1-3C-alkyl, 1-3C-haloalkyl, aloalkoxy, C(O)OR9, C(O)NR10R11, (1-3C-alkylen)-O-(1-3C-alkyl), (e) SO2NR10R11, (f) 3-7C-cycloalkoxy, (g) 1-6C-haloalkoxy, (h) COOR9, (i) -C(O)NR10R11, (j) -O-heteroaryl opt. subst. with CN * O O H (k) O , y the * is the point of attachment, (l) –O-(2-3C-alkylen)-O-(1-3C-alkyl) which is optionally substituted with hydroxy , NH(CO)OR9, R7 is (a) hydrogen, (b)1-3C-alkyl, which is optionally substituted with heteroaryl (c) 1-3C-haloalkyl, (d) 1-3C-hydroxyalkyl, C H 2 (e) O , whereby the * is the point of attachment, (f) (1-3C-alkyl) (g) –C(O)-(1-3C-alkylen)-O-(1-3C-alkyl) [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb (h) –C(O)-(1-3C-alkylen)-O-(2-3C-alkylen)-O-(1-3C-alkyl) (i) –C(O)-heterocyclyl, (j) benzyl whereby the phenyl ring is opt. subst with 1-5 substituents ndently selected from the group consisting of hydrogen, halogen, 1-4C-alkyl, lkoxy, 1-4C-haloalkoxy, cyano, C(O)OR9, (k) heteroaryl optionally, R6 and R7 together with the nitrogen atom to which R7 is at- tached form a ered ring which may contain one further heteroatom selected from the group consisting of O, S, N, and which is optionally substituted by (1-3C-alkyl)-OH, (1-3C-alkyl)-NR10R11, R8 is hydrogen, halogen, hydroxy, cyano, 1-3C-alkyl, 1-3C-hydroxyalkyl, 1-3C- haloalkyl, 1-3C-haloalkoxy, C(O)OR9, C(O)NR10R11, m is 0-4 R9 is (a) hydrogen, (b) 1-3C-alkyl which optionally is substituted with y, R10, R11 are independently from each other hydrogen, 1-3C-alkyl, 1-3C- hydroxyalkyl, 1-3C-alkoxy, -(CO)-(1-3C-alkyl), CHO, COOR9 or together with the nitrogen atom to which they are attached form a 4 membered heterocyclic ring ally ning one further heteroatom selected from the group consisting of O, S or N, which is optionally substi- tuted with 1-2 fluorine atoms or COOR9, or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.
A further aspect of the invention are compounds of formula (I) according to claim 1, wherein R1 is hydrogen, halogen, 1-4C-alkyl, ation] jessb None set by jessb [Annotation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb R2/R3 are independently from each other en, halogen, cyano, 1-4C- haloalkyl, 1-4C-haloalkoxy, R4 is independently hydrogen, halogen, cyano, 1-4C-alkyl, 2-4C-alkenyl, 1-4C- haloalkyl, 1-4C-hydroxyalkyl, lkoxy, 1-4C-haloalkoxy, -C(O)OR9, -(1- 4C-alkylen)-C(O)OR9, (1-4C-alkyl), -C(O)NR10R11, 3-6C-cycloalkyl, -S-(1-6C-haloalkyl), SF5, -SO2NH-(3cycloalkyl), -SO2NR10R11, heteroaryl which optionally is substituted independently one or more times with cyano, 1-4C-alkyl, 1-6C-haloalkyl, 1-6C-haloalkoxy, C(O)OR9, C(O)NR10R11, whereby two of R2, R3 (R4)n, when positioned ortho to each other, may form together with the two carbon atoms to which they are attached, a heterocyclic -, 6- or 7-membered ring containing 1 or 2 atoms selected from O or N, and optionally an additional double bond and/or a carbonyl group and/or an 1-4C-alkyl group, n 0 - 3 R6 is (a) hydrogen; (b) hydroxy; (c) cyano; (d) 1-4C-alkoxy opt. subst. with (d1) 1-2 OH, (d2) NR10R11, (d3) SO2NR10R11, (d4) heterocyclyl, (d5) heteroaryl, which is optionally independently one or more times substituted with cyano, lkyl, 1-6C-haloalkyl, 1-6C-haloalkoxy, C(O)OR9, C(O)NR10R11, (e) SO2NR10R11, ; (f) 3-6C-cycloalkoxy, (g) 1-4C-haloalkoxy, (h) -C(O)NR10R11, [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb (i) O-heteroaryl opt. subst. with CN * O O H (j) O , whereby the * is the point of attachment, R7 is (a) hydrogen, (b)1-4C-alkyl, which is optionally substituted with heteroaryl (c) 1-4C-haloalkyl, (d) 1-4C-hydroxyalkyl, C H 2 (e) O , whereby the * is the point of attachment, (f) -C(O)-(1-4C-alkyl) (g) –C(O)-(1-4C-alkylen)-O-(1-4C-alkyl) (h) –C(O)-(1-4C-alkylen)-O-(1-4C-alkylen)-O-(1-4C-alkyl) (i) –C(O)-heterocyclyl, (j) benzyl whereby the phenyl ring is opt. subst with 1-5 substituents independently selected from the group ting of hydrogen, halogen, 1-4C-alkyl, 1-4C-haloalkyl, 1-4C-alkoxy, 1-4C- haloalkoxy, cyano, C(O)OR9, (k) heteroaryl optionally R6 and R7 together with the nitrogen atom to which they are ed form a 6-membered ring which may contain one further heteroatom selected from the group ting of O, S, N, and which is optionally substituted by hydroxy-(1alkyl), R8 is hydrogen, n, 10R11, C(O)OR9, aloalkyl, 1-4C- haloalkoxy, cyano, m is 0-4 R9 is (a) hydrogen, (b) 1-4C-alkyl which optionally may be substituted with hydroxy, [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb R10, R11 are independently from each other hydrogen, 1-4C-alkyl, 1-4C- hydroxyalkyl, 1-4C-alkoxy, or together with the nitrogen atom to which they are attached form a 5 ed heterocyclic ring optionally ning one further heteroatom selected from the group consisting of O, S or N, or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, er or stereoisomer.
Another aspect of the invention are compounds of a (I) according to claim 1, wherein R1 is hydrogen, 1-3C-alkyl, R2/R3 are ndently from each other hydrogen, halogen, cyano, hydroxy, 1-4C-haloalkyl, 1-4C-alkoxy, R4 is independently hydrogen, hydroxy, halogen, cyano, 1-4C-alkyl, 2-4C- alkenyl, 2-4C-alkynyl, 1-4C-haloalkyl, 1-4C-hydroxyalkyl, 1-4C-alkoxy, -O- (2-4C-alkylen)-O-C(O)-(1-4C-alkyl), 1-4C-haloalkoxy, -C(O)OR9, -(1-4C- alkylen)-C(O)OR9, -C(O)-(1-4C-alkyl), -C(O)NR10R11, 3-7C-cycloalkyl, -S-(1- 4C-haloalkyl), SF5, -SO2NH-(3-7C-cycloalkyl), -SO2NR10R11, NR10R11, heteroaryl which optionally is substituted independently one or more times with cyano, 1-4C-alkyl, 1-4C-haloalkyl, 1-4C-haloalkoxy, C(O)OR9, 10R11, y two of R2, R3 (R4)n, when positioned ortho to each other, may form er with the two carbon atoms to which they are attached, a heterocyclic -, 6- or 7-membered ring containing 1 or 2 heteroatoms selected from O or N, and optionally containing an additional double bond and/or optionally substituted by an oxo (=O) group and/or an 1-4C-alkyl group, n 0 - 3 R6 is (a) hydrogen; (b) hydroxy; (d) lkoxy optionally tuted independently one or more times with (d1) OH, (d2) –O-(1-4C-alkyl) (d3) C(O)OR9, [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb (d4) C(O)NR10R11, (d5) NR10R11, (d6) –S-(1-4C-alkyl), (d7) –S(O)-(1-4C-alkyl), (d8) –SO2-(1-4C-alkyl) (d9) 0R11, (d10) heterocyclyl, which is optionally substituted with C(O)OR9, or oxo (=O), (d11) heteroaryl, which is optionally substituted independently one or more times with cyano, 1-4C-alkyl, 1-4C-haloalkyl, 1-4C-haloalkoxy, C(O)OR9, C(O)NR10R11, (1-4C-alkylen)-O-(1-4C-alkyl), (e) SO2NR10R11, (f) ycloalkoxy, (g) 1-6C-haloalkoxy, (h) COOR9, (i) -C(O)NR10R11, (j) -O-heteroaryl opt. subst. with CN * O O H (k) O , whereby the * is the point of attachment, (l) –O-(2-4C-alkylen)-O-(1-4C-alkyl) which is optionally substituted with hy- droxy, NH(CO)OR9, R7 is (a) hydrogen, (b) (1-4C-alkyl)-heteroaryl (c) aloalkyl, (d) 1-4C-hydroxyalkyl, * C H 2 O H (e) O , whereby * is the point of attachment, (f) -C(O)-(1-4C-alkyl) (g) –C(O)-(1-4C-alkylen)-O-(1-4C-alkyl) (h) –C(O)-(1-4C-alkylen)-O-(2-4C-alkylen)-O-(1-4C-alkyl) [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb (i) –C(O)-heterocyclyl, (j) benzyl y the phenyl ring is opt. subst with 1-5 substituents independently selected from the group consisting of en, halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-haloalkoxy, cyano, C(O)OR9, (k) heteroaryl optionally, R6 and R7 er with the nitrogen atom to which R7 is ed form a ered ring which may contain one further heteroatom selected from the group consisting of O, S, N, and which is optionally substituted by alkyl)-OH, (1-4C-alkyl)-NR10R11, R8 is hydrogen, halogen, hydroxy, cyano, C(O)NR10R11, 1-4C-alkyl, 1-4C- hydroxyalkyl, 1-4C-haloalkyl, 1-4C-haloalkoxy, m is 0-2, R9 is hydrogen, 1-4C-alkyl which optionally is substituted with hydroxy, R10, R11 are independently from each other hydrogen, 1-4C-alkyl, 1-4C- hydroxyalkyl, 1-4C-alkoxy, -C(O)-(1-4C-alkyl), or COOR9 or together with the nitrogen atom to which they are attached form a 4 membered heterocyclic ring ally containing one r heteroatom selected from the group consisting of O, S or N, which is optionally substituted with 1-2 fluorine atoms or COOR9, or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.
A further aspect of the ion are compounds of formula (I) according to claim 1, wherein R1 is hydrogen, halogen, R2/R3 are independently from each other hydrogen, halogen, cyano, 1-4C- haloalkyl, R4 is independently hydrogen, halogen, cyano, 1-4C-alkyl, 2-4C-alkenyl, 1-4C- haloalkyl, 1-4C-hydroxyalkyl, 1-4C-alkoxy, 1-4C-haloalkoxy, -C(O)OR9, -(1- 4C-alkylen)-C(O)OR9, -C(O)-(1-4C-alkyl), -C(O)NR10R11, 3-7C-cycloalkyl, ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 4C-haloalkyl), SF5, -SO2NH-(3cycloalkyl), -SO2NR10R11, heteroaryl which optionally is substituted independently one or more times with cyano, 1-4C-alkyl, 1-6C-haloalkyl, 1-6C-haloalkoxy, 9, C(O)NR10R11, whereby two of R2, R3 (R4)n, when positioned ortho to each other, may form together with the two carbon atoms to which they are attached, a heterocyclic -, 6- or 7-membered ring containing 1 or 2 heteroatoms selected from O or N, and optionally an additional double bond and/or a carbonyl group and/or an 1-4C.alkyl group, n 0 - 3 R6 is (a) hydrogen; (b) hydroxy; (d) 1-6C-alkoxy opt. subst. with (d1) 1-2 OH, (d2) NR10R11, (d3) SO2NR10R11, (g) 1-6C-haloalkoxy, * O O H (k) O , whereby * is the point of attachment, R7 is (a) en, (c) 1-6C-haloalkyl, (d) 1-4C-hydroxyalkyl, * C H 2 O H (e) O , y * is the point of attachment, (f) -C(O)-(1-4C-alkyl) (g) –C(O)-(1-4C-alkylen)-O-(1-4C-alkyl) (h) –C(O)-(1-4C-alkylen)-O-(1-4C-alkylen)-O-(1-4C-alkyl) (i) –C(O)-heterocyclyl, (j) benzyl whereby the phenyl ring is opt. subst with 1-5 substituents independently selected from the group consisting of [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb hydrogen, halogen, 1-4C-alkyl, 1-4C-haloalkyl, 1-4C-alkoxy, 1-4C- haloalkoxy, cyano, C(O)OR9, optionally R6 and R7 together with the nitrogen atom to which they are attached form a 6-membered ring which may contain one further heteroatom selected from the group consisting of O, S, N, and which is optionally substituted by hydroxy-(1-4alkyl), R8 is hydrogen, halogen, C(O)NR10R11, 1-4C-haloalkyl, 1-4C-haloalkoxy, cyano, m is 0-2, R9 is 1-4C-alkyl which optionally may be substituted with hydroxy, R10, R11 are independently from each other hydrogen, 1-4C-alkyl, 1-4C- hydroxyalkyl, 1-4C-alkoxy, or together with the nitrogen atom to which they are attached form a 5 ed heterocyclic ring optionally containing one further heteroatom selected from the group consisting of O, S or N, or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.
A further aspect of the ion are compounds of formula (I) according to claim 1, wherein R1 is hydrogen, R2/R3 are independently from each other hydrogen, halogen, R4 is independently hydrogen, 1-3C-alkyl, 2-3C-alkenyl, 1-3C-haloalkyl, 1-3C- yalkyl, 1-3C-alkoxy, 1-3C-haloalkoxy, -C(O)OR9, -C(O)-(1-3C-alkyl), - 10R11, 3-4C-cycloalkyl, -SO2NR10R11, n 0 - 3 R6 is (a) hydrogen; (b) y; (d) 1-3C-alkoxy opt. subst. with (d1) 1-2 OH, [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb (d2) NR10R11, (g) 1-3C-haloalkoxy, O O H (k) O , R7 is hydrogen, R8 is hydrogen, C(O)NR10R11, 1-3C-haloalkyl, m is 0 - 2, R9 is 1-3C-alkyl which optionally may be substituted with hydroxy, R10, R11 are independently from each other hydrogen, 1-3C-alkyl, 1-3C- hydroxyalkyl, 1-3C-alkoxy, or together with the nitrogen atom to which they are attached form a 5 membered heterocyclic ring optionally containing one further heteroatom ed from the group consisting of O, S or N, or an N-oxide, a salt, a tautomer or a stereoisomer of said nd, or a salt of said N-oxide, tautomer or stereoisomer.
A further aspect of the invention are compounds of formula (I) according to claim 1, nds of formula (I) according to claim 1, wherein, R1 is hydrogen, , R2/R3 is ndently halogen, cyano, hydroxy, 1-3C-haloalkyl, 1-4C-alkoxy or 1- 3C-haloalkoxy, R4 is independently of each other hydrogen, halogen, cyano, NO2, hydroxy, 4C-alkyl, 2-3C-alkenyl, 2-3C-alkynyl, aloalkyl, (1-4C-alkyl)-OH, 1-3C- alkoxy, 1-3C-haloalkoxy, -O-(2-3C-alkylen)-O-C(O)-(1-3C-alkyl), -C(O)(1- 3C-alkyl), -COOH, (1-4C-alkyl), (1-3C-alkyl)-COOH, -(1-4C-alkyl)- C(O)O(1-3C-alkyl), -C(O)NR10R11, -SO2-NH-(3-6C-cycloalkyl), -SO2- 1, NR10R11, heteroaryl, -S-CF3, SF5, whereby two of R2, R3 (R4)n, when positioned ortho to each other may form together -O-CH2-CH2-CH2-O-, -CH2-, -(CH3)C=CH-(C=O)-O-, [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb -CH2-(C=O)-O-, -(CH2)2-(C=O)-NH-, which in addition together with the two carbon atoms to which they are ed form a 5membered ring, n is 0, 1, 2, 3, R6 is hydrogen, hydroxy, cyano, -O-cyclopropyl, 1-3C-alkyoxy, 1-3C- haloalkoxy, -O-(2-3C-alkyl)-OH, 3C-alkyl)-NH2, -O-(2-3C-alkyl)-O(1- 3C-alkyl), -O-(2-3C-alkyl)-O-(2-3C-alkyl)-OH, -O-CH2-CH(OH)-CH2OH, -O- (1-3C-alkyl)-COOH, -O-(1-3C-alkyl)C(O)-O-(1-3C-alkyl), -O-(2-3C-alkyl)-O- alkyl)-NH-C(O)-O-(1-4C-alkyl), C(O)-NH2, -O-CH2-C(O)-(3-fluoro-N-azetidine), -O-CH2-C(O)-(3,3-difluoro-N-azetidine), -O(1-3C-alkyl) -NR10R11, -O-CH2-CH(OH)-CH2-N-piperidinyl, -O-(2-3C-alkyl)-S-(2-3C-alkyl), -O-(2-3C-alkyl)-SO2NH2, -O-(2-3C-alkyl)- SO2-(1-3C-alkyl), * O O H -O-(2-3C-alkyl)-SO-(1-3C-alkyl), O , y * is the point of at- tachment, -O-(1-3C-alkyl)heteroaryl, -O-heteroaryl which is optionally substituted one or more times with cyano, 3C-alkyl)-(heterocyclyl, having 1-2 heteroatoms selected from the group consisting of N, O and which is optionally substituted with oxo (=O)), -O-(1-3C-alkyl)-(heteroaryl)-(1-3C-alkyl)-O-(1-3C-alkyl), -O-(1-3C-alkyl)- heterocyclyl which is optionally substituted with -C(O)-O-(1-4C-alkyl), C(O)NH2, or R6 together with R7 is a 6-membered ring including the nitrogen atom of the R7 bearing amino group which may contain one r heteroatom selected from O, S or N and which in addition may be substituted with oxo (=O), - CH2-NH-CHO or (1-3C-alkyl)-OH, C H 2 R7 is hydrogen, 1-3C-alkyl, 1-3C-haloalkyl, ydroxyalkyl, O , whereby * is the point of attachment, -(1-3C-alkyl)heteroaryl, heteroaryl, heterocyclyl, -C(O)-(1-3C-alkyl)-O- (1-3C-alkyl), -C(O)-(1-3C-alkyl), -C(O)(1-3C-alkyl)-O-(2-3C-alkyl)-O-(1-3C- alkyl), or benzyl which is optionally substituted one or more times with halo- [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb ed set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb gen, cyano, methyl, difluoromethyl, 1-3C-alkoxy, 1-3C-haloalkoxy, - C(O)O(1-3C-alkyl), R8 is hydrogen, fluorine, cyano, CF3, C(O)NH2, C(O)NHCH3, C(O)OH, 1-3Calkyl), C(O)(1-3C-alkyl)-OH, m is 0, 1 or 2 R10/R11 hydrogen, 1-3C-alkyl, (1-3C-alkyl)-OH, C(O)(1-3Calkyl), or an N-oxide, a salt, a er or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.
A further aspect of the invention are compounds of formula (I) according to claim 1, wherein R1 is hydrogen, , R2/R3 is independently fluorine, chlorine, bromine, cyano, CF3, or -O-CH2-CF3, R4 is independently of each other hydrogen, fluorine, ne, bromine or io- dine, cyano, -CH3, -C3H9, cyclopropyl, 1-propenyl, -CF3, -CH2-OH, -CH2- CH2-OH, -C(CH3)2-OH, -CH2-C(CH3)2-OH, -C(CH3)2-CH2-OH, -OCH3, -OCF3, -OCF2H, F3, H3, -COOH, -C(O)OCH3, - C(O)OC2H5, C(CH3)3, -CH2-COOC2H5, -CH2-COOH, -C(CH3)2- COOC2H5, -C(O)NH2, -C(O)NH(CH3), -C(O)N(CH3)2, -C(O)NH-(CH2)2- OH, -C(O)-(N-morpholino), -SO2-NH-cyclopropyl, -SO2-(N-morpholino), 5- methyl-oxa-diazolyl, -S-CF3, SF5, y two of R2, R3 (R4)n, when positioned ortho to each other, form together with the two carbon atoms to which they are attached, -O-CH2-CH2-CH2-O-, -O-CH2-CH2-, -(CH3)C=CH-(C=O)-O-, -CH2-(C=O)-O-, -(CH2)2-(C=O)-NH-, n is 0, 1, 2, 3, R6 is hydrogen, hydroxy, cyano, -O-cyclopropyl, -OCH3, -OCF3, -OCF2H, -OCH2CF3, -O-(CH2)2-OH, -O(CH2)2-N(CH3)2, -O-CH2-SO2NH2, * O O H O , whereby * is the point of attachment, -O-(CH2)2-tetrazolyl, -O-CH2-tetrazolyl, -O-pyridineyl, -O-(3-cyano- pyridineyl), -C(O)NH2, or R6 together with R7 is a 6-membered ring including the nitrogen atom of the [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb R7 bearing amino group which may contain one further heteroatom selected from O, S or N and which in addition may be substituted with a carbonyl group or -CH2-OH, C H 2 R7 is hydrogen, methyl, romethyl, hydroxyethyl, O , whereby * is the point of attachment, -(CH2)2-tetrazolyl, neyl, -C(O)-tetrahydropyranyl, -C(O)-CH2-OCH3 , -C(O)-CH3, H2-O-(CH2)2-O-CH3 or benzyl which is optionally substituted one or more times with fluorine, chlorine, cyano, methyl, difluoromethyl , methoxy, ethoxy, difluormethoxy, trifluoromethoxy, -O-CH2-CF3, - C(O)OCH3, R8 is hydrogen, fluorine, cyano, CF3, C(O)NH2, , C(O)OC2H5, C(O)(CH2)2-OH, m is 0, 1 or 2 R9 is hydrogen, methyl, ethyl, tert.-butyl, hydroxyethyl, R10/R11 is independently from each other hydrogen, methyl, hydroxyethyl, or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.
A further aspect of the ion are compounds of formula (I) according to claim 1, wherein R1 is hydrogen, R2/R3 is independently ne, chlorine, bromine, cyano, CF3, or -O-CH2-CF3, R4 is independently of each other hydrogen, fluorine, chlorine, bromine or iodine , cyano, -CH3, -C3H9, cyclopropyl, 1-propenyl, -CF3, -CH2-OH, -CH2-CH2-OH, -C(CH3)2-OH, (CH3)2-OH, -C(CH3)2-CH2-OH, -OCH3, -OCF3, , -OCH2CF3, -C(O)CH3, -COOH, -C(O)OCH3, -C(O)OC2H5, -C(O)OC(CH3)3, -CH2-COOC2H5, -CH2-COOH, -C(CH3)2-COOC2H5, -C(O)NH2, -C(O)NH(CH3), -C(O)N(CH3)2, -C(O)NH-(CH2)2-OH, -C(O)-(N-morpholino), -SO2-NH-cyclopropyl, -SO2-(N- morpholino), 5-methyl-oxa-diazolyl, whereby two of R2, R3 (R4)n, when oned ortho to each other, form together with the two carbon atoms to which they are attached, [Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb -O-CH2-CH2-CH2-O-, -CH2-, -(CH3)C=CH-(C=O)-O-, -CH2-(C=O)-O-, -(CH2)2-(C=O)-NH-, n 0, 1, 2, or 3, R6 is hydrogen, hydroxy, -OCH3, -OCF3, -OCF2H, -OCH2CF3, -O-(CH2)2-OH, -O(CH2)2-N(CH3)2, -O-CH2-SO2NH2, * O O H O , y * is the point of attachment, R7 is hydrogen, methyl, difluoromethyl, hydroxyethyl, C H 2 O , whereby * is the point of attachment, -C(O)-tetrahydropyranyl, -C(O)-CH2-O-CH3, -C(O)-CH3, -C(O)CH2-O-(CH2)2-O- CH3 or benzyl which is optionally substituted one or more times with ne, chlorine , cyano, methyl, difluoromethyl, methoxy, ethoxy, difluormethoxy, trifluoromethoxy , -O-CH2-CF3, -C(O)OCH3, R8 is hydrogen, fluorine, cyano, C(O)NH2, m is 0, 1 or 2 R9 is hydrogen, methyl, ethyl, butyl, hydroxyethyl, R10/R11 is independently from each other hydrogen, methyl, hydroxyethyl, or an e, a salt, a tautomer or a stereoisomer of said compound, or a salt of said e, tautomer or stereoisomer.
A further aspect of the invention are compounds of formula (I) according to claim wherein, R1 is hydrogen, , R2/R3 is independently hydrogen, fluorine, chlorine, bromine, cyano, hydroxy, CF3, -O-CH3 or -O-CH2-CF3, R4 is independently of each other hydrogen, fluorine, chlorine, e or iodine , cyano, NO2, hydroxy, -CH3, -C3H7, cyclopropyl, 1-propenyl, -C≡CH, -CF3, -CH2-OH, -CH2-CH2-OH, -C(CH3)2-OH, -CH2-C(CH3)2-OH, -C(CH3)2- , -OCH3, -O-CH2-CH3, -OCF3, -OCF2H, -OCH2CF3, -O-(CH2)-O- C(O)-CH3, -C(O)CH3, -COOH, -C(O)OCH3, -C(O)OC2H5, -C(O)OC(CH3)3, -CH2-COOH, -CH2-COOC2H5, -C(CH3)2-COOC2H5, -C(O)NH2, [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb H(CH3), (CH3)2, -C(O)NH-(CH2)2-OH, -C(O)-(N-morpholinyl), -SO2-NH-cyclopropyl, -SO2-(N-morpholinyl), NH2, )(CH3), 5-methyloxa-diazolyl , N-pyrrolyl, N-pyrazolyl, -S-CF3, SF5, whereby two of R2, R3 (R4)n, when positioned ortho to each other, form to- gether -O-CH2-CH2-CH2-O-, -O-CH2-CH2-, -(CH3)C=CH-(C=O)-O-, -CH2-(C=O)-O-, -(CH2)2-(C=O)-NH-, which together with the two carbon atoms to which they are attached form a 5-, 6- or 7-membered ring, n is 0, 1, 2, 3, R6 is en, hydroxy, cyano, -O-cyclopropyl, -OCH3, -OCF3, -OCF2H, -OCH2CF3, -O-(CH2)2-OH, -O-(CH2)2-NH2, -O(CH2)2-N(CH3)2, -O-(CH2)2-OCH3 , -O-(CH2)2-O-(CH2)2-OH, -O-CH2-CH(OH)-CH2OH, -CH(OH)- CH2-NH-C(O)OC(CH3)3, -O-CH2-COOH, -O-CH2-COOC2H5, C(O)NH2, -OCH2-C -fluoro-N-azetidine), -O-CH2-C(O)-(3,3-difluoro-N-azetidine), - O-CH2-CH(OH)-CH2-N-piperidinyl, -O-(CH2)2(morpholineyl), -O-CH2- (morpholineyl), -O-CH2-(morpholineyltert.-butoxycarboxylate), -OCH2- (pyrrolidinoneyl), -O-(CH2)2-S-CH3, -O-(CH2)2-SO-CH3, -O- * O O H (CH2)2-SO2-CH2, -O-CH2-SO2NH2, -SO2-CH(CH3)2, O , whereby * is the point of attachment, -O-(CH2)2-tetrazolyl, -O-CH2-tetrazolyl, -O-pyridineyl, -O-(3-cyano- pyridineyl), or -O-CH2-(oxadiazole)-CH2-O-CH3, C H 2 R7 is en, , difluoromethyl, hydroxyethyl, O , whereby * is the point of attachment, 2-tetrazolyl, pyridineyl, -C(O)-tetrahydropyranyl, -C(O)-CH2-OCH3 , -C(O)-CH3, -C(O)CH2-O-(CH2)2-O-CH3, or benzyl which is optionally substituted one or more times with fluorine, chlorine, bromine, cyano, methyl , difluoromethyl, methoxy, ethoxy, difluormethoxy, trifluoromethoxy, -OCH2-CF3 , -C(O)OCH3, or optionally, when R6 is in position 5 of the pyrimidine ring system, R6 and R7 together with the nitrogen atom to which R7 is attached form a 6-membered [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb ring which may contain one further heteroatom selected from O, S or N and which in addition is optionally substituted by -CH2-OH or -CH2-NH-CHO R8 is hydrogen, fluorine, hydroxy, cyano, CH3, CF3, CH2-OH, OCH3, C(O)OH, C(O)OCH3, C(O)OC2H5, C(O)O(CH2)2-OH, C(O)NH2, C(O)NHCH3, m is 0, 1 or 2 or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, er or stereoisomer.
A further aspect of the invention are nds of formula (I) according to claim 1, wherein wherein R1 is hydrogen or methyl, R2/R3 is independently hydrogen, ne, ne, methyl, R4 is hydrogen, cyclopropyl, , )2-OH, -O-CHF2, -O-CH2-CH3, -CH=CH-CH3, R6 is hydrogen, OCH3, OCHF2, O-CH2-CF3, -O-(CH2)2-OH, -O-(CH2)2-NH2, C H 2 -O-CH2-CH(OH)CH2-OH, O , -O-(CH2)2-SO-CH3, -O-(CH2)2-SO2- CH3, -O-CH2-SO2NH2, -O-CH2-(pyrrolidinonyl), -O-CH2-CH(OH)-CH2-(piperidinyl), -O-CH2-(morpholinyl), R7 is hydrogen R8 is hydrogen, CH2-OH, C(O)NH2, C(O)NHCH3, A further aspect of the invention are compounds of formula (I) according to claim 1, wherein R1 is hydrogen or methyl R2 /R3 is hydrogen, fluorine, chlorine, hydroxy, methyl, methoxy, R4 is cyano, y, nitro, methyl, tert.-butoxy, CF3, methoxy, ethoxy, propoxy, NH2, NH-C(O)-CH3, -O-(CH2)2-OC(O)CH3, C(O)NH2, n is 1 [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb R6 is OCH3, -O-CH2-C(O)OH, 2)2-S-CH3, O-(CH2)2-SO-CH3, -O-(CH2)2-SO2- CH2, -O-(CH2)2-NH2, -O-(CH2)2-O-CH3, -O-(CH2)2-O-(CH2)2-OH, ,-O-(CH2)2-O- (CH2)2-NH-C(O)OC(CH3)3, -O-CH2-[morpholinyl-(4-C(O)OC(CH3)3)], -O-(CHy)2- morpholinyl, -O-CH2-(3-methoxymethyl-oxadiazolyl), -O-CH2-C(O)OC2H2, -O- CH2-C(O)-(3,3-difluoroazetidin), -O-CH2-C(O)-(3-fluoroazetidin), - (pyrrolidinonyl), -O-CH2-CH(OH)-CH2-(1-piperidin), SO2-CH(CH2)2, C(O)OC2H5, R7 is NH-C(O)OC(CH3)3, R8 is fluorine, cyano, hydroxy, methyl, H2, 2H5, CH2-OH, and m is 1, 2 or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.
Yet another aspect of the invention are compounds of formula (I) according to claim 1, wherein R1 is hydrogen, R2/R3 is independently from each other hydrogen, fluorine, chlorine, R4 is –O-(1-4C-alkyl), (2-4C-alkyl)-OH, ycloalkyl, 2-3C-alkenyl, C H 2 R6 is O , whereby * is the point of attachment, -O-(2-3C-alkyl)-NH2, -O-(CH2)heterocyclyl (which optionally is substituted with oxo (=O) or C(O)OR9), -O-(1-3C-alkyl), 3C-alkyl)-OH, -O-(2-3C-alkyl)-SO-(2-3C-alkyl), -O-(2-3C- alkyl)-SO2-(2-3C-alkyl), -O-(2-3Calkyl)-SO2NH2, -O-(CH2)-CH(OH)-(CH2)- heterocyclyl, -O-(CH2)-CH(OH)-(CH2)-OH, 2)-C(O)NR10R11, R7 is hydrogen R8 is hydrogen, C(O)NR10R11, R9 is hydrogen, 1-4C-alkyl which optionally is substituted with hydroxy, R10, R11 are independently from each other hydrogen, 1-4C-alkyl, 1-4C- hydroxyalkyl, lkoxy, -C(O)-(1-4C-alkyl), or COOR9 or together with the nitrogen atom to which they are attached form a 4membered heterocyclic ring optionally containing one further atom selected from the [Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb group ting of O, S or N, which is optionally substituted with 1-2 fluorine atoms or COOR9, or a salt thereof.
A further aspect of the invention are compounds of formula (I) according to claim 1, wherein R1 is en, R2/R3 is ndently from each other hydrogen, ne, chlorine, R4 is –O-CH2-CH3, CH2-OH, C(CH3)3-OH, cyclopropyl, propenyl, -O-C(CH3)3, C H 2 R6 is O , whereby * is the point of attachment, -O(CH2)2-NH2, -O- (CH2)heterocyclyl (which optionally is substituted with oxo (=O) ), -O-CH3, -O- (CH2)2-OH, -O-(CH2)2-SO-CH3, -O-(CH2)2-SO2-CH3, -O-(CH2)2-SO2NH2, -O-(CH2)- CH(OH)-(CH2)-heterocyclyl, -O-(CH2)-CH(OH)-(CH2)-OH, -O-(CH2)-C(O)NR10R11, R7 is hydrogen R8 is hydrogen, C(O)NR10R11, R9 is hydrogen, 1-4C-alkyl which optionally is substituted with hydroxy, R10, R11 are independently from each other en, 1-4C-alkyl, 1-4C- hydroxyalkyl, 1-4C-alkoxy, -C(O)-(1-4C-alkyl), or COOR9 or together with the nitrogen atom to which they are attached form a 4membered cyclic ring optionally containing one further heteroatom selected from the group consisting of O, S or N, which is optionally substituted with 1-2 ne atoms or COOR9, or a salt f.
In one aspect of the invention compounds of formula (I) as described above are selected from the group consisting of: 2-[1-(6-chlorofluoromethylbenzyl)-1H-indazolyl]methoxy-N- (pyridinyl)pyrimidinamine, 2-[1-(6-chlorofluoromethoxybenzyl)-1H-indazolyl]methoxy- N-(pyridinyl)pyrimidinamine, -methoxy{1-[3-(5-methyl-1,2,4-oxadiazolyl)benzyl]-1H-indazol yl}-N-(pyridinyl)pyrimidinamine, 2-[1-(2-chloro-4,5-dimethylbenzyl)-1H-indazolyl]methoxy-N- (pyridinyl)pyrimidinamine, [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb -methoxy{1-[4-(pentafluoro-λ6-sulfanyl)benzyl]-1H-indazolyl}-N- (pyridinyl)pyrimidinamine, 2-[1-(2,6-difluoromethoxybenzyl)-1H-indazolyl]methoxy-N- (pyridinyl)pyrimidinamine, N-(2,6-difluoromethoxybenzyl)[1-(2,6-difluoromethoxybenzyl)- 1H-indazolyl]methoxy-N-(pyridinyl)pyrimidinamine, 2-{1-[(6-bromo-1,3-benzodioxolyl)methyl]-1H-indazolyl} methoxy-N-(pyridinyl)pyrimidinamine, 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]methoxy-N- (pyridinyl)pyrimidinamine, N-(4-ethoxy-2,6-difluorobenzyl)[1-(4-ethoxy-2,6-difluorobenzyl)-1H- indazolyl]methoxy-N-(pyridinyl)pyrimidinamine, 2-({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)benzonitrile, 2-[1-(2-chloromethoxybenzyl)-1H-indazolyl]methoxy-N- (pyridinyl)pyrimidinamine, 2-[1-(3,4-dihydro-2H-1,5-benzodioxepinylmethyl)-1H-indazolyl] y-N-(pyridinyl)pyrimidinamine, 2-[1-(2,6-difluorobenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, N-(2,6-difluorobenzyl)[1-(2,6-difluorobenzyl)-1H-indazolyl] methoxy-N-(pyridinyl)pyrimidinamine, -methoxy-N-(pyridinyl)(1-{3-[(trifluoromethyl)sulfanyl]benzyl}-1H- indazolyl)pyrimidinamine, 2-[1-(2,3-difluoromethylbenzyl)-1H-indazolyl]methoxy-N- inyl)pyrimidinamine, -difluoromethylbenzyl)[1-(2,3-difluoromethylbenzyl)-1H- indazolyl]methoxy-N-(pyridinyl)pyrimidinamine, -methoxy{1-[4-(1H-pyrazolyl)benzyl]-1H-indazolyl}-N-(pyridin- 4-yl)pyrimidinamine, 2-[1-(2,6-dichlorobenzyl)-1H-indazolyl]methoxy-N-(pyridin imidinamine, N-(2,6-dichlorobenzyl)[1-(2,6-dichlorobenzyl)-1H-indazolyl] methoxy-N-(pyridinyl)pyrimidinamine, -methoxy-N-(pyridinyl)(1-{4-[(trifluoromethyl)sulfanyl]benzyl}-1H- indazolyl)pyrimidinamine, 2-chlorobenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, N-(2-chlorobenzyl)[1-(2-chlorobenzyl)-1H-indazolyl]methoxy- N-(pyridinyl)pyrimidinamine, [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb methyl ro({3-[5-methoxy(pyridinylamino)pyrimidinyl]- azolyl}methyl)benzoate, methyl 3-chloro{[(2-{1-[2-chloro(methoxycarbonyl)benzyl]-1H- indazolyl}methoxypyrimidinyl)(pyridin yl)amino]methyl}benzoate, 2-[1-(4-bromo-2,6-difluorobenzyl)-1H-indazolyl]methoxy-N- (pyridinyl)pyrimidinamine, 2-[1-(2-chlorofluoromethoxybenzyl)-1H-indazolyl]methoxy- N-(pyridinyl)pyrimidinamine, 2-[1-(4-ethoxy-2,3-difluorobenzyl)-1H-indazolyl]methoxy-N- (pyridinyl)pyrimidinamine, N-(4-ethoxy-2,3-difluorobenzyl)[1-(4-ethoxy-2,3-difluorobenzyl)-1H- indazolyl]methoxy-N-(pyridinyl)pyrimidinamine, -methoxy-N-(pyridinyl){1-[2,3,5,6-tetrafluoro(2,2,2- trifluoroethoxy)benzyl]-1H-indazolyl}pyrimidinamine, -methoxy-N-(pyridinyl)-N-[2,3,5,6-tetrafluoro(2,2,2- trifluoroethoxy)benzyl]{1-[2,3,5,6-tetrafluoro(2,2,2- trifluoroethoxy)benzyl]-1H-indazolyl}pyrimidinamine, methyl 2,4-dichloro({3-[5-methoxy(pyridinylamino)pyrimidin yl]-1H-indazolyl}methyl)benzoate, -methoxy-N-(pyridinyl)[1-(2,4,6-trifluorobenzyl)-1H-indazol yl]pyrimidinamine, -methoxy-N-(pyridinyl)-N-(2,4,6-trifluorobenzyl)[1-(2,4,6- trifluorobenzyl)-1H-indazolyl]pyrimidinamine, 2-[1-(2-fluorobenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, 2-[1-(2,4-dichlorobenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, 2-[1-(2-fluoroiodobenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, 2-[1-(2-bromobenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, N-(2-bromobenzyl)[1-(2-bromobenzyl)-1H-indazolyl]methoxy- idinyl)pyrimidinamine, [3-fluoro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H- indazolyl}methyl)phenyl]acetic acid, -methoxy-N-(pyridinyl)[1-(2,3,5,6-tetrafluoromethoxybenzyl)- azolyl]pyrimidinamine -methoxy[1-(4-propylbenzyl)-1H-indazolyl]-N-(pyridin yl)pyrimidinamine, 2-{1-[2,6-dichloro(trifluoromethoxy)benzyl]-1H-indazolyl} [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb methoxy-N-(pyridinyl)pyrimidinamine, N-[2,6-dichloro(trifluoromethoxy)benzyl]{1-[2,6-dichloro (trifluoromethoxy)benzyl]-1H-indazolyl}methoxy-N-(pyridin yl)pyrimidinamine, 7-({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)-3,4-dihydroquinolin-2(1H)-one,, 2-[1-(2-chloroiodobenzyl)-1H-indazolyl]methoxy-N-(pyridin imidinamine, 2-[1-(3,5-dimethoxybenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, 2-{1-[2-chloro(trifluoromethyl)benzyl]-1H-indazolyl}methoxy-N- (pyridinyl)pyrimidinamine, 2-[1-(2-chlorofluorobenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, 7-({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol hyl)methyl-2H-chromenone, 3-fluoro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H- indazolyl}methyl)benzonitrile, 4-{[{2-[1-(4-cyanofluorobenzyl)-1H-indazolyl]methoxypyrimidin- pyridinyl)amino]methyl}fluorobenzonitrile, 2-{1-[2,6-dichloro(trifluoromethyl)benzyl]-1H-indazolyl} methoxy-N-(pyridinyl)pyrimidinamine, ethyl [3-({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol- 1-yl}methyl)phenyl]acetate, 2-[1-(4-fluorobenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, N-cyclopropyl({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H- indazolyl}methyl)benzenesulfonamide, [5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)benzofuran-2(3H)-one, 2-{1-[4-(difluoromethoxy)-2,6-difluorobenzyl]-1H-indazolyl} methoxy-N-(pyridinyl)pyrimidinamine, tert-butyl 3-chloro({3-[5-methoxy(pyridinylamino)pyrimidin yl]-1H-indazolyl}methyl)benzoate, ethyl 2-[3-({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H- indazolyl}methyl)phenyl]methylpropanoate,, 4-({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)benzonitrile, -methoxy{1-[4-(morpholinylsulfonyl)benzyl]-1H-indazolyl}-N- (pyridinyl)pyrimidinamine, 2-[1-(2,6-dichloronitrobenzyl)-1H-indazolyl]methoxy-N-(pyridin- ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb yrimidinamine, 3-({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)benzonitrile, N-[4-(difluoromethoxy)-2,6-difluorobenzyl]{1-[4-(difluoromethoxy)- 2,6-difluorobenzyl]-1H-indazolyl}methoxy-N-(pyridin yl)pyrimidinamine, -methoxy-N-(pyridinyl){1-[3-(1H-pyrrolyl)benzyl]-1H-indazol yl}pyrimidinamine, 3,5-difluoro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H- lyl}methyl)benzonitrile, -methoxy{1-[2-methoxy(trifluoromethyl)benzyl]-1H-indazolyl}- N-(pyridinyl)pyrimidinamine, 2-[1-(2,6-difluoromethylbenzyl)-1H-indazolyl]methoxy-N- (pyridinyl)pyrimidinamine, 2-[1-(2-fluoromethoxybenzyl)-1H-indazolyl]methoxy-N-(pyridin- 4-yl)pyrimidinamine, 3,5-difluoro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H- indazolyl}methyl)benzamide, 2-[3,5-difluoro({3-[5-methoxy(pyridinylamino)pyrimidinyl]- 1H-indazolyl}methyl)phenoxy]ethyl acetate, 2-[1-(2,6-difluoropropoxybenzyl)-1H-indazolyl]methoxy-N- (pyridinyl)pyrimidinamine, 2-[1-(4-ethoxyfluoromethoxybenzyl)-1H-indazolyl]methoxy- N-(pyridinyl)pyrimidinamine, 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin o)pyrimidinol, 2-[1-(4-methoxybenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinol, 2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridinylamino)pyrimidin 4-fluorobenzyl)-1H-indazolyl](pyridinylamino)pyrimidin {3-[({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)methyl]oxetanyl}methanol, {3-[({2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)methyl]oxetanyl}methanol, (3-{[(2-[1-(2-fluorobenzyl)-1H-indazolyl]{[3- (hydroxymethyl)oxetanyl]methoxy}pyrimidinyl)(pyridin yl)amino]methyl}oxetanyl)methanol, 1-({2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)methanesulfonamide, ation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb -[2-(dimethylamino)ethoxy][1-(2-fluorobenzyl)-1H-indazolyl]-N- (pyridinyl)pyrimidinamine, 2-[1-(2-fluorobenzyl)-1H-indazolyl]-N-(pyridinyl)[2-(1H-tetrazol- -yl)ethoxy]pyrimidinamine, 2-[1-(2-fluorobenzyl)-1H-indazolyl]-N-(pyridinyl)[2-(1H-tetrazol- -yl)ethoxy]-N-[2-(1H-tetrazolyl)ethyl]pyrimidinamine, -[2-(dimethylamino)ethoxy][1-(4-fluorobenzyl)-1H-indazolyl]-N- (pyridinyl)pyrimidinamine, 2-[1-(2-fluorobenzyl)-1H-indazolyl]-N-(pyridinyl)(1H-tetrazol ylmethoxy)pyrimidinamine, -[2-(dimethylamino)ethoxy][1-(4-ethoxy-2,6-difluorobenzyl)-1H- indazolyl]-N-(pyridinyl)pyrimidinamine 1-({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)(piperidinyl)propanol, 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](2- methoxyethoxy)-N-(pyridinyl)pyrimidinamine, tert-butyl 2-[({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl] (pyridinylamino)pyrimidinyl}oxy)methyl]morpholinecarboxylate, 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl][2-(morpholin yl)ethoxy]-N-(pyridinyl)pyrimidinamine, 2-[1-(2-fluorobenzyl)-1H-indazolyl]{[3-(methoxymethyl)-1,2,4- zolyl]methoxy}-N-(pyridinyl)pyrimidinamine, ethyl ({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)acetate, 1-(3,3-difluoroazetidinyl)({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H- indazolyl](pyridinylamino)pyrimidinyl}oxy)ethanone, 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl][2- (methylsulfanyl)ethoxy]-N-(pyridinyl)pyrimidinamine, 2-[2-({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)ethoxy]ethanol, formic acid - (5S)[({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazol yl](pyridinylamino)pyrimidinyl}oxy)methyl]pyrrolidinone (1:1), (5R)[({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin- 4-ylamino)pyrimidinyl}oxy)methyl]pyrrolidinone, utyl {2-[2-({2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)ethoxy]ethyl}carbamate, [1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)(3-fluoroazetidinyl)ethanone, (5S)[({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin- 4-ylamino)pyrimidinyl}oxy)methyl]pyrrolidinone, [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb tert-butyl [2-({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl] inylamino)pyrimidinyl}oxy)ethyl]carbamate, [1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridinyl)- 7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazinyl}methyl)formamide, 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]-N-(pyridin yl)pyrimidinamine, 2-[1-(4-methoxybenzyl)-1H-indazolyl]-N-(pyridinyl)pyrimidin amine, 2-[1-(2-fluorobenzyl)-1H-indazolyl]-N-(pyridinyl)pyrimidin amine, 2-[1-(4-cyclopropyl-2,6-difluorobenzyl)-1H-indazolyl]methoxy-N- (pyridinyl)pyrimidinamine, 2-(1-{2,6-difluoro[(1E)-propenyl]benzyl}-1H-indazolyl) methoxy-N-(pyridinyl)pyrimidinamine, 1-[3,5-difluoro({3-[5-methoxy(pyridinylamino)pyrimidinyl]- 1H-indazolyl}methyl)phenyl]ethanone, [2,4-dichloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H- indazolyl}methyl)phenyl]methanol, 2-[3-({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)phenyl]ethanol, 2-[3-({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)phenyl]methylpropanol, [4-({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl] methoxypyrimidinyl}amino)pyridinyl]methanol, 2-[3-chloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H- indazolyl}methyl)phenyl]propanol, 1-[3-({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)phenyl]methylpropanol, 2-[2,4-dichloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]- azolyl}methyl)phenyl]propanol -(difluoromethoxy)[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]- N-(pyridinyl)pyrimidinamine, -(difluoromethoxy)-N-(difluoromethyl)[1-(4-ethoxy-2,6- difluorobenzyl)-1H-indazolyl]-N-(pyridinyl)pyrimidinamine, 4-[(difluoromethyl)(pyridinyl)amino][1-(4-ethoxy-2,6- difluorobenzyl)-1H-indazolyl]pyrimidinol, 4-methoxybenzyl)-1H-indazolyl]-N-(pyridinyl)(2,2,2- trifluoroethoxy)pyrimidinamine, 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]-N-(pyridinyl) (2,2,2-trifluoroethoxy)pyrimidinamine, [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 3-({2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)propane-1,2-diol, (2S)({2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)propane-1,2-diol, (2R)({2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)propane-1,2-diol, 2-({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)ethanol, 2-({2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)ethanol, ethyl 4-({2-[1-(2-fluorobenzyl)-1H-indazolyl](2- hydroxyethoxy)pyrimidinyl}amino)pyridinecarboxylate, 4-({2-[1-(2-fluorobenzyl)-1H-indazolyl](2- hydroxyethoxy)pyrimidinyl}amino)-N-methylpyridinecarboxamide, 4-({2-[1-(2-fluorobenzyl)-1H-indazolyl](2- hydroxyethoxy)pyrimidinyl}amino)pyridinecarboxamide, 2-hydroxyethyl 4-({2-[1-(2-fluorobenzyl)-1H-indazolyl](2- yethoxy)pyrimidinyl}amino)pyridinecarboxylate, -(cyclopropyloxy)[1-(4-methoxybenzyl)-1H-indazolyl]-N-(pyridin- 4-yl)pyrimidinamine, 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]methoxy-N- (pyridinyl)pyrimidinamine hydrochloride (1:1), (2S)({2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)propane-1,2-diol hydrochloride (1:1), 2-({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)ethanol hydrochloride (1:1), 2-[1-(2,6-dichlorobenzyl)-1H-indazolyl]methoxy-N-(pyridin imidinamine hydrochloride (1:1), [2,4-dichloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H- indazolyl}methyl)phenyl]methanol hydrochloride (1:1), (2R)({2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)propane-1,2-diol hloride (1:1), N-{2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]pyrimidinyl}-N- (pyridinyl)acetamide, N-{2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]pyrimidinyl} y-N-(pyridinyl)acetamide, N-{2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]pyrimidinyl}-N- (pyridinyl)tetrahydro-2H-pyrancarboxamide, 1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]pyrimidinyl} (2-methoxyethoxy)-N-(pyridinyl)acetamide, [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 2-[{2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]pyrimidin yl}(pyridinyl)amino]ethanol, (3-{[{2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]pyrimidin yl}(pyridinyl)amino]methyl}oxetanyl)methanol, 2-{1-[4-bromofluoro(2,2,2-trifluoroethoxy)benzyl]-1H-indazol yl}methoxy-N-(pyridinyl)pyrimidinamine, 2-{1-[4-bromo-2,6-bis(2,2,2-trifluoroethoxy)benzyl]-1H-indazolyl} methoxy-N-(pyridinyl)pyrimidinamine, 2,4-dichloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H- indazolyl}methyl)benzoic acid, ({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)acetic acid, 2,4-dichloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H- lyl}methyl)-N-methylbenzamide, 2,4-dichloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H- indazolyl}methyl)benzamide, 2,4-dichloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H- indazolyl}methyl)-N,N-dimethylbenzamide, chloro-N-(2-hydroxyethyl)({3-[5-methoxy(pyridin ylamino)pyrimidinyl]-1H-indazolyl}methyl)benzamide, [2,4-dichloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H- indazolyl}methyl)phenyl](morpholinyl)methanone, 3,5-difluoro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H- indazolyl}methyl)-N-methylbenzamide, 2-[1-(4-ethynylfluorobenzyl)-1H-indazolyl]methoxy-N-(pyridin- yrimidinamine, {2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridinyl)-7,8-dihydro-6H- do[5,4-b][1,4]oxazinyl}methanol, 2-[1-(2-fluorobenzyl)-1H-indazolyl]methoxy-N-methyl-N-(pyridin- 4-yl)pyrimidinamine, 4-({2-[1-(2-fluorobenzyl)-1H-indazolyl]methoxypyrimidin yl}amino)pyridinecarbonitrile, 2-[1-(2-fluorobenzyl)-1H-indazolyl]methoxy-N,N-di(pyridin yl)pyrimidinamine, methyl 4-({2-[1-(2-fluorobenzyl)-1H-indazolyl]methoxypyrimidin yl}amino)pyridinecarboxylate, 2-[1-(2-fluorobenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, 4-({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl] methoxypyrimidinyl}amino)pyridinecarbonitrile, [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 2-[(3-{4-[(2,6-dimethylpyridinyl)amino]methoxypyrimidinyl}-1H- indazolyl)methyl]ethoxyfluorophenol, 4-({5-methoxy[1-(4-methoxybenzyl)-1H-indazolyl]pyrimidin yl}amino)pyridin-2(1H)-one, 4-({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl] methoxypyrimidinyl}amino)pyridin-2(1H)-one, 4-({5-methoxy[1-(4-propylbenzyl)-1H-indazolyl]pyrimidin yl}amino)nicotinonitrile, 4-({2-[1-(2-fluorobenzyl)-1H-indazolyl]methoxypyrimidin yl}amino)pyridinecarboxamide, 4-({5-methoxy[1-(4-propylbenzyl)-1H-indazolyl]pyrimidin yl}amino)pyridinecarboxamide, 4-({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl] methoxypyrimidinyl}amino)pyridinecarboxamide, 4-({2-[1-(2,6-difluorohydroxybenzyl)-1H-indazolyl] methoxypyrimidinyl}amino)pyridinecarboxamide, 4-({2-[1-(2-fluorobenzyl)-1H-indazolyl]hydroxypyrimidin yl}amino)pyridinecarbonitrile, 4-({4-[(3-cyanopyridinyl)amino][1-(2-fluorobenzyl)-1H-indazol yl]pyrimidinyl}oxy)pyridinecarbonitrile, -methoxy[1-(4-methoxybenzyl)-1H-indazolyl]-N-[3- (trifluoromethyl)pyridinyl]pyrimidinamine, ro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H- indazolyl}methyl)benzoic acid, formic acid - 3-chloro({3-[5-methoxy(pyridinylamino)pyrimidin- 2-yl]-1H-indazolyl}methyl)-N-methylbenzamide (1:1), ro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H- lyl}methyl)-N-methylbenzamide, 4-({2-[1-(2-fluorobenzyl)-1H-indazolyl]hydroxypyrimidin yl}amino)pyridinecarboxamide, 4-({2-[1-(2-fluorobenzyl)-1H-indazolyl]hydroxypyrimidin yl}amino)pyridinecarboxylic acid, ethyl 4-({2-[1-(2-fluorobenzyl)-1H-indazolyl]hydroxypyrimidin yl}amino)pyridinecarboxylate, 2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridinylamino)pyrimidine- -carbonitrile, 2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridinylamino)pyrimidine- -carboxamide, 4-({2-[1-(2-fluorobenzyl)-1H-indazolyl](2- hydroxyethoxy)pyrimidinyl}amino)pyridinecarboxylic acid hydrochloride (1:1), ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb N-(2-fluoropyridinyl)methoxy[1-(4-methoxybenzyl)-1H-indazol- 3-yl]pyrimidinamine, N-(2,6-difluoropyridinyl)methoxy[1-(4-methoxybenzyl)-1H- indazolyl]pyrimidinamine, N-(3-fluoropyridinyl)methoxy[1-(4-methoxybenzyl)-1H-indazol- 3-yl]pyrimidinamine, -methoxy[1-(4-methoxybenzyl)-1H-indazolyl]-N-(2- methylpyridinyl)pyrimidinamine, luoromethyl)[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]- N-(pyridinyl)pyrimidinamine, 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl][2- (methylsulfinyl)ethoxy]-N-(pyridinyl)pyrimidinamine, 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl][2- (methylsulfinyl)ethoxy]-N-(pyridinyl)pyrimidinamine (Enantiomer 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl][2- (methylsulfinyl)ethoxy]-N-(pyridinyl)pyrimidinamine iomer 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl][2- lsulfonyl)ethoxy]-N-(pyridinyl)pyrimidinamine, -(2-aminoethoxy)[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]- N-(pyridinyl)pyrimidinamine, 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](morpholin ylmethoxy)-N-(pyridinyl)pyrimidinamine, Preparation of ethyl 4-({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazol- 3-yl]methoxypyrimidinyl}amino)pyridinecarboxylate, N-(3,5-difluoropyridinyl)[1-(4-ethoxy-2,6-difluorobenzyl)-1H- indazolyl]methoxypyrimidinamine, 2-[1-(3-amino-2,6-dichlorobenzyl)-1H-indazolyl]methoxy-N- (pyridinyl)pyrimidinamine, N-[2,4-dichloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]- 1H-indazolyl}methyl)phenyl]acetamide, 2-[1-(4-ethoxy-2,6-difluorobenzyl)methyl-1H-indazolyl] methoxy-N-(pyridinyl)pyrimidinamine, or an N-oxide, a salt, a er or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.
One aspect of the invention are all compounds being named in the list below. 2-[1-(2,6-dichloronitrobenzyl)-1H-indazolyl]methoxy-N-(pyridin- [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 4-yl)pyrimidinamine, 3-({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)benzonitrile, 3,5-difluoro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H- indazolyl}methyl)benzonitrile, -methoxy{1-[2-methoxy(trifluoromethyl)benzyl]-1H-indazolyl}- N-(pyridinyl)pyrimidinamine, 2-[1-(2,6-difluoromethylbenzyl)-1H-indazolyl]methoxy-N- inyl)pyrimidinamine, 2-[1-(2-fluoromethoxybenzyl)-1H-indazolyl]methoxy-N-(pyridin- 4-yl)pyrimidinamine, 3,5-difluoro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H- indazolyl}methyl)benzamide, 2-[3,5-difluoro({3-[5-methoxy(pyridinylamino)pyrimidinyl]- 1H-indazolyl}methyl)phenoxy]ethyl acetate, 2-[1-(2,6-difluoropropoxybenzyl)-1H-indazolyl]methoxy-N- (pyridinyl)pyrimidinamine, 2-[1-(4-ethoxyfluoromethoxybenzyl)-1H-indazolyl]methoxy- N-(pyridinyl)pyrimidinamine, 1-({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)(piperidinyl)propanol, 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](2- methoxyethoxy)-N-(pyridinyl)pyrimidinamine, tert-butyl 2-[({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl] (pyridinylamino)pyrimidinyl}oxy)methyl]morpholinecarboxylate, 4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl][2-(morpholin yl)ethoxy]-N-(pyridinyl)pyrimidinamine, 2-[1-(2-fluorobenzyl)-1H-indazolyl]{[3-(methoxymethyl)-1,2,4- zolyl]methoxy}-N-(pyridinyl)pyrimidinamine, ethyl ({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)acetate, 1-(3,3-difluoroazetidinyl)({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H- indazolyl](pyridinylamino)pyrimidinyl}oxy)ethanone, 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl][2- (methylsulfanyl)ethoxy]-N-(pyridinyl)pyrimidinamine, 2-[2-({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)ethoxy]ethanol, formic acid - (5S)[({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazol yl](pyridinylamino)pyrimidinyl}oxy)methyl]pyrrolidinone (1:1), (5R)[({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin- [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 4-ylamino)pyrimidinyl}oxy)methyl]pyrrolidinone, tert-butyl {2-[2-({2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)ethoxy]ethyl}carbamate, [1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)(3-fluoroazetidinyl)ethanone, -[({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin- 4-ylamino)pyrimidinyl}oxy)methyl]pyrrolidinone, N-({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridinyl)- 7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazinyl}methyl)formamide, [4-({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl] methoxypyrimidinyl}amino)pyridinyl]methanol, ({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin o)pyrimidinyl}oxy)acetic acid, 2-[1-(2-fluorobenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, 4-({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl] methoxypyrimidinyl}amino)pyridinecarbonitrile, 2-[(3-{4-[(2,6-dimethylpyridinyl)amino]methoxypyrimidinyl}-1H- indazolyl)methyl]ethoxyfluorophenol, 4-({5-methoxy[1-(4-methoxybenzyl)-1H-indazolyl]pyrimidin no)pyridin-2(1H)-one, 4-({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl] methoxypyrimidinyl}amino)pyridin-2(1H)-one, 4-({5-methoxy[1-(4-propylbenzyl)-1H-indazolyl]pyrimidin yl}amino)nicotinonitrile, 4-({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl] methoxypyrimidinyl}amino)pyridinecarboxamide, 4-({2-[1-(2,6-difluorohydroxybenzyl)-1H-indazolyl] methoxypyrimidinyl}amino)pyridinecarboxamide, -methoxy[1-(4-methoxybenzyl)-1H-indazolyl]-N-(2- methylpyridinyl)pyrimidinamine, 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl][2- (methylsulfinyl)ethoxy]-N-(pyridinyl)pyrimidinamine, 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl][2- (methylsulfinyl)ethoxy]-N-(pyridinyl)pyrimidinamine (Enantiomer 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl][2- (methylsulfinyl)ethoxy]-N-(pyridinyl)pyrimidinamine (Enantiomer 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl][2- (methylsulfonyl)ethoxy]-N-(pyridinyl)pyrimidinamine, [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb -(2-aminoethoxy)[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]- N-(pyridinyl)pyrimidinamine, 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](morpholin ylmethoxy)-N-(pyridinyl)pyrimidinamine, Preparation of ethyl 4-({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazol- 3-yl]methoxypyrimidinyl}amino)pyridinecarboxylate, N-(3,5-difluoropyridinyl)[1-(4-ethoxy-2,6-difluorobenzyl)-1H- indazolyl]methoxypyrimidinamine, 2-[1-(3-amino-2,6-dichlorobenzyl)-1H-indazolyl]methoxy-N- (pyridinyl)pyrimidinamine, N-[2,4-dichloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]- 1H-indazolyl}methyl)phenyl]acetamide, 2-[1-(4-ethoxy-2,6-difluorobenzyl)methyl-1H-indazolyl] methoxy-N-(pyridinyl)pyrimidinamine or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.
In one aspect of the invention compounds of formula (I) as described above are ed from the group consisting of: 2-[1-(6-chlorofluoromethylbenzyl)-1H-indazolyl]methoxy-N- inyl)pyrimidinamine, 2-[1-(6-chlorofluoromethoxybenzyl)-1H-indazolyl]methoxy- N-(pyridinyl)pyrimidinamine, -methoxy{1-[3-(5-methyl-1,2,4-oxadiazolyl)benzyl]-1H-indazol yl}-N-(pyridinyl)pyrimidinamine, 2-chloro-4,5-dimethylbenzyl)-1H-indazolyl]methoxy-N- (pyridinyl)pyrimidinamine, -methoxy{1-[4-(pentafluoro-lambda6-sulfanyl)benzyl]- 1H-indazolyl}-N-(pyridinyl)pyrimidinamine, 2-[1-(2,6-difluoromethoxybenzyl)-1H-indazolyl]methoxy-N- (pyridinyl)pyrimidinamine, N-(2,6-difluoromethoxybenzyl)[1-(2,6-difluoromethoxybenzyl)- 1H-indazolyl]methoxy-N-(pyridinyl)pyrimidinamine, (6-bromo-1,3-benzodioxolyl)methyl]-1H-indazolyl} y-N-(pyridinyl)pyrimidinamine, 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]methoxy-N- (pyridinyl)pyrimidinamine, N-(4-ethoxy-2,6-difluorobenzyl)[1-(4-ethoxy-2,6-difluorobenzyl)-1H- indazolyl]methoxy-N-(pyridinyl)pyrimidinamine, [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 2-({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)benzonitrile, 2-[1-(2-chloromethoxybenzyl)-1H-indazolyl]methoxy-N- inyl)pyrimidinamine, 2-[1-(3,4-dihydro-2H-1,5-benzodioxepinylmethyl)-1H-indazolyl] methoxy-N-(pyridinyl)pyrimidinamine, 2-[1-(2,6-difluorobenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, N-(2,6-difluorobenzyl)[1-(2,6-difluorobenzyl)-1H-indazolyl] methoxy-N-(pyridinyl)pyrimidinamine, -methoxy-N-(pyridinyl)(1-{3-[(trifluoromethyl)sulfanyl]benzyl}-1H- indazolyl)pyrimidinamine, 2-[1-(2,3-difluoromethylbenzyl)-1H-indazolyl]methoxy-N- (pyridinyl)pyrimidinamine, N-(2,3-difluoromethylbenzyl)[1-(2,3-difluoromethylbenzyl)-1H- indazolyl]methoxy-N-(pyridinyl)pyrimidinamine, -methoxy{1-[4-(1H-pyrazolyl)benzyl]-1H-indazolyl}-N-(pyridin- 4-yl)pyrimidinamine, 2-[1-(2,6-dichlorobenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, N-(2,6-dichlorobenzyl)[1-(2,6-dichlorobenzyl)-1H-indazolyl] methoxy-N-(pyridinyl)pyrimidinamine, -methoxy-N-(pyridinyl)(1-{4-[(trifluoromethyl)sulfanyl]benzyl}-1H- indazolyl)pyrimidinamine, 2-[1-(2-chlorobenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, N-(2-chlorobenzyl)[1-(2-chlorobenzyl)-1H-indazolyl]methoxy- idinyl)pyrimidinamine, methyl 3-chloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]- 1H-indazolyl}methyl)benzoate, methyl 3-chloro{[(2-{1-[2-chloro(methoxycarbonyl)benzyl]-1H- indazolyl}methoxypyrimidinyl)(pyridin yl)amino]methyl}benzoate, 2-[1-(4-bromo-2,6-difluorobenzyl)-1H-indazolyl]methoxy-N- (pyridinyl)pyrimidinamine, 2-[1-(2-chlorofluoromethoxybenzyl)-1H-indazolyl]methoxy- idinyl)pyrimidinamine, 2-[1-(4-ethoxy-2,3-difluorobenzyl)-1H-indazolyl]methoxy-N- inyl)pyrimidinamine, N-(4-ethoxy-2,3-difluorobenzyl)[1-(4-ethoxy-2,3-difluorobenzyl)-1H- indazolyl]methoxy-N-(pyridinyl)pyrimidinamine, [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb -methoxy-N-(pyridinyl){1-[2,3,5,6-tetrafluoro(2,2,2- trifluoroethoxy)benzyl]-1H-indazolyl}pyrimidinamine, -methoxy-N-(pyridinyl)-N-[2,3,5,6-tetrafluoro(2,2,2- trifluoroethoxy)benzyl]{1-[2,3,5,6-tetrafluoro(2,2,2- trifluoroethoxy)benzyl]-1H-indazolyl}pyrimidinamine, methyl chloro({3-[5-methoxy(pyridinylamino)pyrimidin yl]-1H-indazolyl}methyl)benzoate, -methoxy-N-(pyridinyl)[1-(2,4,6-trifluorobenzyl)-1H-indazol yl]pyrimidinamine, -methoxy-N-(pyridinyl)-N-(2,4,6-trifluorobenzyl)[1-(2,4,6- trifluorobenzyl)-1H-indazolyl]pyrimidinamine, 2-fluorobenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, 2-[1-(2,4-dichlorobenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, 2-[1-(2-fluoroiodobenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, 2-[1-(2-bromobenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, N-(2-bromobenzyl)[1-(2-bromobenzyl)-1H-indazolyl]methoxy- N-(pyridinyl)pyrimidinamine, [3-fluoro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H- indazolyl}methyl)phenyl]acetic acid, -methoxy-N-(pyridinyl)[1-(2,3,5,6-tetrafluoromethoxybenzyl)- 1H-indazolyl]pyrimidinamine, -methoxy[1-(4-propylbenzyl)-1H-indazolyl]-N-(pyridin yl)pyrimidinamine, 2-{1-[2,6-dichloro(trifluoromethoxy)benzyl]-1H-indazolyl} methoxy-N-(pyridinyl)pyrimidinamine, N-[2,6-dichloro(trifluoromethoxy)benzyl]{1-[2,6-dichloro (trifluoromethoxy)benzyl]-1H-indazolyl}methoxy-N-(pyridin yl)pyrimidinamine [5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)-3,4-dihydroquinolin-2(1H)-one, 2-[1-(2-chloroiodobenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, 2-[1-(3,5-dimethoxybenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, 2-chloro(trifluoromethyl)benzyl]-1H-indazolyl}methoxy-N- (pyridinyl)pyrimidinamine, 2-[1-(2-chlorofluorobenzyl)-1H-indazolyl]methoxy-N-(pyridin [Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb yl)pyrimidinamine, 7-({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)methyl-2H-chromenone, 3-fluoro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H- indazolyl}methyl)benzonitrile, 4-{[{2-[1-(4-cyanofluorobenzyl)-1H-indazolyl]methoxypyrimidin- 4-yl}(pyridinyl)amino]methyl}fluorobenzonitrile, 2-{1-[2,6-dichloro(trifluoromethyl)benzyl]-1H-indazolyl} methoxy-N-(pyridinyl)pyrimidinamine, ethyl [3-({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol- 1-yl}methyl)phenyl]acetate, 2-[1-(4-fluorobenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, N-cyclopropyl({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H- lyl}methyl)benzenesulfonamide, 6-({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)benzofuran-2(3H)-one, 4-(difluoromethoxy)-2,6-difluorobenzyl]-1H-indazolyl} methoxy-N-(pyridinyl)pyrimidinamine, tert-butyl 3-chloro({3-[5-methoxy(pyridinylamino)pyrimidin yl]-1H-indazolyl}methyl)benzoate, ethyl 2-[3-({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H- lyl}methyl)phenyl]methylpropanoate, 4-({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol hyl)benzonitrile -methoxy{1-[4-(morpholinylsulfonyl)benzyl]-1H-indazolyl}-N- (pyridinyl)pyrimidinamine N-[4-(difluoromethoxy)-2,6-difluorobenzyl]{1-[4-(difluoromethoxy)- 2,6-difluorobenzyl]-1H-indazolyl}methoxy-N-(pyridin yl)pyrimidinamine, -methoxy-N-(pyridinyl){1-[3-(1H-pyrrolyl)benzyl]-1H-indazol yl}pyrimidinamine, 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinol, 2-[1-(4-methoxybenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinol, 2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridinylamino)pyrimidin 2-[1-(4-fluorobenzyl)-1H-indazolyl](pyridinylamino)pyrimidin {3-[({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb ylamino)pyrimidinyl}oxy)methyl]oxetanyl}methanol, {3-[({2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)methyl]oxetanyl}methanol, (3-{[(2-[1-(2-fluorobenzyl)-1H-indazolyl]{[3- (hydroxymethyl)oxetanyl]methoxy}pyrimidinyl)(pyridin yl)amino]methyl}oxetanyl)methanol, 1-({2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)methanesulfonamide, dimethylamino)ethoxy][1-(2-fluorobenzyl)-1H-indazolyl]-N- inyl)pyrimidinamine, 2-[1-(2-fluorobenzyl)-1H-indazolyl]-N-(pyridinyl)[2-(1H-tetrazol- -yl)ethoxy]pyrimidinamine, 2-[1-(2-fluorobenzyl)-1H-indazolyl]-N-(pyridinyl)[2-(1H-tetrazol- -yl)ethoxy]-N-[2-(1H-tetrazolyl)ethyl]pyrimidinamine, -[2-(dimethylamino)ethoxy][1-(4-fluorobenzyl)-1H-indazolyl]-N- (pyridinyl)pyrimidinamine, 2-[1-(2-fluorobenzyl)-1H-indazolyl]-N-(pyridinyl)(1H-tetrazol ylmethoxy)pyrimidinamine, -[2-(dimethylamino)ethoxy][1-(4-ethoxy-2,6-difluorobenzyl)-1H- lyl]-N-(pyridinyl)pyrimidinamine, 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]-N-(pyridin yl)pyrimidinamine, 2-[1-(4-methoxybenzyl)-1H-indazolyl]-N-(pyridinyl)pyrimidin amine, 2-[1-(2-fluorobenzyl)-1H-indazolyl]-N-(pyridinyl)pyrimidin amine, 2-[1-(4-cyclopropyl-2,6-difluorobenzyl)-1H-indazolyl]methoxy-N- (pyridinyl)pyrimidinamine, 2-(1-{2,6-difluoro[(1E)-propenyl]benzyl}-1H-indazolyl) methoxy-N-(pyridinyl)pyrimidinamine, 1-[3,5-difluoro({3-[5-methoxy(pyridinylamino)pyrimidinyl]- 1H-indazolyl}methyl)phenyl]ethanone, [2,4-dichloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H- indazolyl}methyl)phenyl]methanol, 2-[3-({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)phenyl]ethanol, 2-[3-({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)phenyl]methylpropanol, 2-[3-chloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H- indazolyl}methyl)phenyl]propanol, 1-[3-({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb yl}methyl)phenyl]methylpropanol, 2-[2,4-dichloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]- 1H-indazolyl}methyl)phenyl]propanol, luoromethoxy)[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]- N-(pyridinyl)pyrimidinamine, -(difluoromethoxy)-N-(difluoromethyl)[1-(4-ethoxy-2,6- difluorobenzyl)-1H-indazolyl]-N-(pyridinyl)pyrimidinamine, 4-[(difluoromethyl)(pyridinyl)amino][1-(4-ethoxy-2,6- robenzyl)-1H-indazolyl]pyrimidinol, 2-[1-(4-methoxybenzyl)-1H-indazolyl]-N-(pyridinyl)(2,2,2- trifluoroethoxy)pyrimidinamine, 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]-N-(pyridinyl) (2,2,2-trifluoroethoxy)pyrimidinamine, 3-({2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)propane-1,2-diol, (2S)({2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)propane-1,2-diol, (2R)({2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)propane-1,2-diol, 2-({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)ethanol, 2-({2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)ethanol, ethyl 4-({2-[1-(2-fluorobenzyl)-1H-indazolyl](2- hydroxyethoxy)pyrimidinyl}amino)pyridinecarboxylate, 4-({2-[1-(2-fluorobenzyl)-1H-indazolyl](2- hydroxyethoxy)pyrimidinyl}amino)-N-methylpyridinecarboxamide, 4-({2-[1-(2-fluorobenzyl)-1H-indazolyl](2- yethoxy)pyrimidinyl}amino)pyridinecarboxamide, 2-hydroxyethyl 4-({2-[1-(2-fluorobenzyl)-1H-indazolyl](2- hydroxyethoxy)pyrimidinyl}amino)pyridinecarboxylate, -(cyclopropyloxy)[1-(4-methoxybenzyl)-1H-indazolyl]-N-(pyridin- 4-yl)pyrimidinamine, 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]methoxy-N- (pyridinyl)pyrimidinamine hloride (1:1), (2S)({2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)propane-1,2-diol hydrochloride (1:1), 2-({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)ethanol hloride (1:1), 2-[1-(2,6-dichlorobenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine hydrochloride (1:1), [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [2,4-dichloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H- lyl}methyl)phenyl]methanol hydrochloride (1:1), -({2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)propane-1,2-diol hydrochloride (1:1), N-{2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]pyrimidinyl}-N- (pyridinyl)acetamide, N-{2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]pyrimidinyl} methoxy-N-(pyridinyl)acetamide, N-{2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]pyrimidinyl}-N- (pyridinyl)tetrahydro-2H-pyrancarboxamide, N-{2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]pyrimidinyl} (2-methoxyethoxy)-N-(pyridinyl)acetamide, 2-[{2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]pyrimidin yl}(pyridinyl)amino]ethanol, 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]pyrimidin yl}(pyridinyl)amino]methyl}oxetanyl)methanol, 2-{1-[4-bromofluoro(2,2,2-trifluoroethoxy)benzyl]-1H-indazol yl}methoxy-N-(pyridinyl)pyrimidinamine, 2-{1-[4-bromo-2,6-bis(2,2,2-trifluoroethoxy)benzyl]-1H-indazolyl} methoxy-N-(pyridinyl)pyrimidinamine, 2,4-dichloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H- indazolyl}methyl)benzoic acid, 2,4-dichloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H- indazolyl}methyl)-N-methylbenzamide, 2,4-dichloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H- indazolyl}methyl)benzamide, 2,4-dichloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H- indazolyl}methyl)-N,N-dimethylbenzamide, 2,4-dichloro-N-(2-hydroxyethyl)({3-[5-methoxy(pyridin ylamino)pyrimidinyl]-1H-indazolyl}methyl)benzamide, [2,4-dichloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H- indazolyl}methyl)phenyl](morpholinyl)methanone, 3,5-difluoro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H- indazolyl}methyl)-N-methylbenzamide, 4-ethynylfluorobenzyl)-1H-indazolyl]methoxy-N-(pyridin- 4-yl)pyrimidinamine, {2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridinyl)-7,8-dihydro-6H- pyrimido[5,4-b][1,4]oxazinyl}methanol, 2-[1-(2-fluorobenzyl)-1H-indazolyl]methoxy-N-methyl-N-(pyridin- 4-yl)pyrimidinamine, [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 4-({2-[1-(2-fluorobenzyl)-1H-indazolyl]methoxypyrimidin yl}amino)pyridinecarbonitrile, 2-[1-(2-fluorobenzyl)-1H-indazolyl]methoxy-N,N-di(pyridin yl)pyrimidinamine, methyl 4-({2-[1-(2-fluorobenzyl)-1H-indazolyl]methoxypyrimidin yl}amino)pyridinecarboxylate, 4-({2-[1-(2-fluorobenzyl)-1H-indazolyl]methoxypyrimidin yl}amino)pyridinecarboxamide, 4-({5-methoxy[1-(4-propylbenzyl)-1H-indazolyl]pyrimidin yl}amino)pyridinecarboxamide, 4-({2-[1-(2-fluorobenzyl)-1H-indazolyl]hydroxypyrimidin yl}amino)pyridinecarbonitrile, 4-({4-[(3-cyanopyridinyl)amino][1-(2-fluorobenzyl)-1H-indazol yl]pyrimidinyl}oxy)pyridinecarbonitrile, oxy[1-(4-methoxybenzyl)-1H-indazolyl]-N-[3- (trifluoromethyl)pyridinyl]pyrimidinamine, 3-chloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H- indazolyl}methyl)benzoic acid, formic acid - 3-chloro({3-[5-methoxy(pyridinylamino)pyrimidin- 2-yl]-1H-indazolyl}methyl)-N-methylbenzamide (1:1), 3-chloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H- indazolyl}methyl)-N-methylbenzamide, [1-(2-fluorobenzyl)-1H-indazolyl]hydroxypyrimidin no)pyridinecarboxamide, [1-(2-fluorobenzyl)-1H-indazolyl]hydroxypyrimidin yl}amino)pyridinecarboxylic acid, ethyl 4-({2-[1-(2-fluorobenzyl)-1H-indazolyl]hydroxypyrimidin yl}amino)pyridinecarboxylate, 2-fluorobenzyl)-1H-indazolyl](pyridinylamino)pyrimidine- -carbonitrile, 2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridinylamino)pyrimidine- -carboxamide, 4-({2-[1-(2-fluorobenzyl)-1H-indazolyl](2- hydroxyethoxy)pyrimidinyl}amino)pyridinecarboxylic acid hydrochloride (1:1), N-(2-fluoropyridinyl)methoxy[1-(4-methoxybenzyl)-1H-indazol- 3-yl]pyrimidinamine, N-(2,6-difluoropyridinyl)methoxy[1-(4-methoxybenzyl)-1H- indazolyl]pyrimidinamine, N-(3-fluoropyridinyl)methoxy[1-(4-methoxybenzyl)-1H-indazol- 3-yl]pyrimidinamine, [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb N-(difluoromethyl)[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]- N-(pyridinyl)pyrimidinamine or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.
One aspect of the invention are nds of formula (I) as described in the ex- amples as characterized by their names in the title as claimed in claim 5 and their structures as well as the subcombinations of all residues specifically disclosed in the compounds of the examples.
Another aspect of the present invention are the intermediates as used for their synthesis.
One special aspect of the invention is intermediate (1-5) wherein , N N R1 (R8) N m 1-5 R6 whereby R1, R6, R7 R8 and m have the meaning according to claim 1.
If ments of the invention as disclosed herein relate to compounds of formula (I), it is understood that those embodiments refer to the compounds of formula (I) as disclosed in the claims and the examples. r aspect of the invention are compounds of formula (I), wherein R1 is en, halogen, lkyl, Another aspect of the invention are compounds of a (I), wherein R1 is halogen.
[Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb Another aspect of the invention are compounds of a (I), wherein R1 is 1-3C-alkyl.
A further aspect of the invention are compounds of formula (I), wherein R1 is hydrogen, 1-3C-alkyl.
Yet another aspect of the ion are compounds of formula (I) according to claims 1, 2, 3, 4, 5 or 6, wherein R1 is en.
A further aspect of the invention are compounds of formula (I), wherein R2/R3 are independently from each other hydrogen, halogen, cyano, hydroxy 1-6C-haloalkyl, 1-6C-haloalkoxy, 1-6C-alkoxy, A r aspect of the invention are compounds of formula (I) according to claim 1, n R2 and/or R3 are independently from each other hydrogen, halogen, cyano, 1-6C-haloalkyl, 1-6C-haloalkoxy.
Another aspect of the ion are nds of formula (I), wherein R2 and/or R3 is halogen, especially fluorine, chlorine or bromine, preferably fluo- rine or chlorine.
Another aspect of the invention are nds of formula (I), wherein R2 and/or R3 is 1-3C-haloalkyl, especially CF3.
Another aspect of the invention are compounds of formula (I), wherein R2 and/or R3 is 1-3C-haloalkoxy, especially -O-CH2-CF3.
Another aspect of the invention are compounds of formula (I), wherein R2 and/or R3 is fluorine, chlorine, bromine, CF3, or -O-CH2-CF3.
Another aspect of the invention are nds of formula (I), wherein R2 and/or R3 is fluorine, chlorine, bromine, hydroxy, methoxy, CF3, or -O-CH2-CF3.
[Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb Yet another aspect of the invention are compounds of formula (I), wherein R2 and R3 are halogen or 1-3C-haloalkoxy, especially fluorine, ne, or -O-CH2- CF3. r aspect of the invention are compounds of formula (I), wherein R2 and/or R3 are hydroxy, (1-6C-alkoxy).
A further aspect of the invention are compounds of formula (I), wherein R2 and R3 are different.
Another aspect of the invention are compounds of formula (I), wherein one position of R2 and R3 is hydrogen and the other is halogen, 1-3C-haloalkyl, 1-3C- haloalkoxy or especially fluorine, chlorine, bromine, CF3, or -O-CH2-CF3. r aspect of the ion are compounds of a (I), wherein R4 is independently hydrogen, hydroxy, halogen, cyano, NO2, 1-6C-alkyl, 2-6C- alkenyl, 2-6C-alkynyl, 1-6C-haloalkyl, 1-6C-hydroxyalkyl, 1-6C-alkoxy, -O-(2-6Calkylen)-O-C(O)-(1-6C-alkyl), 1-6C-haloalkoxy, -C(O)OR9, -(1-6C- alkylen)-C(O)OR9, -C(O)-(1-6C-alkyl), -C(O)NR10R11, 3-7C-cycloalkyl, -S-(1-6C- haloalkyl), SF5, -SO2NH-(3-7C-cycloalkyl), -SO2NR10R11, NR10R11, heteroaryl which optionally is substituted independently one or more times with cyano, 1-4C-alkyl, 1-6C-haloalkyl, 1-6C-haloalkoxy, C(O)OR9, C(O)NR10R11, whereby two of R2, R3 (R4)n, when positioned ortho to each other, may form together with the two carbon atoms to which they are attached, a heterocyclic 5-, 6- or 7-membered ring containing 1 or 2 heteroatoms selected from O or N, and optionally containing an additional double bond and/or optionally substituted by an oxo (=O) group and/or an 1-4C-alkyl group, Another aspect of the invention are compounds of formula (I), n R4 is hydrogen.
Another aspect of the invention are compounds of formula (I), n R4 is hydrogen or halogen, especially hydrogen or fluorine.
[Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb r aspect of the invention are compounds of formula (I), wherein R4 is selected from the group consisting of hydroxy, NO2 or NR10R11.
Another aspect of the invention are compounds of formula (I), wherein R4 is selected from the group consisting of is independently hydrogen, halogen, cyano, 1-6C-alkyl, 2-6C-alkenyl, aloalkyl, 1-6C-hydroxyalkyl, 1-6C-alkoxy, 1-6C-haloalkoxy, -C(O)OR9, -(1-6C-alkylen)-C(O)OR9, -C(O)-(1-6C-alkyl), - C(O)NR10R11, 3-7C-cycloalkyl, 6C-haloalkyl), SF5, -SO2NH-(3-7C-cycloalkyl), -SO2NR10R11, heteroaryl which optionally is substituted independently one or more times with cyano, 1-4C-alkyl, 1-6C-haloalkyl, 1-6C-haloalkoxy, C(O)OR9, C(O)NR10R11, whereby two of R2, R3 (R4)n, when oned ortho to each other, may form together with the two carbon atoms to which they are attached, a heterocyclic 5-, 6- or 7-membered ring containing 1 or 2 heteroatoms selected from O or N, and optionally an additional double bond and/or a carbonyl group and/or an 1-4C-alkyl group. r aspect of the invention are nds of formula (I), wherein R4 is selected from the group consisting of en, n, cyano, 1-3C-alkyl, 3-6C-cycloalkyl, 2-3C-alkenyl, 1-3C-haloalkyl, 1-3C-hydroxyalkyl, 1-3C-alkoxy, 1- 3C-haloalkoxy, -C(O)-(1-3C-alkyl), COOH, (1-3C-alkylen)-COOH, -(1-3C-alkylen)- COO-(1-3C-alkyl), -COO-(1-4C-alkyl), -C(O)NH2, -C(O)NH(1-3C-alkyl), -C(O)N(1-3C-alkyl)2, -C(O)NH-(1-3C-alkyl)-OH, -C(O)-(N-heterocyclyl), -SO2-NH- (3-6C-cycloalkyl), -SO2-(N-heterocyclyl), Yet another aspect of the invention are compounds of formula (I), wherein R4 is selected from the group consisting of hydrogen, hydroxy, fluorine, chlorine, bromine or iodine, cyano, nitro, -CH3, -C3H9, cyclopropyl, 1-propenyl, -CF3, -CH2- OH, H2-OH, -C(CH3)2-OH, -CH2-C(CH3)2-OH, -C(CH3)2-CH2-OH, -OCH3, -OCF3, -OCF2H, -OCH2CF3, -C(O)CH3, -COOH, -C(O)OCH3, C2H5, -C(O)OC(CH3)3, OOC2H5, -CH2-COOH, -C(CH3)2-COOC2H5, -C(O)NH2, [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb -C(O)NH(CH3), -C(O)N(CH3)2, -C(O)NH-(CH2)2-OH, -C(O)-(N-morpholino), -SO2- NH-cyclopropyl, N-morpholino), NH2.
Yet another aspect of the invention are compounds of formula (I), wherein R4 is selected from the group consisting of hydrogen, ne, chlorine, e or iodine, cyano, -CH3, -C3H9, cyclopropyl, 1-propenyl, -CF3, -CH2-OH, -CH2-CH2-OH, -C(CH3)2-OH, -CH2-C(CH3)2-OH, -C(CH3)2-CH2-OH, -OCH3, -OCF3, -OCF2H, - OCH2CF3, -C(O)CH3, -COOH, -C(O)OCH3, -C(O)OC2H5, -C(O)OC(CH3)3, -CH2- COOC2H5, -CH2-COOH, -C(CH3)2-COOC2H5, -C(O)NH2, -C(O)NH(CH3), -C(O)N(CH3)2, -C(O)NH-(CH2)2-OH, -C(O)-(N-morpholino), -SO2-NH-cyclopropyl, - SO2-(N-morpholino).
A further aspect of the invention are compounds of formula (I), wherein y two of R2, R3 (R4)n, when positioned ortho to each other, may form to- gether with the two carbon atoms to which they are attached, a heterocyclic 5-, 6- or 7-membered ring containing 1 or 2 atoms selected from O or N, and optionally an additional double bond and/or a carbonyl group and/or an 1-4C-alkyl group, especially whereby two of R2, R3 (R4)n, when positioned ortho to each other , form er with the two carbon atoms to which they are attached, -O-CH2-CH2-CH2-O-, -O-CH2-CH2-, C=CH-(C=O)-O-, -CH2-(C=O)-O-, -(CH2)2-(C=O)-NH-.
In another embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), wherein n is 0, 1 or 2.
Another aspect of the invention are compounds of formula (I), wherein n is at least 1. r aspect of the invention are compounds of formula (I), wherein n is 1.
Another aspect of the invention are compounds of formula (I), wherein R6 is (a) hydrogen; [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb (b) hydroxy; (c) cyano; (d) 1-6C-alkoxy optionally substituted independently one or more times with (d1) OH, (d2) –O-(1-6C-alkyl) (d3) C(O)OR9, (d4) 10R11, (d5) NR10R11, (d6) –S-(1-6C-alkyl), (d7) –S(O)-(1-6C-alkyl), (d8) –SO2-(1-6C-alkyl) (d9) SO2NR10R11, (d10) cyclyl, which is optionally substituted with C(O)OR9, or oxo (=O), (d11) heteroaryl, which is optionally tuted independently one or more times with cyano, 1-4C-alkyl, 1-6C-haloalkyl, 1-6C-haloalkoxy, C(O)OR9, 10R11, (1-6C-alkylen)-O-(1-6C-alkyl), (e) SO2NR10R11, (f) 3-7C-cycloalkoxy, (g) 1-6C-haloalkoxy, (h) COOR9, (i) R10R11, (j) -O-heteroaryl opt. subst. with CN * O O H (k) O , whereby the * is the point of attachment, (l) –O-(2-6C-alkylen)-O-(1-6C-alkyl) which is optionally substituted with hydroxy, NH(CO)OR9, A further aspect of the invention are compounds of formula (I), wherein R6 is 1-6C-alkoxy which is optionally substituted independently one or more times.
[Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb A further aspect of the invention are compounds of formula (I), n R6 is heteroaryl, which is optionally substituted independently one or more times with cyano, 1-4C-alkyl, 1-6C-haloalkyl, 1-6C-haloalkoxy, C(O)OR9, C(O)NR10R11, (1-6C-alkyl)-O-(1-6C-alkyl). Another aspect of the invention are compounds of formula (I), wherein R6 is –O-(2-6Calkyl)-O-(1-6C-alkyl) which is optionally substituted with hydroxy or )OR9.
Another aspect of the invention are compounds of formula (I), wherein R6 is 1-6C-alkoxy which is optionally substituted independently one or more times with (d1) OH, (d2) –O-(1-6C-alkyl) (d3) C(O)OR9, (d4) C(O)NR10R11, (d5) NR10R11, (d6) –S-(1-6C-alkyl), (d7) –S(O)-(1-6C-alkyl), (d8) –SO2-(1-6C-alkyl) (d9) SO2NR10R11, (d10) heterocyclyl, which is optionally substituted with C(O)OR9, or oxo (=O), (d11) heteroaryl, which is optionally substituted independently one or more times with cyano, 1-4C-alkyl, aloalkyl, 1-6C-haloalkoxy, C(O)OR9, C(O)NR10R11, (2-6C-alkylen)-O-(1-6C-alkyl), Another aspect of the invention are compounds of formula (I), wherein R6 is 1-6C-alkoxy which is optionally tuted independently one or more times with (d2) 9, (d3) C(O)NR10R11, (d4) –S-(1-6C-alkyl), [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb (d6) –S(O)-(1-6C-alkyl), (d7) –SO2-(1-6C-alkyl), (d9) heterocyclyl, which is optionally substituted with C(O)OR9, oxo (=O).
Another aspect of the invention are compounds of formula (I), wherein R6 is (a) hydrogen; (b) hydroxy; (c) cyano; (d) 1-6C-alkoxy opt. subst. with (d1) 1-2 OH, (d2) NR10R11, (d3) 0R11, (d4) heterocyclyl, (d5) heteroaryl, which is optionally substituted independently one or more times with cyano, 1-4Calkyl, 1-6C-haloalkyl, 1-6C-haloalkoxy, C(O)OR9, 10R11, (e) SO2NR10R11, ; (f) 3-7C-cycloalkoxy, (g) aloalkoxy, (h) -C(O)NR10R11, (i) -O-heteroaryl opt. subst. with CN * O O H (j) O , whereby the * is the point of attachment, Another aspect of the invention are compounds of formula (I), wherein R6 is hydrogen, hydroxy, cyano, -O-(3-6C-cycloalkyl), 1-3C-alkoxy, 1-3C-haloalkoxy, -O-(1-3C-alkylen)-OH, -O-(1-3C-alkylen)-NH2, -O-(1-3C-alkylen)-NH(1-3C-alkyl), -O-(1-3C-alkylen)-N(1-3C-alkyl)2, -O-(1-3C-alkylen)-SO2NH2, 3C-alkylen)-SO2N(1-3C-alkyl)2, -O-(1-3C- alkylen)-(optionally substituted heteroaryl), -C(O)NH2, -C(O)N(1-3C-alkyl)2.
[Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb Another aspect of the invention are compounds of formula (I), wherein .
R6 is hydrogen, hydroxy, cyano, -O-cyclopropyl, -OCH3, -OCF3, -OCF2H, -OCH2CF3, -O-(CH2)2-OH, -O-(CH2)2-NH2, -O(CH2)2-N(CH3)2, -O-(CH2)2-O-CH3, - O-(CH2)2-O-(CH2)2-OH, -O-CH2-CH(OH)-CH2OH, -CH(OH)-CH2-NH- C(O)OC(CH3)3, -O-CH2-COOH, -O-CH2-COOC2H5, C(O)NH2, -O-CH2-C(O)-(3- fluoro-N-azetidine), -C(O)-(3,3-difluoro-N-azetidine), -O-CH2-CH(OH)-CH2- N-piperidinyl, -O-(CH2)2(morpholineyl), -O-CH2-(morpholineyl), -O-CH2- (morpholineyltert.-butoxycarboxylate), -O-CH2-(pyrrolidinoneyl), -O- (CH2)2-S-CH3, -O-(CH2)2-SO-CH3, -O-(CH2)2-SO2-CH2, -O-CH2-SO2NH2, -SO2- * O O H CH(CH3)2, O , whereby * is the point of attachment, -O-(CH2)2-tetrazolyl, -O-CH2-tetrazolyl, -O-pyridineyl, -O-(3-cyano-pyridine yl), or - O-CH2-(oxadiazole)-CH2-O-CH3, Another aspect of the invention are nds of a (I), wherein R6 is hydrogen, hydroxy, cyano, -O-cyclopropyl, -OCH3, -OCF3, -OCF2H, O O H -OCH2CF3, -O-(CH2)2-OH, -O(CH2)2-N(CH3)2, -O-CH2-SO2NH2, O , -O-(CH2)2-tetrazolyl, -O-CH2-tetrazolyl, -O-pyridineyl, cyano-pyridine yl), -C(O)NH2.
Another aspect of the invention are compounds of formula (I), wherein R6 is hydrogen, hydroxy, cyano, -O-cyclopropyl, -OCH3, -OCF3, -OCF2H, O O H -OCH2CF3, 2)2-OH, -O(CH2)2-N(CH3)2, -O-CH2-SO2NH2, O , -O-(CH2)2-tetrazolyl, -O-CH2-tetrazolyl, -O-pyridineyl, -O-(3-cyano-pyridineyl), -C(O)NH2.
Another aspect of the ion are compounds of formula (I), wherein if R6 is in the tion of the pyrimidine ring directly neighbouring the R7 bearing amino substituent, R6 together with R7 is a 5 or 6-membered ring including the nitrogen atom of the amino substituent which may contain one further heteroatom selected [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb from O, S or N and which in addition may be substituted with a carbonyl group or -CH2-OH.
Another aspect of the invention are compounds of formula (I), wherein if R6 is in the 5-position of the pyrimidine ring directly neighbouring the R7 bearing amino substituent, R6 together with R7 is a 5 or 6-membered ring including the nitrogen atom of the amino substituent which may n one further heteroatom selected from O, S or N and which in on may be substituted with a carbonyl group or -CH2-OH or O.
Another preferred aspect of the invention are compounds of formula (I), wherein R6 is-O-(3-6C-cycloalkyl), 1-3C-alkoxy, 1-3C-haloalkoxy, -O-(1-3C-alkylen)- OH, -O-(1-3C-alkylen)-NH2, -O-(1-3C-alkylen)-NH(1-3C-alkyl), -O-(1-3C-alkylen)-N(1-3C-alkyl)2, -O-(1-3C-alkylen)-SO2NH2, -O-(1-3C-alkylen)-SO2N(1-3C-alkyl)2, 3C-alkylen)-(optionally substituted heteroaryl), especially -O-cyclopropyl, -OCH3, -OCF3, -OCF2H, -OCH2CF3, -O- O O H (CH2)2-OH, -O(CH2)2-N(CH3)2, -O-CH2-SO2NH2, O , -O-(CH2)2- tetrazolyl, -O-CH2-tetrazolyl, -O-pyridineyl, -O-(3-cyano-pyridineyl).
Another preferred aspect of the invention are compounds of formula (I), wherein R6 is hydrogen, hydroxy, cyano, -O-cyclopropyl, -O(1-3C-alkyl), -O-(1-3C- haloalkyl), -O-(1-3C-alkylen ally tuted by a hydroxy group)-OH, -O(1- 3C-alkylen ally substituted by a hydroxy group)-NR10R11, -O-(1alkylen)-O- (1-3C-alkyl), -O-(1-3C-alkylen)-O-(1-3C-alkyl)-OH, -O-(1-3C-alkylen)-COOR9, C(O)NR10R11, -O-(1-3C-alkylen)-C(O)-(heterocycyl ally substituted 1 or two times by ne), -O-(1alkylen)-(heterocyclyl optionally substituted by an oxo (=O) group and/or COOR9 or a y group), -O-(1-3C-alkylen)-S-CH3, -O-(1- 3C-alkylen)-SO-CH3, -O-(1-3C-alkylen)2-SO2-CH3, -O-(1-3C-alkylen)-SO2NH2, - * O O H SO2-(1-3C-alkyl), O , whereby * is the point of attachment, [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb -O-(1alkylen)-[heteroaryl optionally substituted by CN or (1-3C-alkylen)-O-(1- 3C-alkyl)], Another preferred aspect of the invention are compounds of formula (I), wherein R6 3-6C-cycloalkyl), lkoxy, 1-3C-haloalkoxy, -O-(1-3C-alkylen)- OH, -O-(1-3C-alkylen)-NH2, -O-(1-3C-alkylen)-NH(1-3C-alkyl), -O-(1-3C-alkylen)-N(1-3C-alkyl)2, -O-(1-3C-alkylen)-SO2NH2, -O-(1-3C-alkylen)-SO2N(1-3C-alkyl)2, -O-(1-3C-alkylen)-(optionally tuted heteroaryl), especially -O-cyclopropyl, -OCH3, -OCF3, -OCF2H, -OCH2CF3, -O- O O H (CH2)2-OH, -O(CH2)2-N(CH3)2, -O-CH2-SO2NH2, O , -O-(CH2)2- tetrazolyl, -O-CH2-tetrazolyl, -O-pyridineyl, -O-(3-cyano-pyridineyl).
A further aspect of the ion are compounds of formula (I), n R6 is1-6C-alkoxy which is substituted by –S-(1-6C-alkyl), -SO-(1-6C-alkyl) or – SO2-(1-6C-alkyl).
A further aspect of the invention are compounds of formula (I), wherein R6 is SO2NR10R11.
Another aspect of the invention are compounds of formula (I), wherein R6 is H2, -C(O)N(1-3C-alkyl)2 or cyano especially -C(O)NH2.
Another aspect of the invention are compounds of a (I), wherein R7 is (a) hydrogen, (b)1-6C-alkyl, which is optionally substituted with heteroaryl (c) 1-6C-haloalkyl, (d) 1-6C-hydroxyalkyl, C H 2 (e) O , whereby the * is the point of ment, (f) -C(O)-(1-6C-alkyl) ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb (g) –C(O)-(1-6C-alkylen)-O-(1-6C-alkyl) (h) –C(O)-(1-6C-alkylen)-O-(2-6C-alkylen)-O-(1-6C-alkyl) (i) –C(O)-heterocyclyl, (j) benzyl y the phenyl ring is opt. subst with 1-5 substituents independently selected from the group consisting of hydrogen, halogen, 1-4C-alkyl, aloalkyl, 1-4C-alkoxy, 1-4C-haloalkoxy, cyano, C(O)OR9, (k) heteroaryl optionally, R6 and R7 together with the nitrogen atom to which R7 is attached form a 6-membered ring which may contain one further heteroatom selected from the group consisting of O, S, N, and which is optionally substituted by (1-6C-alkyl)-OH, (1-6C-alkyl)-NR10R11, Another aspect of the invention are compounds of formula (I), wherein R7 is (a) hydrogen, (b)1-6C-alkyl, which is optionally substituted with heteroaryl (c) 1-6C-haloalkyl, (d) 1-6C-hydroxyalkyl, C H 2 (e) O , whereby the * is the point of attachment, (f) -C(O)-(1-6C-alkyl) (g) –C(O)-(1-6C-alkylen)-O-(1-6C-alkyl) (h) –C(O)-(1-6C-alkylen)-O-(2-6C-alkylen)-O-(1-6C-alkyl) (i) –C(O)-heterocyclyl, (j) benzyl whereby the phenyl ring is opt. subst with 1-5 substituents ndently selected from the group ting of hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-haloalkoxy, cyano, C(O)OR9, (k) heteroaryl [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb optionally, R6 and R7 er with the nitrogen atom to which R7 is attached form a 6-membered ring which may contain one further heteroatom selected from the group consisting of O, S, N, and which is optionally substituted by (1-6C-alkyl)-OH, (1-6C-alkyl)-NR10R11, Another aspect of the invention are compounds of formula (I), wherein R7 is (a) hydrogen, C-alkyl, which is optionally substituted with heteroaryl (c) 1-3C-haloalkyl, (d) 1-3C-hydroxyalkyl, C H 2 (e) O , whereby the * is the point of attachment, (f) -C(O)-(1-3C-alkyl) (g) –C(O)-(1-3C-alkylen)-O-(1-3C-alkyl) (h) (1-3C-alkylen)-O-(2-3C-alkylen)-O-(1-3C-alkyl) (i) –C(O)-heterocyclyl, (j) benzyl whereby the phenyl ring is opt. subst with 1-5 substituents independently selected from the group consisting of en, halogen, 1-3C-alkyl, 1-3C-alkoxy, 1-3C-haloalkoxy, cyano, C(O)OR9, (k) heteroaryl optionally, R6 and R7 together with the nitrogen atom to which R7 is attached form a 6-membered ring which may contain one further atom selected from the group consisting of O, S, N, and which is optionally substituted by (1-3C-alkyl)-OH, (1-3C-alkyl)-NR10R11.
[Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb Another aspect of the invention are compounds of formula (I), wherein R7 is (a) hydrogen, (b)1-6C-alkyl, which is optionally substituted with heteroaryl (c) 1-6C-haloalkyl, (d) ydroxyalkyl, C H 2 (e) O , whereby the * is the point of attachment, (f) -C(O)-(1-6C-alkyl) (g) –C(O)-(1-6C-alkylen)-O-(1-6C-alkyl) (h) –C(O)-(1-6C-alkylen)-O-(1-6C-alkylen)-O-(1-6C-alkyl) (i) heterocyclyl, (j) benzyl y the phenyl ring is opt. subst with 1-5 tuents independently selected from the group consisting of hydrogen, halogen, 1-4Calkyl, 1-4C-haloalkyl, 1-4C-alkoxy, 1-4C-haloalkoxy, cyano, C(O)OR9, (k) heteroaryl optionally R6 and R7 er with the nitrogen atom to which they are attached form a 6-membered ring which may contain one further heteroatom selected from the group consisting of O, S, N, and which is optionally substituted by hydroxy-(1-6alkyl), r aspect of the invention are compounds of formula (I), wherein O O H R7 is hydrogen, 1-3C-alkyl, 1-3C-haloalkyl, -(1-3C-alkylen)-OH, O , (1-3C-alkylen)-aryl, -(1-3C-alkylen)-heteroaryl, heteroaryl, -C(O)-(1-3C-alkyl), -C(O)-(1-3C-alkylen)-O-(1-3C-alkyl), -C(O)-(1-3C-alkylen)-O-(1-3C-alkylen)-O-(1- 3C-alkyl), -C(O)-heterocyclyl.
[Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb Another aspect of the invention are compounds of formula (I), wherein O O H R7 is hydrogen, 1-3C-alkyl, 1-3C-haloalkyl, 1-3C-hydroxyalkyl, O , whereby * is the point of attachment, aryl, -(1-3C-alkylen)-heteroaryl, , -C(O)-heterocyclyl, -C(O)-(1-3C-alkylen)- C-alkyl), -C(O)-(1-3C-alkyl), -C(O)CH2-O-(1-3C-alkylen)-O-(1-3C-alkyl), or benzyl which is ally substituted one or more times with halogen, cyano, 1-3C-alkyl, 1-3C-haloalkyl, 1-3C-alkoxy, 1-3C-haloalkoxy, -C(O)O(1alkyl), or optionally, when R6 is in position 5 of the pyrimidine ring system, R6 and R7 together with the nitrogen atom to which R7 is attached form a 6-membered ring which may contain one further heteroatom selected from O, S or N and which in addition is optionally substituted by CH2-OH or -CH2-NH-CHO Another aspect of the invention are compounds of formula (I), wherein O O H R7 is hydrogen, , difluoromethyl, hydroxyethyl, O , -(CH2)2- tetrazolyl, pyridineyl, -C(O)-tetrahydropyranyl, -C(O)-CH2-O-CH3, -C(O)-CH3, -C(O)CH2-O-(CH2)2-O-CH3 or benzyl which is optionally substituted one or more times with fluorine, ne, e, cyano, , methoxy, ethoxy, difluormethoxy , trifluoromethoxy, -CF3, -C(O)OCH3.
Still another aspect of the invention are compounds of formula (I), wherein O O H R7 is hydrogen, methyl, difluoromethyl, hydroxyethyl, O , -(CH2)2- tetrazolyl, pyridineyl, -C(O)-tetrahydropyranyl, -C(O)-CH2-O-CH3, CH3, H2-O-(CH2)2-O-CH3 or benzyl which is optionally substituted one or more times with fluorine, chlorine, cyano, , methoxy, ethoxy, difluormethoxy, tri- fluoromethoxy, -O-CH2-CF3, -C(O)OCH3.
Another aspect of the invention are compounds of formula (I), wherein R7 is optionally one or more times substituted benzyl, the substitutents selected from the group consisting of halogen (especially fluorine, chlorine), cyano, 1-3C- [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb alkoxy (especially methoxy, ), 1-3C-haloalkoxy (especially -OCF3, -O-CF2H, -O-CH2-CF3).
In another aspect the benzyl group is substituted 1-, 2-, 3- or 4 times.
Another aspect of the invention are compounds of formula (I), wherein R8 is hydrogen, halogen, hydroxy, cyano, 1-6C-alkyl, 1-6C-hydroxyalkyl, 1-6C- haloalkyl, 1-6C-haloalkoxy, C(O)OR9, C(O)NR10R11, Another aspect of the ion are compounds of formula (I), wherein R8 is hydrogen, halogen, cyano, 1-6C-haloalkyl, 1-6C-haloalkoxy, C(O)OR9, C(O)NR10R11, Another aspect of the invention are compounds of formula (I), n R8 is hydrogen, cyano, 1-3C-haloalkyl, -C(O)NH2, -C(O)N(1-3C-alkyl), C(O)OH, - C(O)-O(1-4C-alkyl), -C(O)-(1-3C-alkylen)-OH, especially hydrogen, cyano, CF3, 2, , C(O)OC2H5, C(O)O(CH2)2-OH.
Another aspect of the invention are compounds of formula (I), wherein R8 is hydroxy-(1-6C-alkyl).
Another aspect of the invention are compounds of formula (I), wherein R8 is hydrogen, ne, hydroxy, cyano, 1-3C-alkyl, 1-3C-haloalkyl, 1-3C- alkyl, 1-3C-alkoxy, C(O)OR9, C(O)NR10R11, especially hydrogen, fluorine, hydroxy, cyano, methyl, CF3, methoxy, hydroxymethyl, COOH, , COOC2H5, C(O)NH2, C(O)NHCH3.
Still another aspect of the invention are nds of formula (I), wherein m is 0.
Another aspect of the invention are compounds of formula (I), wherein m is 0 or 1.
Another aspect of the invention are compounds of formula (I), wherein m is selected from 0, 1 or 2.
[Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb Another aspect of the invention are compounds of formula (I), wherein R9 is (a) hydrogen, (b) 1-6C-alkyl which optionally is substituted with y, Another aspect of the invention are compounds of formula (I), wherein R9 is hydrogen, 1-4C-alkyl, ydroxyalkyl, especially hydrogen, methyl, ethyl, tert.-butyl, yethyl.
Another aspect of the invention are compounds of formula (I), wherein R10, R11 are independently from each other hydrogen, 1-4C-alkyl, 1-4C- hydroxyalkyl, 1-4C-alkoxy, -(CO)-(1-6C-alkyl), CHO, COOR9, or together with the nitrogen atom to which they are attached form a 4membered heterocyclic ring optionally containing one r heteroatom selected from the group consisting of O, S or N, and which is optionally substituted with 1-2 fluorine atoms or COOR9, Another aspect of the invention are compounds of formula (I), wherein R10/R11 is ndently from each other hydrogen, lkyl, 1-3C-hydroxyalkyl, especially hydrogen, , hydroxyethyl, Another aspect of the invention are nds of formula (I), wherein R10, R11 are independently from each other hydrogen, 1-4C-alkyl, 1-4C- hydroxyalkyl, 1-4C-alkoxy, -(CO)-(1-6C-alkyl) or together with the nitrogen atom to which they are attached form a 4membered heterocyclic ring optionally containing one further heteroatom selected from the group consisting of O, S or N, which is optionally with 1-2 halogen atoms, especially fluorine atoms.
In another of the invention are compounds of formula (I), wherein R10, R11 are independently from each other hydrogen, 1-4C-alkyl, 1-4C- hydroxyalkyl, 1-4C-alkoxy, or [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb er with the nitrogen atom to which they are attached form a 5membered heterocyclic ring optionally containing one further atom selected from the group consisting of O, S or N.
Another aspect of the invention are compounds of formula (I), n R10, R11 form together with the nitrogen atom to which they are attached a 4- membered heterocyclic ring, which is optionally with 1-2 halogen atoms, especially fluorine atoms.
A further aspect of the invention are compounds of formula (I), which are present as their salts, ally as their hydrochlorides.
Another embodiment of the invention are the tautomeric forms of a hydroxypyridine which are defined to be encompassed by the claim, should the compound of formula I include such a hydroxypyridine: N O N OH Another embodiment of the invention are nds according to the claims as disclosed in the Claims section wherein the definitions are limited according to the preferred or more preferred definitions as disclosed below or specifically disclosed residues of the ified nds and subcombinations thereof.
The invention as d herein is defined by the following items 1 to 25: 1. A compound of formula (I) [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb (R4) N (R8) R6 (I) in which R1 is hydrogen, n, 1-3C-alkyl, R2/R3 are independently from each other hydrogen, halogen, cyano, hydroxy 1-6C-haloalkyl, 1-6C-haloalkoxy, 1-6C-alkoxy, R4 is independently hydrogen, hydroxy, halogen, cyano, NO2, 1-6C-alkyl, 2-6C- alkenyl, 2-6C-alkynyl, 1-6C-haloalkyl, 1-6C-hydroxyalkyl, 1-6C-alkoxy, -O-(2-6C-alkylen)-O-C(O)-(1-6C-alkyl), 1-6C-haloalkoxy, R9, -(1-6C- alkylen)-C(O)OR9, -C(O)-(1-6C-alkyl), -C(O)NR10R11, 3-7C-cycloalkyl, -S-(1- oalkyl), SF5, -SO2NH-(3-7C-cycloalkyl), -SO2NR10R11, NR10R11, heteroaryl which optionally is substituted independently one or more times with cyano, 1-4C-alkyl, 1-6C-haloalkyl, 1-6C-haloalkoxy, C(O)OR9, 10R11, whereby two of R2, R3 (R4)n, when positioned ortho to each other, may form together with the two carbon atoms to which they are attached, a cyclic -, 6- or 7-membered ring containing 1 or 2 heteroatoms selected from O or N, and optionally containing an additional double bond and/or optionally substituted by an oxo (=O) group and/or an 1-4C-alkyl group, n 0 - 3 R6 is (a) hydrogen; (b) hydroxy; (c) cyano; (d) 1-6C-alkoxy optionally substituted independently one or more times with (d1) OH, (d2) –O-(1-6C-alkyl) ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb (d3) C(O)OR9, (d4) C(O)NR10R11, (d5) NR10R11, (d6) –S-(1-6C-alkyl), (d7) –S(O)-(1-6C-alkyl), (d8) –SO2-(1-6C-alkyl) (d9) SO2NR10R11, (d10) heterocyclyl, which is optionally substituted with 9, or oxo (=O), (d11) heteroaryl, which is optionally substituted independently one or more times with cyano, lkyl, 1-6C-haloalkyl, 1-6C-haloalkoxy, C(O)OR9, C(O)NR10R11, (1-6C-alkylen)-O-(1-6C-alkyl), (e) SO2NR10R11, (f) 3-7C-cycloalkoxy, (g) 1-6C-haloalkoxy, (h) COOR9, (i) -C(O)NR10R11, (j) eroaryl optionally substituted with CN * O O H (k) O , whereby the * is the point of attachment, (l) –O-(2-6C-alkylen)-O-(1-6C-alkyl) which is optionally tuted with hydroxy , NH(CO)OR9, R7 is (a) hydrogen, (b)1-6C-alkyl, which is optionally substituted with heteroaryl (c) 1-6C-haloalkyl, (d) 1-6C-hydroxyalkyl, C H 2 (e) O , whereby the * is the point of attachment, (f) -C(O)-(1-6C-alkyl), (g) –C(O)-(1-6C-alkylen)-O-(1-6C-alkyl), [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb (h) –C(O)-(1-6C-alkylen)-O-(2-6C-alkylen)-O-(1-6C-alkyl), (i) –C(O)-heterocyclyl, (j) benzyl whereby the phenyl ring is optionally substituted with 1-5 substituents independently selected from the group consisting of hydrogen, halogen, 1-4C-alkyl, 1-4C-haloalkyl, 1-4C-alkoxy, 1-4C-haloalkoxy, cyano, C(O)OR9, (k) aryl optionally, R6 and R7 together with the nitrogen atom to which R7 is attached form a 6-membered ring which may contain one further heteroatom selected from the group consisting of O, S, N, and which is optionally substituted by (1-6C-alkyl)-OH, (1-6C-alkyl)-NR10R11, R8 is hydrogen, halogen, hydroxy, cyano, 1-6C-alkyl, 1-6C-hydroxyalkyl, 1-6C- haloalkyl, 1-6C-haloalkoxy, C(O)OR9, C(O)NR10R11, m is 0-4 R9 is (a) hydrogen, (b) 1-6C-alkyl which optionally is substituted with hydroxy, R10, R11 are independently from each other hydrogen, 1-4C-alkyl, 1-4C- hydroxyalkyl, 1-4C-alkoxy, (1-6C-alkyl), CHO, COOR9, or together with the nitrogen atom to which they are attached form a 4 membered heterocyclic ring optionally containing one r heteroatom selected from the group consisting of O, S or N, and which is optionally substituted with 1-2 fluorine atoms or COOR9, or an N-oxide, a salt, a er or a stereoisomer of said compound, or a salt of said N-oxide, er or stereoisomer. 2. The compound of formula (I) according to item 1, wherein R1 is hydrogen, halogen, 1-3C-alkyl, [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb R2/R3 are independently from each other hydrogen, halogen, cyano, 1-6C- haloalkyl, 1-6C-haloalkoxy, R4 is independently hydrogen, halogen, cyano, lkyl, 2-6C-alkenyl, 1-6C- haloalkyl, ydroxyalkyl, 1-6C-alkoxy, 1-6C-haloalkoxy, -C(O)OR9, -(1- 6C-alkylen)-C(O)OR9, -C(O)-(1-6C-alkyl), -C(O)NR10R11, 3-7C-cycloalkyl, - S-(1-6C-haloalkyl), SF5, -SO2NH-(3cycloalkyl), -SO2NR10R11, heteroaryl which optionally is substituted independently one or more times with cyano, 1-4C-alkyl, 1-6C-haloalkyl, 1-6C-haloalkoxy, C(O)OR9, C(O)NR10R11, whereby two of R2, R3 (R4)n, when positioned ortho to each other, may form together with the two carbon atoms to which they are attached, a cyclic -, 6- or 7-membered ring containing 1 or 2 atoms selected from O or N, and optionally an additional double bond and/or a carbonyl group and/or an 1-4C-alkyl group, n 0 - 3 R6 is (a) hydrogen; (b) y; (c) cyano; (d) 1-6C-alkoxy optionally substituted with (d1) 1-2 OH, (d2) NR10R11, (d3) SO2NR10R11, (d4) heterocyclyl, (d5) heteroaryl, which is ally substituted independently one or more times with cyano, 1-4Calkyl, 1-6C-haloalkyl, 1-6C-haloalkoxy, C(O)OR9, C(O)NR10R11, (e) SO2NR10R11, ; (f) 3-7C-cycloalkoxy, (g) aloalkoxy, (h) -C(O)NR10R11, [Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb (i) -O-heteroaryl ally substituted with CN * O O H (j) O , whereby the * is the point of attachment, R7 is (a) hydrogen, (b)1-6C-alkyl, which is optionally substituted with heteroaryl (c) 1-6C-haloalkyl, (d) 1-6C-hydroxyalkyl, C H 2 (e) O , whereby the * is the point of attachment, (f) -C(O)-(1-6C-alkyl) (g) –C(O)-(1-6C-alkylen)-O-(1-6C-alkyl) (h) (1-6C-alkylen)-O-(1-6C-alkylen)-O-(1-6C-alkyl) (i) –C(O)-heterocyclyl, (j) benzyl whereby the phenyl ring is optionally substituted with 1-5 substituents independently selected from the group consisting of hydrogen, halogen, 1-4Calkyl, 1-4C-haloalkyl, 1-4C-alkoxy, 1-4C- haloalkoxy, cyano, (k) heteroaryl ally R6 and R7 together with the nitrogen atom to which they are attached form a 6-membered ring which may contain one further heteroatom selected from the group consisting of O, S, N, and which is optionally substituted by hydroxy-(1-6alkyl), R8 is hydrogen, halogen, cyano, 1-6C-haloalkyl, 1-6C-haloalkoxy, C(O)OR9, C(O)NR10R11, m is 0-4 R9 is (a) hydrogen, (b) 1-6C-alkyl which optionally may be substituted with hydroxy, [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb R10, R11 are independently from each other hydrogen, 1-4C-alkyl, 1-4C- yalkyl, 1-4C-alkoxy, or together with the nitrogen atom to which they are attached form a 5 membered heterocyclic ring optionally containing one further heteroatom selected from the group consisting of O, S or N, or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer. 3. The compound of formula (I) according to item 1, wherein R1 is hydrogen, halogen, 1-3C-alkyl, R2/R3 are independently from each other hydrogen, n, cyano, hydroxy, 1-3C-haloalkyl, 1-3C-haloalkoxy, 1-3C-alkoxy, R4 is independently hydrogen, y, halogen, cyano, NO2, 1-3C-alkyl, 2-3C- alkenyl, 2-3C-alkynyl, 1-3C-haloalkyl, 1-3C-hydroxyalkyl, 1-3C-alkoxy, -O-(2-3C-alkylen)-O-C(O)-(1-3C-alkyl), 1-3C-haloalkoxy, -C(O)OR9, -(1-3C- alkylen)-C(O)OR9, -C(O)-(1-3C-alkyl), R10R11, 3-7C-cycloalkyl, -S-(1- oalkyl), SF5, -SO2NH-(3-7C-cycloalkyl), -SO2NR10R11, NR10R11, heteroaryl which optionally is substituted independently one or more times with cyano, 1-3C-alkyl, 1-3C-haloalkyl, 1-3C-haloalkoxy, C(O)OR9, C(O)NR10R11, whereby two of R2, R3 (R4)n, when positioned ortho to each other, may form together with the two carbon atoms to which they are attached, a heterocyclic -, 6- or ered ring containing 1 or 2 heteroatoms selected from O or N, and optionally containing an additional double bond and/or optionally substituted by an oxo (=O) group and/or an lkyl group, n 0 - 3 R6 is (a) hydrogen; (b) hydroxy; (c) cyano; (d) 1-6C-alkoxy optionally substituted independently one or more times with (d1) OH, (d2) –O-(1-3C-alkyl) [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb (d3) C(O)OR9, (d4) C(O)NR10R11, (d5) NR10R11, (d6) –S-(1-3C-alkyl), (d7) –S(O)-(1-3C-alkyl), (d8) –SO2-(1-3C-alkyl), (d9) SO2NR10R11, (d10) heterocyclyl, which is optionally tuted with C(O)OR9, or oxo (=O), (d11) heteroaryl, which is optionally tuted ndently one or more times with cyano, 1-3C-alkyl, 1-3C-haloalkyl, 1-3C-haloalkoxy, C(O)OR9, C(O)NR10R11, (1-3C-alkylen)-O-(1-3C-alkyl), (e) SO2NR10R11, (f) ycloalkoxy, (g) 1-6C-haloalkoxy, (h) COOR9, (i) -C(O)NR10R11, (j) -O-heteroaryl optionally substituted with CN * O O H (k) O , whereby the * is the point of attachment, (l) –O-(2-3C-alkylen)-O-(1-3C-alkyl) which is optionally substituted with hydroxy , NH(CO)OR9, R7 is (a) hydrogen, (b)1-3C-alkyl, which is optionally substituted with heteroaryl (c) 1-3C-haloalkyl, (d) 1-3C-hydroxyalkyl, C H 2 (e) O , whereby the * is the point of ment, (f) -C(O)-(1-3C-alkyl) (g) –C(O)-(1-3C-alkylen)-O-(1-3C-alkyl) [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb (h) –C(O)-(1-3C-alkylen)-O-(2-3C-alkylen)-O-(1-3C-alkyl) (i) –C(O)-heterocyclyl, (j) benzyl y the phenyl ring is optionally substituted with 1-5 substituents independently selected from the group consisting of hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-haloalkoxy, cyano, C(O)OR9, (k) aryl optionally, R6 and R7 together with the nitrogen atom to which R7 is attached form a 6-membered ring which may contain one further atom selected from the group consisting of O, S, N, and which is optionally substituted by (1-3C-alkyl)-OH, alkyl)-NR10R11, R8 is hydrogen, halogen, hydroxy, cyano, 1-3C-alkyl, 1-3C-hydroxyalkyl, 1-3C- haloalkyl, 1-3C-haloalkoxy, C(O)OR9, C(O)NR10R11, m is 0-4 R9 is (a) hydrogen, (b) 1-3C-alkyl which optionally is substituted with y, R10, R11 are independently from each other hydrogen, 1-3C-alkyl, 1-3C- hydroxyalkyl, 1-3C-alkoxy, (1-3C-alkyl), CHO, COOR9 or together with the nitrogen atom to which they are attached form a 4 membered heterocyclic ring optionally containing one further heteroatom selected from the group ting of O, S or N, which is optionally substituted with 1-2 fluorine atoms or COOR9, or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer. 4. The compound of formula (I) according to item 1, in which R1 is hydrogen, 1-3C-alkyl, [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb R2/R3 are independently from each other hydrogen, halogen, cyano, hydroxy, 1-4C-haloalkyl, 1-4C-alkoxy, R4 is independently hydrogen, hydroxy, halogen, cyano, 1-4C-alkyl, 2-4C- alkenyl, 2-4C-alkynyl, 1-4C-haloalkyl, 1-4C-hydroxyalkyl, 1-4C-alkoxy, -O-(2-4C-alkylen)-O-C(O)-(1-4C-alkyl), 1-4C-haloalkoxy, -C(O)OR9, -(1-4C- n)-C(O)OR9, -C(O)-(1-4C-alkyl), -C(O)NR10R11, 3-7C-cycloalkyl, -S-(1- 4C-haloalkyl), SF5, -SO2NH-(3-7C-cycloalkyl), -SO2NR10R11, NR10R11, heteroaryl which optionally is substituted independently one or more times with cyano, 1-4C-alkyl, 1-4C-haloalkyl, 1-4C-haloalkoxy, C(O)OR9, C(O)NR10R11, y two of R2, R3 (R4)n, when positioned ortho to each other, may form together with the two carbon atoms to which they are attached, a heterocyclic -, 6- or 7-membered ring containing 1 or 2 heteroatoms selected from O or N, and optionally containing an additional double bond and/or optional- ly substituted by an oxo (=O) group and/or an lkyl group, n 0 - 3 R6 is (a) hydrogen; (b) hydroxy; (d) 1-4C-alkoxy optionally substituted ndently one or more times with (d1) OH, (d2) –O-(1-4C-alkyl) (d3) C(O)OR9, (d4) C(O)NR10R11, (d5) NR10R11, (d6) –S-(1-4C-alkyl), (d7) –S(O)-(1-4C-alkyl), (d8) –SO2-(1-4C-alkyl) (d9) SO2NR10R11, (d10) heterocyclyl, which is optionally substituted with C(O)OR9, or oxo (=O), (d11) heteroaryl, which is optionally substituted independently one or more times with cyano, lkyl, 1-4C-haloalkyl, 1-4C-haloalkoxy, C(O)OR9, C(O)NR10R11, (1-4C-alkylen)-O-(1-4C-alkyl), [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb (e) SO2NR10R11, (f) 3-7C-cycloalkoxy, (g) aloalkoxy, (h) COOR9, (i) -C(O)NR10R11, (j) -O-heteroaryl optionally substituted with CN * O O H (k) O , whereby the * is the point of attachment, (l) –O-(2-4C-alkylen)-O-(1-4C-alkyl) which is optionally substituted with hydroxy , NH(CO)OR9, R7 is (a) hydrogen, (b) (1-4C-alkyl)-heteroaryl (c) 1-4C-haloalkyl, (d) ydroxyalkyl, * C H 2 O H (e) O , whereby * is the point of attachment, (f) -C(O)-(1-4C-alkyl) (g) –C(O)-(1-4C-alkylen)-O-(1-4C-alkyl) (h) –C(O)-(1-4C-alkylen)-O-(2-4C-alkylen)-O-(1-4C-alkyl) (i) –C(O)-heterocyclyl, (j) benzyl whereby the phenyl ring is optionally substituted with 1-5 substituents independently ed from the group consisting of hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-haloalkoxy, cyano, C(O)OR9, (k) heteroaryl or optionally, R6 and R7 er with the nitrogen atom to which R7 is attached form a 6-membered ring which may contain one further heteroatom selected from the group consisting of O, S, N, [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb and which is optionally substituted by (1-4C-alkyl)-OH, (1-4C-alkyl)-NR10R11, R8 is hydrogen, n, hydroxy, cyano, C(O)NR10R11, 1-4C-alkyl, 1-4C- hydroxyalkyl, 1-4C-haloalkyl, 1-4C-haloalkoxy, m is 0-2, R9 is hydrogen, 1-4C-alkyl which optionally is substituted with hydroxy, R10, R11 are independently from each other hydrogen, 1-4C-alkyl, 1-4C- hydroxyalkyl, 1-4C-alkoxy, -C(O)-(1-4C-alkyl), or COOR9 or together with the nitrogen atom to which they are attached form a 4 ed heterocyclic ring optionally containing one further heteroatom selected from the group consisting of O, S or N, which is optionally substituted with 1-2 fluorine atoms or COOR9, or an N-oxide, a salt, a tautomer or a isomer of said compound, or a salt of said N-oxide, tautomer or isomer.
. The compound of formula (I) ing to item 1, wherein, R1 is hydrogen, R2/R3 is independently hydrogen, fluorine, chlorine, bromine, cyano, hydroxy, CF3, -O-CH3 or -CF3, R4 is independently of each other hydrogen, fluorine, chlorine, bromine or iodine , cyano, NO2, hydroxy, -CH3, -C3H7, cyclopropyl, 1-propenyl, -C≡CH, -CF3, -CH2-OH, -CH2-CH2-OH, -C(CH3)2-OH, -CH2-C(CH3)2-OH, -C(CH3)2- CH2-OH, -OCH3, -O-CH2-CH3, -OCF3, -OCF2H, F3, 2)-OC (O)-CH3, -C(O)CH3, -COOH, -C(O)OCH3, -C(O)OC2H5, -C(O)OC(CH3)3, -CH2-COOH, OOC2H5, -C(CH3)2-COOC2H5, -C(O)NH2, -C(O)NH(CH3), -C(O)N(CH3)2, -C(O)NH-(CH2)2-OH, -C(O)-(N-morpholinyl), -SO2-NH-cyclopropyl, -SO2-(N-morpholino), NH2, NH-C(O)(CH3), 5-methyl- oxa-diazolyl, N-pyrrolyl, N-pyrazolyl, -S-CF3, SF5, whereby two of R2, R3 (R4)n, when positioned ortho to each other, form together -O-CH2-CH2-CH2-O-, -O-CH2-CH2-, -(CH3)C=CH-(C=O)-O-, [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb -CH2-(C=O)-O-, -(CH2)2-(C=O)-NH-, which together with the two carbon atoms to which they are attached form a 5-, 6- or 7-membered ring, n is 0, 1, 2, 3, R6 is hydrogen, y, cyano, -O-cyclopropyl, -OCH3, -OCF3, -OCF2H, -OCH2CF3, -O-(CH2)2-OH, -O-(CH2)2-NH2, )2-N(CH3)2, -O-(CH2)2-OCH3 , -O-(CH2)2-O-(CH2)2-OH, -O-CH2-CH(OH)-CH2OH, -O-CH2-CH(OH)- CH2-NH-C(O)OC(CH3)3, -O-CH2-COOH, -O-CH2-COOC2H5, C(O)NH2, -OCH2-C (O)-(3-fluoro-N-azetidine), -O-CH2-C(O)-(3,3-difluoro-N-azetidine), - O-CH2-CH(OH)-CH2-N-piperidinyl, -O-(CH2)2(morpholineyl), -O-CH2- (morpholineyl), -O-CH2-(morpholineyltert.-butoxycarboxylate), -OCH2- (pyrrolidinoneyl), -O-(CH2)2-S-CH3, -O-(CH2)2-SO-CH3, -O- * O O H (CH2)2-SO2-CH2, -O-CH2-SO2NH2, -SO2-CH(CH3)2, O , whereby * is the point of attachment, -O-(CH2)2-tetrazolyl, -O-CH2-tetrazolyl, -O-pyridineyl, -O-(3-cyano- pyridineyl), or - O-CH2-(oxadiazole)-CH2-O-CH3, C H 2 R7 is hydrogen, methyl, difluoromethyl, hydroxyethyl, O , whereby * is the point of attachment, -(CH2)2-tetrazolyl, pyridineyl, -C(O)-tetrahydropyranyl, -C(O)-CH2-O- CH3, -C(O)-CH3, H2-O-(CH2)2-O-CH3, C(O)OCH2-CH=CH2, or benzyl which is optionally substituted one or more times with fluorine, chlorine, bromine, cyano, methyl, difluoromethyl, y, ethoxy, difluormethoxy, oromethoxy, -O-CH2-CF3, -C(O)OCH3, or optionally, R6 and R7 together with the nitrogen atom to which R7 is at- tached form a 6-membered ring which may contain one further heteroatom selected from the group ting of O, S, N and which in on is optionally substituted by -CH2-OH or -CH2-NH-CHO R8 is hydrogen, ne, hydroxy, cyano, CH3, CF3, CH2-OH, OCH3, C(O)OH, C(O)OCH3, C(O)OC2H5, C(O)O(CH2)2-OH, C(O)NH2, C(O)NHCH3, m is 0, 1 or 2 [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb or an N-oxide, a salt, a tautomer or a stereoisomer of said nd, or a salt of said N-oxide, tautomer or stereoisomer. 6. Compounds of formula (I) according to item 1, which is selected from the group consisting of: 2-[1-(6-chlorofluoromethylbenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, 6-chlorofluoromethoxybenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, -methoxy{1-[3-(5-methyl-1,2,4-oxadiazolyl)benzyl]-1H-indazolyl}-N- (pyridinyl)pyrimidinamine, 2-[1-(2-chloro-4,5-dimethylbenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, -methoxy{1-[4-(pentafluoro-λ6-sulfanyl)benzyl]-1H-indazolyl}-N-(pyridin yl)pyrimidinamine, 2-[1-(2,6-difluoromethoxybenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, N-(2,6-difluoromethoxybenzyl)[1-(2,6-difluoromethoxybenzyl)-1H-indazol- 3-yl]methoxy-N-(pyridinyl)pyrimidinamine, (6-bromo-1,3-benzodioxolyl)methyl]-1H-indazolyl}methoxy-N- (pyridinyl)pyrimidinamine, 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, N-(4-ethoxy-2,6-difluorobenzyl)[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]- -methoxy-N-(pyridinyl)pyrimidinamine, 2-({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)benzonitrile, 2-chloromethoxybenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, 2-[1-(3,4-dihydro-2H-1,5-benzodioxepinylmethyl)-1H-indazolyl]methoxy-N- (pyridinyl)pyrimidinamine, 2-[1-(2,6-difluorobenzyl)-1H-indazolyl]methoxy-N-(pyridinyl)pyrimidin amine, N-(2,6-difluorobenzyl)[1-(2,6-difluorobenzyl)-1H-indazolyl]methoxy-N- (pyridinyl)pyrimidinamine, -methoxy-N-(pyridinyl)(1-{3-[(trifluoromethyl)sulfanyl]benzyl}-1H-indazol yl)pyrimidinamine, 2-[1-(2,3-difluoromethylbenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, N-(2,3-difluoromethylbenzyl)[1-(2,3-difluoromethylbenzyl)-1H-indazolyl]- [Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb -methoxy-N-(pyridinyl)pyrimidinamine, -methoxy{1-[4-(1H-pyrazolyl)benzyl]-1H-indazolyl}-N-(pyridin yl)pyrimidinamine 2-[1-(2,6-dichlorobenzyl)-1H-indazolyl]methoxy-N-(pyridinyl)pyrimidin amine, N-(2,6-dichlorobenzyl)[1-(2,6-dichlorobenzyl)-1H-indazolyl]methoxy-N- (pyridinyl)pyrimidinamine, -methoxy-N-(pyridinyl)(1-{4-[(trifluoromethyl)sulfanyl]benzyl}-1H-indazol yl)pyrimidinamine, 2-[1-(2-chlorobenzyl)-1H-indazolyl]methoxy-N-(pyridinyl)pyrimidin amine, N-(2-chlorobenzyl)[1-(2-chlorobenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, methyl ro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol- 1-yl}methyl)benzoate, methyl 3-chloro{[(2-{1-[2-chloro(methoxycarbonyl)benzyl]-1H-indazolyl} methoxypyrimidinyl)(pyridinyl)amino]methyl}benzoate, 2-[1-(4-bromo-2,6-difluorobenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, 2-[1-(2-chlorofluoromethoxybenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, 2-[1-(4-ethoxy-2,3-difluorobenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, N-(4-ethoxy-2,3-difluorobenzyl)[1-(4-ethoxy-2,3-difluorobenzyl)-1H-indazolyl]- -methoxy-N-(pyridinyl)pyrimidinamine, -methoxy-N-(pyridinyl){1-[2,3,5,6-tetrafluoro(2,2,2-trifluoroethoxy)benzyl]- 1H-indazolyl}pyrimidinamine, -methoxy-N-(pyridinyl)-N-[2,3,5,6-tetrafluoro(2,2,2-trifluoroethoxy)benzyl] 3,5,6-tetrafluoro(2,2,2-trifluoroethoxy)benzyl]-1H-indazolyl}pyrimidin amine, methyl 2,4-dichloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H- indazolyl}methyl)benzoate, -methoxy-N-(pyridinyl)[1-(2,4,6-trifluorobenzyl)-1H-indazolyl]pyrimidin amine, -methoxy-N-(pyridinyl)-N-(2,4,6-trifluorobenzyl)[1-(2,4,6-trifluorobenzyl)-1H- indazolyl]pyrimidinamine, 2-[1-(2-fluorobenzyl)-1H-indazolyl]methoxy-N-(pyridinyl)pyrimidinamine 2-[1-(2,4-dichlorobenzyl)-1H-indazolyl]methoxy-N-(pyridinyl)pyrimidin amine, 2-[1-(2-fluoroiodobenzyl)-1H-indazolyl]methoxy-N-(pyridinyl)pyrimidin- 4-amine, [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 2-[1-(2-bromobenzyl)-1H-indazolyl]methoxy-N-(pyridinyl)pyrimidin amine, N-(2-bromobenzyl)[1-(2-bromobenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, [3-fluoro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)phenyl]acetic acid, -methoxy-N-(pyridinyl)[1-(2,3,5,6-tetrafluoromethoxybenzyl)-1H-indazol- 3-yl]pyrimidinamine, -methoxy[1-(4-propylbenzyl)-1H-indazolyl]-N-(pyridinyl)pyrimidin amine, 2-{1-[2,6-dichloro(trifluoromethoxy)benzyl]-1H-indazolyl}methoxy-N- inyl)pyrimidinamine, N-[2,6-dichloro(trifluoromethoxy)benzyl]{1-[2,6-dichloro (trifluoromethoxy)benzyl]-1H-indazolyl}methoxy-N-(pyridinyl)pyrimidin amine, 7-({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazolyl}methyl)-3,4- dihydroquinolin-2(1H)-one, 2-[1-(2-chloroiodobenzyl)-1H-indazolyl]methoxy-N-(pyridinyl)pyrimidin- 4-amine, 2-[1-(3,5-dimethoxybenzyl)-1H-indazolyl]methoxy-N-(pyridinyl)pyrimidin amine, 2-{1-[2-chloro(trifluoromethyl)benzyl]-1H-indazolyl}methoxy-N-(pyridin yl)pyrimidinamine, 2-[1-(2-chlorofluorobenzyl)-1H-indazolyl]methoxy-N-(pyridinyl)pyrimidin- 4-amine, 7-({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazolyl}methyl) methyl-2H-chromenone, 3-fluoro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)benzonitrile, 4-{[{2-[1-(4-cyanofluorobenzyl)-1H-indazolyl]methoxypyrimidin yl}(pyridinyl)amino]methyl}fluorobenzonitrile, 2-{1-[2,6-dichloro(trifluoromethyl)benzyl]-1H-indazolyl}methoxy-N-(pyridin- 4-yl)pyrimidinamine, ethyl -[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)phenyl]acetate, 2-[1-(4-fluorobenzyl)-1H-indazolyl]methoxy-N-(pyridinyl)pyrimidinamine, N-cyclopropyl({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol hyl)benzenesulfonamide, [5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazolyl}methyl) benzofuran-2(3H)-one, [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 2-{1-[4-(difluoromethoxy)-2,6-difluorobenzyl]-1H-indazolyl}methoxy-N- (pyridinyl)pyrimidinamine, tert-butyl 3-chloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H- indazolyl}methyl)benzoate, ethyl 2-[3-({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)phenyl]methylpropanoate, 4-({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)benzonitrile, oxy{1-[4-(morpholinylsulfonyl)benzyl]-1H-indazolyl}-N-(pyridin yl)pyrimidinamine, 2,6-dichloronitrobenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, [5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)benzonitrile, N-[4-(difluoromethoxy)-2,6-difluorobenzyl]{1-[4-(difluoromethoxy)-2,6- difluorobenzyl]-1H-indazolyl}methoxy-N-(pyridinyl)pyrimidinamine, -methoxy-N-(pyridinyl){1-[3-(1H-pyrrolyl)benzyl]-1H-indazol yl}pyrimidinamine, 3,5-difluoro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)benzonitrile -methoxy{1-[2-methoxy(trifluoromethyl)benzyl]-1H-indazolyl}-N-(pyridin- 4-yl)pyrimidinamine, 2-[1-(2,6-difluoromethylbenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, 2-[1-(2-fluoromethoxybenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, 3,5-difluoro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)benzamide, 2-[3,5-difluoro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)phenoxy]ethyl acetate, 2-[1-(2,6-difluoropropoxybenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, 2-[1-(4-ethoxyfluoromethoxybenzyl)-1H-indazolyl]methoxy-N-(pyridin imidinamine, 4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridinylamino)pyrimidin- -ol 2-[1-(4-methoxybenzyl)-1H-indazolyl](pyridinylamino)pyrimidinol, 2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridinylamino)pyrimidinol, 2-[1-(4-fluorobenzyl)-1H-indazolyl](pyridinylamino)pyrimidinol, {3-[({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb ylamino)pyrimidinyl}oxy)methyl]oxetanyl}methanol, {3-[({2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridinylamino)pyrimidin yl}oxy)methyl]oxetanyl}methanol, 2-[1-(2-fluorobenzyl)-1H-indazolyl]{[3-(hydroxymethyl)oxetan yl]methoxy}pyrimidinyl)(pyridinyl)amino]methyl}oxetanyl)methanol, 1-({2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridinylamino)pyrimidin yl}oxy)methanesulfonamide, -[2-(dimethylamino)ethoxy][1-(2-fluorobenzyl)-1H-indazolyl]-N-(pyridin yl)pyrimidinamine, 2-[1-(2-fluorobenzyl)-1H-indazolyl]-N-(pyridinyl)[2-(1H-tetrazol yl)ethoxy]pyrimidinamine, 2-[1-(2-fluorobenzyl)-1H-indazolyl]-N-(pyridinyl)[2-(1H-tetrazol yl)ethoxy]-N-[2-(1H-tetrazolyl)ethyl]pyrimidinamine, -[2-(dimethylamino)ethoxy][1-(4-fluorobenzyl)-1H-indazolyl]-N-(pyridin yl)pyrimidinamine, 2-[1-(2-fluorobenzyl)-1H-indazolyl]-N-(pyridinyl)(1H-tetrazol ylmethoxy)pyrimidinamine, dimethylamino)ethoxy][1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]-N- (pyridinyl)pyrimidinamine, 1-({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)(piperidinyl)propanol, 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](2-methoxyethoxy)-N- (pyridinyl)pyrimidinamine, tert-butyl 2-[({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)methyl]morpholinecarboxylate, 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl][2-(morpholinyl)ethoxy]-N- (pyridinyl)pyrimidinamine, 2-fluorobenzyl)-1H-indazolyl]{[3-(methoxymethyl)-1,2,4-oxadiazol yl]methoxy}-N-(pyridinyl)pyrimidinamine, ethyl ({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)acetate, -difluoroazetidinyl)({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]- 4-(pyridinylamino)pyrimidinyl}oxy)ethanone, 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl][2-(methylsulfanyl)ethoxy]-N- (pyridinyl)pyrimidinamine, 2-[2-({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)ethoxy]ethanol, formic acid - (5S)[({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl] (pyridinylamino)pyrimidinyl}oxy)methyl]pyrrolidinone (1:1), (5R)[({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)methyl]pyrrolidinone, ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb tert-butyl {2-[2-({2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)ethoxy]ethyl}carbamate, 2-({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)(3-fluoroazetidinyl)ethanone, (5S)[({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)methyl]pyrrolidinone, tert-butyl [2-({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)ethyl]carbamate, N-({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridinyl)-7,8-dihydro- 6H-pyrimido[5,4-b][1,4]oxazinyl}methyl)formamide, 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]-N-(pyridinyl)pyrimidin amine, 2-[1-(4-methoxybenzyl)-1H-indazolyl]-N-(pyridinyl)pyrimidinamine, 2-[1-(2-fluorobenzyl)-1H-indazolyl]-N-(pyridinyl)pyrimidinamine, 2-[1-(4-cyclopropyl-2,6-difluorobenzyl)-1H-indazolyl]methoxy-N-(pyridin imidinamine, 2-(1-{2,6-difluoro[(1E)-propenyl]benzyl}-1H-indazolyl)methoxy-N- (pyridinyl)pyrimidinamine, 1-[3,5-difluoro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)phenyl]ethanone, ichloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)phenyl]methanol, 2-[3-({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)phenyl]ethanol, 2-[3-({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)phenyl]methylpropanol, [4-({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]methoxypyrimidin yl}amino)pyridinyl]methanol, 2-[3-chloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)phenyl]propanol, 1-[3-({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)phenyl]methylpropanol, 2-[2,4-dichloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)phenyl]propanol, -(difluoromethoxy)[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]-N-(pyridin- yrimidinamine, -(difluoromethoxy)-N-(difluoromethyl)[1-(4-ethoxy-2,6-difluorobenzyl)-1H- indazolyl]-N-(pyridinyl)pyrimidinamine, 4-[(difluoromethyl)(pyridinyl)amino][1-(4-ethoxy-2,6-difluorobenzyl)-1H- indazolyl]pyrimidinol, [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 2-[1-(4-methoxybenzyl)-1H-indazolyl]-N-(pyridinyl)(2,2,2- trifluoroethoxy)pyrimidinamine, 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]-N-(pyridinyl)(2,2,2- trifluoroethoxy)pyrimidinamine, [1-(2-fluorobenzyl)-1H-indazolyl](pyridinylamino)pyrimidin yl}oxy)propane-1,2-diol, (2S)({2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridinylamino)pyrimidin yl}oxy)propane-1,2-diol, (2R)({2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridinylamino)pyrimidin yl}oxy)propane-1,2-diol, 2-({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)ethanol, 2-({2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridinylamino)pyrimidin yl}oxy)ethanol, ethyl 4-({2-[1-(2-fluorobenzyl)-1H-indazolyl](2-hydroxyethoxy)pyrimidin yl}amino)pyridinecarboxylate, 4-({2-[1-(2-fluorobenzyl)-1H-indazolyl](2-hydroxyethoxy)pyrimidin yl}amino)-N-methylpyridinecarboxamide, [1-(2-fluorobenzyl)-1H-indazolyl](2-hydroxyethoxy)pyrimidin yl}amino)pyridinecarboxamide, oxyethyl 4-({2-[1-(2-fluorobenzyl)-1H-indazolyl](2- hydroxyethoxy)pyrimidinyl}amino)pyridinecarboxylate, -(cyclopropyloxy)[1-(4-methoxybenzyl)-1H-indazolyl]-N-(pyridin yl)pyrimidinamine, 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine hydrochloride (1:1), (2S)({2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridinylamino)pyrimidin yl}oxy)propane-1,2-diol hydrochloride (1:1), 2-({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)ethanol hydrochloride (1:1), 2-[1-(2,6-dichlorobenzyl)-1H-indazolyl]methoxy-N-(pyridinyl)pyrimidin amine hydrochloride (1:1), [2,4-dichloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)phenyl]methanol hydrochloride (1:1), (2R)({2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridinylamino)pyrimidin yl}oxy)propane-1,2-diol hloride (1:1), N-{2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]pyrimidinyl}-N-(pyridin tamide, N-{2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]pyrimidinyl}methoxy-N- (pyridinyl)acetamide, [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb N-{2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]pyrimidinyl}-N-(pyridin yl)tetrahydro-2H-pyrancarboxamide, N-{2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]pyrimidinyl}(2- methoxyethoxy)-N-(pyridinyl)acetamide, 2-[{2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]pyrimidinyl}(pyridin yl)amino]ethanol, (3-{[{2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]pyrimidinyl}(pyridin yl)amino]methyl}oxetanyl)methanol, 2-{1-[4-bromofluoro(2,2,2-trifluoroethoxy)benzyl]-1H-indazolyl}methoxy- N-(pyridinyl)pyrimidinamine, 2-{1-[4-bromo-2,6-bis(2,2,2-trifluoroethoxy)benzyl]-1H-indazolyl}methoxy-N- (pyridinyl)pyrimidinamine, 2,4-dichloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)benzoic acid, -(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin o)pyrimidinyl}oxy)acetic acid, 2,4-dichloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)-N-methylbenzamide, 2,4-dichloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)benzamide, 2,4-dichloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)-N,N-dimethylbenzamide, 2,4-dichloro-N-(2-hydroxyethyl)({3-[5-methoxy(pyridinylamino)pyrimidin yl]-1H-indazolyl}methyl)benzamide, [2,4-dichloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)phenyl](morpholinyl)methanone, 3,5-difluoro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol hyl)-N-methylbenzamide, 2-[1-(4-ethynylfluorobenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, {2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridinyl)-7,8-dihydro-6H-pyrimido[5,4- b][1,4]oxazinyl}methanol, 2-[1-(2-fluorobenzyl)-1H-indazolyl]methoxy-N-methyl-N-(pyridin imidinamine, 4-({2-[1-(2-fluorobenzyl)-1H-indazolyl]methoxypyrimidinyl}amino)pyridine- 3-carbonitrile, 2-[1-(2-fluorobenzyl)-1H-indazolyl]methoxy-N,N-di(pyridinyl)pyrimidin amine, methyl 4-({2-[1-(2-fluorobenzyl)-1H-indazolyl]methoxypyrimidin yl}amino)pyridinecarboxylate, [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 2-[1-(2-fluorobenzyl)-1H-indazolyl]methoxy-N-(pyridinyl)pyrimidinamine, 4-({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]methoxypyrimidin yl}amino)pyridinecarbonitrile, {4-[(2,6-dimethylpyridinyl)amino]methoxypyrimidinyl}-1H-indazol yl)methyl]ethoxyfluorophenol, methoxy[1-(4-methoxybenzyl)-1H-indazolyl]pyrimidin yl}amino)pyridin-2(1H)-one, 4-({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]methoxypyrimidin yl}amino)pyridin-2(1H)-one, 4-({5-methoxy[1-(4-propylbenzyl)-1H-indazolyl]pyrimidin yl}amino)nicotinonitrile, 4-({2-[1-(2-fluorobenzyl)-1H-indazolyl]methoxypyrimidinyl}amino)pyridine- oxamide, 4-({5-methoxy[1-(4-propylbenzyl)-1H-indazolyl]pyrimidinyl}amino)pyridine- 3-carboxamide, 4-({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]methoxypyrimidin yl}amino)pyridinecarboxamide, 4-({2-[1-(2,6-difluorohydroxybenzyl)-1H-indazolyl]methoxypyrimidin yl}amino)pyridinecarboxamide, 4-({2-[1-(2-fluorobenzyl)-1H-indazolyl]hydroxypyrimidinyl}amino)pyridine- onitrile, 4-({4-[(3-cyanopyridinyl)amino][1-(2-fluorobenzyl)-1H-indazolyl]pyrimidin- -yl}oxy)pyridinecarbonitrile, -methoxy[1-(4-methoxybenzyl)-1H-indazolyl]-N-[3-(trifluoromethyl)pyridin yl]pyrimidinamine, 3-chloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)benzoic acid, formic acid - 3-chloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H- lyl}methyl)-N-methylbenzamide (1:1), 3-chloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)-N-methylbenzamide, 4-({2-[1-(2-fluorobenzyl)-1H-indazolyl]hydroxypyrimidinyl}amino)pyridine- 3-carboxamide, 4-({2-[1-(2-fluorobenzyl)-1H-indazolyl]hydroxypyrimidinyl}amino)pyridine- 3-carboxylic acid, ethyl 4-({2-[1-(2-fluorobenzyl)-1H-indazolyl]hydroxypyrimidin yl}amino)pyridinecarboxylate, 2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridinylamino)pyrimidinecarbonitrile 2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridinylamino)pyrimidine carboxamide, [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 4-({2-[1-(2-fluorobenzyl)-1H-indazolyl](2-hydroxyethoxy)pyrimidin yl}amino)pyridinecarboxylic acid hydrochloride (1:1), N-(2-fluoropyridinyl)methoxy[1-(4-methoxybenzyl)-1H-indazol yl]pyrimidinamine, N-(2,6-difluoropyridinyl)methoxy[1-(4-methoxybenzyl)-1H-indazol yl]pyrimidinamine, N-(3-fluoropyridinyl)methoxy[1-(4-methoxybenzyl)-1H-indazol yl]pyrimidinamine, -methoxy[1-(4-methoxybenzyl)-1H-indazolyl]-N-(2-methylpyridin yl)pyrimidinamine, N-(difluoromethyl)[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]-N-(pyridin yl)pyrimidinamine, 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl][2-(methylsulfinyl)ethoxy]-N- (pyridinyl)pyrimidinamine, 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl][2-(methylsulfinyl)ethoxy]-N- inyl)pyrimidinamine iomer 1), 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl][2-(methylsulfinyl)ethoxy]-N- (pyridinyl)pyrimidinamine (Enantiomer 2), 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl][2-(methylsulfonyl)ethoxy]-N- (pyridinyl)pyrimidinamine, -(2-aminoethoxy)[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]-N-(pyridin yl)pyrimidinamine, 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](morpholinylmethoxy)-N- (pyridinyl)pyrimidinamine, Preparation of ethyl 4-({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl] ypyrimidinyl}amino)pyridinecarboxylate, N-(3,5-difluoropyridinyl)[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl] methoxypyrimidinamine, 3-amino-2,6-dichlorobenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, -dichloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)phenyl]acetamide, 2-[1-(4-ethoxy-2,6-difluorobenzyl)methyl-1H-indazolyl]methoxy-N-(pyridin- 4-yl)pyrimidinamine, or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer. 7. A compound of formula (I), [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb (R4) N (R8) R6 (I) wherein, R1 is hydrogen, R2/R3 is independently hydrogen, fluorine, chlorine, bromine, cyano, hydroxy, CF3, -O-CH3 or -O-CH2-CF3, R4 is independently of each other hydrogen, fluorine, chlorine, bromine or iodine , cyano, NO2, hydroxy, -CH3, -C3H7, cyclopropyl, 1-propenyl, -C≡CH, -CF3, -CH2-OH, -CH2-CH2-OH, -C(CH3)2-OH, -CH2-C(CH3)2-OH, -C(CH3)2- CH2-OH, -OCH3, -O-CH2-CH3 ally tuted one or more times with hydroxy, -OCF3, -OCF2H, -OCH2CF3, -O-(CH2)-O-C(O)-CH3, -C(O)CH3, -COOH, -C(O)OCH3, -C(O)OC2H5, -C(O)OC(CH3)3, -CH2-COOH, -CH2- COOC2H5, -C(CH3)2-COOC2H5, -C(O)NH2, H(CH3), -C(O)N(CH3)2, -C(O)NH-(CH2)2-OH, (N-morpholinyl), -SO2-NH-cyclopropyl, -SO2-(N- morpholino), NH2, NH-C(O)(CH3), 5-methyl-oxa-diazolyl, olyl, N- pyrazolyl, -S-CF3, SF5, whereby two of R2, R3 (R4)n, when positioned ortho to each other, form together -O-CH2-CH2-CH2-O-, -O-CH2-CH2-, -(CH3)C=CH-(C=O)-O-, -CH2-(C=O)-O-, -(CH2)2-(C=O)-NH-, which together with the two carbon at- oms to which they are attached form a 5-, 6- or ered ring, n is 0, 1, 2, 3, R6 is en, hydroxy, cyano, -O-cyclopropyl, -OCH3, -OCF3, -OCF2H, -OCH2CF3, -O-(CH2)2-OH, -O-(CH2)2-NH2, -O(CH2)2-N(CH3)2, -O-(CH2)2-OCH3 , -O-(CH2)2-O-(CH2)2-OH, -CH(OH)-CH2OH, -O-CH2-CH(OH)- CH2-NH-C(O)OC(CH3)3, -O-CH2-COOH, -O-CH2-COOC2H5, C(O)NH2, -O- [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb O)-(3-fluoro-N-azetidine), -O-CH2-C(O)-(3,3-difluoro-N-azetidine), - CH(OH)-CH2-N-piperidinyl, -O-(CH2)2(morpholineyl), -O-CH2- (morpholineyl), -O-CH2-(morpholineyltert.-butoxycarboxylate), -OCH2- (pyrrolidinoneyl), -O-(CH2)2-S-CH3, 2)2-SO-CH3, -O- * O O H (CH2)2-SO2-CH2, -O-CH2-SO2NH2, -SO2-CH(CH3)2, O , whereby * is the point of attachment, -O-(CH2)2-tetrazolyl, -O-CH2-tetrazolyl, -O-pyridineyl, -O-(3-cyano- pyridineyl), or - O-CH2-(oxadiazole)-CH2-O-CH3, C H 2 R7 is hydrogen, methyl, romethyl, hydroxyethyl, O , whereby * is the point of attachment, -(CH2)2-tetrazolyl, neyl, -C(O)-tetrahydropyranyl, -C(O)-CH2-OCH3 , -C(O)-CH3, -C(O)CH2-O-(CH2)2-O-CH3, C(O)OCH2-CH=CH2, or benzyl which is optionally substituted one or more times with fluorine, chlorine, e, cyano, methyl, difluoromethyl, methoxy, ethoxy, difluormethoxy, trifluoromethoxy, -O-CH2-CF3, -C(O)OCH3, or optionally, R6 and R7 together with the nitrogen atom to which R7 is attached form a 6-membered ring which may contain one further heteroatom selected from the group consisting of O, S, N and which in addition is op- tionally substituted by -CH2-OH or -CH2-NH-CHO R8 is hydrogen, fluorine, hydroxy, cyano, CH3, CF3, CH2-OH, OCH3, C(O)OH, C(O)OCH3, C(O)OC2H5, C(O)O(CH2)2-OH, 2, C(O)NHCH3, m is 0, 1 or 2 or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer. 8. A nd of formula (I) [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb (R4) N (R8) R6 (I) in which R1, R2, R3, n, R6, R7, R8 and m have the meanings according to item 7, and R4 is ndently of each other hydrogen, fluorine, ne, bromine or iodine, cyano, NO2, hydroxy, -CH3, -C3H7, cyclopropyl, 1-propenyl, -C≡CH, -CF3, H, -CH2-CH2-OH, -C(CH3)2-OH, -CH2-C(CH3)2-OH, -C(CH3)2-CH2-OH, -OCH3, -O-CH2-CH3, -OCF3, -OCF2H, -OCH2CF3, -O-(CH2)-O-C(O)-CH3, -C(O)CH3, -COOH, -C(O)OCH3, -C(O)OC2H5, -C(O)OC(CH3)3, -CH2-COOH, -CH2-COOC2H5, -C(CH3)2-COOC2H5, -C(O)NH2, -C(O)NH(CH3), -C(O)N(CH3)2, -C(O)NH-(CH2)2-OH, -C(O)-(N-morpholinyl), -SO2-NH- cyclopropyl, -SO2-(N-morpholino), NH2, NH-C(O)(CH3), 5-methyl-oxa-diazol- 3-yl, N-pyrrolyl, zolyl, and -S-CF3, SF5, said group being optionally substituted, one or more times, identically or different- ly, with a substituent selected from: hydroxy, halogen, cyano, 1-6C-alkyl, 1-4C-haloalkyl, and 1-6C-alkoxy, whereby two of R2, R3 (R4)n, when positioned ortho to each other, form together -O-CH2-CH2-CH2-O-, -CH2-, -(CH3)C=CH-(C=O)-O-, -CH2-(C=O)-O-, -(CH2)2-(C=O)-NH-, which together with the two carbon atoms to which they are attached form a 5-, 6- or 7-membered ring, or an e, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.
[Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 9. A compound of formula (I) (R4) N (R8) R6 (I) in which R1, R2, R3, n, R6, R7, R8 and m have the meanings according to item 7, and R4 is selected from the group consisting of en, n, cyano, 1-3C-alkyl, 3-6C-cycloalkyl, 2-3C-alkenyl, 1-3C-haloalkyl, 1-3C-hydroxyalkyl, 1-3C-alkoxy, 1- 3C-haloalkoxy, -C(O)-(1-3C-alkyl), COOH, (1-3C-alkylen)-COOH, -alkylen)- COO-(1-3C-alkyl), 1-4C-alkyl), -C(O)NH2, -C(O)NH(1-3C-alkyl), -C(O)N(1-3C-alkyl)2, -C(O)NH-(1-3C-alkyl)-OH, -C(O)-(N-heterocyclyl), -SO2-NH- (3-6C-cycloalkyl), -SO2-(N-heterocyclyl), said group being optionally substituted, one or more times, identically or different- ly, with a substituent selected from: hydroxy, halogen, cyano, 1-6C-alkyl, 1-4C-haloalkyl, and 1-6C-alkoxy, or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, er or stereoisomer.
. Process for the manufacture of compounds of general formula (I) according to item 1, wherein R7 is hydrogen as reflected in formula (Ia), characterized in that a compound of formula (1-4) [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb (R4) N R3 N 2 whereby R1, R2, R3, R4, R6 and n have the meaning ing to item 1, is reacted with a compound of formula (C) (R8) X' whereby R8 and m have the meaning according to item 1, and X’ represents F, Cl, Br, I, boronic acid or a boronic acid ester in the ce of a suitable base, and a suitable palladium catalyst, optionally in the presence of a suitable ligand, forming a compound of formula (Ia) (R4)n N R3 N R1 (R8) N m N H (Ia) which is optionally subsequently ected to form a compound of l formula (I) wherein R7 is hydrogen and R1, R2, R3, R4, R6, R8 and n and m have the meaning as defined in item 1. 11. Process for the manufacture of compounds of general formula (I) according to item 1, wherein [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb a compound of formula (Ib) R2 O N R3 N R1 (R8) N m (Ib) R6 whereby R1, R2, R3, R6, R7, R8 and m have the meaning according to item 1 and R’ is 1-6C-alkyl or benzyl, is treated with a suitable acid system to cleave the ic group in order to obtain a compound of formula 1-5 N N R1 (R8) N m 1-5 R6 followed by reacting the compound of formula 1-5 with a compound of general formula (B), X R3 B wherein R2, R3, R4 and n have the meaning according to item 1 and X ents a leaving group, in a suitable solvent system, in the presence of a suitable base, in a temperature range from room temperature to the boiling point of the respective solvent, to fur- nish compounds of general formula (I). 12. An intermediate compound of general formula (1-5), ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb ation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb N N R1 (R8) N m 1-5 R6 whereby R1, R6, R7, R8 and m have the meaning according to any one of items 1 to 5. 13. Use of a compound of formula 1-5 ing to item 12 for the manufacture of a compound of formula (I) according to any one of items 1 to 9. 14. An intermediate compound of general formula (1-4), (R4) N R3 N 2 whereby R1, R2, R3, R4, R6 and n have the meaning according to any one of items 1 to 5 or 7 to 9 and R2 and R3 are halogen.
. The intermediate compound of general formula (1-4) according to item 14, wherein R² and R³ are fluorine, chlorine or bromine. 16. The intermediate compound of general formula (1-4) according to item 14, wherein R² and R³ are fluorine or chlorine. 17. Use of a compound of formula (1-4) [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb (R4) N R3 N 2 whereby R1, R2, R3, R4, R6 and n have the meaning ing to any one of items 1 to 5 or 7 to 9, for the manufacture of a compound of formula (I) according to any one of items 1 to 9. 18. Use of a compound of general formula (I) according to any one of items 1 to 9 for the manufacture of a medicament for the treatment or prophylaxis of diseases. 19. Use of a compound of l formula (I) according to item 18, whereby the diseases are hyperproliferative diseases and/or disorders responsive to induction of apoptosis.
. Use of a nd of general formula (I) according to ing to item 19, whereby the hyperproliferative diseases and/or disorders responsive to induction of apoptosis are haemotological tumours, solid tumours and/or metastases thereof. 21. Use of a compound of formula (I) ing to item 20, whereby the tumors are cervical -, breast -, non-small cell lung -, prostate -, colon – or melanoma tumors and/or metastases thereof. 22. A pharmaceutical composition comprising at least one compound of general formula (I) ing to any one of items 1 to 9, together with at least one pharma- ceutically acceptable auxiliary.
[Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 23. A composition according to item 22 for the treatment of haemotological s , solid tumours and/or metastases thereof. 24. A combination comprising one or more first active ingredients selected from a compound of general formula (I) according to any one of items 1 to 9, and one or more second active ingredients selected from chemotherapeutic anti-cancer agents and -specific anti-cancer agents.
. The compound of formula (I) according to item 1, 7, 8 or 9, the process accord- ing to item 10 or 11, the intermediate compound of l formula (1-5) ing to item 12, the intermediate compound of general a (1-4) according to item 14, the use according to item 18, the composition ing to item 23 or the combination according to item 24, substantially as herein described with reference to any one of the Examples.
Definitions Constituents which are ally substituted as stated herein, may be substituted , unless otherwise noted, one or more times, independently from one another at any possible position. When any le occurs more than one time in any constituent, each definition is independent.
Unless d otherwise in the claims and in the description, the constituents defined below can optionally be substituted, one or more times, identically or differ- ently, with a substituent selected from: hydroxy, halogen, cyano, 1-6C-alkyl, aloalkyl, 1-6C-alkoxy, -NR10R11, cyano, (=O), -C(O)NR10R11, -C(O)OR9, -NHC(O)R11, -NHS(O)2R11. An alkyl constituent being multiply substituted by halogen includes also a completely halogenated alkyl moiety such as e.g. CF3.
Should a constituent be composed of more than one part, e.g. –O-(1-6Calkyl)-(3- 7C-cycloalkyl), the position of a possible substituent can be at any of these parts at any le position. A hyphen at the beginning of the constituent marks the [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb point of attachment to the rest of the molecule. Should a ring be substituted the substitutent could be at any suitable position of the ring, also on a ring nitrogen atom if le.
The term "comprising" when used in the specification includes "consisting of".
If it is referred to "as mentioned above" or "mentioned above" within the description it is referred to any of the disclosures made within the specification in any of the preceding pages. "suitable" within the sense of the ion means chemically le to be made by s within the knowledge of a skilled . "1-6C-alkyl" is a straight-chain or branched alkyl group having 1 to 6 carbon at- oms. Examples are methyl, ethyl, n propyl, iso-propyl, n butyl, iso-butyl, sec-butyl and tert-butyl, pentyl, hexyl, preferably 1-4 carbon atoms (1-4C-alkyl), more preferably 1-3 carbon atoms alkyl). Other alkyl constituents mentioned herein having another number of carbon atoms shall be defined as ned above taking into account the different length of their chain. Those parts of constituents con- g an alkyl chain as a bridging moiety between two other parts of the constituent which usually is called an "alkylene" moiety is defined in line with the definition for alkyl above including the preferred length of the chain e.g. methylen, ne, n-propylen, iso-propylen, n-butylen, isobutylene, tert-butylen. "2-6C-Alkenyl" is a straight chain or branched alkenyl radical having 2 to 6 carbon atoms. Examples are the butenyl, enyl (homoallyl), propenyl, prop enyl (allyl) and the ethenyl (vinyl) radicals.
"Mono- or di4C-alkylamino" radicals contain in addition to the nitrogen atom, independently one or two of the above mentioned 1-4C-alkyl radicals. Examples are the methylamino, the ethylamino, the isopropylamino, the dimethylamino, the diethylamino and the diisopropylamino radical.
[Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb "Halogen" within the meaning of the t invention is iodine, bromine, chlorine or fluorine, preferably "halogen" within the meaning of the present ion is chlorine or fluorine. "1-6C-Haloalkyl" is a straight-chain or branched alkyl group having 1 to 6 carbon atoms in which at least one hydrogen is substituted by a halogen atom. Examples are chloromethyl or 2-bromoethyl. For a partially or completely fluorinated C1-C4- alkyl group, the following partially or tely fluorinated groups are ered , for example: fluoromethyl, difluoromethyl, oromethyl, fluoroethyl, 1,1- difluoroethyl, 1,2-difluoroethyl, 1,1,1-trifluoroethyl, tetrafluoroethyl, and pentafluoroethyl , whereby difluoromethyl, trifluoromethyl, or 1,1,1-trifluoroethyl are preferred. All possible partially or completely fluorinated 1-6C-alkyl groups are considered to be encompassed by the term 1-6C-haloalkyl.
Hydroxyalkyl" is a straight-chain or branched alkyl group having 1 to 6 carbon atoms in which at least one hydrogen atom is tuted by a hydroxy group. Examples are hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2- dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 2,3-dihydroxypropyl, 3-hydroxy- 2-methyl-propyl, 2-hydroxymethyl-propyl, 1-hydroxymethyl-propyl. "1-6C-Alkoxy" represents radicals, which in addition to the oxygen atom, contain a straight-chain or branched alkyl radical having 1 to 6 carbon atoms. Examples which may be mentioned are the hexoxy, pentoxy, , isobutoxy, sec-butoxy, tert-butoxy, y, isopropoxy, ethoxy and methoxy radicals, preferred are methoxy, ethoxy, y, isopropoxy. "1-6C-Haloalkoxy" represents radicals, which in addition to the oxygen atom, contain a straight-chain or branched alkyl radical having 1 to 6 carbon atoms in which at least one hydrogen is substituted by a halogen atom. Examples are –O- CFH2, –O-CF2H, -O-CF3, -O-CH2-CFH2, -CF2H, -O-CH2-CF3. Preferred are –O-CF2H, -O-CF3, -O-CH2-CF3.
[Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb "3-7C-Cycloalkyl" stands for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, preferably cyclopropyl. "3-7C-Cycloalkyloxy" or "–O-(3-7C-cycloalkyl)" stands for e.g. cyclopropyloxy, utyloxy, cyclopentyloxy, cyclohexyloxy or cycloheptyloxy, ably cyclopropyloxy. "3-7C-Heterocyclyl", or "heterocyclyl" represents a mono- or polycyclic, preferably mono- or bicyclic, more preferably monocyclic, nonaromatic heterocyclic radical containing, 4 to 10, preferably 4 to 7, more preferably 5 to 6 ring atoms, and 1,2 or 3, preferably 1 or 2, hetero atoms and/or hetero groups independently selected from the series consisting of N, O, S, SO, SO2. The heterocyclyl radicals can be saturated or partially unsaturated and, unless stated otherwise, may be optionally substituted, one or more times, identically or differently, with a substituent selected from: 1-4C-alkyl, 1-4C-haloalkyl, 1-4C-alkoxy, hydroxy, fluorine or (=O) whereby the 1-4C-alkyl may be optionally further substituted with hydroxy and the double bonded oxygen atom leads to a carbonyl group together with the carbon atom of the heterocyclyl ring at any suitable position. Particularly preferred heterocyclic radicals are 4- to 7-membered monocyclic ted heterocyclyl radicals having up to two hetero atoms from the series consisting of O, N and S, more preferred 5- 6-membered heterocyclic radicals. The ing may be ned by way of example and by ence: oxetanyl, tetrahydrofuranyl, ydropyranyl, azetidinyl , 3-hydroxyazetidinyl, 3-fluoroazetidinyl, 3,3-difluoroazetidinyl, pyrrolidinyl, 3- hydroxypyrrolidinyl, pyrrolinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, 3- hydroxypiperidinyl, 4-hydroxypiperidinyl, 3-fluoropiperidinyl, 3,3-difluoropiperidinyl, 4-fluoropiperidinyl, 4,4-difluoropiperidinyl, zinyl, N-methyl-piperazinyl, N-(2- hydroxyethyl)-piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, homopiperazinyl , N-methyl-homopiperazinyl.
"N-heterocyclyl" represents a heterocyclic radical which is connected to the re- maining le via its nitrogen atom contained in the heterocyclic ring.
The term "heteroaryl" represents a clic 5- or 6-membered aromatic heterocycle or a fused bicyclic aromatice moiety comprising without being [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb restricted thereto, the 5-membered heteroaryl radicals furyl, thienyl, pyrrolyl, oxazolyl , olyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl (1,2,4- triazolyl, 1,3,4-triazolyl or 1,2,3-triazolyl), thiadiazolyl (1,3,4-thiadiazolyl, 1,2,5- thiadiazolyl, thiadiazolyl or 1,2,4-thiadiazolyl) and oxadiazolyl - oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl or 1,2,4-oxadiazolyl), as well as the 6-membered heteroaryl radicals pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl as well as the fused ring systems such as e.g. phthalidyl-, thiophthalidyl-, indolyl-, isoindolyl-, oindolyl-, dihydroisoindolyl-, indazolyl-, benzothiazolyl-, benzofuranyl-, benzimidazolyl-, benzoxazinonyl-, chinolinyl-, isochinolinyl-, chinazolinyl-, chinoxalinyl-, cinnolinyl-, phthalazinyl-, 1,7- or 1,8-naphthyridinyl-. cumarinyl-, isocumarinyl-, indolizinyl-, isobenzofuranyl-, azaindolyl-, indolyl-, furanopyridyl-, furanopyrimidinyl-, furanopyrazinyl-, furanopyidazinyl-, red fused ring system is indazolyl. Preferred 5- or ered heteroaryl radicals are furanyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, thiadiazolyl, zolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl. More preferred 5- or 6-membered heteroaryl radicals are furanyl, thienyl, pyrrolyl, thiazolyl, yl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl, pyridinyl, pyridinyl, pyrimidinyl, pyrimidinyl, pyrazin yl or pyridazinyl.
In general and unless otherwise mentioned, the heteroarylic or arylenic radicals include all the possible isomeric forms thereof, e.g. the positional isomers thereof. Thus, for some rative non-restricting example, the term pyridinyl or pyridinylene includes nyl, pyridinylene, pyridinyl, pyridinylene, pyridinyl and pyridinylene; or the term thienyl or thienylene includes thien yl, thienylene, thienyl and thienylene.
The heteroarylic, heteroarylenic, or heterocyclic groups mentioned herein may be tuted by their given substituents or parent lar groups, unless otherwise noted, at any possible position, such as e.g. at any substitutable ring carbon or ring nitrogen atom. Analogously it is being understood that it is possible for any heteroaryl or heterocyclyl group to be attached to the rest of the le via any suitable atom if chemically suitable. Unless otherwise noted, any heteroatom of a heteroarylic or heteroarylenic ring with unsatisfied valences [Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb mentioned herein is d to have the hydrogen atom(s) to satisfy the valences. Unless otherwise noted, rings containing quaternizable amino- or iminotype ring nitrogen atoms (-N=) may be preferably not quaternized on these aminoor imino-type ring nitrogen atoms by the mentioned tuents or parent molecular groups.
The NR10R11 group includes, for e, NH2, N(H)CH3, N(CH3)2, N(H)CH2CH3 and N(CH3)CH2CH3. In the case of -NR 10R11, when R10 and R11 together with the en atom to which they are attached form a 4membered heterocyclic ring optionally containing one further heteroatom selected from the group ting of O, S or N, the term "heterocyclic ring" is defined above. Especially preferred is morpholinyl.
The C(O)NR10R11 group includes, for example, C(O)NH2, H)CH3, C(O)N(CH3)2, C(O)N(H)CH2CH3, CH3)CH2CH3 or C(O)N(CH2CH3)2. If R 10 or R11 are not hydrogen, they may be substituted by hydroxy, In the case of -NR10R11, when R10 and R11 together with the nitrogen atom to which they are attached form a 4membered cyclic, the term "heterocyclic ring" is defined above and can be used analogously for C(O)NR10R11.
The C(O)OR9 group includes for example C(O)OH, C(O)OCH3, C(O)OC2H5, C(O)C3H7, C(O)CH(CH3)2, C(O)OC4H9, C(O)OC5H11, C(O)OC6H13; for C(O)O(1-6Calkyl), the alkyl part may be straight or branched and may be substituted.
In the context of the properties of the compounds of the present invention the term "pharmacokinetic profile" means one single parameter or a combination thereof including permeability, bioavailability, exposure, and pharmacodynamic parameters such as duration, or ude of pharmacological effect, as measured in a suitable experiment. Compounds with improved pharmacokinetic profiles can, for example, be used in lower doses to achieve the same effect, may achieve a longer duration of action, or a may achieve a combination of both effects.
[Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb Salts of the nds according to the invention include all inorganic and organic acid addition salts and salts with bases, especially all pharmaceutically acceptable inorganic and c acid addition salts and salts with bases, particularly all pharmaceutically acceptable inorganic and organic acid addition salts and salts with bases customarily used in pharmacy.
One aspect of the invention are salts of the compounds ing to the invention including all inorganic and organic acid on salts, especially all pharmaceutically acceptable inorganic and organic acid addition salts, particularly all pharmaceutically acceptable inorganic and c acid addition salts arily used in cy. Another aspect of the ion are the salts with di- and tricarboxylic acids.
Examples of acid addition salts include, but are not limited to, hydrochlorides, hydrobromides, phosphates, nitrates, sulfates, salts of sulfamic acid, formates, acetates, propionates, citrates, D-gluconates, benzoates, 2-(4-hydroxybenzoyl)- benzoates, butyrates, salicylates, sulfosalicylates, lactates, maleates, laurates, s, fumarates, succinates, oxalates, malonates,pyruvates, acetoacetates, tartarates, stearates, benzensulfonates, toluenesulfonates, methanesulfonates, trifluoromethansulfonates, 3-hydroxynaphthoates, benzenesulfonates, naphthalinedisulfonates and trifluoroacetates.
Examples of salts with bases include, but are not limited to, m, sodium, potassium, calcium, aluminum, magnesium, titanium, meglumine, ammonium, salts optionally derived from NH3 or organic amines having from 1 to 16 C-atoms such as e.g. ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, hanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, ne, lysine, ethylendiamine, N-methylpiperindine and and guanidinium salts.
The salts include water-insoluble and, particularly, water-soluble salts.
[Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb According to the person skilled in the art the compounds of formula (I) according to this invention as well as their salts may n, e.g. when isolated in crystalline form, varying amounts of solvents. Included within the scope of the ion are therefore all solvates and in particular all hydrates of the compounds of formula (I) according to this invention as well as all solvates and in particular all hydrates of the salts of the compounds of formula (I) according to this invention.
The term "combination" in the present invention is used as known to persons skilled in the art and may be present as a fixed combination, a non-fixed combina- tion or kit-of-parts.
A "fixed combination" in the present invention is used as known to persons d in the art and is defined as a combination wherein the said first active ingredient and the said second active ingredient are present together in one unit dosage or in a single entity. One example of a "fixed combination" is a pharmaceutical composition n the said first active ingredient and the said second active ingredient are present in admixture for simultaneous administration, such as in a formulation.
Another example of a "fixed combination" is a ceutical ation wherein the said first active ingredient and the said second 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 the said first active ingredient and the said second 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 said first active ingredient and the said second active ingredient are present tely. The components of the non-fixed ation or kit-of-parts may be administered separately, sequentially, simultaneously, concurrently or chronologically staggered.
The term "(chemotherapeutic) anti-cancer agents", includes but is not d to 131I-chTNT, abarelix, abiraterone, aclarubicin, aldesleukin, alemtuzumab, alitretinoin , altretamine, aminoglutethimide, cin, ine, ozole, arglabin, [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb arsenic de, asparaginase, azacitidine, basiliximab, BAY 80-6946, BAY 1000394, belotecan, bendamustine, zumab, bexarotene, bicalutamide, bisantrene , bleomycin, omib, buserelin, busulfan, cabazitaxel, calcium folinate, calcium levofolinate, capecitabine, carboplatin, carmofur, carmustine, catumax- omab, celecoxib, celmoleukin, cetuximab, chlorambucil, chlormadinone, chlormethine , cisplatin, cladribine, clodronic acid, clofarabine, crisantaspase, cyclophosphamide , cyproterone, bine, dacarbazine, dactinomycin, darbepoetin alfa, dasatinib, daunorubicin, decitabine, degarelix, ukin diftitox, denosumab, deslorelin, dibrospidium chloride, docetaxel, uridine, doxorubicin, doxorubicin + estrone, umab, edrecolomab, inium acetate, eltrombopag, endostatin, enocitabine, epirubicin, epitiostanol, epoetin alfa, epoetin beta, eptaplatin, eribulin, erlotinib, estradiol, estramustine, etoposide, everolimus, exemestane, ole, filgrastim, fludarabine, fluorouracil, flutamide, formestane, fotemustine, trant, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, glutoxim, goserelin, ine dihydrochloride, histrelin, hydroxycarbamide, I-125 seeds, ibandronic acid, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan , interferon alfa, eron beta, interferon gamma, ipilimumab, irinotecan, ixabepilone , lanreotide, lapatinib, lenalidomide, lenograstim, lentinan, letrozole, leuprorelin, levamisole, lisuride, atin, lomustine, lonidamine, masoprocol, medroxyprogesterone, megestrol, lan, mepitiostane, mercaptopurine, methotrexate, methoxsalen, Methyl aminolevulinate, methyltestosterone, mifamurtide , miltefosine, atin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane , mitoxantrone, nedaplatin, bine, nilotinib, nilutamide, nimotuzumab, nimustine, nitracrine, ofatumumab, omeprazole, oprelvekin, oxaliplatin, p53 gene therapy, paclitaxel, palifermin, palladium-103 seed, pamidronic acid, panitumumab , pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin beta), pegfilgrastim, peginterferon alfa-2b, pemetrexed, pentazocine, pentostatin, peplomycin, famide, picibanil, pirarubicin, plerixafor, plicamycin, poliglusam, polyestradiol phosphate, polysaccharide-K, porfimer sodium, pralatrexate, predni- mustine, bazine, quinagolide, radium-223 chloride, raloxifene, rexed, ranimustine, razoxane, refametinib , regorafenib, risedronic acid, rituximab, romidepsin , romiplostim, sargramostim, sipuleucel-T, sizofiran, sobuzoxane, sodium glycididazole, nib, streptozocin, sunitinib, talaporfin, tamibarotene, tamoxi- [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb fen, tasonermin, teceleukin, tegafur, r + gimeracil + oteracil, temoporfin, temozolomide , olimus, teniposide, testosterone, tetrofosmin, omide, thiotepa , thymalfasin, tioguanine, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, trastuzumab, lfan, tretinoin, trilostane, triptorelin, trofosfamide, tryptophan, ubenimex, valrubicin, vandetanib, vapreotide, vemurafenib, stine , vincristine, vindesine, vinflunine, vinorelbine, vorinostat, vorozole, yttrium-90 glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid, zorubicin.
The compounds according to the invention and their salts can exist in the form of tautomers which are ed in the embodiments of the invention.
The compounds of the invention may, depending on their structure, exist in different stereoisomeric forms. These forms include configurational isomers or optionally conformational isomers (enantiomers and/or diastereoisomers including those of somers). The present invention therefore includes enantiomers, diastereoisomers as well as mixtures thereof. From those mixtures of enantiomers and/or disastereoisomers pure stereoisomeric forms can be isolated with s known in the art, preferably methods of tography, especially high pressure liquid chromatography (HPLC) using achiral or chiral phase. The invention further includes all mixtures of the stereoisomers ned above independent of the ratio, including the racemates.
Some of the compounds and salts according to the invention may exist in different crystalline forms orphs) which are within the scope of the ion.
Furthermore, derivatives of the compounds of a (I) and the salts thereof which are converted into a compound of formula (I) or a salt thereof in a biological system (bioprecursors or pro-drugs) are covered by the invention. Said biological system is e.g. a mammalian organism, particularly a human subject. The bioprecursor is, for example, converted into the compound of formula (I) or a salt thereof by metabolic processes.
[Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb It has now been found, and this constitutes the basis of the present invention, that said compounds of the present invention have sing and advantageous properties.
In particular, said compounds of the present ion have surprisingly been found to effectively inhibit Bub1 kinase and may therefore be used for the treatment or prophylaxis of diseases of uncontrolled cell growth, proliferation and/or survival, opriate cellular immune responses, or inappropriate cellular inflammatory responses or diseases which are accompanied with uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, particularly in which the uncontrolled cell growth, proliferation and/or survival, opriate cellular immune responses , or inappropriate cellular inflammatory responses is mediated by Bub1 kinase, such as, for example, haemotological tumours, solid tumours, and/or me- tastases thereof, e.g. leukaemias and myelodysplastic syndrome, malignant lymphomas , head and neck s including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, intestinal tumours, endocrine tumours, mammary and other gynaecological tumours , ical tumours including renal, bladder and prostate tumours, skin tu- mours, and sarcomas, and/or metastases thereof.
The intermediates used for the synthesis of the compounds of claims 1-6 as bed below, as well as their use for the synthesis of the compounds of claims 1-6, are one further aspect of the present ion. Preferred intermediates are the Intermediate Examples as disclosed below.
General Procedures The nds according to the invention can be prepared according to the following schemes 1 through 6, The schemes and procedures described below illustrate tic routes to the nds of general formula (I) of the invention and are not intended to be limit- [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb ed set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb ing. It is obvious to the person skilled in the art that the order of transformations as exemplified in the Schemes can be modified in various ways. The order of transformations exemplified in the Schemes is therefore not intended to be ng. In addition, interconversion of any of the substituents, R1, R2, R3, R4, R6, R7 or R8 can be achieved before and/or after the exemplified transformations. These modifications can be such as the introduction of protecting groups, cleavage of protecting groups, ion or oxidation of functional groups, halogenation, metallation, substitution or other reactions known to the person skilled in the art. These ormations include those which introduce a functionality which allows for further inter- conversion of substituents. Appropriate protecting groups and their introduction and cleavage are well-known to the person skilled in the art (see for example T.W.
Greene and P.G.M. Wuts in Protective Groups in c Synthesis, 3rd edition, Wiley 1999). Specific examples are described in the subsequent paragraphs.
One route for the preparation of compounds of l formula (Ia) is described in Scheme 1. In instances where this route is not feasible, scheme 2 can be applied. ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb Scheme 1 (R4) n R2 (R4)n X R3 N B N N R3 A 1-1 N CH CH R2 3 N 3 R2 (R4) (R4) n CH n 3 N CH3 R6 N R3 N R3 N N R1 R1 NH N 1-2 NH N 2 N R2 (R4) (R8) X' C N R3 N R1 (R8) N m N H (Ia) Scheme 1 Route for the preparation of compounds of general formula (Ia), where- in R1, R2, R3, R4, R6, R8, m and n have the meaning as given for general formula (I), supra. In addition, interconversion of any of the substituents, R1, R2, R3, R4, R6 or R8 can be achieved before and/or after the exemplified transformations. These modifications can be such as the uction of protecting groups, cleavage of [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb ting groups, reduction or ion of functional groups, halogenation, metallation , substitution or other reactions known to the person skilled in the art. These transformations include those which introduce a functionality which allows for further interconversion of substituents. Appropriate protecting groups and their intro- duction and ge are well-known to the person skilled in the art (see for example T.W. Greene and P.G.M. Wuts in Protective Groups in Organic Synthesis, 3rd edition, Wiley 1999). Specific es are described in the subsequent paragraphs.
Compounds A, B, and C are either commercially available or can be prepared ac- cording to procedures available from the public domain, as understandable to the person skilled in the art. Specific examples are described in the subsequent paragraphs.
X represents a leaving group such as for example a Cl, Br or I, or X stands for an aryl sulfonate such as for example p-toluene sulfonate, or for an alkyl sulfonate such as for example methane sulfonate or trifluoromethane sufonate. X’ represents F, Cl, Br, I, c acid or a boronic acid ester, such as for example 4,4,5,5-tetramethylphenyl-1,3,2-dioxaborolane (boronic acid pinacole ester).
A suitably substituted 1H-indazolecarbonitrile (A) can be reacted with a suitably substituted benzyl halide or benzyl sulfonate of general formula (B), such as, for example, a benzyl bromide, in a suitable solvent system, such as, for e, N,N-dimethylformamide, in the presence of a suitable base, such as, for example, cesium carbonate at temperatures g from -78°C to room temperature, preferably the reaction is carried out at room temperature, to furnish 1-benzyl-1H- indazolecarbonitrile intermediates of l formula (1-1).
Intermediates of l formula (1-1) can be converted to intermediates of general formula (1-2) by on with a suitable alcoholate, such as, for example sodium methanolate, in a suitable solvent system, such as, for example, the corresponding alcohol, e.g. methanol, at a temperature between room temperature and the boiling point of the respective solvent, preferably the reaction is carried out at room ature, and subsequent ent with a suitable source of ammonium , such as for example, ammonium chloride in the presence of a suitable acid, such as for example acetic acid in a temperature range from room temperature to [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb the boiling point of the respective solvent, ably the reaction is carried out at 50°C.
Intermediates of general formula (1-2) are reacted with a suitably substituted 3,3- bis(dimethylamino)propanenitrile of the general formula (1-3), such as, for e 3,3-bis(dimethylamino)methoxypropanenitrile, in the presence of a suitable base, such as, for example dine, in a suitable solvent system, such as, for example, 3-methylbutanol, in a temperature range from room temperature to the boiling point of the respective solvent, preferably the reaction is carried out at 100°C, to furnish intermediates of l formula (1-4).
Intermediates of general formula (1-4) can be reacted with a suitable 4- halopyridine of the general a (C), such as, for example 4-bromopyridine, in the presence of a suitable base, such as, for example sodium 2-methylpropan olate or potassium carbonate. Optionally, a suitable ium st, such as for example (1E,4E)-1,5-diphenylpenta-1,4-dienone–palladium, and a suitable ligand , such as for example 1'-binaphthalene-2,2'-diylbis(diphenylphosphane), can be added. The reaction is carried out in a suitable solvent system, such as, for example , N,N-dimethylformamide, in a temperature range from room temperature to the boiling point of the respective solvent, preferably the reaction is carried out at 100°C to furnish compounds of general formula (Ia). Alternatively, the ing palladium catalysts can be used: Allylpalladium chloride dimer, Dichlorobis(benzonitrile)palladium (II), Palladium (II) acetate, Palladium (II) chloride, is(triphenylphosphine)palladium (0), ibenzylideneacetone)dipalladium (0), optionally with addition of the following ligands: racemic-2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl, rac-BINAP, 1,1'-Bis(diphenylphosphino )ferrocene, Bis(2-diphenylphosphinophenyl)ether, Di-t-butylmethylphosphonium tetrafluoroborate, 2-(Di-t-butylphosphino)biphenyl, Tri-t-butylphospho- nium tetrafluoroborate, Trifurylphosphine, Tris(2,4-di-t-butylphenyl)phosphite, Tri-o-tolylphosphine, or, ably, (9,9-dimethyl-9H-xanthene-4,5- diyl)bis(diphenylphosphine).
[Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb Alternatively, intermediates of general formula (1-4) can be reacted with a suitable boronic acid or boronic acid pinacole ester of general formula (C), such as, for e (2-fluoropyridinyl)boronic acid, in the presence of a suitable base, such as, for example triethylamine, a suitable activating agent such as for example N,N- dimethylpyridinamine and a suitable copper salt, such as for example copper (II) e, in a suitable solvent system, such as, for example, trichloromethane, in a temperature range from room temperature to the g point of the respective solvent, preferably the reaction is carried out at room temperature to h compounds of general formula (Ia).
Alternatively, intermediates of general formula (1-4) can be reacted with a suitable pyridyl fluoride of general formula (C, with X’ being F), such as, for example 4- fluoro pyridine hydrochloride, in the presence of a suitable base, such as, for example sodium hydride, in a suitable solvent system, such as, for example, dime- thyl formamide, in a ature range from room temperature to the boiling point of the respective solvent, preferably the reaction is carried out at 90°C to furnish compounds of l formula (Ia).
[Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb Compounds of general formula (I) can also be synthesised according to the procedure ed in Scheme 2.
Scheme 2 R2 O N R3 N N N N N R1 (R8) N m R1 (R8) N m N N R7 R7 (Ib) R6 1-5 R6 )n (R4) X R3 N R3 N B N R1 (R8) N m Scheme 2 Alternative route for the preparation of compounds of general formula (I), wherein R1, R2, R3, R4, R6, R7, R8, m and n have the meaning as given for gen- eral a (I), supra. R’ is for example alkyl or benzyl, preferably methyl or ethyl.
In addition, interconversion of any of the substituents, R1, R2, R3, R4, R6, R7 or R8 can be achieved before and/or after the ified transformations. These modifications can be such as the introduction of protecting groups, cleavage of protecting groups, ion or oxidation of functional groups, halogenation, metallation, substitution or other reactions known to the person skilled in the art. These transformations include those which introduce a functionality which allows for fur-ther interconversion of substituents. Appropriate protecting groups and their intro- [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb duction and cleavage are well-known to the person skilled in the art (see for example T.W. Greene and P.G.M. Wuts in Protective Groups in Organic sis, 3rd edition, Wiley 1999). Further specific examples are described in the subsequent paragraphs.
Compounds of the formula (Ib) can be prepared using the synthetic methods described in context of Scheme 1; the introduction of R7 different from hydrogen may be accomplished inter alia by the methods bed in Scheme 5. Compounds B are either commercially available or can be prepared according to procedures ble from the public domain, as understandable to the person skilled in the art as referred to below scheme 1 above.
Compounds of l formula (Ib) are converted to intermediates of general formula (1-5) by treatment with a suitable acid system, such as, for example a mixture of trifluoroacetic acid and trifluoromethanesulfonic acid, in a suitable solvent, such as, for example, dichloroethan, in a temperature range from room temperature to the boiling point of the respective t, preferably the reaction is carried out at room temperature.
Intermediates of general formula (1-5) can be reacted with a suitably substituted benzyl halide or benzyl sulfonate of general formula (B), such as, for example, a benzyl e, in a le solvent system, such as, for example, tetrahydrofuran , in the ce of a suitable base, such as, for example, sodium hydride in a temperature range from room temperature to the boiling point of the respective solvent, preferably the reaction is carried out at room temperature, to h com- pounds of l formula (I). Said reaction can also result in double conversion of ediate (1-5) if R7 is en, giving rise to compounds formed alongside the target compounds, in which R7 is a benzylic group identical with the benzylic moiety attached to the indazole nitrogen.
Compounds of general formula (Ia) in some instances can be advantageously prepared via a route that utilizes additional protecting groups, according to the procedure depicted in Scheme 2a, in order to avoid the aforementioned bisben- ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb zylation. Preferably, examples 23, 23, 23, 23, 23, 23, 23, 23, 23 were ed via this route.
Scheme 2a N N N N N N R1 (R8) R1 (R8)m N m N N N N N H H R6 1-8 R6 1-5a 1 H N N N N N N R1 (R8)m R1 (R8) N N m N N N N PG2 PG2 1-9 R6 1-10 R6 R2 R2 (R4)n (R4)n X R3 N R3 N B N R1 (R8)m 1-11 R6 (R4) N R3 N R1 (R8) N m (Ia) Scheme 2a Modified route for the preparation of compounds of general formula (Ia), wherein R1, R2, R3, R4, R6, R8, m and n have the meaning as given for gen- [Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb eral formula (I), supra. PG1 and PG2 are independently from each other a protecting group, for example t-butoxycarbonyl (boc), allyloxycarbonyl (alloc) or benzoyl.
In addition, interconversion of any of the substituents, R1, R2, R3, R4, R6 or R8 can be achieved before and/or after the exemplified transformations. These modifica- tions can be such as the introduction of protecting groups, ge of protecting groups, reduction or oxidation of onal groups, halogenation, metallation, substitution or other reactions known to the person d in the art. These transformations include those which introduce a onality which allows for further onversion of substituents. Appropriate protecting groups and their introduction and cleavage are well-known to the person skilled in the art (see for example T.W.
Greene and P.G.M. Wuts in Protective Groups in c Synthesis, 3rd edition, Wiley 1999). Further specific examples are described in the subsequent paragraphs.
Compounds B are either commercially available or can be prepared according to ures available from the public domain, as understandable to the person skilled in the art as referred to below scheme 1 above.
Intermediates of general formula (1-5a), accessible in analogy to Scheme 2, can be protected by a suitable protecting group such as, for example, tert- butoxycarbonyl with a le reagent, such as, for example, di-tertbutyldicarbonate , in the presence of a suitable base, such as, for example, sodium ide in water, in a suitable solvent system, such as, for example, methanol in a temperature range from 0 °C to room temperature, preferable the reaction is carried out at room temperature, to furnish compounds of general formula (1-8).
Intermediates of general a (1-8) can be protected with a le protection group such as, for example, allyloxycarbonyl or benzoyl with a suitable reagent, such as, for example, allyl chloroformate or benzoyl chloride, in a suitable solvent system, such as, for example, pyridine, in a ature range from room - ature to the boiling point of the respective solvent, preferably the reaction is carried out at room temperature, to furnish compounds of general formula (1-9).
[Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb Intermediates of general a (1-9) can be deprotected under suitable conditions such as, for example, hydrochloric acid or oroacetic acid, in a suitable solvent system, such as, for example, dioxane or dichloromethane, in a ature range from 0 °C to room temperature, to furnish compounds of general formu- la (1-10) Intermediates of l formula (1-10) can be reacted with a suitably substituted benzyl halide or benzyl sulfonate of l formula (B), such as, for example, a benzyl bromide, in a suitable t system, such as, for example, tetrahydrofu- ran, in the presence of a suitable base, such as, for example, sodium hydride in a temperature range from room temperature to the g point of the respective solvent, preferably the reaction is carried out at room temperature, to furnish compounds of general formula (1-11).
Intermediates of general formula (1-11) can be deprotected under suitable conditions such as, for example, pyrrolidine, tetrakis(triphenylphosphin)palladium or sodium hydride, or potassium hydroxide, in a suitable solvent system, such as, for example, dioxane, water, tetrahydrofuran oder ethanol, in a temperature range from 0 °C to room temperature to furnish compounds of general formula (Ia).
Compounds of l formula (Ie) and (Id) can be synthesised from compounds of general formula (Ic), according to the procedure depicted in Scheme 3.
[Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb Scheme 3 R2 R2 (R4) (R4) n n N R3 N N R3 N N N R1 (R8) (R8) N m R1 N m N N N N R7 R7 (Ic) O (Id) OH (R4) XR'' N R3 N D N R1 (R8) N m (Ie) Scheme 3 Process for the preparation of compounds of general formula (Id) via de-methylation of compounds of general formula (Ic) and subsequent etherification to furnish compounds of general formula (Ie), wherein R1, R2, R3, R4, R7, R8, m and n have the meaning as given for general a (I), supra. In addition, interconversion of any of the substituents, R1, R2, R3, R4, R7 or R8 can be ed before and/or after the exemplified transformations. These modifications can be such as the uction of protecting groups, cleavage of protecting , reduction or oxidation of functional groups, halogenation, metallation, substitution or other reactions known to the person skilled in the art. These ormations include those which introduce a functionality which allows for further interconversion [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb of substituents. Appropriate protecting groups and their introduction and cleavage are well-known to the person skilled in the art (see for example T.W. Greene and P.G.M. Wuts in Protective Groups in c Synthesis, 3rd edition, Wiley 1999). nds of the formula (Ic) can be prepared using the synthetic methods de- scribed in context of Scheme 1; the uction of R7 different from hydrogen may be lished inter alia by the methods described in Scheme 5.
Compounds of general formula D are commercially available, wherein X represents leaving group such as for example a Cl, Br or I, or X stands for an aryl sulfonate such as for example p-toluene sulfonate, or for an alkyl sulfonate such as for example methane sulfonate or trifluoromethane sulfonate (triflate group). R’’ = 1-6C-alkyl (independently one or more times optionally substituted with hydroxy, 9, C(O)NR10R11, 1, -S-(1-6C-alkyl), -S(O)-(1-6C-alkyl), -(1- 6C-alkyl), SO2NR10R11, cyclyl (which itself is optionally substituted with C(O)OR9 or oxo (=O)), heteroaryl (which itself is optionally substituted one or more times with cyano, 1-4C-alkyl, aloalkyl, 1-6C-haloalkoxy, C(O)OR9, C(O)NR10R11, -(2-6C-alkyl)-O6C-alkyl), 3-7C-cycloalkyl, n, or * O O H O , whereby the * is the point of attachment.
Compounds of general formula (Ic) are converted to compounds of general formu- la (Id) by treatment with a le demethylating agent, such as for example benzenethiol , in a suitable solvent, such as, for example, 1-methylpyrrolidinone, in the presence of a suitable base, such as, for example potassium carbonate, in a temperature range from room temperature to the boiling point of the respective t, ably the reaction is carried out at 190°C.
Compounds of general formula (Id) are then reacted with a compound of general a (D) as mentioned above, in a suitable solvent, such as, for example, N,N- dimethylformamide, in the presence of a suitable base, such as, for example, potassium carbonate in a temperature range from room temperature to the boiling point of the respective solvent, preferably the reaction is carried out at room temperature , to furnish compounds of general formula (Ie).
[Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb Compounds of general formula (Id) can be converted into compounds of l a (If) according to the procedure depicted in Scheme 4.
Scheme 4 During step 2 of this sequence the residues might potentially undergo a modification , e.g. reduction.
R2 R2 (R4) (R4) n n N R3 N N R3 N N N R1 (R8) (R8) N m R1 N m N N N N R7 R7 (Id) OH (I-6) O R''' (R4) N R3 N R1 (R8) N m (If) Scheme 4. Process for the transformation of compounds of general formula (Id) into compounds of general formula (If), via an intermediate of the general formula (I-6), wherein R1, R2, R3, R4, R7, R8, m and n have the meaning as given for gen- eral a (I), supra. In addition, interconversion of any of the tuents, R1, R2, R3, R4, R7 or R8 can be achieved before and/or after the exemplified transformations.
These modifications can be such as the introduction of protecting groups, [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb cleavage of protecting groups, reduction or oxidation of functional groups, halogenation , metallation, substitution or other reactions known to the person skilled in the art. These transformations include those which introduce a functionality which allows for further interconversion of substituents. riate protecting groups and their introduction and cleavage are well-known to the person skilled in the art (see for example T.W. Greene and P.G.M. Wuts in Protective Groups in Organic Synthesis, 3rd edition, Wiley 1999).
O-R’’’ ents a suitable leaving group, e.g. a triflate group, nonaflate group.
Compounds of general formula (Id) can be converted to intermediates of general formula (I-6) by reaction with a suitable sulfonic acid derivative, such as, for example trifluoromethanesulfonic anhydride or 2,3,3,4,4,4-nonafluorobutane sulfonyl de, in a suitable solvent, such as, for example, dichloromethane, in the presence of a suitable base, such as, for example pyridine, in a temperature range from room temperature to the boiling point of the respective solvent, preferably the reaction is carried out at room temperature.
Intermediates of general a (I-6) are then reacted with a suitable hydride source, such as, for example, triethylsilane, in a suitable solvent such as, for ex- ample, methyl formamide (DMF), in the presence of a suitable alyst, such as, for example, palladium (II) acetate er with a suitable ligand, such as, for e, propane-1,3-diylbis(diphenylphosphane) in a temperature range from room temperature to the boiling point of the respective solvent, preferably the reaction is carried out at 60°C, to furnish compounds of general formula (If).
Compounds of general formula (If ’) which is a compound of formula (If) wherein R7 = en, can be converted into compounds of general formula (Ig and Ih) ing to the procedure depicted in Scheme 5.
[Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb Scheme 5 R2 R2 (R4) (R4)n N R3 N N R3 N N R7a X N R1 (R8) (R8) N m R1 N m N N N H N (If') H (Ig) H (R4)n R7b Z N R3 N R1 (R8) N m (Ih) H Scheme 5. Process for the transformation of compounds of general formula (If’) into compounds of general formula (Ig) and (Ih), wherein R1, R2, R3, R4, R8, m and n have the meaning as given for general formula (I), supra. In addition, interconversion of any of the substituents, R1, R2, R3, R4, R7a, R7b or R8 can be achieved before and/or after the exemplified transformations. These modifications can be such as the introduction of ting groups, ge of protecting groups, reduction or oxidation of functional groups, halogenation, metallation, substitution or other reactions known to the person d in the art. These ormations include those which introduce a functionality which allows for further interconversion of substituents. Appropriate protecting groups and their introduction and cleavage are well-known to the person skilled in the art (see for example T.W. Greene and P.G.M. Wuts in tive Groups in Organic Synthesis, 3rd edition, Wiley 1999).
[Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb R7a represents 1-6C-alkyl, independently one or more times optionally substituted * C H 2 with heteroaryl, n, hydroxy, or R7a stands for O , y the * is the point of attachment, or R7a represents benzyl, whereby the phenyl ring is opt. subst with 1-5 substituents independently selected from the group consist- ing of hydrogen, halogen, 1-4Calkyl, 1-4C-haloalkyl, 1-4C-alkoxy, 1-4C- haloalkoxy, cyano, C(O)OR9. X as defined below scheme 1, supra, or for example 1,3,2-dioxathiolane 2-oxide.
R7b represents an acyl moiety, such as -C(O)-(1-6C-alkyl), –C(O)-(1-6C-alkylen)- O-(1-6C-alkyl), (1-6C-alkylen)-O-(2-6C-alkylen)-O-(1-6C-alkyl), –C(O)-hete- rocyclyl and Z represents a halogen, hydroxy or -O-R7b.
Compounds of general formula (If’) are converted into compounds of l a (Ig) by reaction with a suitable haloalkyl or dioxathiolane 2-oxide, such as, for example 1,3,2-dioxathiolane 2-oxide, in a suitable solvent system, such as, for example, N,N-dimethyl formamide, in the presence of a suitable base, such as, for example cesium carbonate, in a temperature range from room temperature to the boiling point of the respective solvent, preferably the reaction is carried out at 60°C.
Compounds of general formula (If’) are converted into compounds of general formula (Ih) by reaction with a suitable ylic acid derivative, such as for example a carboxylic acid halogenide e.g. carboxylic acid choride, or a carboxylic acid anhydride, in a le solvent, such as, for example, romethane, in the presence of a suitable base, such as, for example N,N-diethylethanamine, in a temperature range from room temperature to the boiling point of the respective solvent, preferably the reaction is d out at room ature.
Compounds of l formula (Ii) and (Ij) can be synthesised according to the procedure depicted in Scheme 6.
[Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb Scheme 6 R2 R2 3CH CH O O 3 (R4) (R4)n O O N R3 N R3 N N R1 R1 NH N O-Na+ NH N 1-2 2 1-12 O CH R2 R2 (R4)n N (R4)n (R8) N R3 N R3 N N 2NH F N R1 O-Na+ N Cl 1-13 1-14 O N R2 R2 (R4)n (R4) N R3 N R3 N N N N R1 (R8) R1 (R8)m N m N N N N H N H N R10 N (Ii) (Ij) R11 Scheme 6 Route for the preparation of compounds of general formula (Ii) and (Ij), wherein R1, R2, R3, R4, R8, m and n have the meaning as given for general formula (I), supra. In addition, interconversion of any of the substituents, R1, R2, R3, R4 or [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb R8 can be achieved before and/or after the exemplified transformations. These modifications can be such as the introduction of protecting groups, cleavage of protecting groups, reduction or oxidation of functional groups, halogenation, metallation , substitution or other reactions known to the person skilled in the art. These transformations include those which introduce a functionality which allows for further interconversion of substituents. Appropriate protecting groups and their introduction and cleavage are well-known to the person skilled in the art (see for example T.W. Greene and P.G.M. Wuts in Protective Groups in Organic Synthesis, 3rd edition, Wiley 1999).
Compounds E and F are commercially available. R10 and R11 have the meaning as given for general a (I), supra.
A suitably tuted carboximidamide or its respective hydrochloride of general formula (1-2), such as for e, 1-(2-fluorobenzyl)-1H-indazolecarboximid- amide hydrochloride (1:1), can be reacted with yl (methoxymethylidene)- propanedioate (E), in a suitable solvent system, such as, for example, methanol, in the presence of a suitable base, such as, for e, sodium methanolate at temperatures ranging from room temperature to the boiling point of the solvent, preferably the reaction is carried out at 60°C, to furnish intermediates of l formula (1-12).
Intermediates of general formula (1-12) can be converted to intermediates of general formula (1-13) by reaction with a suitable source of ammonia, such as, for example 7N ammonia, in a suitable solvent system, such as, for example methanol, at temperatures ranging from room temperature to the boiling point of the solvent, preferably the reaction is d out at 60°C, to furnish intermediates of general formula (1-13).
Intermediates of general a (1-13) can be converted to intermediates of gen- eral a (1-14) by reaction with a suitable source of de, such as, for example phosphoric trichloride, neat, in the presence of a suitable base, such as, for example, N,N-diethylaniline, at temperatures ranging from room temperature to [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb the boiling point of the solvent, preferably the on is carried out at 90°C, to furnish intermediates of general formula (1-14).
Intermediates of general formula (1-14) can be converted to intermediates of gen- eral a (Ii) by reaction with a suitably substituted pyridinamine, such as, for example pyridinamine, in a suitable solvent system, such as, for e N,N- dimethylformamide, at temperatures ranging from room temperature to the boiling point of the solvent, preferably the reaction is carried out at room temperature, to furnish compounds of general formula (Ii).
Compounds of general formula (Ii) can be converted into compounds of general formula (Ij) by ent with a suitable acid, such as, for example concentrated ic acid, at temperatures g from 0°C to room temperature, preferably the reaction is carried out at room temperature, to furnish nds of general formula (Ij).
One red aspect of the invention is the process for the preparation of the compounds of claims 1-6 according to the Examples.
A special aspect of the present invention are the following two process steps: 1. Process for the manufacture of compounds of general formula (I) according to claim 1, wherein R7 is hydrogen as reflected in formula (Ia), characterized in that a compound of formula (1-4) (R4) N R3 N 2 whereby R1, R2, R3, R4, R6 and n have the meaning according to claim 1, is reacted with a compound of formula (C) [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb (R8) X' C whereby R8 and m have the meaning according to claim 1, and X’ represents F, Cl, Br, I, boronic acid or a boronic acid ester, in the presence of a suitable base, and a suitable ium catalyst, optionally in the presence of a suitable , forming a compound of formula (Ia) (R4) N R3 N R1 (R8) N m N H (Ia) which is optionally subsequently ected to form a compound of general formula (I) wherein R7 is hydrogen and R1, R2, R3, R4, R6, R8 and n and m have the meaning as defined in claim 1. 2. Process for the manufacture of compounds of general formula (I) according to claim 1, wherein a compound of formula (Ib) R2 O N R3 N R1 (R8) N m (Ib) R6 whereby R1, R2, R3, R6, R7 R8 and m have the meaning according to claim 1 and R’ is 1-6C-alkyl or benzyl, [Annotation] jessb None set by jessb ation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb is treated with a suitable acid system to cleave the benzylic group in order to obtain a compound of formula 1-5 N N R1 (R8)m 1-5 R6 followed by reacting the compound of formula 1-5 with a compound of general formula (B), X R3 wherein R2, R3, R4 and n have the meaning according to claim 1, and wherein X ents a leaving group, in a suitable t system, in the presence of a suitable base, in a ature range from room temperature to the boiling point of the respective solvent, to furnish compounds of general formula (I).
Another aspect of the ion is the intermediate of general formula (1-5).
It is known to the person skilled in the art that, if there are a number of reactive centers on a starting or intermediate compound, it may be necessary to block one or more reactive centers temporarily by protective groups in order to allow a reaction to proceed specifically at the desired reaction center. A detailed description for the use of a large number of proven protective groups is found, for example, in T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, 1999, 3rd Ed., or in P. Kocienski, Protecting Groups, Thieme Medical Publishers, 2000.
The compounds according to the invention are isolated and ed in a manner known per se, e.g. by ling off the solvent in vacuo and recrystallizing the [Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb residue obtained from a suitable solvent or subjecting it to one of the customary purification methods, such as chromatography on a suitable support material.
Furthermore, reverse phase preparative HPLC of compounds of the present invention which possess a sufficiently basic or acidic functionality, may result in the formation of a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or e salt for example, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt for example. Salts 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. Additionally, the drying process during the isolation of compounds of the present invention may not fully remove traces of ents, ally such as formic acid or trifluoroacetic acid, to give solvates or inclusion complexes. The person skilled in the art will ise which solvates or inclusion complexes are acceptable to be used in subsequent biological assays. It is to be understood that the specific form (e.g. salt, free base, solvate, ion complex) of a compound of the present invention as isolated 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 ical activity.
Salts of the compounds of formula (I) according to the ion can be obtained by dissolving the free compound in a suitable solvent (for example a ketone such as acetone, methylethylketone or methylisobutylketone, an ether such as diethyl ether, tetrahydrofuran or dioxane, a chlorinated hydrocarbon such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol such as methanol, l or isopropanol) which ns the desired acid or base, or to which the desired acid or base is then added. The acid or base can be ed in salt preparation, depending on whether a mono- or polybasic acid or base is ned and depending on which salt is desired, in an equimolar quantitative ratio or one differing rom. The salts are obtained by filtering, reprecipitating, precipitating with a non-solvent for the salt or by evaporating the solvent. Salts obtained can be converted into the free compounds which, in turn, can be converted into salts. In this manner, pharmaceutically unacceptable salts, which ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb can be obtained, for example, as process products in the manufacturing on an industrial scale, can be converted into pharmaceutically acceptable salts by processes known to the person skilled in the art. Especially preferred are hydrochlorides and the process used in the example section.
Pure diastereomers and pure enantiomers of the compounds and salts according to the ion can be obtained e.g. by asymmetric synthesis, by using chiral starting compounds in synthesis and by ing up enantiomeric and diasteriomeric es obtained in synthesis. omeric and reomeric mixtures can be split up into the pure enantiomers and pure diastereomers by methods known to a person skilled in the art. Preferably, diastereomeric mixtures are separated by crystallization, in particular fractional crystallization, or chromatography. Enantiomeric mixtures can be separated e.g. by g diastereomers with a chiral auxiliary agent, resolving the diastereomers obtained and removing the chiral auxiliary agent. As chiral auxiliary agents, for example, chiral acids can be used to te enantiomeric bases such as e.g. mandelic acid and chiral bases can be used to separate enantiomeric acids via formation of diastereomeric salts. Furthermore, diastereomeric tives such as diastereomeric esters can be formed from enantiomeric mixtures of alcohols or enantiomeric mixtures of acids, respectively, using chiral acids or chiral alcohols, respectively, as chiral auxiliary agents.
Additionally, diastereomeric complexes or diastereomeric clathrates may be used for separating enantiomeric mixtures. Alternatively, enantiomeric mixtures can be split up using chiral separating columns in chromatography. Another suitable method for the isolation of omers is the enzymatic separation.
One preferred aspect of the invention is the process for the preparation of the compounds of claims 1-5 according to the es.
Optionally, compounds of the formula (I) can be converted into their salts, or, optionally , salts of the compounds of the formula (I) can be converted into the free compounds. Corresponding ses are ary for the skilled person.
[Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb ed set by jessb Optionally, compounds of the formula (I) can be converted into their N-oxides. The N-oxide may also be uced by way of an intermediate. N-oxides may be prepared by treating an appropriate sor with an oxidizing agent, such as meta- perbenzoic acid, in an riate solvent, such as dichloromethane, at suitable temperatures, such as from 0 °C to 40 °C, whereby room temperature is generally preferred. Further corresponding processes for forming N-oxides are customary for the skilled person.
Commercial utility As mentioned supra, the compounds of the t invention have surprisingly been found to effectively inhibit Bub1 finally resulting in sis and cell death and may therefore be used for the treatment or laxis of diseases of uncon- trolled cell growth, proliferation and/or survival, inappropriate cellular immune ses , or inappropriate cellular inflammatory responses, or diseases which are accompanied with rolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses , particularly in which the uncontrolled cell growth, proliferation and/or al, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses is mediated by Bub1, such as, for example, benign and ant neoplasia , more specifically haematological tumours, solid tumours, and/or metastases thereof, e.g. leukaemias and myelodysplastic syndrome, malignant lymphomas , head and neck tumours including brain tumours and brain metastases, tu- mours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof, especially haematological tumours, solid tumours, and/or metastases of breast, bladder, bone, brain, central and peripheral nervous system, cervix, colon, endocrine glands (e.g. thyroid and adrenal cortex), endocrine tumours, endometrium, esophagus, intestinal tumours, germ cells, kidney, liver, lung, larynx and hypopharynx, mesothelioma, ovary, pancreas, prostate, rectum, renal, small intes- [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb tine, soft tissue, stomach, skin, testis, ureter, vagina and vulva as well as malignant neoplasias including primary tumors in said organs and corresponding secondary tumors in distant organs ("tumor metastases"). Haematological tumors can e.g be exemplified by aggressive and indolent forms of leukemia and ma, namely non-Hodgkins e, chronic and acute myeloid ia (CML / AML), acute lymphoblastic leukemia (ALL), Hodgkins disease, multiple myeloma and T- cell lymphoma. Also included are myelodysplastic syndrome, plasma cell sia , paraneoplastic syndromes, and cancers of unknown primary site as well as AIDS related malignancies.
A further aspect of the invention is the use of the compounds according to formula (I) for the treatment of cer-vical -, breast -, non-small cell lung -, prostate -, colon – and melanoma tumors and/or metastases thereof, especially preferred for the treatment f as well as a method of ent of al -, breast -, non-small cell lung -, prostate -, colon – and ma tumors and/or metastases thereof comprising stering an effective amount of a compound of formula (I).
One aspect of the invention is the use of the compounds according to formula (I) for the treatment of cervix tumors as well as a method of treatment of cervix tu- mors comprising administering an effective amount of a compound of formula (I).
In accordance with an aspect of the present invention therefore the ion relates to a compound of general formula I, or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoiso- mer particularly a pharmaceutically acceptable salt thereof, or a mixture of same, as described and defined herein, for use in the treatment or prophylaxis of a disease , especially for use in the treatment of a disease.
Another ular aspect of the present invention is therefore the use of a com- pound of general formula I, described supra, or a stereoisomer, a tautomer, an N- oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, for the prophylaxis or treatment of hyperproliferative disorders or disorders sive to induction of apoptosis, [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb ally for the treatment of hyperproliferative disorders or ers responsive to induction of apoptosis .
The term "inappropriate" within the context of the present invention, in particular in the context of "inappropriate cellular immune responses, or inappropriate cellular inflammatory responses", as used herein, is to be understood as preferably meaning a response which is less than, or greater than normal, and which is associated with, sible for, or results in, the ogy of said es.
Preferably, the use is in the treatment or prophylaxis of diseases, ally the treatment, wherein the diseases are haemotological tumours, solid tumours and/or metastases f. A preferred aspect is the use of a compound of formula (I) for the prophylaxis and/or treatment of cervical -, breast -, non-small cell lung -, prostate -, colon – and/or melanoma tumors, especially preferred for the treatment f.
Another aspect is the use of a compound of formula (I) is for the treatment of cervical -, breast -, non-small cell lung -, prostate -, colon – and melanoma tumors and/or metastases thereof, especially preferred for the treatment f.
Method of ng hyper-proliferative disorders The present invention relates to a method for using the compounds of the present invention and compositions thereof, to treat mammalian hyper-proliferative disorders.
Compounds can be utilized to inhibit, block, reduce, decrease, etc., cell pro- liferation and/or cell on, and/or produce apoptosis. This method comprises administering to a mammal in need thereof, including a human, an amount of a compound of this invention, or a pharmaceutically acceptable salt, isomer, polymorph , metabolite, hydrate, solvate or ester thereof ; etc. which is effective to treat the disorder. Hyper-proliferative disorders include but are not limited, e.g., psoria- sis, 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, thy- [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb roid, parathyroid and their distant metastases. Those ers also include mas , sarcomas, and leukaemias.
Examples of breast cancer include, but are not limited to invasive ductal carcinoma , invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.
Examples of cancers of the respiratory tract include, but are not limited to smallcell and non-small-cell lung oma, as well as ial adenoma and pleuropulmonary blastoma.
Examples of brain cancers include, but are not limited to brain stem and hypo- phtalmic 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. s of the female reproductive organs include, but are not d 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, adder, gastric, pancreatic, rectal, 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 d 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 ma, Merkel cell skin cancer, and non-melanoma skin cancer.
[Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 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 ma of the central nervous system.
Sarcomas include, but are not d to sarcoma of the soft tissue, osteosarcoma, ant s histiocytoma, lymphosarcoma, and rhabdomyosarcoma. ias e, but are not limited to acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.
These disorders have been well characterized in humans, but also exist with a similar etiology in other mammals, and can be treated by administering pharmaceutical compositions of the t invention.
The term ing" or "treatment" as stated throughout this document is used con- ventionally, e.g., the management or care of a subject for the purpose of combating , alleviating, reducing, relieving, improving the condition of, etc., of a disease or disorder, such as a carcinoma.
Methods of treating kinase disorders The present invention also provides s for the treatment of ers asso- ciated with aberrant mitogen extracellular kinase activity, including, but not limited to stroke, heart failure, hepatomegaly, cardiomegaly, diabetes, Alzheimer's e , cystic fibrosis, symptoms of xenograft rejections, septic shock or asthma.
Effective amounts of nds of the t invention can be used to treat such disorders, including those diseases (e.g., cancer) mentioned in the Back- ground section above. Nonetheless, such cancers and other diseases can be treated with compounds of the present invention, less of the mechanism of action and/or the relationship between the kinase and the disorder.
[Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb The phrase "aberrant kinase activity" or "aberrant tyrosine kinase activity," includes any abnormal expression or activity of the gene encoding the kinase or of the polypeptide it encodes. Examples of such aberrant ty, include, but are not limited to, over-expression of the gene or polypeptide ; gene amplification ; mutations which produce constitutively-active or ctive kinase activity ; gene ons, deletions, tutions, additions, etc.
The present invention also provides for methods of inhibiting a kinase activity, especially of mitogen extracellular , comprising stering an effective amount of a compound of the present invention, including salts, polymorphs, me- tabolites, hydrates, solvates, prodrugs (e.g.: esters) thereof, and diastereoisomeric forms thereof. Kinase activity can be inhibited in cells (e.g., in , or in the cells of a mammalian subject, especially a human patient in need of treatment. s of treating angiogenic disorders The present invention also provides methods of treating disorders and 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 ated with the growth of extraneous blood s. These include, e.g., diabetic pathy, 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], lated macular de- generation [AMD ; see, Lopez et al. Invest. Opththalmol. Vis. Sci. 1996, 37, 855], neovascular ma, psoriasis, retrolental fibroplasias, angiofibroma, inflammation , rheumatoid arthritis (RA), restenosis, in-stent restenosis, vascular graft restenosis , etc. In addition, the sed 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 the t invention can be utilized to treat and/or prevent any of the aforementioned angiogenesis disorders, e.g., by inhibiting and/or reducing blood vessel ion ; by inhibiting, blocking, [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb reducing, decreasing, etc. endothelial cell proliferation or other types involved in angiogenesis, as well as causing cell death or apoptosis of such cell types.
Preferably, the diseases of said method are haematological tumours, solid tumour and/or metastases thereof.
The compounds of the present invention can be used in particular in therapy and tion i.e. laxis, especially in therapy of tumour growth and metastases , especially in solid s of all indications and stages with or without pretreatment of the tumour growth.
Pharmaceutical compositions of the compounds of the invention This invention also relates to pharmaceutical compositions containing one or more compounds of the present invention. These compositions can be utilised to achieve the desired pharmacological effect by administration to a patient in need f. A patient, for the purpose of this invention, is a mammal, including a hu- man, in need of treatment for the particular condition or disease.
Therefore, the present invention includes pharmaceutical compositions that are sed of a ceutically acceptable carrier or auxiliary and a pharmaceutically effective amount of a compound, or salt thereof, of the present invention. r aspect of the ion is a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula (I) and a pharmaceutically acceptable auxiliary for the treatment of a disease mentioned supra, especially for the ent of haemotological tumours, solid tumours and/or metastases thereof.
A pharmaceutically acceptable r or auxiliary is preferably a carrier that is non-toxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side s ascribable to the carrier do not vitiate the beneficial effects of the active ingredient. Carriers and auxiliaries are all kinds of additives assisting to the composition to be suitable for administration.
[Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb A pharmaceutically effective amount of nd is preferably that amount which produces a result or exerts the intended influence on the particular condition being treated.
The nds of the present invention can be administered with pharmaceutical- ly-acceptable carriers or auxiliaries well known in the art using any effective conventional dosage unit forms, including immediate, slow and timed e preparations , orally, parenterally, topically, y, ophthalmically, lly, gually, rectally, vaginally, and the like.
For oral administration, the compounds can be formulated into solid or liquid prep- arations such as capsules, pills, tablets, troches, lozenges, melts, powders, solutions , suspensions, or emulsions, and may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions. The solid unit dosage forms can be a capsule that can be of the ordinary hard- or softshelled gelatine type containing auxiliaries, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and corn starch.
In another embodiment, the compounds of this ion may be tableted with conventional tablet bases such as lactose, sucrose and cornstarch in combination with binders such as acacia, corn starch or ne, disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn starch, and guar gum, gum tragacanth, acacia, lubricants intended to e the flow of tablet granulation and to prevent the adhesion of tablet material to the es of the tablet dies and punches, for example talc, stearic acid, or magnesium, calcium or zinc stearate, dyes, colouring agents, and flavouring agents such as peppermint, oil of wintergreen, or cherry flavouring, intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient. Suitable excipients for use in oral liquid dosage forms include dicalcium phosphate and ts such as water and alcohols, for example, ethanol, benzyl alcohol, and polyethylene alcohols, either with or without the on of a pharmaceutically acceptable tant, suspending agent or fying agent. Various other materials may be present as coatings or to [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb otherwise modify the physical form of the dosage unit. For instance s, pills or capsules may be coated with shellac, sugar or both.
Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example those sweetening, flavouring and colouring agents described above, may also be present.
The pharmaceutical compositions of this invention may also be in the form of oil- er emulsions. The oily phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils. le emulsifying agents may be (1) naturally occurring gums such as gum acacia and gum tragacanth, (2) naturally occurring phosphatides such as soy bean and lecithin, (3) esters or partial esters derived form fatty acids and l anhydrides, for example, an monooleate, (4) condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene an monooleate. The emulsions may also contain sweetening and flavouring agents.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as, for example, s oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent such as, for example, beeswax, hard paraffin, or cetyl alcohol. The suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate ; one or more colouring agents ; one or more flavouring agents ; and one or more sweetening agents such as sucrose or rin.
Syrups and elixirs may be formulated with sweetening agents such as, for e , glycerol, ene glycol, ol or sucrose. Such formulations may also contain a demulcent, and preservative, such as methyl and propyl parabens and flavouring and colouring agents.
The compounds of this invention may also be administered erally, that is, subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly, or [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb interperitoneally, as injectable dosages of the compound in ably a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid or mixture of liquids such as water, saline, aqueous dextrose and d sugar solutions, an alcohol such as ethanol, isopropanol, or hexadecyl l, glycols such as propylene glycol or polyethylene glycol, ol ketals such as 2,2- dimethyl-1,1-dioxolanemethanol, ethers such as poly(ethylene glycol) 400, an oil, a fatty acid, a fatty acid ester or, a fatty acid glyceride, or an acetylated fatty acid glyceride, with or without the addition of a pharmaceutically acceptable surfactant such as a soap or a detergent, suspending agent such as pectin, car- bomers, methycellulose, hydroxypropylmethylcellulose, or ymethylcellulose, or emulsifying agent and other ceutical adjuvants.
Illustrative of oils which can be used in the parenteral formulations of this ion are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum and min- eral oil. Suitable fatty acids include oleic acid, stearic acid, isostearic acid and ic acid. Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate. Suitable soaps include fatty acid alkali metal, ammonium, and anolamine salts and suitable detergents include cationic detergents, for example dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine ace- tates ; anionic detergents, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin , ether, and monoglyceride sulfates, and sulfosuccinates ; non-ionic detergents, for example, fatty amine oxides, fatty acid lamides, and poly(oxyethyleneoxypropylene )s or ethylene oxide or propylene oxide copolymers ; and amphoteric detergents, for example, alkyl-beta-aminopropionates, and 2-alkylimidazoline quarternary ammonium salts, as well as mixtures.
The parenteral compositions of this invention will typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and s may also be used advantageously. In order to minimise or eliminate irritation at the site of injection, such compositions may contain a non-ionic surfactant having a hydrophile-lipophile balance (HLB) preferably of from about 12 to about 17. The quantity of surfactant in such formulation preferably ranges from about 5% to [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb about 15% by weight. The surfactant can be a single component having the above HLB or can be a mixture of two or more ents having the desired HLB.
Illustrative of surfactants used in eral formulations are the class of polyethylene sorbitan fatty acid esters, for example, sorbitan eate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
The pharmaceutical compositions may be in the form of sterile injectable aqueous suspensions. Such suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents such as, for example, sodium carboxymethylcellulose, methylcellulose, ypropylmethylcellulose , sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia ; dispersing or wetting agents which may be a naturally occurring phosphatide such as lecithin, a condensation product of an alkylene oxide with a fatty acid, for example , yethylene stearate, a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadeca-ethyleneoxycetanol, a condensation t of ethylene oxide with a l ester derived form a fatty acid and a hexitol such as polyoxyethylene sorbitol monooleate, or a condensation product of an ethylene oxide with a partial ester derived from a fatty acid and a hexitol ide, for example polyoxyethylene sorbitan monooleate.
The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Diluents and solvents that may be employed are, for e, water, Ringer’s solution, isotonic sodium chloride ons and isotonic glucose solutions. In addition, sterile fixed oils are conventionally employed as solvents or suspending media. For this pur- pose, any bland, fixed oil may be employed including tic mono- or diglycerides.
In addition, fatty acids such as oleic acid can be used in the preparation of injectables.
A composition of the invention may also be administered in the form of suppositories for rectal stration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rec- [Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb tum to release the drug. Such materials are, for example, cocoa butter and polyethylene Controlled release formulations for parenteral administration include liposomal, polymeric microsphere and polymeric gel formulations that are known in the art.
It may be ble or necessary to introduce the pharmaceutical composition to the patient via a mechanical delivery device. The uction and use of mechanical delivery devices for the delivery of pharmaceutical agents is well known in the art. Direct techniques for stration, for example, stering a drug directly to the brain usually involve placement of a drug delivery catheter into the patient’s ventricular system to bypass the blood-brain barrier. One such implantable delivery system, used for the ort of agents to specific anatomical s of the body, is described in US Patent No. 5,011,472, issued April 30, 1991.
The compositions of the invention can also contain other tional pharmaceutically acceptable compounding ingredients, generally referred to as carriers or diluents, as necessary or desired. Conventional procedures for preparing such compositions in appropriate dosage forms can be utilized.
Such ingredients and procedures include those described in the following nces , each of which is incorporated herein by reference: Powell, M.F. et al., "Compendium of Excipients for Parenteral Formulations" PDA Journal of Pharma- ceutical Science & Technology 1998, 52(5), 238-311 ; Strickley, R.G "Parenteral Formulations of Small Molecule Therapeutics Marketed in the United States (1999)-Part-1" PDA Journal of Pharmaceutical e & Technology 1999, 53(6), 324-349 ; and Nema, S. et al., "Excipients and Their Use in Injectable Products" PDA Journal of Pharmaceutical Science & Technology 1997, 51(4), 166- 171.
Commonly used pharmaceutical ingredients that can be used as appropriate to ate the composition for its intended route of administration include: acidifying agents (examples include but are not limited to acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid) ; [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb nizing agents les include but are not limited to ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium ide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine) ; ents (examples include but are not limited to powdered cellulose and acti- vated charcoa)l ; aerosol propellants (examples include but are not limited to carbon dioxide, CCl2F2, F2ClC-CClF2 and CClF3) air displacement agents - examples e but are not d to nitrogen and argon antifungal preservatives (examples include but are not d to benzoic acid, butylparaben , ethylparaben, methylparaben, propylparaben, sodium benzoate) ; antimicrobial preservatives (examples include but are not limited to benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol , phenol, ethyl alcohol, phenylmercuric nitrate and thimerosal) ; antioxidants (examples include but are not limited to ascorbic acid, ascorbyl palmitate , butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorus acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite) ; binding materials les include but are not limited to block polymers, natural and tic rubber, polyacrylates, polyurethanes, silicones, polysiloxanes and styrene-butadiene copolymers) ; buffering agents (examples include but are not limited to potassium metaphosphate , ssium phosphate, sodium acetate, sodium citrate anhydrous and sodium citrate dihydrate); ng agents (examples e but are not limited to acacia syrup, aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orange syrup, syrup, corn oil, mineral oil, peanut oil, sesame oil, bacteriostatic sodium chloride injection and bacteriostatic water for injection); [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb chelating agents (examples include but are not limited to edetate disodium and edetic acid); colourants (examples include but are not limited to FD&C Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No. 8, caramel and ferric oxide red) ; clarifying agents (examples include but are not limited to bentonite) ; emulsifying agents (examples include but are not limited to acacia, cetomacrogol, cetyl l, glyceryl monostearate, lecithin, sorbitan monooleate, polyoxyethylene 50 monostearate) ; ulating agents les include but are not limited to gelatin and cellulose acetate phthalate), flavourants (examples include but are not limited to anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and in) ; humectants (examples include but are not limited to glycerol, propylene glycol and sorbitol) ; levigating agents (examples include but are not limited to mineral oil and glycerin) ; oils (examples include but are not limited to arachis oil, mineral oil, olive oil, peanut oil, sesame oil and ble oil) ; nt bases les include but are not limited to lanolin, hydrophilic oint- ment, polyethylene glycol ointment, petrolatum, hilic petrolatum, white ointment , yellow ointment, and rose water ointment) ; penetration enhancers (transdermal delivery) (examples include but are not limited to monohydroxy or polyhydroxy alcohols, mono-or polyvalent alcohols, saturated or rated fatty alcohols, saturated or unsaturated fatty esters, ted or unsaturated oxylic acids, essential oils, phosphatidyl derivatives, cephalin, terpenes, amides, ethers, ketones and ureas), [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb plasticizers (examples e but are not d to diethyl phthalate and glycerol ts (examples include but are not limited to ethanol, corn oil, cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid, peanut oil, purified water, water for injection, sterile water for injection and sterile water for irrigation) ; stiffening agents (examples include but are not limited to cetyl alcohol, cetyl esters wax, microcrystalline wax, paraffin, stearyl alcohol, white wax and yellow wax) ; itory bases (examples include but are not limited to cocoa butter and polyethylene glycols (mixtures)) ; surfactants (examples include but are not limited to benzalkonium chloride, nonoxynol , oxtoxynol 9, polysorbate 80, sodium lauryl sulfate and sorbitan monopalmitate ding agents (examples include but are not limited to agar, bentonite, carbomers , carboxymethylcellulose sodium, hydroxyethyl ose, hydroxypropyl cellulose, ypropyl methylcellulose, kaolin, methylcellulose, tragacanth and veegum) ; sweetening agents (examples include but are not limited to aspartame, dextrose, glycerol, mannitol, propylene glycol, saccharin , sorbitol and sucrose) ; tablet anti-adherents (examples include but are not limited to magnesium stearate and talc) ; tablet s (examples include but are not limited to acacia, alginic acid, carboxymethylcellulose sodium, compressible sugar, ellulose, gelatin, liquid glucose , methylcellulose, non-crosslinked polyvinyl pyrrolidone, and pregelatinized starch) ; tablet and capsule diluents les include but are not limited to dibasic calcium phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powdered cellulose , precipitated calcium carbonate, sodium carbonate, sodium phosphate, ol and starch) ; [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb tablet coating agents (examples include but are not limited to liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, cellulose acetate phthalate and shellac) ; tablet direct compression excipients (examples include but are not limited to diba- sic calcium phosphate) ; tablet disintegrants (examples include but are not limited to alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose, illin potassium, crosslinked polyvinylpyrrolidone, sodium alginate, sodium starch glycollate and starch) ; tablet glidants les include but are not limited to colloidal silica, corn starch and talc) ; tablet lubricants (examples include but are not limited to calcium stearate, magnesium stearate, mineral oil, stearic acid and zinc stearate) ; /capsule opaquants (examples include but are not d to titanium dioxide tablet polishing agents (examples include but are not limited to carnuba wax and white wax) ; thickening agents les include but are not limited to beeswax, cetyl l and paraffin) ; tonicity agents (examples include but are not limited to dextrose and sodium chlo- ride) ; viscosity increasing agents (examples include but are not d to alginic acid, bentonite, ers, carboxymethylcellulose sodium, methylcellulose, polyvinyl idone, sodium alginate and tragacanth) ; and wetting agents (examples include but are not limited to heptadecaethylene ox- ycetanol, lecithins, sorbitol eate, polyoxyethylene sorbitol eate, and polyoxyethylene stearate).
[Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb Pharmaceutical compositions according to the present invention can be illustrated as follows: Sterile i.v. solution: A 5 mg/mL solution of the desired compound of this invention can be made using sterile, injectable water, and the pH is adjusted if necessary.
The solution is diluted for administration to 1 – 2 mg/mL with sterile 5% dextrose and is administered as an i.v. infusion over about 60 minutes.
Lyophilised powder for i.v. stration: A sterile preparation can be prepared with (i) 100 - 1000 mg of the d compound of this invention as a lyophilised , (ii) 32- 327 mg/mL sodium citrate, and (iii) 300 – 3000 mg Dextran 40.
The formulation is reconstituted with sterile, injectable saline or dextrose 5% to a concentration of 10 to 20 mg/mL, which is further diluted with saline or dextrose % to 0.2 – 0.4 mg/mL, and is stered either IV bolus or by IV infusion over – 60 s.
Intramuscular suspension: The following solution or suspension can be prepared, for intramuscular injection: 50 mg/mL of the desired, water-insoluble compound of this invention mg/mL sodium carboxymethylcellulose 4 mg/mL TWEEN 80 9 mg/mL sodium chloride 9 mg/mL benzyl alcohol Hard Shell Capsules: A large number of unit es are prepared by filling standard two-piece hard galantine capsules each with 100 mg of ed active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stea- rate.
Soft Gelatin Capsules: A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into molten gelatin to form soft gelatin es containing 100 mg of the active ingredient. The capsules are washed and dried. The active [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water miscible ne mix.
Tablets: A large number of tablets are prepared by conventional procedures so that the dosage unit is 100 mg of active ingredient, 0.2 mg. of dal silicon diox- ide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg. of starch, and 98.8 mg of lactose. Appropriate aqueous and non-aqueous coatings may be applied to increase palatability, improve ce and stability or delay absorption.
Immediate Release s/Capsules: These are solid oral dosage forms made by conventional and novel processes. These units are taken orally without water for immediate ution and delivery of the medication. The active ingredient is mixed in a liquid containing ingredient such as sugar, gelatin, pectin and sweeteners.
These liquids are solidified into solid s or s by freeze drying and solid state extraction techniques. The drug compounds may be compressed with viscoelastic and thermoelastic sugars and rs or effervescent components to e porous matrices intended for ate release, without the need of water.
Dose and administration Based upon standard laboratory techniques known to evaluate compounds useful for the treatment of hyper-proliferative disorders and angiogenic disorders, by standard toxicity tests and by standard pharmacological assays for the determination of treatment of the conditions fied above in mammals, and by comparison of these results with the results of known medicaments that are used to treat these conditions, the effective dosage of the compounds of this invention can readily be determined for treatment of each desired indication. The amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.
[Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb The total amount of the active ient to be administered will generally range from about 0.001 mg/kg to about 200 mg/kg body weight per day, and preferably from about 0.01 mg/kg to about 20 mg/kg body weight per day. Clinically useful dosing schedules will range from one to three times a day dosing to once every four weeks dosing. In addition, "drug holidays" in which a patient is not dosed with a drug for a certain period of time, may be beneficial to the overall e n pharmacological effect and tolerability. A unit dosage may contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day or less than once a day. The average daily dosage for ad- ministration by injection, ing 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 . The e 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 stered 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 nd 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.
Combination Therapies The compounds of this invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutical agents where the combination causes no unacceptable adverse effects. Those combined pharma- [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb ceutical agents can be other agents having antiproliferative effects such as for e for the treatment of haemotological tumours, solid tumours and/or metastases thereof and/or agents for the treatment of undesired side effects.The present invention s also to such combinations.
Other yper-proliferative agents suitable for use with the composition of the invention include but are not limited to those compounds acknowledged to be used in the treatment of neoplastic diseases in Goodman and Gilman's The cological Basis of Therapeutics (Ninth Edition), editor Molinoff et al., publ. by McGraw-Hill, pages 1225-1287, (1996), which is hereby orated by refer- ence, ally (chemotherapeutic) anti-cancer agents as defined supra. The ation can be a non-fixed combination or a fixed-dose combination as the case may be.
Methods of testing for a particular pharmacological or pharmaceutical ty are well known to persons skilled in the art.
The example g experiments described herein serve to illustrate the present invention and the invention is not limited to the examples given.
As will be appreciated by persons skilled in the art, the invention is not limited to the particular embodiments described herein, but covers all modifications of said embodiments that are within the spirit and scope of the invention as defined by the appended claims.
The following examples illustrate the invention in greater detail, without restricting it. Further compounds according to the invention, of which the preparation is not explicitly described, can be prepared in an analogous way.
The compounds, which are mentioned in the es and the salts thereof represent preferred embodiments of the invention as well as a claim ng all subcombinations of the residues of the compound of formula (I) as disclosed by the specific examples.
[Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb The term "according to" within the mental section is used in the sense that the procedure referred to is to be used "analogously to".
[Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb MENTAL PART The following table lists the abbreviations used in this paragraph and in the Intermediate Examples and Examples section as far as they are not explained within the text body.
Abbreviation Meaning aq. aqueous alloc allyloxycarbonyl boc t-butoxycarbonyl br broad CI chemical tion d doublet dd doublet of doublet DAD diode array detector DCM dichloromethane DMF N,N-dimethylformamide ELSD Evaporative Light Scattering Detector EtOAc ethyl acetate Eq. lent ESI electrospray (ES) ionisation HATU 2-(7-aza-1H-benzotriazoleyl)-1,1,3,3- tetramethyluronium hexafluorophosphate (CAS number 1) HPLC high performance liquid chromatography LC-MS liquid chromatography mass spectrometry m multiplet MS mass spectrometry n-BuLi n-butyllithium NMR nuclear magnetic resonance spectroscopy : chemical shifts (δ) are given in ppm. The al shifts were corrected by setting the DMSO signal to 2.50 [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb ppm using unless otherwise stated.
PDA Photo Diode Array PoraPakTM; a HPLC column obtainable from Waters q quartet r.t. or rt room temperature RT retention time (as ed either with HPLC or UPLC) in minutes s singlet SM starting material SQD Single-Quadrupol-Detector t triplet THF ydrofuran UPLC ultra performance liquid tography Other abbreviations have their meanings customary per se to the skilled person.
The various aspects of the invention described in this application are illustrated by the following examples which are not meant to limit the invention in any way.
Specific Experimental Descriptions NMR peak forms in the following specific experimental descriptions are stated as they appear in the spectra, possible higher order effects have not been consid- ered. Reactions employing microwave ation may be run with a Biotage Initator  microwave oven optionally equipped with a robotic unit. The ed reaction times employing microwave heating are intended to be understood as fixed on times after reaching the indicated reaction temperature. The compounds and intermediates 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 compounds may be purified by crystallization. In some cases, impurities may be stirred out using a suitable solvent. In some cases, the compounds may be purified by chro- aphy, particularly flash column tography, using for example pre- [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb packed silica gel cartridges, e.g. from Separtis such as Isolute® Flash silica gel or Isolute® Flash NH2 silica gel in combination with a Isolera® rifier (Biotage) and eluents such as gradients of e.g. hexane/ethyl acetate or DCM/methanol. In some cases, the compounds may be purified by preparative HPLC using for ex- ample a Waters autopurifier equipped with a diode array detector and/or on-line electrospray ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluents such as 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 pro- vide 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 ical 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 as bed 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.
The percentage yields ed in the following examples are based on the ng component that was used in the lowest molar amount. Air and moisture sensitive liquids and ons were erred via e or a, and introduced into reaction vessels h rubber septa. Commercial grade reagents and solvents were used without r purification. The term "concentrated in vacuo" refers to use of a Buchi rotary evaporator at a minimum pressure of approximately mm of Hg. All temperatures are reported ected in degrees Celsius (°C).
In order that this invention may be better understood, the following examples are set forth. These examples are for the purpose of illustration only, and are not to be construed as limiting the scope of the invention in any . All publications mentioned herein are orated by reference in their entirety.
[Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb Analytical LC-MS conditions LC-MS-data given in the subsequent specific experimental descriptions refer (unless ise noted) to the following conditions: Waters Acquity UPLC-MS: Binary Solvent Manager, Sample Manag- System: er/Organizer, Column Manager, PDA, ELSD, SQD 3001 or ZQ4000 Column: Acquity UPLC BEH C18 1.7 50x2.1mm A1 = water + 0.1% vol. formic acid (99%) Solvent: A2 = water + 0.2% vol. ammonia (32%) B1 = acetonitrile Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B Flow: 0.8 mL/min Tempera- 60°C ture: Injection: 2.0 µl Detection: DAD scan range 210-400 nm -> Peaktable ELSD MS ESI+, ESI- Switch -> various scan ranges (Report Header) Method 1: A1 + B1 = C:\MassLynx\Mass_100_1000.flp Method 2: A1 + B1 = C:\MassLynx\Mass_160_1000.flp s: Method 3: A1 + B1 = C:\MassLynx\Mass_160_2000.flp Method 4: A1 + B1 = C:\MassLynx\Mass_160_1000_BasicReport.flp Method 5: A2 + B1 = C:\MassLynx\NH3_Mass_100_1000.flp Method 6: A2 + B1 = sLynx\NH3_Mass_160- _1000_BasicReport.flp [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb Preparative HPLC conditions ication by ative HPLC" in the subsequent specific experimental ptions refers to (unless otherwise noted) the following conditions: Analytics (pre- and post analytics: Method B): Waters Aqcuity UPLC-MS: Binary Solvent Manager, Sample System: Manager/Organizer, Column Manager, PDA, ELSD, SQD 3001 Column: Aqcuity BEH C18 1.7 50x2.1mm Solvent: A = water + 0.1% vol. formic acid (99%) B = acetonitrile Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B Flow: 0.8 mL/min Temperature: 60°C Injection: 2.0 µl ion: DAD scan range 210-400 nm MS ESI+, ESI-, scan range 160-1000 m/z ELSD Methods: Purify_pre.flp Purify_post.flp Preparation: Waters Autopurificationsystem: Pump 2545, Sample Manager System: 2767, CFO, DAD 2996, ELSD 2424, SQD 3001 Column: XBrigde C18 5µm 100x30 mm Solvent: A = water + 0.1% vol. formic acid (99%) B = acetonitrile Gradient: 0–1 min 1% B, 1-8 min 1-99% B, 8-10 min 99% B [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb Flow: 50 mL/min Temperature: RT Solution: max. 250 mg / 2.5 mL dimethyl de or DMF Injection: 1 x 2.5 mL Detection: DAD scan range 210–400 nm MS ESI+, ESI-, scan range 160-1000 m/z Chiral HPLC conditions If not ied otherwise, chiral HPLC-data given in the subsequent specific experimental descriptions refer to the following ions: Analytics: System: Dionex: Pump 680, ASI 100, Waters: UV-Detektor 2487 Column: Chiralpak IC 5µm 150x4.6 mm Solvent: hexane / ethanol 80:20 + 0.1% lamine Flow: 1.0 mL/min Temperature: 25°C Solution: 1.0 mg/mL ethanol/methanol 1:1 Injection: 5.0 µl Detection: UV 280 nm Preparation: Agilent: Prep 1200, 2xPrep Pump, DLA, MWD, Prep FC, ESA: System: Corona Column: Chiralpak IC 5µm 250x30 mm Solvent: hexane / ethanol 80:20 + 0.1% diethylamine Flow: 40 mL/min Temperature: RT [Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb Solution: 660 mg / 5.6 mL ethanol Injection: 8 x 0.7 mL Detection: UV 280 nm Flash column chromatography ions "Purification by (flash) column chromatography" as stated in the subsequent specific experimental descriptions refers to the use of a Biotage Isolera purification system. For technical specifications see "Biotage product catalogue" on www.biotage.com.
Determination of optical rotation conditions Optical rotations were measured in dimethyl sulfoxide at 589 nm ngth, °C, tration 1.0000 g/100ml, integration time 10 s, film thickness 100.00 [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb EXAMPLES Synthetic Intermediates Intermediate 11 ation of 1-(4-methoxybenzyl)-1H-indazolecarbonitrile 6,47 g of 1H-indazolecarbonitrile (45,2 mmol, 1 eq.) were dissolved in 65 ml of dry DMF. 10 g of 1-(bromomethyl)methoxybenzene (49,7 mmol, 1,1 eq.) and 17,7 g of cesium carbonate (54,2 mmol, 1,2 eq.) were added. The e was stirred at room temperature for 18 hours under nitrogen atmosphere. Then the re- action mixture was partitioned between water and tert-butyl methyl ether. The ted aqueous layer was extracted twice with tert-butyl methyl ether. The combined organic layers were washed with brine, dried over ium sulfate and concentrated in vacuo. The crystallization from methanol provided 9,25 g (35,1 mmol, 77,7%) of analytically pure target compound.
NMR (300 MHz, DMSO-d6) δ [ppm]= 3.64 - 3.71 (s, 3 H), 5.70 (s, 2 H) 6.81 - 6.89 (m, 2 H), 7.22 - 7.29 (m, 2 H), 7.38 (ddd, 1 H), 7.55 (ddd, 1 H), 7.85 (dt, 1 H) 7.97 (dt, 1 H) LC-MS: retention time: 1.27 min MS ES+: 264.31 [M+H]+ [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb The following intermediates were ed according to the same procedure using the respective commercially available starting materials: 12 CH 1H-NMR (300MHz, DMSO-d 3 1-(4- 6): propylben- δ [ppm]= 0.75 - 0.86 (m, 3H), zyl)-1H- 1.41 - 1.56 (m, 2H), 2.41 - indazole 2.51 (t, 2H), 5.74 (s, 2H), 7.08 N carbonitrile - 7.13 (d, 2H), 7.16 - 7.22 (d, 2H), 7.38 (ddd, 1H), 7.55 N (ddd, 1H), 7.85 (dt, 1H), 7.92 - 7.98 (dt, 1H).
LC-MS: retention time: 1,50 min MS ES+: 276.0 [M+H]+ Method B 13 CH methyl {4- 1H-NMR (500MHz, DMSO-d 3 6): OO [(3-cyano- δ [ppm]= 3.58 (s, 3H), 3.64 (s, 1H-indazol- 2H), 5.81 (s, 2H), 7.21 - 7.25 1- (m, 2H), 7.25 - 7.29 (m, 2H), yl)methyl]ph 7.43 (td, 1H), 7.59 (ddd, 1H), N enyl}acetate 7.89 - 7.92 (m, 1H), 8.00 (d, 1H).
LC-MS: retention time: 1,24 min MS ES+: 306.0 [M+H]+ Method B ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 14 1-(2- 1H-NMR (300MHz, DMSO- fluoroben- d6): δ [ppm]= 5.84 (s, 2H), zyl)-1H- 7.11 - 7.45 (m, 5H), 7.58 (ddd, N F N indazole 1H), 7.87 (d, 1H), 7.96 (d, itrile 1H).
LC-MS: retention time: 1.29 min MS ES+: 251.9 [M+H]+ Method B F O 1-(4-ethoxy- 1H-NMR (300MHz, DMSO- 2,6- d6): δ [ppm]= 1.26 (t, 3H), difluoroben- 4.01 (q, 2H), 5.72 (s, 2H), N F N zyl)-1H- 6.70 - 6.76 (m, 2H), 7.34 - indazole 7.47 (m, 1H), 7.56 - 7.67 (m, N carbonitrile 1H), 7.80 - 7.88 (m, 1H), 7.91 - 8.01 (m, 1H).
LC-MS: retention time: 1.44 min MS ES+: 314.2 [M+H]+ 16 F 1-(4- 1H-NMR (500MHz, DMSO-d fluoroben- δ [ppm]= 5.79 (s, 2H), 7.14 zyl)-1H- (m, 2H), 7.31 - 7.43 (m, 3H), N le 7.56 (ddd, 1H), 7.87 (d, 1H), carbonitrile 7.98 (d, 1H). 17 F O 1-(4-ethoxy- H-NMR (400MHz, DMSO-d6): 2,6- δ [ppm]= 1.26 (t, 3H), 2.64 (s, difluoroben- 3H), 4.01 (q, 2H), 5.68 (s, N F N zyl) 2H), 6.70 - 6.76 (m, 2H), 7.13 methyl-1H- (d, 1H), 7.46 (dd, 1H), 7.74 (d, N indazole ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb itrile 1H).
Intermediate 11 Preparation of 1-(4-methoxybenzyl)-1H-indazolecarboximidamide 9,25 g of 1-(4-methoxybenzyl)-1H-indazolecarbonitrile , 35,1 mmol, 1 eq.) were suspended in 128 ml of dry methanol under a nitrogen atmosphere. 0,949 g (17,6 mmol, 0.5 eq.) of sodium methanolate were added. The reaction mixture was stirred for 18 hours at room temperature. To the resulting mixture were added 2,82 g (52,7 mmol, 1.5 eq.) of ammonium chloride and 1,0 ml (17,6 mmol, 0.5 eq.) of 100% acetic acid and stirred for 5 hours at 50°C. After cooling down at room temperature the mixture was concentrated in vacuo. The residue was partitioned be- tween aq. half saturated sodium hydrogen carbonate solution and dichloromethane /isopropanol 4:1. The aqueous layer was extracted three times with dichloromethane /isopropanol 4:1. The combined organic layers were washed with brine, dried over magnesium e and concentrated in vacuo. The residue was ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb purified by flash chromatography to yield 6,45 g (23 mmol, 65,5%) of the analytically pure target compound. 1H NMR (300 MHz, DMSO-d6) δ [ppm]= 3.62 - 3.70 (s, 3 H), 5.57 (s, 2 H), 6.37 (br. s., 3 H), 6.78 - 6.88 (m, 2 H), 7.10 - 7.23 (m, 3 H), 7.35 (ddd, 1 H), 7.68 (d, 1 H), 8.27 (d, 1 H) LC-MS: retention time: 0.75 min MS ES+: 281.34 [M+H]+ The following intermediates were prepared according to the same procedure from the indicated starting als (SM = starting material): 12 CH 1H-NMR (300MHz, DMSO-d 3 1-(4- 6): ben- δ [ppm]= 0.80 (t, 3H), 1.38 - 1.56 SM = 12 zyl)-1H- (m, 2H), 2.41 - 2.49 (t, 2H), 5.61 indazole (s, 2H), 6.41 (br. s., 3H), 7.04 - N carboximid- 7.19 (m, 5H), 7.36 (ddd, 1H), amide 7.67 (d, 1H), 8.28 (d, 1H). 2 LC-MS: retention time: 0,94 min MS ES+: 293.0 [M+H]+ Method B 13 1-(2- 1H-NMR (300MHz, DMSO-d6): δ fluoroben- [ppm]= 5.72 (s, 2H), 6.73 (br. s., SM = 14 zyl)-1H- 3H), 7.01 - 7.13 (m, 2H), 7.15 - N F N indazole 7.23 (m, 2H), 7.27 - 7.36 (m, carboximid- 1H), 7.40 (ddd, 1H), 7.69 (d, NH amide 1H), 8.27 (d, 1H).
LC-MS: retention time: 0.75 min [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb MS ES+: 268.9 [M+H]+ Method B 14 F O 1-(4-ethoxy- 1H-NMR (400MHz, DMSO-d6): δ 2,6- [ppm]= 1.26 (t, 3H), 4.01 (q, 2H), SM = difluoro- 5.73 (s, 2H), 6.70 -6.76 (m, 2H), N F N benzyl)-1H- 7.33 - 7.41 (m, 1H), 7.52 - 7.63 NH indazole (m, 1H), 7.88 (d, 1H), 7.97 (d, x HCl 2 carboximid- 1H), 9.26 (br. s., 3H). amide hy- LC-MS: drochloride retention time: 0.87 min (1:1) MS ES+: 332.2 [M+H]+ F 1-(4- 1H-NMR (400MHz, DMSO-d6): δ fluoroben- [ppm]= 5.81 (s, 2H), 7.10 - 7.17 SM = 16 zyl)-1H- (m, 2H), 7.35 - 7.42 (m, 3H), N indazole 7.51 - 7.57 (m, 1H), 7.93 (d, 1H), carboximid- 8.00 (d, 1H), 9.34 (br. s., 3H).
NH x HCl amide hy- LC-MS: oride retention time: 0.71 min (1:1) MS ES+: 269.0 [M+H]+ Method B 16 F O 1-(4-ethoxy- 1H-NMR (400MHz, DMSO-d6): δ 2,6- [ppm]= 1.26 (t, 3H), 2.49 (s, 3H), SM = 17 ro- 3.99 (q, 2H), 5.66 (s, 2H), 6.69 - N F N ) 6.79 (m, 2H), 7.10 (d, 1H), 7.46 NH methyl-1H- (t, 1H), 7.74 (d, 1H), 7.77 (br. s., x HCl 2 indazole 3H). carboximidamide hy- LC-MS (Method 1): drochloride retention time: 0.93 min (1:1) MS ES+: 345.0 [M+H]+ [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb Intermediate 11 Preparation of 3,3-bis(dimethylamino)methoxypropanenitrile CH3 CH3 CH3 O 360,4 g of 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (Bredereck's reagent ) (2068 mmol, 1 eq.) and 150,0 g of methoxyacetonitrile (2068 mmol, 1 eq.) were stirred for 18 hours at 80°C. The reaction mixture was trated in vacuo.
The residue was purified by vacuum distillation to yield 117 g (687 mmol, 33,0%) of the analytical pure target compound as a yellowish . 1H-NMR (400 MHz, DMSO-d6): δ [ppm]= 2.23 (s, 6H), 2.29 (s, 6H), 3.23 (d, 1H), 3.36 - 3.41 (s, 3H), 4.73 (d, 1H).
LC-MS: retention time: 0.79 min MS ES+: 172.09 [M+H]+ Intermediate 11 Preparation of 5-methoxy[1-(4-methoxybenzyl)-1H-indazolyl]pyrimidin amine N 2 [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 6,45 g of 1-(4-methoxybenzyl)-1H-indazolecarboximidamide (23,0 mmol, 1 eq.), ,40 g of 3,3-bis(dimethylamino)methoxypropanenitrile (11, 31,5 mmol, 1,37 eq.) and 0,455 ml of dine (4,60 mmol, 0,2 eq.) were dissolved in 82,7 ml of dry 3-methylbutanol, put under a nitrogen here and stirred at 100°C for 3 days. The mixture was cooled down at room temperature and stirred for 18 hours for crystallization. The resulting suspension was filtered off. The crystals were washed with cold methanol and dried in vacuo at 50°C. The crystallization was repeated twice with cold ol to recieve 2 r filter cakes and a combined yield of 6,87 g (19 mmol, 82,5%) of the analytically pure target compound. 1H-NMR (300 MHz, DMSO-d 6): δ [ppm]= 3.62 - 3.69 (s, 3H), 3.85 (s, 3H), 5.59 (s, 2H), 6.78 - 6.90 (m, 4H), 7.11 - 7.23 (m, 3H), 7.35 (ddd, 1H), 7.68 (d, 1H), 7.95 (s, 1H), 8.53 (d, 1H).
LC-MS: Method B retention time: 0.87 min MS ES+: 362.0 [M+H]+ The ing intermediates were prepared according to the same procedure from the indicated starting materials (SM = starting material): 12 2-[1-(2- 1H-NMR (400 MHz, fluorobenzyl)- DMSO-d6): δ [ppm]= 3.85 SM = 13 1H-indazol (s, 3H), 5.73 (s, 2H), 6.85 N F yl] N (br. s., 2H), 7.01 - 7.13 (m, methoxypyrim- 2H), 7.15 - 7.24 (m, 2H), N idinamine 7.27 - 7.42 (m, 2H), 7.69 N 2 (d, 1H), 7.95 (s, 1H), 8.55 O (d, 1H).
LC-MS: retention time: 0.88 min MS ES+: 350.0 [M+H]+ [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb Method B 13 CH 2-[1-(4-ethoxy- 1H-NMR (400MHz, DMSO- F O 2,6- d6): δ [ppm]= 1.26 (t, 3H), SM = 14 difluorobenzyl)- 3.84 (s, 3H), 3.96 - 4.05 1H-indazol (m, 2H), 5.59 (s, 2H), 6.72 N F yl] (d, 2H), 6.77 - 6.86 (br. s, methoxypyrim- 2H), 7.15 - 7.21 (m, 1H), N idinamine 7.40 (ddd, 1H), 7.69 (d, N NH 2 1H), 7.93 (s, 1H), 8.52 (d, 1H).
O CH LC-MS: retention time: 1.03 min MS ES+: 412.2 [M+H]+ 14 CH 1H-NMR (400MHz, DMSO- 3 5-methoxy[1- (4- d6): δ [ppm]= 0.80 (t, 3H), SM = 12 propylbenzyl)- 1.40 - 1.54 (m, 2H), 2.42 – 1H-indazol 2.46 (t, 2H), 3.85 (s, 3H), N yl]pyrimidin 5.62 (s, 2H), 6.83 (br. s., amine 2H), 7.06 - 7.20 (m, 5H), N 7.35 (ddd, 1H), 7.68 (d, 2 1H), 7.95 (s, 1H), 8.54 (d, CH 1H).
LC-MS: retention time: 1.06 min MS ES+: 374.0 [M+H]+ Method B ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb 2-[1-(4- 1H-NMR (300MHz, DMSO- fluorobenzyl)- d6): δ [ppm]= 3.85 (s, 3H), SM = N azol 5.67 (s, 2H), 6.84 (br. s., N yl] 2H), 7.06 - 7.21 (m, 3H), methoxypyrim- 7.23 - 7.31 (m, 2H), 7.36 N NH idinamine (td, 1H), 7.70 (d, 1H), 7.95 (s, 1H), 8.54 (d, 1H).
O CH 3 LC-MS: retention time: 0.87 min MS ES+: 350.0 [M+H]+ Method B 16 CH 2-[1-(4-ethoxy- 1H-NMR (400MHz, DMSO- F O 2,6- d6): δ [ppm]= 1.26 (t, 3H), SM = 16 difluorobenzyl)- 2.34 (s, 3H), 3.85 (s, 3H), N F 4-methyl-1H- 4.00 (q, 2H), 5.52 (s, 2H), N indazolyl] 6.63 - 6.74 (m, 2H),6.78 CH N methoxypyrim- (br s, 2H), 6.87 (d, 1H), NH idinamine 7.27 (dd, 1H), 7.54 (d, 1H), O 7.90 (s, 1H).
LC-MS: retention time: 1.32 min MS ES+: 427.08 [M+H]+ Intermediate 11 Preparation of 5-methoxy[1-(4-methoxybenzyl)-1H-indazolyl]-N-(pyridin yl)pyrimidinamine [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb N N N H O CH 205 mg of 5-methoxy[1-(4-methoxybenzyl)-1H-indazolyl]pyrimidinamine (11, 0,568 mmol, 1 eq.), 121,6 mg of 4-bromopyridine hydrochloride (1:1) (0,625 mmol. 1,1 eq.), 136,5 mg of sodium 2-methylpropanolate (1,42 mmol, 2,5 eq.), 106,2 mg of 1'-binaphthalene-2,2'-diylbis(diphenylphosphane) (0,171 mmol, 0,3 eq.) and 52,0 mg of (1E,4E)-1,5-diphenylpenta-1,4-dienone - palladium (3:2) (0,057 mmol, 0,1 eq.) were suspended in 3 ml of dry DMF under nitrogen atmosphere. The reaction mixture was stirred for two days at 100°C. 122 mg of 4- yridine hydrochloride (1:1) (0,625 mmol. 1,1 eq.), 137 mg of sodium 2- methylpropanolate (1,42 mmol, 2,5 eq.), 106 mg of 1'-binaphthalene-2,2'- s(diphenylphosphane) (0,171 mmol, 0,3 eq.) and 52,0 mg of (1E,4E)-1,5- diphenylpenta-1,4-dienone - palladium (3:2) (0,057 mmol, 0,1 eq.) were added and stirred for further 24 hours. The mixture was cooled down to room tempera- ture, diluted with 10 ml dichloromethane and filtered off. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography to yield 126 mg ( 0,23 mmol, 81%) of the analytically pure target nd. 1H-NMR (300 MHz, DMSO-d6): δ [ppm]= 3.66 (s, 3H), 4.02 (s, 3H), 5.65 (s, 2H), 6.86 (d, 2H), 7.15 - 7.25 (m, 1H), 7.27 - 7.44 (m, 3H), 7.78 (d, 1H), 8.08 - 8.17 (m, 2H), 8.31 - 8.46 (m, 4H), 9.42 (s, 1H).
LC-MS: retention time: 0.95 min MS ES+: 439.31 [M+H]+ [Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb ation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb Method B Intermediate 11 Preparation of 2-(1H-indazolyl)methoxy-N-(pyridinyl)pyrimidinamine N N N H O CH 13,4 g of 5-methoxy[1-(4-methoxybenzyl)-1H-indazolyl]-N-(pyridinyl)- pyrimidinamine (11, 30,6 mmol, 1 eq.) was suspended in 121 ml of 1,2- dichloroethan. First 71 ml of trifluoroacetic acid (918 mmol, 30 eq.) were added dropwise, followed by 27 ml of trifluoromethanesulfonic acid (306 mmol, 10 eq.).
The reaction mixture was stirred for three days under nitrogen atmosphere. The mixture was cooled with an ice bath to + 3°C, upon which 2M aq. sodium hydroxide solution was added until pH = 12. The resulting brown suspension was stirred for 18 hours at room temperature and then the precipitate was filtered off and dried under vacuo at 70°C to yield 9,74g (27,7 mmol, 90,3%) of the analytically pure target compound as a light brown solid. 1H-NMR (300 MHz, DMSO-d 6): δ [ppm]= 4.02 (s, 3H), 7.11 - 7.26 (m, 1H), 7.37 (t, 1H), 7.56 (d, 1H), 8.17 (d, 2H), 8.32 - 8.53 (m, 4H), 9.39 (s, 1H), 13.39 (s, 1H).
LC-MS: retention time: 0.68 min MS ES+: 319.0 [M+H]+ Method B [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb Intermediate 11 Preparation of 2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridinylamino)- pyrimidinyl trifluoromethanesulfonate N F N N H O F 120 mg of 2-fluorobenzyl)-1H-indazolyl](pyridinylamino)pyrimidinol (3-3, 0,291 mmol, 1 eq.) was suspended in 1,9 ml of dry dichloromethane and 0,059 ml of pyridine (0,73 mmol, 2,5 eq.) were added under nitrogen atmosphere.
The mixture was cooled with an ice bath to +3°C and l of trifluoro- methanesulfonic anhydride ( 0,364 mmol, 1,25 eq.) were added dropwise. Upon completion of addition the ice bath was removed and the on mixture was stirred for 18 hours. The reaction mixture was cooled again with an ice bath and 0,059 ml of pyridine (0,727 mmol, 2,5 eq.) and 0,061 ml of trifluoromethanesulfonic anhydride ( 0,364 mmol, 1,25 eq.) were added and stirred for 3 hours. This proce- dure was repeated and stirred for r 24 hours. The reaction e was filtered off a short silica column and diluted with dichloromethane. The filtrate was concentrated in vacuo. The liquid residue was dissolved with toluene and again concentrated in vacuo. Yield = 106,1 mg with 37% purity ( 0,07 mmol, 24,78%) LC-MS: retention time: 1.18 min [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb MS ES+: 545.08 [M+H]+ The following intermediate was prepared according to the same procedure using the indicated starting materials (SM = starting material): 12 F O 2-[1-(4-ethoxy- R (300MHz, 2,6- 6): δ [ppm]= SM = 3-1 difluorobenzyl)- 1.20 - 1.30 (m, 3H), 4.00 N F N N 1H-indazolyl]- (q, 2H), 5.68 - 5.78 (m, N 4-(pyridin 2H), 6.78 (d,2H), 7.26 - N H yla- 7.36 (m, 1H), 7.52 (t, O mino)pyrimidin- 1H), 7.89 (d, 1H), 8.30 - S 5-yl trifluoro- 8.45 (m, 3H), 8.66 (d, O F F methanesul- 2H), 9.05 (s, 1H), 11.15 fonate - 11.43 (m, 1H).) LC-MS: retention time: 1.03 min MS ES+: 475.1 [M+H]+ Method B Intermediate 11 Preparation of utyl 3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H- indazolecarboxylate 3 CH3 3CH O [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 100 mg of [2-(1H-Indazolyl)methoxy-pyrimidinyl]-pyridinyl-amine (11, 0,314 mmol, 1 eq.) was dissolved in 2 ml of acetonitrile and 0,131 ml of ylamine (0,942 mmol, 3 eq.). 3,83 mg of 4-Dimethylaminopyridin (0,031 mmol, 0,1 eq.) and 89,1 mg of di-tert-butyl dicarbonate (0,408 mmol, 1.3 eq.) dissolved in 0,5 ml of acetonitrile were added. The solution was stirred for 24 hours at room ature under nitrogen atmosphere. The resulting suspension was filtered off and the filter cake was washed with acetonitrile to yield 100 mg (0,24 mmol, 76,1%) of the analytically pure target compound. 1H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.68 (br. s., 9H), 4.05 (br. s., 3H), 7.43 (br. s., 1H), 7.62 (br. s., 1H), 8.18 (br. s., 3H), 8.33 - 8.45 (m, 3H), 8.57 (d, 1H), 9.53 (br. s., 1H).
LC-MS: retention time: 0.97 min MS ES+: 419.1 [M+H]+ Intermediate 11 Preparation of tert-butyl 3-(5-methoxy{[(propenyloxy)carbonyl](pyridin yl)amino}pyrimidinyl)-1H-indazolecarboxylate 3 CH O O [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 96,3 mg of tert-butyl 3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H- indazolecarboxylate (11, 0,23 mmol, 1 eq.) was suspended in 7 ml of pyridine. 27.7 mg of propenyl carbonochloridate (0,23 mmol, 1 eq.) were added and stirred for two hours at room temperature. Twice 27.7 mg of -enyl carbonochloridate (0,23 mmol, 1 eq.) were added again and d the first time for 24 hours and the second time for three days at room temperature. The reaction mixture was concentrated in vacuo. To the residue was added water and acidified with 1M aq. hydrogen chloride on. This aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over a ne filter and concentrated under vacuo. Purification by flash chromatography (ethyl acetate/ methanol 0-50%) provided 50,8 mg (0,09 mmol, 39,97%) of the analytically pure target compound. 1H-NMR (300MHz, CHLOROFORM-d): δ [ppm]= 1.74 (s, 9H), 4.01 (s, 3H), 4.71 (d, 2H), 5.14 - 5.29 (m, 2H), 5.76 - 5.95 (m, 1H), 7.20 - 7.25 (m, 2H), 7.28 - 7.36 (m, 1H), 7.50 - 7.59 (m, 1H), 8.25 (t, 2H), 8.50 - 8.61 (m, 2H), 8.71 (s, 1H) LC-MS: retention time: 1.21 min MS ES+: 503,3 [M+H]+ Intermediate 11 Preparation of propenyl [2-(1H-indazolyl)methoxypyrimidinyl]pyridin- 4-ylcarbamate O O [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 1.22 g of tert-butyl 3-(5-methoxy{[(propenyloxy)carbonyl](pyridin yl)amino}pyrimidinyl)-1H-indazolecarboxylate , 2,43 mmol, 1 eq.) was suspended in 1,4-dioxane. 2,43 ml of hydrogen acid 4M in 1,4-dioxane (9,711 mmol, 4 eq.) were added dropwise. The reaction mixture was stirred for 24 hours at room temperature. 2,43 ml of en acid 4M in 1,4-dioxane (9,711 mmol, 4 eq.) were added dropwise again and stirred for r two hours. The reaction mixture was concentrated under vacuo. The residue was extracted with saturated aq. sodium hydrogen carbonate – solution and ethyl acetate. The aqueous layer was reextracted twice by ethyl acetate. The combined organic layers were dried over a silicone filter and concentrated under vacuo. Purification by flash chromatography (ethyl acetate/ methanol 0-25%) provided 877 mg (1,96 mmol, 80.8%) of the ically pure target compound. 1H-NMR (400MHz, 6): δ [ppm]= 4.00 (s, 3H), 4.71 - 4.81 (m, 2H), 5.12 - .23 (m, 2H), 5.79 - 5.93 (m, 1H), 7.13 - 7.23 (m, 1H), 7.33 - 7.41 (m, 1H), 7.54 - 7.62 (m, 1H), 7.82 - 7.91 (m, 2H), 8.25 - 8.31 (m, 1H), 8.71 - 8.79 (m, 2H), 9.09 (s, LC-MS: retention time: 0.84 min MS ES+: 403,3 [M+H]+ Intermediate 11 Preparation of 4-amino[1-(2-fluorobenzyl)-1H-indazolyl]pyrimidinol [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb N F N 2 558 mg of 2-[1-(2-fluorobenzyl)-1H-indazolyl]methoxypyrimidinamine (1 2, 1,60mmol, 1 eq.) was suspended in 10 ml of 1-methylpyrrolidon. 623 mg of sodium sulfidosodium (7,99 mmol, 5 eq.) were added and stirred for an hour at 140°C. The reaction mixture was extracted with half-saturated aq. ammonium chloride – solution and ethyl acetate. The s layer was reextracted twice by ethyl acetate. The aqueous layer gave a precipitate, which was filtered off and first purified by flash chromatography (hexane/ dichloro methane/ methanol), followed by a HPLC purification. This provided 23,4 mg (0,07 mmol, 4,37%) of the analytically pure target compound. 1H-NMR z, DMSO-d6): δ [ppm]= 5.68 - 5.74 (s, 2H), 6.61 - 6.67 (d, 1H), 7.01 - 7.13 (m, 2H), 7.14 - 7.23 (m, 2H), 7.25 - 7.33 (m, 2H), 7.34 - 7.42 (t, 1H), 7.64 - 7.71 (d, 1H), 7.74 - 7.80 (s, 1H), 8.51 - 8.56 (d, 1H), 9.74 - 9.87 (s, 1H).
LC-MS: retention time: 0.92 min MS ES+: 336.1 [M+H]+ Intermediate 11 Preparation of sodium 2-[1-(2-fluorobenzyl)-1H-indazolyl] (methoxycarbonyl)pyrimidinolate [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb N F O + N Na CH O 2,5 g of 1-(2-fluorobenzyl)-1H-indazolecarboximidamide hydrochloride (1:1) (1- 2-3 x HCl, 8,20 mmol, 1 eq.), 1,43 g of dimethyl (methoxymethyli- dene)propanedioate (8,20 mmol, 1 eq.) and 50 ml of methanol and 443 mg of sodium methanolate were stirred under en atmosphere at 60°C bath temperature for 24 hours. The clear yellowish solution turned into a suspension which was filtered off. The crystals were washed with cold methanol to yield 1,64 g (4,1 mmol, 50%) of the analytically pure target compound. 1H-NMR (300MHz, DMSO-d 6): δ [ppm]= 3.67 (s, 3H), 5.76 (s, 2H), 7.05 - 7.36 (m, 5H), 7.42 (ddd, 1H), 7.71 (d, 1H), 8.44 - 8.55 (m, 2H).
LC-MS: retention time: 1.16 min MS ES+: 379.1 [M+H]+ ediate 11 Preparation of sodium 5-carbamoyl[1-(2-fluorobenzyl)-1H-indazolyl]pyrimidin- 4-olate [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb N F O + N Na 100 mg of sodium 2-[1-(2-fluorobenzyl)-1H-indazolyl](methoxycarbonyl)pyrimidinolate (11, 0,25 mmol, 1 eq.) were dissolved in 26,8 ml of 7N ammonia in methanol (187 mmol, 750 eq.) and stirred under a nitrogen atmosphere at 60°C bath temperature for 24 hours, then at 65°C bath ature for six hours and r 24 hours at 70°C bath temperature. The reaction mixture was trated in vacuo to yield 96 mg (0,22 mmol, 89,8%) of the analytically pure target compound. 1H-NMR (400MHz, DMSO-d6): δ [ppm]= 5.82 (s, 2H), 7.07 - 7.26 (m, 3H), 7.27 - 7.42 (m, 3H), 7.47 (t, 1H), 7.77 (d, 1H), 8.47 (d, 1H), 8.58 (br. s., 1H), 9.07 - 9.32 (m, 1H).
LC-MS: retention time: 1.10 min MS ES+: 364.12 [M+H]+ Intermediate 11 Preparation of 4-chloro[1-(2-fluorobenzyl)-1H-indazolyl]pyrimidine carbonitrile [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb N F 88 mg of sodium 5-carbamoyl[1-(2-fluorobenzyl)-1H-indazolyl]pyrimidin olate (11, 0,228 mmol, 1 eq.) were suspended in 0,915 ml of phosphoric tri- chloride (9,82 mmol, 43 eq.) and 69 µl of N,N-diethylaniline (0,457 mmol, 2 eq.).
The suspension was stirred at 90°C bath temperature for 24 hours and then dropped to an ice cooled saturated aqueous sodium hydrogen carbonate solution.
The resulting suspension was filtered off and dried in vacuo to yield 82 mg (0,21 mmol, 93.77%) of the analytically pure target nd. 1H-NMR (400MHz, DMSO-d6): δ [ppm]= 5.87 - 5.91 (m, 2H), 7.08 - 7.26 (m, 3H), 7.30 - 7.44 (m, 2H), 7.53 (td, 1H), 7.88 (d, 1H), 8.45 (d, 1H), 9.39 (s, 1H).
LC-MS: Method B ion time: 1.38 min MS ES+: 364.0 [M+H]+ Intermediate 11 Preparation of 2-(bromomethyl)(difluoromethoxy)-1,3-difluorobenzene [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb F F F O Step 1: [4-(difluoromethoxy)-2,6-difluorophenyl]methanol 1 g of 3,5-difluoro(hydroxymethyl)phenol (6,245 mmol, 1 eq.) were dissolved in 16 ml of DMF 1,047 g of sodium chloro(difluoro)acetate (6,87 mmol, 1,1 eq.), 2,442 g of cesium carbonate (7,494 mmol, 1,2 eq.) and 400 µl of water were added.
The mixture was stirred at 100 °C bath temperature for 2 hours under en here. Then the reaction mixture was ioned between water and ethyl acetate. The separated aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over a silicone filter and concentrated in vacuo. The e was purified by flash chromatography to yield 763,3 mg (3,63 mmol, 58,2%) of the analytically pure target compound. 1H-NMR (400MHz, DMSO-d6): δ [ppm]= 4.42 (d, 2H), 5.21 (t, 1H), 6.99 (d, 2H), 7.09 - 7.50 (t, 1H).
Step 2: 2-(bromomethyl)(difluoromethoxy)-1,3-difluorobenzene 0,76 g of [4-(difluoromethoxy)-2,6-difluorophenyl]methanol (3,62 mmol, 1 eq.) were dissolved in 1,72 ml of 33% hydrogen bromide in glacial acetic acid ( 9,97 mmol, 2,75 eq.) and stirred at room temperature for 2 hours. 25 ml of diethyl ether were added and the mixture was stirred at room temperature for 15 min. The reaction mixture was added dropwise to 80 ml of aqueous saturated sodium hydrogen carbonate solution and stirred again at room temperature for 15 min. The separated aqueous layer was ted twice with diethyl ether. The combined organic layers were washed with brine, dried over a silicone filter and concentrated in vacuo to yield 991 mg (3,56 mmol, 98,4%) of the analytically pure target compound.
[Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 1H-NMR (300MHz, 6): δ [ppm]= 4.60 (s, 2H), 7.08 - 7.14 (d, 2H), 7.08 - 7.59 (t, 1H).
Intermediate 11 Preparation of 7-bromomethyl-3,4-dihydro-1H-quinolinone N O 500 mg of 7-(hydroxymethyl)-3,4-dihydroquinolin-2(1H)-one (2,82 mmol, 1 eq.) were dissolved in 1,77 ml of 33% hydrogen e in glacial acetic acid ( 31,0 mmol, 11 eq.) under nitrogen atmosphere and stirred at room temperature for 30 minutes. The reaction mixture was ioned between aq. saturated sodium hydrogen carbonate solution and dichloromethane/ isopropanol 4+1. The aqueous layer was extracted three times with dichloromethane/ isopropanol 4+1. The combined organic layers were washed with brine, dried over a silicone filter and concentrated in vacuo. The crude product was purified by flash chromatography to yield 175 mg (0,66 mmol, 23,3%) of the analytically pure target nd. 1H-NMR (400MHz, DMSO-d6): δ [ppm]= 2.40 (dd, 2H), 2.82 (t, 2H), 4.60 (s, 2H), 6.87 (d, 1H), 6.94 (dd, 1H), 7.10 (d, 1H).
LC-MS: retention time: 0,91 min MS ES+: 240.2 [M+H]+ The following compounds were prepared according to the same procedure from the ted starting materials (SM = starting material): 12 F O 2- SM = Br (bromomethyl)- 11 F 1,3-difluoro propoxybenzene [Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 13 F O CH 3 2- Br (bromomethyl)- SM = 12 F 1,3-difluoro(2- methoxyethoxy )benzene Intermediate 11 Preparation of 4-(bromomethyl)-N-cyclopropylbenzenesulfonamide O O g of 4-(bromomethyl)benzenesulfonyl chloride (18.6 mmol, 1 eq.) were dissolved under argon atmosphere in 82,5 ml of dichloromethane and cooled down at -10°C internal temperature. A on of 1.29 ml cyclopropanamine (18.6 mmol, 1 eq.) and 2.59 ml of triethylamine (18.6 mmol, 1 eq.) in 82,5 ml of dichloromethane were added dropwise at – 10°C internal temperature and stirred at this temperature for one hour. The reaction mixture was washed once with 1 M aqueous ene solution and twice with distilled water. The c layer was dried over sodium sulfate and concentrated in vacuo. The crude product contained a mixture of bromomethyl- and chloromethyl- substituents.
Intermediate 11 Preparation of (2,6-difluoropropoxyphenyl)methanol F O 200 mg of 3,5-difluoro(hydroxymethyl)phenol (1.25 mmol, 1.0 eq.) and 184 mg 1-bromopropane (1.50 mmol, 1.2 eq.) were dissolved in 17 ml N,N- [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb dimethylformamide. 863 mg ium (6.25 mmol, 5.0 eq.) were added and the reaction mixture was stirred at 0 °C over night. The reaction mixture was separated n water and ethyl acetate. The aqueous layer was extracted with ethyl acetate twice. The combined organic layers were dried over a silicone filter and concentrated in vacuo. to yield 283 mg (1.19 mmol, 95 %) of the crude product which was used without further purification. 1H-NMR (300MHz, DMSO-d6): δ [ppm]= 0.92 (t, 3H), 1.54 - 1.78 (m, 2H), 3.90 (t, 2H), 4.36 (s, 2H), 5.06 (br. s., 1H), 6.53 - 6.79 (m, 2H).
The following intermediate was prepared according to the same procedure from cial (2-Bromethyl)-methylether and 3,5-difluoro(hydroxymethyl)phenol: 12 F O CH [2,6-difluoro 1H-NMR (300MHz, O 3 OH (2- DMSO-d6): δ [ppm]= F methoxyeth- 3.25 (s, 3H), 3.50 - 3.65 oxy)phenyl]meth (m, 2H), 3.99 - 4.14 (m, anol 2H), 4.37 (br. s., 2H), .07 (br. s., 1H), 6.52 - 6.75 (m, 2H) [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb EXAMPLE NDS Example 21 Preparation of 2-[1-(6-chlorofluoromethylbenzyl)-1H-indazolyl]methoxy- N-(pyridinyl)pyrimidinamine 80 mg of 2-(1H-indazolyl)methoxy-N-(pyridinyl)pyrimidinamine (11, 0.251 mmol, 1. eq.) were suspended in dry tetrahydrofuran under a nitrogen atmosphere. ,2 mg of sodium hydride (60% purity) were added and stirred at room temperature for 10 s. Then 59,7 mg of 2-(bromomethyl)chloro fluoromethylbenzene were added. The reaction mixture was stirred for 18 hours at room temperature. Then the mixture was partitioned between half ted aq. ammonium chloride solution and dichloromethane/ isopropanol 4:1. The phases were separated and the aqueous layer was extracted twice with dichloro- methane/isopropanol 4:1. The combined organic layers were washed with brine, dried over a silicone filter and trated in vacuo. ative HPLC purification provided 29 mg (0,06 mmol, 24,1%) of the analytically pure target compound. 1H-NMR (300 MHz, DMSO-d6): δ [ppm]= 2.19 (d, 3H), 4.00 (s, 3H), 5.80 (d, 2H), 7.17 - 7.37 (m, 3H), 7.42 - 7.53 (m, 1H), 7.89 (d, 1H), 8.13 - 8.22 (m, 2H), 8.29 - 8.40 (m, 3H), 8.46 (d, 1H), 9.39 (s, 1H).
LC-MS: ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb retention time: 1.01 min MS ES+: 475.4 [M+H]+ Method B The following compounds were prepared according to the same procedure from the indicated starting materials (SM = starting material): 21 CH 2-[1-(6-chloro 1H-NMR (400 MHz, 3 O F DMSO-d6): δ [ppm]= SM = 11 methoxybenzyl)- 3.82 (s, 3H), 4.00 (s, 1H-indazolyl]- 3H), 5.77 (d, 2H), 7.17 - N Cl N 5-methoxy-N- 7.36 (m, 3H), 7.47 (ddd, (pyridin 1H), 7.89 (d, 1H), 8.13 - N yl)pyrimidin 8.20 (m, 2H), 8.29 - 8.40 N N H amine (m, 3H), 8.46 (d, 1H), O CH3 9.39 (s, 1H).
LC-MS: retention time: 0.99 min MS ES+: 491.3 [M+H]+ Method B 21 CH3 2-[1-(2-chloro- 1H-NMR (300 MHz, SM = CH3 4,5- DMSO-d6): δ [ppm]= 11 dimethylbenzyl)- 2.09 (s, 3H), 2.15 (s, N azolyl]- 3H), 3.96 - 4.05 (m, 3H), -methoxy-N- 5.71 (s, 2H), 7.09 (s, (pyridin 1H), 7.19 - 7.31 (m, 2H), N yl)pyrimidin 7.43 (s, 1H), 7.78 (d, H amine 1H), 8.11 - 8.17 (m, 2H), O 8.30 - 8.40 (m, 3H), 8.46 (d, 1H), 9.44 (s, 1H).
LC-MS: retention time: 1.04 min [Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb MS ES+: 471.4 [M+H]+ Method B 21 2-[1-(2,6- 1H-NMR (300 MHz, O 3 difluoro DMSO-d6): δ [ppm]= SM = 11 F methoxybenzyl)- 3.78 (s, 3H), 4.00 (s, 1H-indazolyl]- 3H), 5.74 (s, 2H), 7.02 - N F 5-methoxy-N- 7.30 (m, 3H), 7.42 - 7.52 N N (pyridin (m, 1H), 7.84 (d, 1H), N yl)pyrimidin 8.10 - 8.19 (m, 2H), 8.28 N N H amine - 8.48 (m, 4H), 9.38 (s, 1H).
O CH LC-MS: retention time: 0.95 min MS ES+: 475.0 [M+H]+ Method B 21 CH3 2-[1-(4-ethoxy- 1H-NMR (300 MHz, SM = F O 2,6- DMSO-d6): δ [ppm]= 11 difluorobenzyl)- 1.25 (t, 3H), 3.93 - 4.09 1H-indazolyl]- (m, 5H), 5.64 (s, 2H), N F 5-methoxy-N- 6.68 - 6.82 (m, 2H), 7.23 N N in (t, 1H), 7.40 - 7.51 (m, N yl)pyrimidin 1H), 7.81 (d, 1H), 8.11 - N N H amine 8.20 (m, 2H), 8.29 - 8.48 O CH3 (m, 4H), 9.37 (s, 1H).
LC-MS: retention time: 1.05 min MS ES+: 489.0 [M+H]+ Method B [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 21 CH 1H-NMR (300 MHz, 3 2-[1-(2-chloro O methoxybenzyl)- DMSO-d6): δ [ppm]= SM = 11 1H-indazolyl]- 3.72 (s, 3H), 4.01 (s, N 5-methoxy-N- 3H), 5.72 (s, 2H), 6.90 N (pyridin (dd, 1H), 7.07 (d, 1H), N yl)pyrimidin 7.19 - 7.28 (m, 2H), 7.43 N amine (t, 1H), 7.79 (d, 1H), 8.08 - 8.16 (m, 2H), 8.30 3 - 8.41 (m, 3H), 8.45 (d, 1H), 9.40 (s, 1H).
LC-MS: retention time: 0.99 min MS ES+: 473.4 [M+H]+ Method B 21 F 2-[1-(2,6- 1H-NMR (300 MHz, difluorobenzyl)- 6): δ [ppm]= SM = 11 1H-indazolyl]- 4.00 (s, 3H), 5.75 (s, N F N N 5-methoxy-N- 2H), 7.15 (t, 1H), 7.24 (t, (pyridin 1H), 7.38 - 7.52 (m, 2H), N N imidin 7.81 - 7.89 (m, 1H), 7.85 amine (d, 1H), 8.09 - 8.18 (m, O CH3 2H), 8.29 - 8.39 (m, 3H), 8.41 - 8.47 (m, 1H), 9.38 (s, 1H).
LC-MS: retention time: 0.97 min MS ES+: 445.0 [M+H]+ Method B [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 21 F 2-[1-(2,3- 1H-NMR (300 MHz, F CH 3 difluoro DMSO-d6): δ [ppm]= SM = 11 benzyl)- 2.21 (d, 3H), 4.01 (s, 1H-indazolyl]- 3H), 5.77 (s, 2H), 7.00 - N N 5-methoxy-N- 7.09 (m, 2H), 7.24 (t, (pyridin 1H), 7.44 (t, 1H), 7.81 N N yl)pyrimidin (d, 1H), 8.08 - 8.17 (m, amine 2H), 8.30 - 8.50 (m, 4H), O CH 3 9.39 (s, 1H).
LC-MS: retention time: 1.01 min MS ES+: 459.0 [M+H]+ Method B 21 Cl 2-[1-(2,6- 1H-NMR (300 MHz, dichlorobenzyl)- DMSO-d6): δ [ppm]= SM = 11 azolyl]- 3.99 (s, 3H), 5.87 (s, N Cl N N 5-methoxy-N- 2H), 7.25 (t, 1H), 7.39 - (pyridin 7.53 (m, 2H), 7.55 - 7.62 N N yl)pyrimidin (m, 2H), 7.90 (d, 1H), amine 8.13 (d, 2H), 8.28 - 8.40 O CH3 (m, 3H), 8.48 (d, 1H), 9.32 (s, 1H).
LC-MS: retention time: 1.13min MS ES+: 477.22 [M+H]+ [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 21 2- 1H-NMR (300 MHz, chlorobenzyl)- DMSO-d6): δ [ppm]= SM = 11 1H-indazolyl]- 4.01 (s, 3H), 5.81 (s, N Cl N N 5-methoxy-N- 2H), 7.15 (dd, 1H), 7.20 (pyridin - 7.38 (m, 3H), 7.39 - N N yl)pyrimidin 7.54 (m, 2H), 7.78 (d, amine 1H), 8.05 - 8.15 (m, 2H), O CH3 8.29 - 8.40 (m, 3H), 8.47 (d, 1H), 9.38 (s, 1H).
LC-MS: retention time: 1.00 min MS ES+: 443.0 [M+H]+ Method B 21 O methyl 3-chloro- 1H-NMR (300 MHz, 3 4-({3-[5- DMSO-d6): δ [ppm]= SM = O 11 methoxy 3.81 (s, 3H), 4.01 (s, Cl (pyridin 3H), 5.89 (s, 2H), 7.18 - N N yla- 7.31 (m, 2H), 7.45 (t, mino)pyrimidin- 1H), 7.79 (d, 1H), 7.85 N N 2-yl]-1H-indazol- (dd, 1H), 7.98 (d, 1H), 1- 8.06 - 8.13 (m, 2H), 8.30 O CH yl}methyl)benzo - 8.39 (m, 3H), 8.48 (d, ate 1H), 9.40 (s, 1H).
LC-MS: retention time: 0.96 min MS ES+: 501.1 [M+H]+ Method B [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 21 F Br 2-[1-(4-bromo- 1H-NMR (400 MHz, 2,6- DMSO-d6): δ [ppm]= SM = 11 difluorobenzyl)- 4.00 (s, 3H), 5.72 (s, N F N N 1H-indazolyl]- 2H), 7.25 (t, 1H), 7.44 - -methoxy-N- 7.52 (m, 1H), 7.54 - 7.61 N N (pyridin (m, 2H), 7.85 (d, 1H), yl)pyrimidin 8.12 - 8.18 (m, 2H), 8.32 O CH 3 amine (s, 1H), 8.35 - 8.40 (m, 2H), 8.44 (d, 1H), 9.40 (s, 1H).
LC-MS: retention time: 0.99 min MS ES+: 525.3 [M+H]+ Method B 21 F 2-[1-(2-chloro 1H-NMR (400 MHz, SM = CH fluoro DMSO-d6): δ [ppm]= O 3 11 methoxybenzyl)- 3.85 (d, 3H), 4.01 (s, N Cl N N 1H-indazolyl]- 3H), 5.79 (s, 2H), 6.91 -methoxy-N- (dd, 1H), 7.21 - 7.32 (m, (pyridin 2H), 7.44 (td, 1H), 7.80 N N H yl)pyrimidin (d, 1H), 8.08 - 8.13 (m, O CH3 amine 2H), 8.33 (s, 1H), 8.35 - 8.39 (m, 2H), 8.47 (d, 1H), 9.42 (s, 1H).
LC-MS: retention time: 0.98 min MS ES+: 491.3 [M+H]+ Method B [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 21 CH 1H-NMR (300 MHz, 3 2-[1-(4-ethoxy- 2,3- DMSO-d6): δ [ppm]= SM = F O 11 difluorobenzyl)- 1.28 (t, 3H), 3.94 - 4.13 azolyl]- (m, 5H), 5.73 (s, 2H), N 5-methoxy-N- 6.92 - 7.03 (m, 1H), 7.08 (pyridin - 7.18 (m, 1H), 7.23 (t, N yl)pyrimidin 1H), 7.44 (t, 1H), 7.83 N N H amine (d, 1H), 8.10 - 8.16 (m, O CH 3 2H), 8.33 (s, 1H), 8.36 - 8.40 (m, 2H), 8.43 (d, 1H), 9.41 (s, 1H).
LC-MS: retention time: 1.03 min MS ES+: 489.0 [M+H]+ Method B 21 F 1H-NMR z, F 5-methoxy-N- (pyridinyl) DMSO-d6): δ [ppm]= SM = F F 11 F O {1-[2,3,5,6- 4.04 - 4.07 (s, 3H), 4.99 tetrafluoro (q, 2H), 5.90 (s, 2H), F (2,2,2- 7.31 (t, 1H), 7.55 (t, 1H), N F N N trifluoroeth- 7.93 (d, 1H), 8.23 (d, oxy)benzyl]-1H- 2H), 8.38 (s, 1H), 8.42 indazol (d, 2H), 8.49 (d, 1H), N N H yl}pyrimidin 9.46 (s, 1H).
O CH 3 amine LC-MS: retention time: 1.21 min MS ES+: 579.1 [M+H]+ Method B [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 21 O O methyl 2,4- 1H-NMR (400 MHz, Cl dichloro({3-[5- DMSO-d6): δ [ppm]= SM = 11 methoxy 3.85 (s, 3H), 4.02 (s, in 3H), 5.96 (s, 2H), 7.29 N Cl N yla- (t, 1H), 7.48 - 7.55 (m, mino)pyrimidin- 1H), 7.73 - 7.78 (m, 1H), N 2-yl]-1H-indazol- 7.80 - 7.84 (m, 1H), 7.94 N N H 1- (d, 1H), 8.11 - 8.16 (m, O CH 3 yl}methyl)benzo 2H), 8.34 (s, 1H), 8.38 ate (d, 2H), 8.52 (d, 1H), 9.34 (s, 1H).
LC-MS: retention time: 1.08 min MS ES+: 535.22 [M+H]+ 21 F F 5-methoxy-N- 1H-NMR (300 MHz, (pyridinyl) DMSO-d6): δ [ppm]= SM = 11 [1-(2,4,6- 4.00 (s, 3H), 5.68 - 5.76 N F N N trifluorobenzyl)- (m, 2H), 7.20 - 7.34 (m, 1H-indazol 3H), 7.43 - 7.51 (m, 1H), N N yl]pyrimidin 7.84 (d, 1H), 8.12 - 8.18 amine (m, 2H), 8.32 (s, 1H), O CH 3 8.37 (d, 2H), 8.44 (d, 1H), 9.35 - 9.40 (m, 1H).
LC-MS: retention time: 1.03 min MS ES+: 463.31 [M+H]+ [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 21 F 2-[1-(2- 1H-NMR (300MHz, fluorobenzyl)- DMSO-d6): δ [ppm]= SM = 11 1H-indazolyl]- 4.01 (s, 3H), 5.77 (s, N 5-methoxy-N- 2H), 7.10 - 7.49 (m, 6H), (pyridin 7.75 - 7.84 (m, 1H), 8.07 N yl)pyrimidin - 8.17 (m, 2H), 8.33 (s, N H N amine 1H), 8.35 - 8.40 (m, 2H), 8.40 - 8.48 (m, 1H), 9.35 CH3 - 9.45 (m, 1H).
LC-MS: retention time: 1.01 min MS ES+: 427.19 [M+H]+ 21 Cl 2-[1-(2,4- 1H-NMR (300 MHz, dichlorobenzyl)- DMSO-d6): δ [ppm]= SM = 11 1H-indazolyl]- 4.01 (s, 3H), 5.80 (s, N Cl N N 5-methoxy-N- 2H), 7.15 - 7.29 (m, 2H), (pyridin 7.38 - 7.49 (m, 2H), 7.68 N N yl)pyrimidin (d, 1H), 7.79 (d, 1H), amine 8.05 - 8.13 (m, 2H), 8.31 O CH3 - 8.40 (m, 3H), 8.47 (d, 1H), 9.40 (s, 1H).
LC-MS: retention time: 1.07 min MS ES+: 477.35 [M+H]+ [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb 21 I 2-[1-(2-fluoro 1H-NMR (400 MHz, iodobenzyl)-1H- 6): δ [ppm]= SM = 11 indazolyl] 4.01 (s, 3H), 5.73 (s, N F N N methoxy-N- 2H), 7.07 (t, 1H), 7.24 (t, (pyridin 1H), 7.44 (ddd, 1H), N N yl)pyrimidin 7.55 (dd, 1H), 7.67 (dd, amine 1H), 7.79 (d, 1H), 8.08 - O CH3 8.13 (m, 2H), 8.33 (s, 1H), 8.36 - 8.40 (m, 2H), 8.44 (d, 1H), 9.42 (s, 1H).
LC-MS: retention time: 1.00 min MS ES+: 553.3 [M+H]+ Method B 21 2-[1-(2- 1H-NMR (400 MHz, bromobenzyl)- DMSO-d6): δ [ppm]= SM = 11 1H-indazolyl]- 4.01 (s, 3H), 5.79 (s, N Br N N 5-methoxy-N- 2H), 7.08 (dd, 1H), 7.22 (pyridin - 7.28 (m, 2H), 7.30 - N N yl)pyrimidin 7.36 (m, 1H), 7.44 (ddd, amine 1H), 7.67 (dd, 1H), 7.78 O CH (d, 1H), 8.08 - 8.13 (m, 2H), 8.32 - 8.39 (m, 3H), 8.48 (d, 1H), 9.38 (s, 1H).
LC-MS: retention time: 1.02 min MS ES+: 486.9 [M+H]+ Method B [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb 21 F OH [3-fluoro({3- 1H-NMR (300MHz, SM = O [5-methoxy DMSO-d6): δ [ppm]= 11 (pyridin 3.54 (s, 2H), 4.01 (s, N N yla- 3H), 5.74 (s, 2H), 7.01 - mino)pyrimidin- 7.07 (m, 1H), 7.12 (d, N N 2-yl]-1H-indazol- 1H), 7.19 - 7.29 (m, 2H), 1- 7.38 - 7.47 (m, 1H), 7.79 O CH3 yl}methyl)phenyl] (d, 1H), 8.08 - 8.16 (m, acetic acid 2H), 8.33 (s, 1H), 8.36 - 8.48 (m, 3H), 9.39 (s, 1H).
LC-MS: retention time: 0.86 min MS ES+: 485.1 [M+H]+ Method B 21 O 5-methoxy[1- 1H-NMR (300 MHz, (4- DMSO-d6): δ [ppm]= SM = 11 methoxybenzyl)- 3.66 (s, 3H), 4.02 (s, N 1H-indazolyl]- 3H), 5.65 (s, 2H), 6.86 N N-(pyridin (d, 2H), 7.15 - 7.25 (m, N yl)pyrimidin 1H), 7.27 - 7.44 (m, 3H), H amine 7.78 (d, 1H), 8.08 - 8.17 CH3 (m, 2H), 8.31 - 8.46 (m, 4H), 9.42 (s, 1H).
LC-MS: retention time: 0.95 min MS ES+: 439.31 [M+H]+ Method B [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 21 F CH oxy-N- 1H-NMR (300 MHz, F O (pyridinyl) DMSO-d6): δ [ppm]= SM = 11 [1-(2,3,5,6- 4.00 (s, 3H), 4.01 (s, N F tetrafluoro 3H), 5.81 (s, 2H), 7.26 N N methoxybenzyl)- (t, 1H), 7.49 (t, 1H), 7.87 N 1H-indazol (d, 1H), 8.14 - 8.22 (m, N N yl]pyrimidin 2H), 8.31 - 8.40 (m, 3H), amine 8.45 (d, 1H), 9.40 - 9.45 O CH3 (m, 1H).
LC-MS: retention time: 1.09 min MS ES+: 511.17 [M+H]+ 21 CH 3 5-methoxy[1- 1H-NMR (300 MHz, (4-propylbenzyl)- DMSO-d6): δ [ppm]= SM = 11 1H-indazolyl]- 0.80 (t, 3H), 1.20 (br. s., N idin 2H), 1.40 - 1.57 (m, 2H), yl)pyrimidin 4.02 (s, 3H), 5.68 (s, N amine 2H), 7.12 (d, 2H), 7.17 - H 7.30 (m, 2H), 7.40 (t, CH 1H), 7.78 (d, 1H), 8.12 (d, 2H), 8.21 (s, 1H), 8.32 - 8.46 (m, 4H), 9.42 (s, 1H).
LC-MS: retention time: 1.15 min MS ES+: 451.3 [M+H]+ ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 21 F 2-{1-[2,6- 1H-NMR (400 MHz, dichloro DMSO-d6): δ [ppm]= SM = Cl O 11 (trifluorometh- 4.02 (s, 3H), 5.90 (s, oxy)benzyl]-1H- 2H), 7.29 (t, 1H), 7.52 N Cl indazolyl} (ddd, 1H), 7.83 (d, 2H), N N y-N- 7.94 (d, 1H), 8.12 - 8.18 N (pyridin (m, 2H), 8.35 (s, 1H), N N H yl)pyrimidin 8.37 - 8.40 (m, 2H), 8.51 amine (d, 1H), 9.35 (s, 1H).
O CH LC-MS: retention time: 1.15 min MS ES+: 561.0 [M+H]+ Method B 21 7-({3-[5- 1H-NMR (400 MHz, methoxy DMSO-d6): δ [ppm]= SM = N O 11 H (pyridin 2.35 (t, 2H), 2.77 (t, 2H), N yla- 4.02 (s, 3H), 5.65 (s, N mino)pyrimidin- 2H), 6.77 (s, 1H), 6.88 N 2-yl]-1H-indazol- (d, 1H), 7.09 (d, 1H), N 1-yl}methyl)-3,4- 7.22 (t, 1H), 7.40 (t, 1H), O dihydroquinolin- 7.71 (d, 1H), 8.11 (d, one 2H), 8.28 - 8.51 (m, 4H), 9.42 (s, 1H), 10.01 (s, 1H).
LC-MS: retention time: 1.04 min MS ES+: 478.1 [M+H]+ Method B ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 21 I 2-[1-(2-chloro 1H-NMR (400 MHz, iodobenzyl)-1H- DMSO-d6): δ [ppm]= SM = 11 indazolyl] 4.01 (s, 3H), 5.76 (s, N Cl N N methoxy-N- 2H), 6.93 (d, 1H), 7.25 (pyridin (t, 1H), 7.44 (ddd, 1H), N N yl)pyrimidin 7.68 (dd, 1H), 7.78 (d, amine 1H), 7.89 (d, 1H), 8.07 - O CH 3 8.12 (m, 2H), 8.31 - 8.40 (m, 3H), 8.47 (d, 1H), 9.39 (s, 1H).
LC-MS: ion time: 1.08 min MS ES+: 568.9 [M+H]+ Method B 21 CH 1H-NMR (300 MHz, 3 2-[1-(3,5- dimethoxyben- DMSO-d6): δ [ppm]= SM = 11 zyl)-1H-indazol- 3.64 (s, 6H), 4.02 (s, O 3-yl]methoxy- 3H), 5.65 (s, 2H), 6.38 N N N-(pyridin (s, 1H), 6.48 (d, 2H), yl)pyrimidin 7.22 (t, 1H), 7.36 - 7.45 amine (m, 1H), 7.77 (d, 1H), N N 8.09 - 8.17 (m, 2H), 8.31 O CH 3 - 8.47 (m, 4H), 9.42 (s, 1H).
LC-MS: retention time: 0.89 min MS ES+: 469.4 [M+H]+ Method B ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 21 F 2-{1-[2-chloro 1H-NMR (300 MHz, F (trifluorome- DMSO-d6): δ [ppm]= SM = 11 thyl)benzyl]-1H- 3.98 (s, 3H), 5.83 (s, indazolyl} 2H), 7.26 (t, 1H), 7.44 - N methoxy-N- 7.53 (m, 1H), 7.63 - 7.71 N (pyridin (m, 1H), 7.83 - 7.97 (m, N yl)pyrimidin 3H), 8.02 - 8.10 (m, 2H), N amine 8.22 - 8.33 (m, 3H), 8.48 O (d, 1H), 9.32 (s, 1H).
LC-MS: retention time: 1.12 min MS ES+: 511.36 [M+H]+ 21 F 2-[1-(2-chloro 1H-NMR (400 MHz, fluorobenzyl)- DMSO-d6): δ [ppm]= SM = 11 1H-indazolyl]- 4.01 (s, 3H), 5.80 (s, -methoxy-N- 2H), 7.11 (dd, 1H), 7.20 N Cl N N (pyridin - 7.29 (m, 2H), 7.42 - yl)pyrimidin 7.50 (m, 1H), 7.56 (dd, N N amine 1H), 7.83 (d, 1H), 8.07 - 8.15 (m, 2H), 8.31 - 8.40 O CH 3 (m, 3H), 8.47 (d, 1H), 9.42 (s, 1H).
LC-MS: retention time: 1.02 min MS ES+: 461.0 [M+H]+ Method B [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 21 CH 1H-NMR (300 MHz, 3 7-({3-[5- y DMSO-d6): δ [ppm]= SM = 11 (pyridin 2.34 (d, 3H), 4.02 (s, O O yla- 3H), 5.86 (s, 2H), 6.32 N N mino)pyrimidin- (d, 1H), 7.19 - 7.31 (m, 2-yl]-1H-indazol- 2H), 7.34 (s, 1H), 7.42 N N 1-yl}methyl) (t, 1H), 7.71 (d, 1H), methyl-2H- 7.81 (d, 1H), 8.07 - 8.15 O CH 3 chromenone (m, 2H), 8.31 - 8.48 (m, 4H), 9.41 (s, 1H).
LC-MS: ion time: 0.89 min MS ES+: 491.0 [M+H]+ Method B 21 N 3-fluoro({3-[5- 1H-NMR (300 MHz, methoxy DMSO-d6): δ [ppm]= SM = 11 (pyridin 4.01 (s, 3H), 5.87 (s, N yla- 2H), 7.21 - 7.30 (m, 1H), N N mino)pyrimidin- 7.38 (t, 1H), 7.42 - 7.50 N 2-yl]-1H-indazol- (m, 1H), 7.67 (dd, 1H), N N H 1- 7.81 (d, 1H), 7.90 (dd, yl}methyl)benzo 1H), 8.04 - 8.12 (m, 2H), O CH3 nitrile 8.33 (s, 1H), 8.37 (d, 2H), 8.45 (d, 1H), 9.37 - 9.43 (m, 1H).
LC-MS: retention time: 0.92 min MS ES+: 452.0 [M+H]+ Method B [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 21 F 2-{1-[2,6- 1H-NMR (400 MHz, F F dichloro DMSO-d6): δ [ppm]= SM = 11 (trifluorome- 3.99 (s, 3H), 5.97 (s, thyl)benzyl]-1H- 2H), 7.27 (t, 1H), 7.48 - N Cl indazolyl} 7.54 (m, 1H), 7.83 - 7.89 N N methoxy-N- (m, 1H), 7.93 (d, 2H), N (pyridin 8.08 - 8.13 (m, 2H), 8.31 N N H yl)pyrimidin - 8.36 (m, 3H), 8.49 (d, amine 1H), 9.35 (s, 1H).
O CH LC-MS: retention time: 1.17 min MS ES+: 545.0 [M+H]+ Method B 21 ethyl -[5- 1H-NMR (300 MHz, methoxy DMSO-d6): δ [ppm]= SM = O CH 11 N (pyridin 0.28 (t, 3H), 2.72 - 2.77 N N yla- (m, 2H), 3.20 (q, 2H), N N mino)pyrimidin- 4.05 (s, 3H), 4.92 (s, 1H-indazol- 2H), 6.30 - 6.49 (m, 5H), O CH 1- 6.54 - 6.63 (m, 1H), 6.69 yl}methyl)phenyl] - 6.77 (m, 1H), 7.21 - acetate 7.27 (m, 2H), 7.45 (s, 1H), 7.53 - 7.61 (m, 2H), 7.65 (d, 1H).
LC-MS: retention time: 0.97 min MS ES+: 495.39 [M+H]+ [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 21 2-[1-(4- 1H-NMR (400 MHz, fluorobenzyl)- DMSO-d6): δ [ppm]= SM = 11 N 1H-indazolyl]- 4.02 (s, 3H), 5.73 (s, N N -methoxy-N- 2H), 7.10 - 7.18 (m, 2H), N (pyridin 7.19 - 7.27 (m, 1H), 7.35 N N H yl)pyrimidin - 7.46 (m, 3H), 7.80 (d, amine 1H), 8.08 - 8.14 (m, 2H), O CH 8.34 (s, 1H), 8.37 - 8.44 (m, 3H), 9.43 (s, 1H).
LC-MS: retention time: 0.92 min MS ES+: 427.0 [M+H]+ Method B 21 N-cyclopropyl 1H-NMR (300 MHz, ({3-[5-methoxy- DMSO-d6): δ [ppm]= SM = O 11 S 4-(pyridin 0.31 (d, 2H), 0.38 (d, yla- 2H), 1.91 - 2.06 (m, 1H), mino)pyrimidin- 4.02 (s, 3H), 5.86 (s, N N 2-yl]-1H-indazol- 2H), 7.24 (t, 1H), 7.37 - 1- 7.46 (m, 1H), 7.51 (d, yl}methyl)benze 2H), 7.68 - 7.81 (m, 3H), N N nesulfonamide 7.84 (br. s., 1H), 8.10 (d, O CH 3 2H), 8.32 - 8.41 (m, 3H), 8.45 (d, 1H), 9.37 - 9.44 (m, 1H).
LC-MS: retention time: 0.90 min MS ES+: 528.24 [M+H]+ [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 21 6-({3-[5- 1H-NMR (400 MHz, O methoxy DMSO-d6): δ [ppm]= SM = (pyridin 4.05 (s, 3H), 5.34 (s, 11 N N N yla- 2H), 5.95 (s, 2H), 7.26 yrimidin- (t, 1H), 7.45 (t, 1H), 7.52 1H-indazol- - 7.58 (m, 2H), 7.83 (t, N N H 1-yl}methyl) 2H), 8.10 - 8.15 (m, 2H), O CH 3 uran- 8.37 (s, 1H), 8.39 - 8.43 2(3H)-one (m, 2H), 8.48 (d, 1H), 9.43 (s, 1H).
LC-MS: retention time: 0.81 min MS ES+: 465.0 [M+H]+ Method B 21 F 2-{1-[4- 1H-NMR (300MHz, (difluorometh- DMSO-d6): δ [ppm]= SM = F O 11 oxy)-2,6- 3.93 - 4.05 (s, 3H), 5.73 difluorobenzyl]- (s, 2H), 7.13 (d, 2H), N F 1H-indazolyl}- 7.20 - 7.28 (m, 1H), 7.30 N N 5-methoxy-N- (t, 1H), 7.47 (t, 1H), 7.84 (pyridin (d, 1H), 8.15 (d, 2H), N N yl)pyrimidin 8.32 (s, 1H), 8.38 (d, amine 2H), 8.44 (d, 1H), 9.38 O CH 3 (s, 1H).
LC-MS: retention time: 1.01 min MS ES+: 511.0 [M+H]+ Method B [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb 21 O CH tert-butyl 3- 1H-NMR (400 MHz, CH3 3 O CH3 chloro({3-[5- DMSO-d6): δ [ppm]= SM = 11 methoxy 1.52 (s, 9H), 4.04 (s, N Cl (pyridin 3H), 5.90 (s, 2H), 7.25 - N N yla- 7.33 (m, 2H), 7.44 - 7.51 N yrimidin- (m, 1H), 7.78 - 7.86 (m, N N H 2-yl]-1H-indazol- 2H), 7.93 (d, 1H), 8.07 - O CH3 1- 8.12 (m, 2H), 8.33 - 8.40 yl}methyl)benzo (m, 3H), 8.47 - 8.52 (m, ate 1H), 9.40 (s, 1H).
LC-MS: retention time: 1.18 min MS ES+: 543.1 [M+H]+ Method B 21 ethyl 2-[3-({3-[5- 1H-NMR (300 MHz, SM = O CH3 methoxy DMSO-d6): δ [ppm]= 11 CH3 N CH3 (pyridin 0.89 (t, 3H), 1.39 (s, N N yla- 6H), 3.87 (d, 2H), 4.02 N N mino)pyrimidin- (s, 3H), 5.74 (s, 2H), 2-yl]-1H-indazol- 7.14 - 7.31 (m, 5H), 7.40 O CH 1- (t, 1H), 7.77 (d, 1H), yl}methyl)phenyl] 8.08 - 8.16 (m, 2H), 8.31 - 8.47 (m, 4H), 9.41 (s, methylpropano- 1H).
LC-MS: retention time: 1.04 min MS ES+: 523.88 [M+H]+ [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb [Annotation] jessb ed set by jessb 21 N 4-({3-[5- 1H-NMR (300 MHz, methoxy DMSO-d6): δ [ppm]= SM = 11 (pyridin 4.02 (s, 3H), 5.86 (s, N yla- 2H), 7.20 - 7.28 (m, 1H), N N mino)pyrimidin- 7.41 - 7.48 (m, 3H), 7.73 N 2-yl]-1H-indazol- - 7.83 (m, 3H), 8.06 - N N H 1- 8.12 (m, 2H), 8.31 - 8.49 O CH yl}methyl)benzo (m, 4H), 9.42 (s, 1H). nitrile LC-MS: retention time: 0.82 min MS ES+: 434.4 [M+H]+ Method B 21 5-methoxy{1- 1H-NMR (300 MHz, SM = N [4-(morpholin DMSO-d6): δ [ppm]= 11 O ylsulfonyl)benzyl 2.73 - 2.83 (m, 4H), 3.50 ]-1H-indazol - 3.59 (m, 4H), 4.02 (s, N yl}-N-(pyridin 3H), 5.89 (s, 2H), 7.20 - yl)pyrimidin 7.28 (m, 1H), 7.43 (t, amine 1H), 7.54 (d, 2H), 7.70 N N (d, 2H), 7.79 (d, 1H), O CH 3 8.06 - 8.14 (m, 2H), 8.32 - 8.49 (m, 4H), 9.39 - 9.43 (m, 1H).
LC-MS: retention time: 0.90 min MS ES+: 558.23 [M+H]+ [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 21 Cl 2-[1-(2,6- 1H-NMR (300MHz, SM = + O dichloro DMSO-d6): δ [ppm]= 11 N Cl O nitrobenzyl)-1H- 3.99 (s, 3H), 5.96 (s, indazolyl] 2H), 7.20 - 7.34 (m, 1H), N methoxy-N- 7.46 - 7.56 (m, 1H), 7.86 H in - 7.99 (m, 2H), 8.06 - O CH 3 imidin 8.16 (m, 3H), 8.29 - 8.39 amine (m, 3H), 8.50 (d, 1H), 9.36 (s, 1H).
LC-MS: retention time: 1.03 min MS ES+: 522.1 [M+H]+ 21 N 3-({3-[5- 1H-NMR (400MHz, methoxy METHANOL-d4): δ SM = 11 (pyridin [ppm]= 4.08 (s, 3H), yla- 5.79 (s, 2H), 7.20 - 7.28 N mino)pyrimidin- (m, 1H), 7.41 - 7.50 (m, N 2-yl]-1H-indazol- 2H), 7.55 - 7.63 (m, 3H), N 1- 7.70 (s, 1H), 8.06 (d, H yl}methyl)benzo 2H), 8.27 (s, 1H), 8.36 - 3 e 8.42 (m, 2H), 8.47 (s, 1H).
LC-MS: retention time: 0.94 min MS ES+: 434.44 [M+H]+ ation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 21 N 1H-NMR (300MHz, F 3,5-difluoro ({3-[5-methoxy- DMSO-d6): δ [ppm]= SM = 11 4-(pyridin 4.00 (s, 3H), 5.82 (s, N F N yla- 2H), 7.25 (t, 1H), 7.49 (t, N mino)pyrimidin- 1H), 7.85 - 7.94 (m, 3H), N 2-yl]-1H-indazol- 8.08 - 8.20 (m, 2H), 8.32 H 1- (s, 1H), 8.37 - 8.46 (m, 3 yl}methyl)benzo 3H), 9.41 (s, 1H). nitrile LC-MS: retention time: 0.99 min MS ES+: 470.35 [M+H]+ 21 F 5-methoxy{1- 1H-NMR (300MHz, F [2-methoxy DMSO-d6): δ [ppm]= SM = 11 (trifluorome- 3.93 (s, 3H), 4.12 (s, N O N thyl)benzyl]-1H- 3H), 5.61 (s, 2H), 7.17 - N indazolyl}-N- 7.26 (m, 1H), 7.34-7.45 H (pyridin (m, 3H), 7.58 (d, 1H), CH yl)pyrimidin 7.63 - 7.70 (m, 1H), 8.42 amine - 8.50 (m, 1H), 8.51 - 8.68 (m, 6H).
LC-MS: retention time: 1.03 min MS ES+: 507.42 [M+H]+ 21 F 2-[1-(2,6- 1H-NMR (400MHz, CH3 difluoro DMSO-d6): δ [ppm]= SM = 11 N F N methylbenzyl)- 2.16 (s, 3H), 4.00 (s, N 1H-indazolyl]- 3H), 5.74 (s, 2H), 7.06 N 5-methoxy-N- (t, 1H), 7.21 - 7.34 (m, O CH in 2H), 7.47 (t, 1H), 7.85 yl)pyrimidin (d, 1H), 8.07 - 8.20 (m, amine 2H), 8.28 - 8.50 (m, 4H), [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb ation] jessb Unmarked set by jessb 9.40 (br. s, 1H).
LC-MS: retention time: 1.03 min MS ES+: 459.2 [M+H]+ 21 CH3 2-fluoro 1H-NMR (400MHz, methoxybenzyl)- DMSO-d6): δ [ppm]= SM = 11 1H-indazolyl]- 3.80 (s, 3H), 3.85 (s, N F N 5-methoxy-N- 3H), 5.09 (s, 2H), 6.85 - N (pyridin 6.99 (m, 4H), 7.06 (t, N yl)pyrimidin 1H), 7.31 (t, 1H), 7.36 - O CH amine 7.48 (m, 1H), 7.51 (d, 1H), 7.62 (d, 2H), 8.16 (s, 1H), 8.39 (d, 1H), 13.15 (br.s., 1H).
LC-MS: retention time: 0.90 min MS ES+: 457.2 [M+H]+ 21 O 3,5-difluoro 1H-NMR (400MHz, SM = 2 ({3-[5-methoxy- Methanol-d4): δ [ppm]= 11 4-(pyridin 4.07 (s, 3H), 5.81 (s, N F yla- 2H), 7.25 (t, 1H), 7.47 (t, mino)pyrimidin- 1H), 7.50 - 7.58 (m, 2H), N 2-yl]-1H-indazol- 7.72 (d, 1H), 8.18 (s, H 1- 1H), 8.27 - 8.38 (m, 3H), CH3 yl}methyl)benza 8.39 - 8.49 (m, 3H) mide LC-MS: retention time: 0.87 min MS ES+:488.39 [M+H]+ [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb 21 CH 1H-NMR (600MHz, 3 2-[3,5-difluoro O ({3-[5-methoxy- DMSO-d6): δ [ppm]= SM = F 11 O 4-(pyridin 2.00 (s, 3H), 4.04 (s, yla- 3H), 4.21 (t, 2H), 4.29 (t, N mino)pyrimidin- 2H), 5.69 (s, 2H), 6.80 - N 2-yl]-1H-indazol- 6.94 (m, 2H), 7.19 - 7.34 N 1- (m, 1H), 7.42 - 7.55 (m, O yl}methyl)pheno 1H), 7.79 - 7.90 (m, 1H), xy]ethyl acetate 8.10 - 8.25 (m, 2H), 8.35 (s, 1H), 8.39 - 8.44 (m, 2H), 8.44 - 8.51 (m, 1H), 9.41 (s, 1H).
LC-MS (Method 5): ion time: 1.22 min MS ES+: 547.3 [M+H]+ 21 CH3 2-[1-(2,6- 1H-NMR (300MHz, F ro DMSO-d6): δ [ppm]= SM = O 11 propoxybenzyl)- 0.93 (t, 3H), 1.59 - 1.79 F 1H-indazolyl]- (m, 2H), 3.94 (t, 2H), N 5-methoxy-N- 4.04 (s, 3H), 5.68 (s, N (pyridin 2H), 6.74 - 6.94 (m, 2H), H yl)pyrimidin 7.21 - 7.35 (m, 1H), 7.42 O CH3 amine - 7.62 (m, 1H), 7.80 - 7.90 (m, 1H), 8.15 - 8.26 (m, 2H), 8.36 (s, 1H), 8.37 - 8.43 (m, 2H), 8.43 - 8.51 (m, 1H), 9.44 (s, 1H).
LC-MS: retention time: 1.14 min [Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb MS ES+: 503.37 [M+H]+ The following compound was also isolated from the reaction leading to 21: 21 CH 3 2-[1-(4-ethoxy- 1H-NMR (300MHz, O O 2-fluoro DMSO-d6): δ [ppm]= methoxyben- 1.26 (t, 3H), 3.72 (s, SM = N F zyl)-1H-indazol- 3H), 3.92 - 4.10 (m, 5H), N N 3-yl] 5.54 (s, 2H), 6.40 (s, 11 N methoxy-N- 1H), 6.50 (dd, 1H), 7.13 N N H (pyridin - 7.27 (m, 1H), 7.37 - O CH 3 yl)pyrimidin 7.49 (m, 1H), 7.79 (d, amine 1H), 8.16 (d, 2H), 8.31 (s, 1H), 8.35 - 8.47 (m, 3H), 9.38 (s, 1H).
The following bis-benzyl nds were also formed during the above described procedure using the indicated starting materials (SM = ng material): 22 1H-NMR (300MHz, O CH 3 N-(2,6-difluoro- 3- DMSO-d6): δ [ppm]= methoxybenzyl)- 3.77 (d, 6H), 3.82 (s, SM = F N 2-[1-(2,6- 3H), 5.22 (s, 2H), 5.69 N difluoro (s, 2H), 6.86 (d, 2H), 11 N N methoxybenzyl)- 6.97 - 7.06 (m, 1H), azolyl]- 7.06 - 7.19 (m, 3H), O F CH F 3 5-methoxy-N- 7.21 - 7.30 (m, 1H), O 3 (pyridin 7.41 (t, 1H), 7.57 (d, yl)pyrimidin 2H), 7.74 (d, 1H), 8.12 amine (s, 1H), 8.37 (d, 1H). ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb LC-MS: retention time: 1.16 min MS ES+: 631.24 [M+H]+ 22 F CH N-(4-ethoxy-2,6- 1H-NMR z, O difluorobenzyl)- DMSO-d6): δ [ppm]= N 2-[1-(4-ethoxy- 1.21 - 1.32 (m, 6H), SM = N 2,6- 3.78 (s, 3H), 4.02 (dq, N difluorobenzyl)- 4H), 5.13 (s, 2H), 5.59 11 N N 1H-indazolyl]- (s, 2H), 6.69 (d, 2H), O 5-methoxy-N- 6.78 - 6.93 (m, 4H), CH3 (pyridin 7.09 (t, 1H), 7.39 (t, F O yl)pyrimidin 1H), 7.56 (d, 2H), 7.71 CH 3 amine (d, 1H), 8.12 (s, 1H), 8.37 (d, 1H).
LC-MS: retention time: 1.26 min MS ES+: 659.0 [M+H]+ Method B 22 F N-(2,6- 1H-NMR (300MHz, difluorobenzyl)- DMSO-d6): δ [ppm]= N F 2-[1-(2,6- 3.77 (s, 3H), 5.24 (s, N N SM = difluorobenzyl)- 2H), 5.69 (s, 2H), 6.89 N 1H-indazolyl]- (d, 2H), 7.03 - 7.15 (m, 11 N N F 5-methoxy-N- 3H), 7.22 (t, 3H), 7.36 - F (pyridin 7.46 (m, 2H), 7.58 (d, yl)pyrimidin 2H), 7.75 (d, 1H), 8.12 amine (s, 1H), 8.38 (d, 1H).
LC-MS: retention time: 1.13 min MS ES+: 571.18 [M+H]+ [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 22 F F N-(2,3-difluoro- 1H-NMR (300MHz, 4-methylbenzyl)- DMSO-d6): δ [ppm]= CH N 2-[1-(2,3- 2.19 (d, 3H), 2.25 (d, SM = N difluoro 3H), 3.79 (s, 3H), 5.19 methylbenzyl)- (s, 2H), 5.68 - 5.77 (s, 11 N N N 1H-indazolyl]- 2H), 6.77 - 6.87 (m, -methoxy-N- CH O 3H), 6.98 (t, 1H), 7.03 - (pyridin 7.19 (m, 3H), 7.38 (t, F CH 3 yl)pyrimidin 1H), 7.61 - 7.74 (m, amine 3H), 8.11 - 8.17 (m, 1H), 8.37 - 8.45 (m, 1H).
LC-MS: retention time: 1.20 min MS ES+: 599.25 [M+H]+ 22 Cl N-(2,6- 1H-NMR (400MHz, dichlorobenzyl)- DMSO-d6): δ [ppm]= 2-[1-(2,6- 3.78 (s, 3H), 5.43 (s, N Cl SM = N N dichlorobenzyl)- 2H), 5.79 (s, 2H), 7.09 - 1H-indazolyl]- 7.18 (m, 3H), 7.30 - 11 N N N 5-methoxy-N- 7.45 (m, 4H), 7.50 - (pyridin 7.60 (m, 3H), 7.63 - 3 yl)pyrimidin 7.68 (d, 2H), 7.77 (d, amine 1H), 8.12 (s, 1H), 8.42 (d, 1H).
LC-MS: retention time: 1.26 min MS ES+: 637.09 [M+H]+ [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 22 N-(2- 1H-NMR (400MHz, chlorobenzyl) DMSO-d6): δ [ppm]= N Cl [1-(2- 3.81 (s, 3H), 5.23 (s, N N SM = chlorobenzyl)- 2H), 5.76 (s, 2H), 6.81 - N 1H-indazolyl]- 6.89 (m, 3H), 7.12 (t, 11 N N -methoxy-N- 1H), 7.19 (td, 1H), 7.23 CH3 (pyridin - 7.30 (m, 2H), 7.34 - Cl yl)pyrimidin 7.42 (m, 3H), 7.47 (dd, amine 1H), 7.54 (dd, 1H), 7.63 - 7.69 (m, 3H), 8.15 (s, 1H), 8.47 (d, 1H).
LC-MS: ion time: 1.12 min MS ES+: 567.2 [M+H]+ 22 O methyl 3-chloro- 1H-NMR (400MHz, O CH3 -{1-[2- DMSO-d6): δ [ppm]= Cl chloro 3.79 (s, 3H), 3.85 (s, SM = N (methoxycar- 3H), 3.97 (s, 3H), 5.60 N bonyl)benzyl]- (s, 2H), 5.87 (s, 2H), 11 N CH3 1H-indazolyl}- 7.00 (d, 1H), 7.23 (t, CH3 O - 1H), 7.33 (d, 1H), 7.40 - O methoxypyrim- 7.46 (m, 1H), 7.71 - idinyl)(pyridin- 7.80 (m, 2H), 7.90 - 4- 7.97 (m, 3H), 8.01 (d, yl)amino]methyl} 1H), 8.25 (s, 1H), 8.29 benzoate (d, 2H), 8.42 - 8.50 (m, 2H).
LC-MS: retention time: 1.17 min MS ES+: 683.1 [M+H]+ Method B [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 22 F N-(4-ethoxy-2,3- 1H-NMR (300MHz, F CH O difluorobenzyl)- DMSO-d6): δ [ppm]= N 2-[1-(4-ethoxy- 1.22 - 1.36 (m, 6H), SM = N 2,3- 3.79 (s, 3H), 3.99 - 4.18 N difluorobenzyl)- (m, 4H), 5.14 (s, 2H), 11 N O 1H-indazolyl]- 5.68 (s, 2H), 6.81 (d, 3 CH O 3 F 5-methoxy-N- 2H), 6.92 (d, 2H), 7.00 - (pyridin 7.22 (m, 3H), 7.38 (t, yl)pyrimidin 1H), 7.61 - 7.74 (m, amine 3H), 8.14 (s, 1H), 8.40 (d, 1H).
LC-MS: ion time: 1.22 min MS ES+: 659.0 [M+H]+ Method B 22 F 5-methoxy-N- 1H-NMR z, F F (pyridinyl)-N- DMSO-d6): δ [ppm]= F O [2,3,5,6- 4.00 (s, 3H), 4.93 (qd, SM = N F tetrafluoro 4H), 5.31 (s, 2H), 5.63 N N (2,2,2- (s, 2H), 7.21 (t, 1H), 11 N N N F trifluoroeth- 7.36 (ddd, 1H), 7.64 (d, O oxy)benzyl]{1- 1H), 8.04 - 8.11 (m, 3 F O F F [2,3,5,6- 2H), 8.27 - 8.33 (m, F tetrafluoro 2H), 8.43 (d, 1H), 9.35 (2,2,2- (s, 1H). trifluoroeth- LC-MS: oxy)benzyl]-1H- retention time: 1.42 min indazol MS ES+: 837.1 [M+H]+ yl}pyrimidin amine Method B [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb 22 F F 5-methoxy-N- 1H-NMR (300MHz, (pyridinyl)-N- DMSO-d6): δ [ppm]= N F (2,4,6- 3.78 (s, 3H), 5.20 (s, N N SM = trifluorobenzyl)- 2H), 5.66 (s, 2H), 6.86 11 N N F 2-[1-(2,4,6- (d, 2H), 7.07 - 7.26 (m, trifluorobenzyl)- 3H), 7.29 - 7.46 (m, 3 1H-indazol 3H), 7.58 (d, 2H), 7.75 F F yl]pyrimidin (d, 1H), 8.13 (s, 1H), amine 8.38 (d, 1H).
LC-MS: retention time: 1.12 min MS ES+: 608.17 [M+H]+ 22 N-(2- 1H-NMR (300MHz, bromobenzyl) DMSO-d6): δ [ppm]= Br [1-(2- 3.81 (s, 3H), 5.20 (s, SM = enzyl)- 2H), 5.73 (s, 2H), 6.69 - 1H-indazolyl]- 6.76 (m, 1H), 6.87 (d, 11 N N 5-methoxy-N- 2H), 7.08 - 7.26 (m, (pyridin 4H), 7.28 - 7.48 (m, CH3 yl)pyrimidin 3H), 7.60 - 7.73 (m, amine 5H), 8.15 (s, 1H), 8.48 (d, 1H).
LC-MS: retention time: 1.30 min MS ES+: 657.04 [M+H]+ [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb 22 F 1H-NMR z, FF N-[2,6-dichloro- Cl O 4- DMSO-d6): δ [ppm]= (trifluorometh- 3.78 (s, 3H), 5.40 (s, SM = N Cl N N oxy)benzyl]{1- 2H), 5.81 (s, 2H), 6.99 N [2,6-dichloro 11 Cl (d, 2H), 7.12 (t, 1H), N N F F (trifluorometh- 7.42 (t, 1H), 7.55 (d, O O 3 Cl oxy)benzyl]-1H- 2H), 7.64 (s, 2H), 7.76 - indazolyl} 7.85 (m, 3H), 8.12 (s, methoxy-N- 1H), 8.42 (d, 1H). (pyridin imidin LC-MS: amine retention time: 1.39 min MS ES+: 804.9 [M+H]+ Method B 22 N 4-{[{2-[1-(4- 1H-NMR (300MHz, cyano DMSO-d6): δ [ppm]= N fluorobenzyl)- 3.80 (s, 3H), 5.28 (s, N N SM = 1H-indazolyl]- 2H), 5.84 (s, 2H), 6.83 N N 5- (d, 2H), 7.09 - 7.19 (m, 11 N CH methoxypyrim- 2H), 7.43 (dt, 2H), 7.56 3 F idinyl}(pyridin- - 7.79 (m, 5H), 7.84 - 4- 7.98 (m, 2H), 8.17 (s, yl)amino]methyl} 1H), 8.44 (d, 1H). fluorobenzo- LC-MS: nitrile retention time: 1.01 min MS ES+: 586.2 [M+H]+ [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb 22 H F N-[4- 1H-NMR (300MHz, F F O (difluorometh- DMSO-d6): δ [ppm]= N oxy)-2,6- 3.78 (s, 3H), 5.20 (s, SM = N difluorobenzyl]- 2H), 5.67 (s, 2H), 6.84 N 2-{1-[4- (d, 2H), 7.01 - 7.21 (m, 11 N F O (difluorometh- 5H), 7.31 (d, 1H), 7.41 3CH F F O F oxy)-2,6- (t, 1H), 7.51 - 7.60 (m, robenzyl]- 3H), 7.75 (d, 1H), 8.13 1H-indazolyl}- (s, 1H), 8.38 (d, 1H). -methoxy-NLC-MS (pyridin retention time: 1.17 min yl)pyrimidin MS ES+: 703.1 [M+H]+ amine Method B The following compounds were prepared following the procedure described in scheme 2a using the indicated starting materials (SM = starting material): 23 5-methoxy-N- H-NMR (300MHz, (pyridinyl)- OL-d4): δ SM = N 11 2-{1-[3-(1H- [ppm]= 4.06 (s, 3H), pyrrol 5.77 (s, 2H), 6.16 - yl)benzyl]-1H- 6.25 (m, 2H), 7.09 N indazol (s, 3H), 7.18 - 7.27 yl}pyrimidin (m, 1H), 7.30 - 7.37 N amine (m, 2H), 7.37 - 7.49 N (m, 2H), 7.57 - 7.64 (m, 1H), 8.05 - 8.14 3 (m, 2H), 8.24 - 8.41 (m, 3H), 8.42 - 8.51 (m, 1H) ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb LC-MS: retention time: 1.07 MS ES+: 474.4 [M+H]+ Method B 23 CH3 5-methoxy 1H-NMR (400MHz, O {1-[3-(5- CHLOROFORM-d): SM = N N 11 methyl-1,2,4- δ [ppm]= 2.64 (s, oxadiazol 3H), 4.08 (s, 3H), yl)benzyl]-1H- 5.82 (s, 2H), 7.35 - indazolyl}- 7.45 (m, 5H), 7.82 - N N-(pyridin 7.90 (m, 2H), 7.94 - N yl)pyrimidin 8.01 (m, 1H), 8.12 N amine N (s, 1H), 8.25 (s, 1H), N 8.52 - 8.63 (m, 3H) O CH 3 LC-MS: retention time: 0.95 MS ES+: 491.3 [M+H]+ 23 F 5-methoxy 1H-NMR (300MHz, F F F {1-[4- CHLOROFORM-d): SM = 11 (pentafluoro- δ [ppm]= 4.08 (s, λ6- 3H), 5.79 (s, 2H), N sulfa- 7.28 - 7.50 (m, 5H), N nzyl]- 7.68 (d, 2H), 7.80 - N 1H-indazol 7.89 (m, 2H), 8.24 N yl}-N-(pyridin- (s, 1H), 8.53 - 8.66 O 4-yl)pyrimidin- (m, 3H) 3 4-amine LC-MS: [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb retention time: 1.07 MS ES+: 535.2 [M+H]+ 23 Br O 2-{1-[(6- 1H-NMR (300MHz, bromo-1,3- CHLOROFORM-d): 11 O benzodioxol- δ [ppm]= 4.08 (s, N 5-yl)methyl]- 3H), 5.76 (s, 2H), N 1H-indazol 5.89 (s, 2H), 6.45 (s, N yl}methoxy- 1H), 7.04 (s, 1H), N N-(pyridin 7.41 - 7.43 (m, 3H), yl)pyrimidin 7.79 - 7.90 (m, 2H), 3CH amine 8.24 (s, 1H), 8.47 - 8.65 (m, 3H) LC-MS: ion time: 1.09 MS ES+: 509.1 [M+H]+ Method B 23 N 2-({3-[5- 1H-NMR (300MHz, methoxy CHLOROFORM-d): SM = 11 (pyridin δ [ppm]= 4.08 (s, N yla- 3H), 5.98 (s, 2H), mino)pyrimidi 7.13 - 7.22 (m, 1H), nyl]-1H- 7.30 - 7.53 (m, 5H), N l 7.67 - 7.77 (m, 1H), H hyl)ben 7.79 - 7.94 (m, 2H), O zonitrile 8.25 (s, 1H), 8.51 - 8.70 (m, 3H) [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb LC-MS: retention time: 0.90 MS ES+: 434.2 [M+H]+ 23 3,4- 1H-NMR (300MHz, dihydro-2H- FORM-d): SM = O 11 1,5- δ [ppm]= 2.20 benzodiox- (quint, 2H), 4.06 (s, N epin 3H), 4.14 (t, 2H), ylmethyl)-1H- 4.19 (t, 2H), 5.76 (s, indazolyl]- 2H), 6.73 - 6.83 (m, N 5-methoxy-N- 2H), 6.87 - 6.96 (m, H (pyridin 1H), 7.33 - 7.54 (m, yl)pyrimidin 3H), 7.80 - 7.91 (m, amine 2H), 8.23 (s, 1H), 8.54 - 8.58 (m, 3H) LC-MS: retention time: 0.95 MS ES+: 481.3 [M+H]+ [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 23 F 5-methoxy-N- 1H-NMR (300MHz, SM = F S (pyridinyl)- FORM-d): 11 2-(1-{3- δ [ppm]= 4.08 (s, [(trifluorome- 3H), 5.77 (s, 2H), thyl)sulfanyl]b 7.30 -7.42 (m, 5H), enzyl}-1H- 7.51 - 7.66 (m, 2H), indazol 7.83 (d, 2H), 8.24 N yl)pyrimidin (s, 1H), 8.55 - 8.61 N amine (m, 3H) O LC-MS: 3 retention time: 1.08 MS ES+: 509.2 [M+H]+ 23 N 5-methoxy LC-MS: N {1-[4-(1H- ion time: 0.98 SM = 11 pyrazol min yl)benzyl]-1H- MS ES+: 475.42 N indazolyl}- [M+H]+ N N-(pyridin N yl)pyrimidin N amine [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 23 F 5-methoxy-N- H-NMR z, (pyridinyl)- METHANOL-d4): δ SM = 11 2-(1-{4- [ppm]= 4.09 (s, 3H), [(trifluorome- 5.82 (s, 2H), 7.21 - N thyl)sulfanyl]b 7.30 (m, 1H), 7.34 - N enzyl}-1H- 7.49 (m, 2H), 7.49 - N indazol 7.73 (m, 4H), 8.01 - N yl)pyrimidin 8.09 (m, 2H), 8.28 H amine (s, 1H), 8.35 - 8.43 O (m, 2H), 8.50 (d, 3 1H) LC-MS: retention time: 1.16 MS ES+: 509.39 [M+H]+ Example 3-1 Preparation of 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinol [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb F 3 1,32 g of 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]methoxy-N-(pyridin- 4-yl)pyrimidinamine (21, 2,70 mmol, 1. eq.) were dissolved in 117 ml of dry 1-methylpyrrolidinone. 142 mg of potassium carbonate were added under nitro- gen atmosphere. Then 0,42 ml of benzenethiol were added dropwise. The reaction e was stirred for an hour at 190°C and cooled over the weekend at room temperature. Then the mixture was portioned n half ted aq. ammonium chloride solution and dichloromethane/ isopropanol 4:1. The phases were separated and the aqueous layer was extracted twice with dichloromethane/ isopro- panol 4:1. The combined organic layers were washed with brine, dried over a silicone filter and concentrated in vacuo. The e was purified by flash chromatography to yield 781 mg (1,65 mmol, 60,9%) of the analytically pure target compound. 1H-NMR (300 MHz, DMSO-d 6): δ [ppm]= 1.25 (t, 3H), 4.00 (q, 2H), 5.63 (s, 2H), 6.71 - 6.81 (m, 2H), 7.21 (t, 1H), 7.44 (td, 1H), 7.80 (d, 1H), 8.09 - 8.18 (m, 3H), 8.33 - 8.38 (m, 2H), 8.42 (d, 1H), 9.28 (s, 1H), 10.78 (br. s., 1H).
LC-MS: retention time: 0.97 min MS ES+: 475.59 [M+H]+ The following compounds were prepared according to the same procedure using the indicated starting materials (SM = starting material): [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 3-2 O 1H-NMR (400 MHz, CH 2-[1-(4- methoxyben- DMSO-d6): δ [ppm]= 3.66 SM = 11 zyl)-1H-indazol- (s, 3H), 5.64 (s, 2H), 6.83 N 3-yl](pyridin- - 6.88 (m, 2H), 7.19 (t, 4- 1H), 7.27 - 7.33 (m, 2H), N yla- 7.38 (ddd, 1H), 7.76 (d, N mino)pyrimidin- H 1H), 8.10 - 8.15 (m, 3H), OH 5-ol 8.34 - 8.43 (m, 2H), 9.31 (s, 1H).
LC-MS: retention time: 0.83 min MS ES+: 425.1 [M+H]+ Method B 3-3 F 2- 1H-NMR (400 MHz, fluorobenzyl)- DMSO-d6): δ [ppm]= 5.76 SM = 21 1H-indazol (s, 2H), 7.12 - 7.18 (m, N yl](pyridin 1H), 7.19 - 7.38 (m, 4H), yla- 7.43 (ddd, 1H), 7.78 (d, N mino)pyrimidin- 1H), 8.09 - 8.14 (m, 3H), N H N 5-ol 8.33 - 8.37 (m, 2H), 8.43 (d, 1H), 9.30 (s, 1H), .71 - 10.92 (s, 1H).
LC-MS: retention time: 0.86 min MS ES+: 413.2 [M+H]+ [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb 3-4 2-[1-(4- 1H-NMR (400 MHz, fluorobenzyl)- DMSO-d6): δ [ppm]= 5.70 SM = 21 N 1H-indazol - 5.73 (m, 2H), 7.10 - N N yl](pyridin 7.23 (m, 3H), 7.34 - 7.44 N yla- (m, 3H), 7.78 (d, 1H), N N H mino)pyrimidin- 8.07 - 8.14 (m, 3H), 8.34 -ol - 8.39 (m, 2H), 8.42 (d, 1H), 9.31 (s, 1H), 10.83 - 11.18 (m, 1H).
LC-MS: retention time: 0.85 min MS ES+: 413.0 [M+H]+ Method B Example 4-1 ation of {3-[({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)methyl]oxetanyl}methanol F O N F N N N N [Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 100 mg of 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinol (3-1, 0.21 mmol, 1. eq.) were dissolved in 1,6 ml of DMF under a en atmosphere, then 87 mg of potassium carbonate (0.63 mmol, 3 eq.) and 40 mg of [3-(bromomethyl)oxetanyl]methanol (0.21 mmol, 1 eq.) were added. The resulting mixture was stirred at room temperature for 18 hours. 6,0mg of [3-(bromomethyl)oxetanyl]methanol (0,032 mmol, 0,15 eq.) were added and stirred again for 24 hours. Then the mixture was partitioned between half saturated aq. ammonium chloride solution and dichloromethane/ isopropanol 4:1. The phases were separated and the aqueous layer was extracted twice with dichloro- methane/isopropanol 4:1. The ed organic layers were washed with brine, dried over a silicone filter and concentrated in vacuo. The residue was purified by flash chromatography to yield 75 mg (0.13 mmol, 61,9%) of the analytically pure target nd. 1H-NMR (400 MHz, DMSO-d 6): δ [ppm]= 1.26 (t, 3H), 3.83 (d, 2H), 4.01 (q, 2H), 4.39 - 4.50 (m, 6H), 5.06 (t, 1H), 5.65 (s, 2H), 6.72 - 6.81 (m, 2H), 7.23 (t, 1H), 7.46 (ddd, 1H), 7.82 (d, 1H), 8.01 - 8.09 (m, 2H), 8.38 - 8.46 (m, 4H), 8.90 (s, 1H).
LC-MS: retention time: 1.00 min MS ES+: 574.82 [M+H]+ The following compounds were prepared according to the same procedure using the indicated starting materials (SM = starting al): 41 F {3-[({2-[1-(2- 1H-NMR (300 MHz, fluorobenzyl)- DMSO-d6): δ [ppm]= SM = 3-3 N 1H-indazolyl]- 3.83 (br. s., 2H), 4.39 - N 4-(pyridin 4.48 (m, 6H), 5.06 (br.
N yla- s., 1H), 5.78 (s, 2H), N H N mino)pyrimidin- 7.11 - 7.38 (m, 5H), - 7.40 - 7.49 (m, 1H), N yl}oxy)methyl]ox 7.80 (d, 1H), 8.00 (d, etan 2H), 8.37 - 8.46 (m, [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb yl}methanol 4H), 8.92 (br. s., 1H).
LC-MS: retention time: 0.92 min MS ES+: 513.25 [M+H]+ 42 F (3-{[(2-[1-(2- LC-MS: fluorobenzyl)- retention time: 0.93 min SM = 3-3 N 1H-indazolyl]- MS ES+: 613.26 [M+H]+ OH 5-{[3- N (hydroxyme- thyl)oxetan yl]methoxy}pyri midin O yl)(pyridin yl)amino]methyl} oxetan yl)methanol 4-3 F 1-({2-[1-(2- 1H-NMR (400 MHz, fluorobenzyl)- DMSO-d6): δ [ppm]= SM = N azolyl]- 5.30 (s, 2H), 5.79 (s, 3-3 N 4-(pyridin 2H), 7.12 - 7.38 (m, yla- 5H), 7.41 - 7.48 (m, N H yrimidin- 3H), 7.82 (d, 1H), 8.03 - - 8.09 (m, 2H), 8.39 - )methanes 8.45 (m, 3H), 8.56 (s, O ulfonamide 1H), 9.18 - 9.22 (m, O NH2 1H).
LC-MS (Method 2): retention time: 1.32 min MS ES+: 506.00 [M+H]+ [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 4-4 F 5-[2- 1H-NMR (400 MHz, (dimethyla- DMSO-d6): δ [ppm]= SM = N thoxy] 2.25 (s, 6H), 2.68 - 2.75 3-3 N [1-(2- (m, 2H), 4.29 (t, 2H), fluorobenzyl)- 5.78 (s, 2H), 7.12 - 7.38 N H 1H-indazolyl]- (m, 5H), 7.44 (ddd, 1H), N-(pyridin 7.80 (d, 1H), 8.01 - yl)pyrimidin 8.06 (m, 2H), 8.37 - CH amine 8.46 (m, 4H), 9.42 (s, 3 N CH 1H).
LC-MS: retention time: 0.77 min MS ES+: 484.3 [M+H]+ 41 F 2-[1-(2- 1H-NMR (300 MHz, fluorobenzyl)- 6): δ [ppm]= SM = N 1H-indazolyl]- 3.17 - 3.24 (m, 4H), 3-3 N N-(pyridinyl)- 4.41 (t, 2H), 5.79 (s, -[2-(1H- 2H), 7.12 - 7.39 (m, N H tetrazol 5H), 7.40 - 7.49 (m, yl)ethoxy]pyrimi 1H), 7.80 (d, 1H), 8.39 - dinamine 8.49 (m, 6H).
N LC-MS: N NH retention time: 0.91 min MS ES+: 509.36 [M+H]+ [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb 42 F 2-[1-(2- LC-MS: fluorobenzyl)- retention time: 0.95 min SM = 3-3 N N 1H-indazolyl]- MS ES+: 605.32 [M+H]+ N N N-(pyridinyl)- NH N 5-[2-(1H- tetrazol N yl)ethoxy]-N-[2- N (1H-tetrazol N NH N yl)ethyl]pyrimidin amine 4-6 5-[2- 1H-NMR (300 MHz, (dimethyla- DMSO-d6): δ [ppm]= SM = N mino)ethoxy] 2.24 (s, 6H), 2.65 - 2.75 3-4 N [1-(4- (m, 2H), 4.29 (s, 2H), N fluorobenzyl)- 5.73 (s, 2H), 7.09 - 7.30 N H N 1H-indazolyl]- (m, 4H), 7.35 - 7.45 (m, O N-(pyridin 2H), 7.74 - 7.83 (m, N yl)pyrimidin 1H), 8.03 (d, 2H), 8.36 - N amine 8.46 (m, 4H), 9.41 - CH3 9.47 (m, 1H).
LC-MS: retention time: 0.88 min MS ES+: 484.0 [M+H]+ Method B 4-7 F 2-[1-(2- 1H-NMR (300MHz, fluorobenzyl)- 6): δ [ppm]= SM = N 1H-indazolyl]- 5.70 (s, 2H), 5.79 (s, 3-3 N N-(pyridinyl)- 2H), 7.11 - 7.39 (m, N 5-(1H-tetrazol 5H), 7.45 (t, 1H), 7.81 N H N ylmethoxy)pyrim (d, 1H), 8.19 (d, 2H), O idinamine 8.39 - 8.50 (m, 3H), N N 8.59 (s, 1H), 9.61 (br.s., N N [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 1H).
LC-MS: retention time: 0.92 min MS ES+: 495.2 [M+H]+ 4-8 CH3 1H-NMR (400 MHz, F 5-[2- O (dimethyla- DMSO-d6): δ [ppm]= SM = 3-1 N mino)ethoxy] 1.25 (t, 3H), 2.24 (s, [1-(4-ethoxy-2,6- 6H), 2.69 (t, 2H), 4.01 N difluorobenzyl)- (q, 2H), 4.20 (t, 2H), H 1H-indazolyl]- 5.56 (s, 2H), 6.76 (d, CH N-(pyridin 2H), 7.23 (t, 1H), 7.46 N yl)pyrimidin (td, 1H), 7.82 (d, 1H), amine 8.07 (dd, 2H), 8.36 - 8.45 (m, 4H), 9.38 (s, 1H).
LC-MS: retention time: 0.80 min MS ES+: 546.2 [M+H]+ 4-9 CH3 1-({2-[1-(4- 1H-NMR (500 MHz, F O ethoxy-2,6- DMSO-d6): δ [ppm]= SM = 3-1 difluorobenzyl)- 1.30 (t, 3H), 1.38 (m, N F 1H-indazolyl]- 2H), 1.50 (m, 4H), 2.37 N N 4-(pyridin (m, 1H), 2.38-2.54 (m, N N yla- 4H), 2.65 (m, 1H), 4.06 mino)pyrimidin- (q, 2H), 4.09 (br. d, -yl}oxy) 1H), 4.11 (br. s, 1H), idin 4.29 (br. d, 1H), 5.19 yl)propanol (br. d, 1H), 5.70 (s, 2H), [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 6.81 (d, 2H), 7.28 (t, 1H), 7.50 (br. t, 1H), 7.86 (d, 1H), 8.12 (br. d, 2H), 8.38 (s, 1H), 8.45 - 8.48 (m, 3H), 9.14 (s, 1H).
LC-MS (Method 5): ion time: 1.45 min MS ES+: 616.3 [M+H]+ 4-10 CH3 2-[1-(4-ethoxy- 1H-NMR (300 MHz, F O 2,6- DMSO-d6): δ [ppm]= SM = 3-1 difluorobenzyl)- 1.25 (t, 3H), 3.32 (s, N F 1H-indazolyl]- 3H), 3.76 (m, 2H), 4.01 N N -(2- (q, 2H), 4.36 (m, 2H), N N methoxyethoxy)- 5.65 (s, 2H), 6.76 (m, N-(pyridin 2H), 7.23 (t, 1H), 7.46 yl)pyrimidin (br. t, 1H), 7.82 (d, 1H), O amine 8.12 (br. d, 2H), 8.35 - 3 8.45 (m, 4H), 9.13 (s, 1H). 4-11 CH3 F tert-butyl 2-[({2- 1H-NMR (300 MHz, O [1-(4-ethoxy-2,6- DMSO-d6): δ [ppm]= SM = 3-1 N difluorobenzyl)- 1.25 (t, 3H), 1.37 (s, 1H-indazolyl]- 9H), 2.91 (m, 2H), 3.45 N 4-(pyridin (br. t, 1H), 3.70 (br. d, H yla- 1H), 3.80 - 4.06 (m, O CH3 CH mino)pyrimidin- 5H), 4.27 (d, 2H), 5.65 O O 5- (s, 2H), 6.76 (m, 2H), O yl}oxy)methyl]m 7.23 (t, 1H), 7.46 (t, orpholine 1H), 7.82 (d, 1H), 8.11 [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb carboxylate (br. d, 2H), 8.35 - 8.45 (m, 4H), 9.10 (s, 1H). 4-12 CH3 F 2-[1-(4-ethoxy- 1H-NMR (300MHz, O 2,6- DMSO-d6): δ [ppm]= SM = 3-1 N difluorobenzyl)- 1.25 (t, 3H), 2.79 (t, 1H-indazolyl]- 2H), 3.51(m, 4H), 3.70 N morpholin- (br. d, 1H), 4.01 (q, H 4-yl)ethoxy]-N- 2H), 4.34 (t, 2H), 5.65 O in (s, 2H), 6.76 (m, 2H), O yl)pyrimidin 7.23 (t, 1H), 7.46 (t, amine 1H), 7.82 (d, 1H), 8.12 (br. d, 2H), 8.35 - 8.45 (m, 4H), 9.08 (s, 1H).
LC-MS (Method 5): retention time: 1.14 min MS ES+: 588.2 [M+H]+ 4-13 2-[1-(2- 1H-NMR (300MHz, fluorobenzyl)- DMSO-d6): δ [ppm]= SM = 3-3 N F 1H-indazolyl]- 3.30 (s, 3H), 4.55 (s, N N -{[3- 2H), 5.78 (s, 4H), 7.12- N N (methoxyme- 7.39 (m, 5H), 7.44 (br. thyl)-1,2,4- t, 1H), 7.81 (d, 1H), O oxadiazol 8.12 (br. d, 2H), 8.37 - N N yl]methoxy}-N- 8.47 (m, 4H), 9.50 (s, O (pyridin 1H). 3 yl)pyrimidin LC-MS (Method 5): amine retention time: 1.20 min MS ES+: 539.3 [M+H]+ [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 4-14 CH3 F ethyl ({2-[1-(4- LC-MS (Method 5): O ethoxy-2,6- SM = retention time: 1.38 min 3-1 N difluorobenzyl)- N MS ES+: 561.2 [M+H]+ 1H-indazolyl]- N 4-(pyridin H yla- O yrimidin- O 5-yl}oxy)acetate 4-15 CH3 F 1-(3,3- 1H-NMR (300MHz, O roazetidin- DMSO-d6): δ [ppm]= SM = 3-1 N 1-yl)({2-[1-(4- 1.25 (t, 3H), 4.01 (q, ethoxy-2,6- 2H), 4.39 (br. t, 2H), N difluorobenzyl)- 4.73 (br. t, 2H), 4.98 (s, H 1H-indazolyl]- 2H), 5.66 (s, 2H), 6.76 O 4-(pyridin (m, 2H), 7.23 (t, 1H), N yla- 7.46 (t, 1H), 7.82 (d, F mino)pyrimidin- 1H), 8.17 (d, 2H), 8.30 - (s, 1H), 8.38 - 8.45 (m, yl}oxy)ethanone 3H), 9.56 (s, 1H).
LC-MS (Method 5): retention time: 1.31 min MS ES+: 608.2 [M+H]+ 4-16 CH3 F 2-[1-(4-ethoxy- 1H-NMR (300MHz, O 2,6- DMSO-d6): δ [ppm]= SM = 3-1 N robenzyl)- 1.25 (t, 3H), 2.15 (s, 1H-indazolyl]- 3H), 2.96 (t, 2H), 4.01 N 5-[2- (q, 2H), 4.39 (t, 2H), H (methylsulfa- 5.56 (s, 2H), 6.76 (m, O nyl)ethoxy]-N- 2H), 7.23 (t, 1H), 7.46 S (pyridin (t, 1H), 7.82 (d, 1H), [Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb yl)pyrimidin 8.12 (d, 2H), 8.37 - amine 8.45 (m, 4H), 9.11 (s, 1H).
LC-MS (Method 5): retention time: 1.42 min MS ES+: 550.5 [M+H]+ 4-17 CH3 F 2-[2-({2-[1-(4- 1H-NMR (300MHz, O ethoxy-2,6- DMSO-d6): δ [ppm]= SM = 3-1 N difluorobenzyl)- 1.26 (t, 3H), 3.52 (s, 1H-indazolyl]- 4H), 3.85 (m, 2H), 4.01 N 4-(pyridin (q, 2H), 4.36 (m, 2H), H yla- 4.63 (m, 1H), 5.56 (s, O yrimidin- 2H), 6.76 (m, 2H), 7.23 O 5- (t, 1H), 7.46 (t, 1H), yl}oxy)ethoxy]et 7.82 (d, 1H), 8.12 (d, hanol 2H), 8.35 - 8.45 (m, 4H), 9.10 (s, 1H).
LC-MS d 5): retention time: 1.24 min MS ES+: 561.4 [M+H]+ 4-18 CH3 Chiral formic acid - 1H-NMR (400MHz, F O (5S)[({2-[1-(4- DMSO-d6): δ [ppm]= SM = 3-1 ethoxy-2,6- N F N N 1.25 (t, 3H), 1.64 - 1.85 difluorobenzyl)- N (m, 1H), 2.13 - 2.29 (m, N N 1H-indazolyl]- H O 3H), 3.86 - 4.09 (m, O H OH 4-(pyridin 4H), 4.28 - 4.38 (m, yla- HN 1H), 5.65 (s, 2H), 6.71 O mino)pyrimidin- – 6.88 (m, 2H), 7.23 (t, 1H), 7.43 – 7.48 (m, yl}oxy)methyl]py ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb rrolidinone 1H), 7.81 (d, 1H), 8.00 - (1:1) 8.15 (m, 3H), 8.23 - 8.35 (m, 2H), 8.37 - 8.50 (m, 3H), 8.90 (s, 1H).
LC-MS: retention time: 0.96 min MS ES+: 572.3 [M+H]+ 4-19 CH3 Chiral (5R)[({2-[1-(4- 1H-NMR (300MHz, F O ethoxy-2,6- DMSO-d6): δ [ppm]= SM = 3-1 difluorobenzyl)- 1.26 (t, 3H), 2.14-2.28 N F 1H-indazolyl]- (m, 4H), 3.88-4.06 (m, N N 4-(pyridin 2H), 4.01 (q, 2H), 4.32 N N yla- (br. d, 1H), 5. 65 (s, mino)pyrimidin- 2H), 6.76 (m, 2H), 7.23 - (t, 1H), 7.46 (t, 1H), NH yl}oxy)methyl]py 7.82 (d, 1H), 8.07 (d, O rrolidinone 2H), 8.26-8.33 (m, 2H), 8.39-8.46 (m, 3H), 8.90 (s, 1H).
LC-MS (Method 5): retention time: 1.22 min MS ES+: 572.3 [M+H]+ 4-20 tert-butyl {2-[2- 1H-NMR (400MHz, ({2-[1-(2- DMSO-d6): δ [ppm]= SM = N F 3-3 N fluorobenzyl)- 1.31 (s, 9H), 3.03 - 3.13 N N H 1H-indazolyl]- (m, 2H), 3.46 (t, 2H), O 4-(pyridin 3.77 - 3.87 (m, 2H), O ylamino)pyrimidi 4.31 - 4.42 (m, 2H), NH CH3 CH3 CH3 n 5.78 (s, 2H), 6.76 - 6.85 O O [Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb yl}oxy)ethoxy]et (m, 1H), 7.12 - 7.38 (m, hyl}carbamate 5H), 7.40 - 7.48 (m, 1H), 7.80 (d, 1H), 8.08 – 8.12 (m, 2H), 8.35 - 8.47 (m, 4H), 9.18 (s, LC-MS: retention time: 1.07 min MS ES+: 600.3 [M+H]+ 4-21 CH3 F 2-({2-[1-(4- 1H-NMR (300MHz, O ethoxy-2,6- DMSO-d6): δ [ppm]= SM = 3-1 N difluorobenzyl)- 1.25 (t, 3H), 3.90 - 3.97 1H-indazolyl]- (m, 1 H), 4.01 (q, 2H), N 4-(pyridin 4.29 (m, 2H), 4.56 (m, H yla- 1H), 4.91 (s, 2H), 5.29 - O yrimidin- 5.54 (m, 1H), 5.66 (s, N 5-yl}oxy)(3- 2H), 6.76 (m, 2H), 7.24 F fluoroazetidin (t, 1H), 7.46 (t, 1H), yl)ethanone 7.82 (d, 1H), 8.16 (d, 2H), 8.26 (s, 1H), 8.38 - 8.45 (m, 3H), 9.61 (s, 1H).
LC-MS (Method 5): retention time: 1.29 min MS ES+: 590.4 [M+H]+ [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 4-22 CH 3 Chiral (5S)[({2-[1-(4- 1H-NMR (300MHz, F O -2,6- DMSO-d6): δ [ppm]= SM = 3-1 difluorobenzyl)- 1.25 (t, 3H), 1.64 - 1.88 N F N N 1H-indazolyl]- (m, 1H), 2.15 – 2.28 N 4-(pyridin (m, 3H), 3.84 - 4.09 (m, N N H yla- 4H), 4.32 (dd, 1H), 5.65 O mino)pyrimidin- (s, 2H), 6.73 – 6.81 (m, - 2H), 7.24 (t, 1H), 7.46 yl}oxy)methyl]py (t, 1H), 7.82 (d, 1H), rrolidinone 8.07 (d, 2H), 8.24 - 8.50 (m, 5H), 8.94 (s, 1H).
LC-MS: retention time: 1.21 min MS ES+: 572.3 [M+H]+ [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 4-23 CH 3 utyl [2-({2- LC-MS (Method 5): F O [1-(4-ethoxy-2,6- SM = retention time: 1.43 min 3-1 difluorobenzyl)- N F N N 1H-indazolyl]- MS ES+: 618.3 [M+H]+ N 4-(pyridin N N H yla- O mino)pyrimidin- O yl}oxy)ethyl]carb amate The following compound was formed according to the same procedure using 5- chloromethyloxazolidinone and the indicated ng material (SM = starting material): [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb 4-24 CH3 N-({2-[1-(4-ethoxy- F O fluorobenzyl)- SM = 3-1 1H-indazolyl] N F N N (pyridinyl)-7,8- N dihydro-6H- N N pyrimido[5,4- O N O b][1,4]oxazin yl}methyl)formamide Example 5-1 Preparation of 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]-N-(pyridinyl)- pyrimidinamine F O N F N N N N 100 mg of 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin o)pyrimidinyl trifluoromethanesulfonate (12, 0.165 mmol, 1. eq.), 0,74 mg of palladium (II) acetate (0,003 mmol, 0,02 eq.) and 1,36 mg of propane-1,3- diylbis(diphenylphosphane) were dissolved in 1 ml of DMF under a en atmosphere.
The mixture was heated to 60°C bath temperature. Then 0,66 ml of triethylsilane (0.41 mmol, 2,5 eq.) were added. The resulting mixture was stirred at 60 °C bath temperature for 18 hours. Then the mixture was partitioned between [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb saturated aq. sodium en carbonate solution and dichloromethane. The phases were separated and the aqueous layer was extracted twice with dichloromethane.
The combined organic layers were washed with brine, dried over a silicone filter and concentrated in vacuo. Preparative HPLC purification provided 16 mg (0.03 mmol, 20,1%) of the analytically pure target compound. 1H-NMR (300 MHz, DMSO-d 6): δ [ppm]= 1.25 (t, 3H), 4.00 (q, 2H), 5.68 (s, 2H), 6.70 - 6.86 (m, 3H), 7.26 (t, 1H), 7.42 - 7.53 (m, 1H), 7.78 - 7.97 (m, 2H), 8.11 (s, 1H), 8.38 (br. s., 2H), 8.44 - 8.57 (m, 2H), 10.07 (s, 1H).
LC-MS: retention time: 0.97 min MS ES+: 459.1 [M+H]+ Method B The following compounds were prepared according to the same procedure using the indicated ng materials (SM = starting material): -2 CH3 2-[1-(4- 1H-NMR (400MHz, DMSO- O yben- d6): δ [ppm]= 3.70 (s, 3H), zyl)-1H- 5.72 (s, 2H), 6.90 (d, 3H), N indazolyl]-N- 7.28 (t, 1H), 7.35 (d, 2H), N N in 7.45 (t, 1H), 7.83 (d, 1H), N yl)pyrimidin 7.92 (br. s., 2H), 8.37 - 8.55 N N H amine (m, 3H), 8.58 (d, 1H), 10.13 (s, 1H).
LC-MS: retention time: 0.86 min MS ES+: 409.1 [M+H]+ Method B [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb -3 F 2-[1-(2- 1H-NMR (400 MHz, DMSO- fluorobenzyl)- d6): δ [ppm]= 5.81 (s, 2H), SM = 11 N 1H-indazol 6.84 (d, 1H), 7.13 - 7.39 (m, N yl]-N-(pyridin- 5H), 7.43 - 7.49 (m, 1H), 4-yl)pyrimidin- 7.79 - 7.89 (m, 3H), 8.38 (d, N H 4-amine 2H), 8.49 (d, 1H), 8.53 (d, 1H), 10.07 (s, 1H).
N LC-MS: ion time: 0.93 min MS ES+: 397.25 [M+H]+ Example 6-1 Preparation of 2-[1-(4-cyclopropyl-2,6-difluorobenzyl)-1H-indazolyl]methoxy- N-(pyridinyl)pyrimidinamine N F N N N N O CH 100 mg of 2-[1-(4-bromo-2,6-difluorobenzyl)-1H-indazolyl]methoxy-N- (pyridinyl)pyrimidinamine (21, 0.191 mmol, 1. eq.) were suspended in 3 ml of dry e. 21,3 mg of cyclopropylboronic acid (0,248 mmol, 1,3 eq.) 5,36 mg of tricyclohexylphosphane (0,019 mmol, 0,1 eq.), 142 mg of potassium phosphate (0,669 mmol, 3,5 eq.) and 50 µl of water were added. Then 2,15 mg of pal- [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb ladium (II) acetate (0,01 mmol, 0,05 eq.) were added under a nitrogen atmosphere.
The e was stirred at 100 °C bath temperature for 5 hours. Upon the mixture was cooled to room temperature it was partitioned between water and dichloromethane / isopropanol 4:1. The phases were separated and the aqueous layer was extracted twice with dichloromethane/ isopropanol 4:1. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo.
Preparative HPLC purification provided 28,7 mg (0.06 mmol, 31%) of the ically pure target compound. 1H-NMR (400 MHz, DMSO-d 6): δ [ppm]= 0.66-0.74 (m, 2H), 0.89-0.98 (m, 2H), 1.93 (m, 1H), 4.00 (s, 3H), 5.67 (s, 2H), 6.85 - 6.92 (m, 2H), 7.23 (t, 1H), 7.46 (t, 1H), 7.83 (d, 1H), 8.13 - 8.20 (m, 2H), 8.32 (s, 1H), 8.34 - 8.40 (m, 2H), 8.43 (d, 1H), 9.41 (s, 1H).
LC-MS: retention time: 1.06 min MS ES+: 485.1 [M+H]+ Method B The following compounds were prepared according to the same procedure using the indicated starting materials (SM = ng material): 6-2 CH 1H-NMR (400 3 2,6-difluoro- F 4-[(1E)-propen- MHz, DMSO-d6): δ SM = 1-yl]benzyl}-1H- [ppm]= 1.82 (d, 21 indazolyl) 3H), 4.03 (s, 3H), N F N N methoxy-N- 5.73 (s, 2H), 6.33 - (pyridin 6.55 (m, 2H), 7.17 N N yl)pyrimidin - 7.30 (m, 3H), amine 7.45 - 7.53 (m, O CH3 1H), 7.86 (d, 1H), 8.14 - 8.22 (m, 2H), 8.34 (s, 1H), 8.37 - 8.42 (m, 2H), 8.46 (d, 1H), ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb 9.40 (s, 1H).
LC-MS: retention time: 8.67 min MS ES+: 485.1 [M+H]+ Example 7-1 Preparation of 1-[3,5-difluoro({3-[5-methoxy(pyridinylamino)pyrimidinyl]- 1H-indazolyl}methyl)phenyl]ethanone N F N N N N O CH Step 1: 2-{1-[4-(1-ethoxyethenyl)-2,6-difluorobenzyl]-1H-indazolyl}methoxy- N-(pyridinyl)pyrimidinamine 100mg of 2-[1-(4-bromo-2,6-difluorobenzyl)-1H-indazolyl]methoxy-N-(pyridin- 4-yl)pyrimidinamine (21, 0,191 mmol, 1 eq.) was suspended in dry toluol. 1,34 mg of dichloropalladium - triphenylphosphane (1:2) (0,002 mmol, 0,01 eq.) and 71 µl of tributyl(1-ethoxyethenyl)stannane (0,21 mmol, 1,2 eq.) were added.
The mixture was stirred for 5 hours at 100°C bath temperature and for 18 hours at 120°C bath temperature. 5 mg of dichloropalladium - nylphosphane (1:2) (0,007 mmol, 0,035 eq.) and 140 µl of tributyl(1-ethoxyethenyl)stannane (0,42 [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb mmol, 2,4 eq.) and 1 ml of 1-methylpyrrolidinone were added. The solution was stirred for 3 days at 100°C bath ature. 5 mg of dichloropalladium - triphenylphosphane (1:2) ( 0,007 mmol, 0,035 eq.) and 140 µl of tributyl(1- ethoxyethenyl)stannane ( 0,42 mmol, 2,4 eq.) were added and stirred at 100 °C again for 22 hours. The reaction mixture was concentrated in vacuo and ed by flash chromatography to yield 119 mg (0.2 mmol, 107%) of the analytically pure target compound. 1H-NMR (300MHz, DMSO-d6): δ [ppm]= 1.25 - 1.33 (t, 3H), 3.78 - 3.89 (m, 2H), 4.00 (s, 3H), 4.34 - 4.41 (d, 1H), 4.91 - 4.97 (d, 1H), 5.74 (s, 2H), 7.24 (t, 1H), 7.37 (d, 1H), 7.43 - 7.64 (m, 2H), 7.84 (d, 1H), 8.09 - 8.18 (dd, 2H), 8.32 (s, 1H), 8.34 - 8.39 (dd, 2H), 8.44 (d, 1H), 9.32 - 9.41 (s, 1H).
LC-MS: retention time: 1.09 min MS ES+: 515.1 [M+H]+ Method B Step 2: 1-[3,5-difluoro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H- indazolyl}methyl)phenyl]ethanone 119 mg of 2-{1-[4-(1-ethoxyethenyl)-2,6-difluorobenzyl]-1H-indazolyl} methoxy-N-(pyridinyl)pyrimidinamine (0,231 mmol, 1 eq.) and 66 mg of 4- methylbenzenesulfonic acid hydrate (1:1) (0,347 mmol, 1,5 eq.) were dissolved in 2,4 ml of ethanol and 0,6 ml of water. The e was stirred for one hour at 80°C bath temperature. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium hydrogen carbonate solution. The phases were separated and the aqueous layer was extracted twice with ethyl e. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography and preparative HPLC purification to yield 26 mg (0.05 mmol, 22,7%) of the ically pure target compound.
[Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 1H-NMR (300MHz, DMSO-d 6): δ [ppm]= 2.54 (s, 3H), 4.00 (s, 3H), 5.82 (s, 2H), 7.25 (t, 1H), 7.49 (t, 1H), 7.69 (d, 2H), 7.87 (d, 1H), 8.14 (d, 2H), 8.31 (s, 1H), 8.37 (d, 2H), 8.44 (d, 1H), 9.38 (s, 1H).
LC-MS: retention time: 0.95 min MS ES+: 487.1 [M+H]+ Method B Example 8-1 Preparation of [2,4-dichloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]- 1H-indazolyl}methyl)phenyl]methanol N Cl N N N N O CH 3 80 mg of methyl 2,4-dichloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]- 1H-indazolyl}methyl)benzoate (21, 0.149 mmol, 1. eq.) was ded in 2,4 ml of dry tetrahydrofuran under nitrogen atmosphere. The suspension was cooled with an ice bath to +3 °C, upon which 254 µl of a 1 M lithium aluminium e solution in tetrahydrofuran (0,254 mmol, 1,7 eq.) were added dropwise.
The ice bath was remove and the mixture was stirred at room temperature for 30 minutes. Then the mixture was ied by 2 M sulfuric acid. The mixture formed a [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb suspension which was ed off and washed with water. The precipitate was dried in vacuo at 60 °C for 18 hours to yield 60 mg (0.11 mmol, 74,4%) of the analytically pure target compound. 1H-NMR (300 MHz, DMSO-d 6): δ [ppm]= 4.02 (s, 3H), 4.51 (s, 2H), 5.47 - 5.57 (m, 1H), 5.90 (s, 2H), 7.26 (t, 1H), 7.49 (t, 1H), 7.54 - 7.67 (m, 2H), 7.91 (d, 1H), 8.34 - 8.41 (m, 2H), 8.42 - 8.49 (m, 4H), 9.98 (s, 1H).
LC-MS: retention time: 0.91 min MS ES+: 507.3 [M+H]+ Method B The following nds were prepared according to the same procedure using the indicated starting materials (SM = starting material): 8-2 2-[3-({3-[5-methoxy 1H-NMR (pyridin (300MHz, DMSOSM = N OH ylamino)pyrimidinyl]- d6): δ [ppm]= 2.59 21 N 1H-indazol - 2.67 (m, 2H), N yl}methyl)phenyl]ethano 3.51 (d, 2H), 4.02 H l (s, 3H), 4.58 (s, CH 1H), 5.69 (s, 2H), 7.06 - 7.14 (m, 2H), 7.16 - 7.26 (m, 3H), 7.40 (t, 1H), 7.77 (d, 1H), 8.12 (dd, 2H), 8.31 - 8.46 (m, 4H), 9.42 (s, 1H).
LC-MS: retention time: [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 0.87 min MS ES+: 453.22 [M+H]+ 8-3 2-[3-({3-[5-methoxy 1H-NMR (pyridin (300MHz, DMSO- SM = CH N 3 CH ylamino)pyrimidinyl]- d6): δ [ppm]= 1.13 21 N N 1H-indazol (s, 6H), 4.05 (s, N hyl)phenyl] 3H), 4.57 - 4.66 N N H methylpropanol (m, 1H), 5.69 - O CH 5.76 (m, 4H), 7.03 (d, 1H), 7.15 - 7.27 (m, 3H), 7.37 - 7.48 (m, 2H), 7.79 (d, 1H), 8.32 - 8.54 (m, 6H), 9.97 - 10.04 (m, 1H).
LC-MS: retention time: 0.87 min MS ES+: 481.4 [M+H]+ Method B 8-4 F [4-({2-[1-(4-ethoxy-2,6- 1H-NMR CH3 difluorobenzyl)-1H- (300MHz, DMSOSM = N F indazolyl] d6): δ [ppm]= 39-1 N N ypyrimidin 1.25 (t, 3H),3.99 N yl}amino)pyridin (s, 3H), 4.01 (q, OH yl]methanol 2H), 4.67 (d, 2H), 3 5. 64 (s, 2H), 5. 96 (t, 1H), 6.76 (m, 2H), 7.23 (t, [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 1H), 7.45 (t, 1H), 7.81 (d, 1H), 8.32-8.44 (m, 4H), 8.82 (d, 1H), 9.52 (s, 1H).
LC-MS (Method retention time: 1.03 min MS ES+: 481.4 [M+H]+ Example 9-1 Preparation of 2-[3-chloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]- 1H-indazolyl}methyl)phenyl]propanol N Cl N N N N 36 mg of methyl 3-chloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H- indazolyl}methyl)benzoate (21, 0.072 mmol, 1. eq.) were suspended in 583 µl of dry tetrahydrofuran under nitrogen here. The suspension was cooled with a freezing mixture to -75 °C. Then 90 µl of 1,6 M methyllithium solution in di- [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb ethyl ether (0,144 mmol, 2 eq.) were added dropwise. The freezing mixture was removed and the reaction mixture was stirred at room temperature for 24 hours.
The reaction mixture was cooled with a freezing mixture to -75 °C. 90 µl of 1,6 M methyllithium solution in l ether (0,144 mmol, 2 eq.) were added dropwise again. The freezing mixture was removed and the on mixture was stirred at room temperature for further 24 hours. Then the mixture was partitioned between water and dichloromethane/ isopropanol 4:1. The phases were ted and the aqueous layer was extracted twice with dichloromethane/ isopropanol 4:1. The combined c layers were washed with brine, dried over a silicone filter and trated in vacuo. The residue was purified by preparative TLC to yield 3,5 mg (0.01 mmol, 9,3%) of the analytically pure target compound. 1H-NMR (400 MHz, DMSO-d 6): δ [ppm]= 1.34 (s, 6H), 4.01 (s, 3H), 5.11 (s, 1H), .77 (s, 2H), 7.13 (d, 1H), 7.21 - 7.27 (m, 1H), 7.34 (dd, 1H), 7.44 (ddd, 1H), 7.54 (d, 1H), 7.79 (d, 1H), 8.10 - 8.15 (m, 2H), 8.34 (s, 1H), 8.35 - 8.40 (m, 2H), 8.46 (d, 1H), 9.41 (s, 1H).
LC-MS: retention time: 0.99 min MS ES+: 501.2 [M+H]+ The following compounds were prepared according to the same procedure using the indicated starting als (SM = starting material): 9-2 1-[3-({3-[5- 1H-NMR (300MHz, 3 CH 3 methoxy DMSO-d6): δ SM = N (pyridin [ppm]= 0.94 (s, 6H), 21 N N ylamino)pyrimidin- 1.18 - 1.22 (m, 2H), N 1H-indazol 4.02 (s, 3H), 4.24 N N H yl}methyl)phenyl]- (s, 1H), 5.70 (s, O CH 3 2-methylpropan 2H), 7.03 - 7.25 (m, ol 5H), 7.38 (t, 1H), 7.74 (d, 1H), 8.12 (dd, 2H), 8.32 - [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 8.46 (m, 4H), 9.40 - 9.45 (m, 1H).
LC-MS: retention time: 0.95 MS ES+: 481.26 [M+H]+ 9-3 OH CH 3 2-[2,4-dichloro 1H-NMR (400MHz, Cl 3 ({3-[5-methoxy DMSO-d6): δ SM = (pyridin [ppm]= 1.51 (s, 6H), 21 ylamino)pyrimidin- 4.00 (s, 3H), 5.37 N Cl N N 2-yl]-1H-indazol (s, 1H), 5.91 (s, N yl}methyl)phenyl]pr 2H), 7.22 - 7.28 (t, N N H opanol 1H), 7.45 - 7.50 (m, O CH3 1H), 7.62 (d, 1H), 7.86 - 7.91 (m, 2H), 8.14 (d, 2H), 8.32 (s, 1H), 8.37 (d, 2H), 8.48 (d, 1H), 9.35 (s, 1H).
LC-MS: ion time: 1.09 MS ES+: 535.2 [M+H]+ Example 10-1 Preparation of 5-(difluoromethoxy)[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazol- 3-yl]-N-(pyridinyl)pyrimidinamine [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb F 3 100 mg of 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinol (3-1, 0.211 mmol, 1. eq.) were suspended in 843 µl of 30% aq. potassium hydroxide solution (5,72 mmol, 27 eq.) and 843µl of acetonitrile.
The suspension was cooled with a freezing e to -75 °C. 93 µl of 2-chloro- 2,2-difluorophenylethanone (0,632 mmol, 3 eq.) were added dropwise. The freezing mixture was removed. The reaction mixture was stirred at 80 °C bath temperature for 4 hours. Then the mixture was partitioned between water and dichloromethane / isopropanol 4:1. The phases were separated and the aqueous layer was extracted twice with dichloromethane/ isopropanol 4:1. The combined organic layers were washed with brine, dried over a ne filter and concentrated in vacuo. Preparative HPLC cation provided 4 mg (0.01 mmol, 3,2%) of the analytically pure target compound. 1H-NMR (500 MHz, DMSO-d 6): δ [ppm]= 1.30 (t, 3H), 4.05 (q, 2H), 5.73 (s, 2H), 6.81 (d, 2H), 7.16 - 7.48 (m, 2H), 7.50 - 7.57 (m, 1H), 7.90 (d, 1H), 8.12 - 8.17 (m, 2H), 8.44 - 8.49 (m, 3H), 8.54 (s, 1H), 9.71 (s, 1H).
LC-MS: retention time: 1.65 min MS ES+: 525.02 [M+H]+ The ing compounds were also formed during the same procedure: ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb -2 CH 5- 1H-NMR (300MHz, F 3 O (difluorometh- DMSO-d6): δ [ppm]= SM = N oxy)-N- 1.25 (t, 3H), 4.00 (q, 3-1 N (difluoromethyl)- 2H), 5.65 (s, 2H), 6.72 2-[1-(4-ethoxy- (d, 2H), 6.91 (d, 1H), N 2,6- 7.16 - 7.25 (m, 1H), 6.97 O F difluorobenzyl)- - 7.47 (t, 2H), 7.34 - 7.60 F F azolyl]- (m, 2H), 7.76 (d, 1H), N-(pyridin 7.91 (d, 2H), 8.36 (d, yl)pyrimidin 1H), 8.46 (s, 1H). amine LC-MS: retention time: 1.15 min MS ES+: 575.1 [M+H]+ -3 CH 3 4- 1H-NMR (600MHz, [(difluorome- DMSO-d6): δ [ppm]= SM = pyridin 1.29 (t, 4H), 4.04 (q, 3-1 N yl)amino][1-(4- 3H), 5.63 (s, 2H), 6.71 - N ethoxy-2,6- 6.79 (m, 2H), 7.04 (br.
N difluorobenzyl)- s., 1H), 7.20 (t, 1H), N 1H-indazol 7.44 (td, 1H), 7.49 - 7.71 H yl]pyrimidinol (m, 1H), 7.74 (d, 1H), OH F F 7.91 (d, 2H), 8.15 (s, 1H), 8.41 (d, 1H).
LC-MS: retention time: 1.10 min MS ES+: 525.0 [M+H]+ Example 11-1 [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb ation of 2-[1-(4-methoxybenzyl)-1H-indazolyl]-N-(pyridinyl)(2,2,2- oroethoxy)pyrimidinamine 143 mg of 2-[1-(4-methoxybenzyl)-1H-indazolyl](pyridinylamino)pyrimidin- 5-ol (3-2, 0.337 mmol, 1. eq.) were dissolved in 500 µl of dry DMF. Then 117 mg of 2,2,2-trifluoroethyl trifluoromethanesulfonate (0,505 mmol, 1,5 eq.), 93,1 mg of potassium carbonate (0,674 mmol, 2 eq.) and 24 µl of acetonitrile were added.
The resulting mixture was stirred at 150 °C for 30 minutes in a microwave. Then the mixture was partitioned between water and dichloromethane/ isopropanol 4:1.
The phases were separated and the aqueous layer was extracted twice with dichloromethane / isopropanol 4:1. The combined organic layers were washed with brine, dried over a silicone filter and concentrated in vacuo. The residue was purified by flash chromatography and preparative TLC to yield 7,7 mg (0.01 mmol, 3,9%) of the analytically pure target nd. 1H-NMR (300 MHz, DMSO-d 6): δ [ppm]= 3.66 (s, 3H), 4.95 - 5.08 (m, 2H), 5.65 (s, 2H), 6.83 - 6.90 (m, 2H), 7.16 - 7.24 (m, 1H), 7.30 (d, 2H), 7.36 - 7.45 (m, 1H), 7.78 (d, 1H), 8.00 - 8.11 (m, 2H), 8.35 - 8.52 (m, 4H), 9.32 (s, 1H).
LC-MS: retention time: 1.03 min MS ES+: 507.1 [M+H]+ [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb Method B The following compounds were prepared according to the same ure using the indicated starting materials (SM = starting material): 11-2 CH 4-ethoxy-2,6- 1H-NMR F 3 O difluorobenzyl)-1H- (400MHz, SM = N indazolyl]-N- DMSO-d6): δ 3-1 N (pyridinyl) [ppm]= 1.28 (t, N (2,2,2- 3H), 4.04 (q, N trifluoroeth- 2H), 5.03 (q, O oxy)pyrimidin 2H), 5.69 (s, F amine 2H), 6.79 (d, 2H), 7.22 - 7.30 (m, 1H), 7.49 (ddd, 1H), 7.85 (d, 1H), 8.10 - 8.16 (m, 2H), 8.40 - 8.46 (m, 3H), 8.50 (s, 1H), 9.32 (s, 1H).
LC-MS: ion time: 1.11 min MS ES+: 557.1 [M+H]+ Method B Example 12-1 Preparation of 3-({2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridinylamino)- pyrimidinyl}oxy)propane-1,2-diol [Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb ation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb N N N N ,0 mg of 2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridinylamino)pyrimidin ol (3-3, 0,06 mmol, 1 eq.), 28,2 mg of 3-bromo-propane-1,2-diol (0,18 mmol, 3 eq.) and 41,9 mg of potassium carbonate (0,30 mmol, 5 eq.) were suspended in 466 µl of dry DMF. The reaction mixture was stirred at 100 °C oil bath temperature for 18 hours. Then the mixture was partitioned between half ted aq. sodium chloride solution and ethyl acetate. The phases were separated and the aqueouse layer was extracted once more with ethyl acetate and once with dichloromethane /isopropanol 4:1. The combined organic layers were dried over magnesi- um sulfate and concentrated in vacuo. The residue was purified by preparative thin layer chromatography to yield 2,60 mg (5.34 µmol, 9%) of the analytically pure target nd.
LC-MS: retention time: 1.00 min MS ES+: 487.41 [M+H]+ Example 12-2 Preparation of (2R)({2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)propane-1,2-diol [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb N N N N Step 1: 5-{[(4S)-2,2-dimethyl-1,3-dioxolanyl]methoxy}[1-(2-fluorobenzyl)-1H- indazolyl]-N-(pyridinyl)pyrimidinamine 200 mg of 2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridinylamino)pyrimidinol (3-3, 0,49 mmol, 1 eq.), 94,6 mg of 2,2-dimethyl-4(R)bromomethyl-1,3- ane (0,49 mmol, 1 eq.) and 134 mg of potassium carbonate (0,97 mmol, 2 eq.) were suspended in 3,7 ml of dry DMF. The reaction mixture was d at 50 °C oil bath temperature for 18 hours. 201 mg of potassium carbonate (1,46 mmol, 3 eq.) were added and the e was stirred at 90 °C oil bath temperature for further 24 hours. Then the mixture was partitioned between half saturated aq. ammonium chloride solution and dichloromethane/isopropanol 4:1. The phases were separated and the aqueous layer was extracted twice with dichloromethane opanol 4:1. The combined organic layers were washed with brine, dried over a silicone filter and concentrated in vacuo. The e was purified by flash chromatography to yield 126 mg (0.27 mmol, 44%) of the analytically pure target compound. 1H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.29 (s, 3H), 1.34 (s, 3H), 3.86 (dd, 1H), 4.15 (dd, 1H), 4.27 (dd, 2H), 4.54 (m, 1H), 5.78 (s, 2H), 7.12 - 7.38 (m, 5H), 7.40 - 7.47 (m, 1H), 7.80 (d, 1H), 8.04 - 8.09 (m, 2H), 8.38 - 8.46 (m, 4H), 9.11 (s, 1H).
LC-MS: retention time: 1.00 min ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb MS ES+: 527.39 [M+H]+ Step 2: (2R)({2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridinylamino)- pyrimidinyl}oxy)propane-1,2-diol hydrochloride (1:1) 124 mg of 5-{[(4S)-2,2-dimethyl-1,3-dioxolanyl]methoxy}[1-(2-fluorobenzyl)- 1H-indazolyl]-N-(pyridinyl)pyrimidinamine (0.24 mmol, 1. eq.) were dissolved in 12 ml of acetonitrile. 515 µl of conc. hydrogen chloride (6,00 mmol, 20,8 eq.) were added se. The reaction mixture was stirred at room temperature for 18 hours. The sion was filtered off and washed with acetonitrile. The precipitate was dried at 45 °C under vacuo to yield 119 mg (0.23 mmol, 97%) of the analytically pure target compound. 1H-NMR (600MHz, DMSO d 6): δ [ppm]= 3.49 (m, 2H), 3.94 (m, 1H), 4.14 (dd, 1H), 4.34 (dd, 1H), 4.73 (br. s, 2H), 5.82 (s, 2H), 7.15 (td, 1H), 7.19 - 7.30 (m, 2H), 7.34 (m, 1H), 7.46 (td, 1H), 7.49 (ddd, 1H), 7.80 (d, 1H), 8.41 (d, 1H), 8.58 (s, 1H), 8.65 (d, 2H), 8.75 (d, 2H), 10.72 (s, 1H), 14.82 (br. s., 1H).
LC-MS: retention time: 0.86 min MS ES+: 487.34 [M+H]+ Step 3: -({2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridinylamino)pyrimidinyl }oxy)propane-1,2-diol 84,5 mg of (2R)({2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridinylamino)- pyrimidinyl}oxy)propane-1,2-diol hydrochloride (1:1) was dissolved in water. 2M aq. sodium hydroxide solution was added. The mixture was stirred at room tem- perature for 3 hours. The resulting suspension was filtered off and washed with water to yield 52,9 mg (0,11 mmol, 67%) of the analytically pure target compound. 1H-NMR (300 MHz, DMSO-d 6): δ [ppm]= 3.50 (d, 2H), 3.85 - 3.97 (m, 1H), 4.01 - 4.13 (m, 1H), 4.23 - 4.30 (m, 1H), 4.79 (s, 1H), 5.20 - 5.27 (m, 1H), 5.78 (s, 2H), 7.11 - 7.39 (m, 5H), 7.44 (t, 1H), 7.80 (d, 1H), 7.99 - 8.07 (m, 2H), 8.33 (s, 1H), 8.39 - 8.46 (m, 3H), 9.14 (s, 1H).
[Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb LC-MS (chiral): retention time: 0.85 min MS ES+: 487.35 [M+H]+ The following enatiomer was ed according to the same procedure using the indicated starting material (SM = starting material) and methyl-4(S) bromomethyl-1,3-dioxalane: 12-3 F (2S)({2-[1-(2- 1H-NMR (300 MHz, DMSO- fluorobenzyl)- d6): δ [ppm]= 3.50 (d, 2H), SM = N 1H-indazolyl]- 3.86 - 3.98 (m, 1H), 4.08 (s, 3-3 N N 4-(pyridin 1H), 4.19 - 4.30 (m, 1H), N yla- 4.79 (s, 1H), 5.25 (d, 1H), N N H mino)pyrimidin- 5.78 (s, 2H), 7.11 - 7.39 (m, - 5H), 7.44 (t, 1H), 7.80 (d, OH )propane- 1H), 8.01 - 8.07 (m, 2H), OH 1,2-diol 8.33 (s, 1H), 8.39 - 8.47 (m, 3H), 9.14 (s, 1H).
LC-MS (chiral): retention time: 0.90 min MS ES+: 487.21 [M+H]+ Example 13-1 Preparation of 2-({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)ethanol [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb F O N F N N N N Step 1: 182 mg of 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinol (3-1, 0,383 mmol, 1 eq.), 110 mg of (2-bromoethoxy)(tert- butyl)dimethylsilane ( 0,459 mmol, 1,2 eq.) and 159 mg of potassium carbonate were suspended in 3 ml of dry DMF under en atmosphere and stirred for 3 days at room temperature. Then the mixture was ioned between water and dichloromethane. The phases were separated and the s layer was extracted twice with dichloromethane. The combined organic layers were washed with half ted aq. sodium chloride solution, dried over a silicone filter and concentrated in vacuo to yield 224 mg (0.32 mmol, 82,3%) of the analytically pure target compound. 1H-NMR (300MHz, DMSO-d6): δ [ppm]= 0.00 (s, 6H), 0.79 (s, 9H), 1.25 (t, 3H), 4.01 (d, 4H), 4.30 - 4.39 (m, 2H), 5.65 (s, 2H), 6.77 (d, 2H), 7.23 (t, 1H), 7.46 (t, 1H), 7.82 (d, 1H), 8.07 - 8.14 (m, 2H), 8.34 - 8.45 (m, 4H), 9.07 - 9.14 (m, 1H).
LC-MS: retention time: 1.70 min MS ES+: 633.4 [M+H]+ [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb Step 2: 224 mg of 5-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)[1-(4-ethoxy-2,6-difluorobenzyl )-1H-indazolyl]-N-(pyridinyl)pyrimidinamine (0.337 mmol, 1. eq.) were dissolved in 3 ml of dry dioxane under nitrogen here. 442 µl of 4 M hydrogen chloride solution in dioxane were added and gave ately a suspension.
This suspension was stirred for 30 minutes. Then 10 ml of a aq. ted sodium hydrogen carbonate solution were added. The suspension was filtered off and washed with water to yield 210 mg (0.34 mmol, 97,0%) of the analytically pure target compound. 1H-NMR (400 MHz, DMSO-d 6): δ [ppm]= 1.28 (t, 3H), 3.83 (d, 2H), 4.04 (q, 2H), 4.24 (t, 2H), 5.11 (br. s., 1H), 5.68 (s, 2H), 6.75 - 6.84 (m, 2H), 7.26 (t, 1H), 7.45 - 7.52 (m, 1H), 7.85 (d, 1H), 8.09 - 8.14 (m, 2H), 8.36 (s, 1H), 8.41 - 8.48 (m, 3H), 9.12 (s, 1H).
LC-MS: retention time: 0.95 min MS ES+: 519.4 [M+H]+ Method B The following compounds were prepared according to the same two-step proce- dure using the indicated starting materials (SM = starting material): 13-2 2-({2-[1-(2- 1H-NMR (400 MHz, DMSO- fluorobenzyl)- d6): δ [ppm]= 3.77 - 3.85 SM = 3-3 1H-indazolyl]- (m, 2H), 4.22 (t, 2H), 5.10 N 4-(pyridin (t, 1H), 5.78 (s, 2H), 7.12 - N yla- 7.39 (m, 5H), 7.44 (td, 1H), N mino)pyrimidin- 7.80 (d, 1H), 8.04 - 8.09 (m, H 5-yl}oxy)ethanol 2H), 8.35 (s, 1H), 8.40 - O 8.46 (m, 3H), 9.17 (s, 1H).
LC-MS: retention time: 0.95 min MS ES+: 457.32 [M+H]+ [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb 13-3 F ethyl 4-({2-[1-(2- 1H-NMR (400 MHz, DMSO- fluorobenzyl)- d6): δ [ppm]= 1.35 (t, 3H), SM = -3 N 1H-indazolyl]- 3.83 (q, 2H), 4.33 (t, 2H), CH 5-(2- 4.40 (q, 2H), 4.90 (t, 1H), N O N H yeth- 5.79 (s, 2H), 7.12 - 7.39 (m, oxy)pyrimidin 5H), 7.46 (t, 1H), 7.82 (d, N yl}amino)pyridin 1H), 8.45 (d, 1H), 8.50 (s, OH ecarboxylate 1H), 8.58 (d, 1H), 9.02 - 9.09 (m, 1H), 9.29 (d, 1H), 11.23 (s, 1H).
LC-MS: retention time: 1.12 min MS ES+: 529.0 [M+H]+ Method B 13-4 F 4-({2-[1-(2- 1H-NMR (400MHz, DMSO- benzyl)- d6): δ [ppm]= 2.81 (d, 3H), SM = 13-3 N 1H-indazolyl]- 3.83 (q, 2H), 4.29 (t, 2H), -(2- 4.83 (t, 1H), 5.79 (s, 2H), N O CH3 N H N N hydroxyeth- 7.12 - 7.38 (m, 5H), 7.41 - O oxy)pyrimidin 7.49 (m, 1H), 7.81 (d, 1H), yl}amino)-N- 8.42 - 8.47 (m, 2H), 8.50 (d, methylpyridine- 1H), 8.84 (s, 1H), 8.91 (d, 3-carboxamide 1H), 9.15 (d, 1H), 11.91 (s, (derived from 13-3 via amidation and subse- 1H). quent desilylation) LC-MS: retention time: 0.93 min MS ES+: 514.4 [M+H]+ Method B [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb 13-5 F [1-(2- LC-MS: fluorobenzyl)- retention time: 0.96 min SM = N -1 N azolyl]- MS ES+: 500.1 [M+H]+ N 5-(2- Method B N H N NH 2 hydroxyeth- O oxy)pyrimidin yl}amino)pyridin ecarboxamide 13-6 F 2-hydroxyethyl 1H-NMR (300MHz, DMSO- 4-({2-[1-(2- d6): δ [ppm]= 3.69 - 3.77 SM = -2 N N fluorobenzyl)- (m, 2H), 3.79 - 3.88 (m, 1H-indazolyl]- 2H), 4.28 - 4.40 (m, 4H), N O N H O N 5-(2- 4.86 - 4.94 (m, 1H), 4.96 - O hydroxyeth- 5.04 (m, 1H), 5.76 - 5.83 N oxy)pyrimidin (m, 2H), 7.13 - 7.40 (m, OH yl}amino)pyridin 5H), 7.46 (t, 1H), 7.82 (d, ecarboxylate 1H), 8.45 (d, 1H), 8.51 (s, 1H), 8.59 (d, 1H), 9.15 (s, 1H), 9.30 (d, 1H), 11.22 - 11.27 (m, 1H).
LC-MS: retention time: 1.15 min MS ES+: 545.0 [M+H]+ Method B Example 14-1 Preparation of 5-(cyclopropyloxy)[1-(4-methoxybenzyl)-1H-indazolyl]-N- (pyridinyl)pyrimidinamine [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 100 mg of 2-[1-(4-methoxybenzyl)-1H-indazolyl](pyridinylamino)pyrimidin- -ol (3-2, 0.236 mmol, 1. eq.), 34,2 mg of bromocyclopropane (0,283 mmol, 1,2 eq.), 44,9 mg of copper (I) chloride (0,236 mmol, 1 eq.) and 154 mg of cesium carbonate (0,471 mmol, 2 eq.) were suspended in 3 ml of dry DMF. The reaction mixture was stirred at 60 °C bath temperature for 18 hours. Then the mixture was partitioned between half saturated aq. ammonium chloride on and romethane / isopropanol 4:1. The phases were separated and the aqueous layer was extracted twice with dichloromethane/ isopropanol 4:1. The ed c lay- ers were washed with brine including a precipitate which was separated with filtering it off. The precipitate was purified by preparative HPLC to yield 2,58 mg (0.047 mmol, 2%) of the analytically pure target compound. 1H-NMR (300 MHz, DMSO-d 6): δ [ppm]= 3.65 (s, 3H), 4.90 (d, 2H), 5.19 - 5.40 (m, 2H), 5.60 (s, 2H), 6.01 - 6.18 (m, 1H), 6.85 (d, 2H), 7.09 - 7.18 (m, 1H), 7.26 (d, 2H), 7.34 (t, 1H), 7.65 (d, 1H), 7.94 (s, 1H), 8.28 (br. s., 1H), 8.43 (dd, 3H), 8.57 (br. s., 2H).
LC-MS: retention time: 0.95 min MS ES+: 465.1 [M+H]+Method B [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb Example 15-1 Preparation of 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]methoxy-N- (pyridinyl)pyrimidinamine hydrochloride (1:1) F 3 N x HCl 3 150 mg of 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]methoxy-N- (pyridinyl)pyrimidinamine (21, 0.307 mmol, 1. eq.) were dissolved in a mixture of 5,9 ml of dry dichloromethane and 2,5 ml of dry methanol. 0,25 ml of 1,25 M hydrogen chloride on in methanol were added. The mixture was stirred at room temperature for 1 hour. Then the mixture was concentrated in vacuo to yield 161 mg (0.29 mmol, 95,9%) of the analytically pure target compound. 1H-NMR (300 MHz, DMSO-d 6): δ [ppm]= 1.25 (t, 3H), 3.93 - 4.08 (m, 5H), 5.66 (s, 2H), 6.72 - 6.82 (m, 2H), 7.24 (t, 1H), 7.42 - 7.51 (m, 1H), 7.82 (d, 1H), 8.34 (d, 2H), 8.39 - 8.48 (m, 4H), 9.85 (s, 1H).
LC-MS: retention time: 1.08 min MS ES+: 489.1 [M+H]+ Method B [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb -2 F (2S)({2-[1-(2- 1H-NMR (600MHz, x HCl fluorobenzyl)-1H- DMSO d6): δ [ppm]= 3.50 SM = N indazolyl] - 3.58 (m, 2H), 3.95 - N N 12-2 (pyridin 4.01 (m, 1H), 4.18 (dd, N ylamino)pyrimidin 1H), 4.38 (dd, 1H), 5.85 N N H yl}oxy)propane-1,2- (s, 2H), 7.18 (td, 1H), O diol hydrochloride 7.24 - 7.28 (m, 1H), 7.28 OH (1:1) - 7.33 (m, 2H), 7.35 - 7.40 (m, 1H), 7.49 (ddd, 1H), 7.83 (d, 1H), 8.45 (d, 1H), 8.62 (s, 1H), 8.68 (d, 2H), 8.76 (d, 2H), 10.69 (s, 1H), 14.79 (br. s., 1H).
LC-MS: retention time: 0.87 min MS ES+: 487.45 [M+H]+ -3 CH 3 2-({2-[1-(4-ethoxy- 1H-NMR (400 MHz, O 2,6-difluorobenzyl)- DMSO-d6): δ [ppm]= 1.25 SM = 1H-indazolyl] (t, 3H), 3.81 (d, 2H), 4.01 13-1 N x HC l F (pyridin (q, 2H), 4.26 (t, 2H), 5.09 N ylamino)pyrimidin (br. s., 1H), 5.66 (s, 2H), N yl}oxy)ethanol hy- 6.73 - 6.81 (m, 2H), 7.25 H drochloride (1:1) (t, 1H), 7.47 (t, 1H), 7.82 O (d, 1H), 8.33 - 8.44 (m, OH 3H), 8.45 - 8.54 (m, 3H), 9.74 (br. s., 1H).
LC-MS: retention time: 1.04 min MS ES+: 519.1 [M+H]+ Method B [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb -4 Cl 2-[1-(2,6- 1H-NMR (300 MHz, x HCl dichlorobenzyl)-1H- DMSO-d6): δ [ppm]= 4.01 SM = N Cl indazolyl] (s, 3H), 5.88 (s, 2H), 7.26 N N 21 methoxy-N-(pyridin- (t, 1H), 7.39 - 7.53 (m, N 4-yl)pyrimidin 2H), 7.56 - 7.62 (m, 2H), N N H amine hydrochloride 7.91 (d, 1H), 8.27 (d, 2H), O CH3 (1:1) 8.37 - 8.43 (m, 3H), 8.47 (d, 1H), 9.69 (s, 1H).
LC-MS: retention time: 1.05 min MS ES+: 476.9 [M+H]+ -5 OH ichloro({3- 1H-NMR (300 MHz, Cl [5-methoxy DMSO-d6): δ [ppm]= 3.96 SM = (pyridin - 4.02 (m, 3H), 4.52 (s, 8-1 N ylamino)pyrimidin 2H), 5.47 - 5.55 (m, 1H), x HCl N yl]-1H-indazol 5.89 (s, 2H), 7.25 (t, 1H), N yl}methyl)phenyl]me 7.48 (t, 1H), 7.55 - 7.66 N thanol hydrochloride (m, 2H), 7.90 (d, 1H), H (1:1) 8.09 - 8.15 (m, 2H), 8.31 3 (s, 1H), 8.34 - 8.39 (m, 2H), 8.48 (d, 1H), 9.32 (s, 1H).
LC-MS: retention time: 0.99 min MS ES+: 507.0 [M+H]+ Method B [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb -6 F (2R)({2-[1-(2- 1H-NMR (400 MHz, x HCl fluorobenzyl)-1H- DMSO-d6): δ [ppm]= 3.43 SM = N lyl] - 3.54 (m, 2H), 3.90 - N N 12-3 (pyridin 3.98 (m, 1H), 4.14 (dd, N ylamino)pyrimidin 1H), 4.34 (dd, 1H), 5.82 N N H )propane-1,2- (s, 2H), 7.11 - 7.18 (m, O diol hydrochloride 1H), 7.19 - 7.38 (m, 4H), OH (1:1) 7.46 (ddd, 1H), 7.80 (d, 1H), 8.41 (d, 1H), 8.58 (s, 1H), 8.65 (d, 2H), 8.74 (d, 2H), 10.72 (s, 1H).
LC-MS: retention time: 0.86 min MS ES+: 487.34 [M+H]+ Example 16-1 Preparation of N-{2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]pyrimidin yl}-N-(pyridinyl)acetamide F 3 [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 100 mg of 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]-N-(pyridinyl)- pyrimidinamine (51, 0.218 mmol, 1. eq.) was dissolved in 2 ml of dry dichloromethane.
First 94 µl of dry N,N-diethylethanamine (0.676 mmol, 3,1 eq.) and then 23 µl of acetyl chloride (0,327 mmol, 1,5 eq,) were added under nitrogen at- mosphere. The reaction mixture was d at room temperature for 18 hours.
Then the mixture was partitioned between water and dichloromethane. The phases were separated and the aqueous layer was extracted twice with dichloromethane.
The combined organic layers were washed with brine, dried over a silicon filter and concentrated in vacuo. The residue was purified by flash chromatog- raphy and preparative TLC to yield 29,8 mg (0.06 mmol, 26,8%) of the analytically pure target compound. 1H-NMR (300MHz, DMSO-d 6): δ [ppm]= 1.25 (t, 3H), 2.08 (s, 3H), 4.00 (q, 2H), .61 (s, 2H), 6.63 - 6.75 (m, 2H), 6.85 - 6.93 (m, 1H), 7.09 (d, 1H), 7.36 (ddd, 1H), 7.52 - 7.57 (m, 2H), 7.70 (d, 1H), 7.93 (d, 1H), 8.73 - 8.83 (m, 3H).
LC-MS: retention time: 1.21 min MS ES+: 501.1 [M+H]+ Method B The following compounds were ed according to the same procedure using the indicated starting materials (SM = starting material): 16-2 CH 1H-NMR (300MHz, 3 N-{2-[1-(4- O ethoxy-2,6- DMSO-d6): δ [ppm]= 1.25 difluorobenzyl)- (s, 3H), 3.94 - 4.05 (m, SM = N F 1H-indazol 2H), 4.11 (s, 3H), 5.62 (s, N imidin 2H), 5.72 (s, 2H), 6.71 (d, 51 N yl}methoxy- 2H), 6.90 - 7.00 (m, 1H), N idin 7.28 (d, 1H), 7.38 (t, 1H), yl)acetamide 7.52 - 7.58 (m, 2H), 7.70 O CH 3 - 7.77 (m, 2H), 8.72 - [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 8.84 (m, 3H).
LC-MS: retention time: 1.22 min MS ES+: 531.1 [M+H]+ Method B 16-3 CH 1H-NMR (300MHz, 3 N-{2-[1-(4- O ethoxy-2,6- DMSO-d6): δ [ppm]= 1.25 difluorobenzyl)- (t, 3H), 1.59 - 1.83 (m, SM = N F 1H-indazol 4H), 2.71 - 2.84 (m, 1H), yl]pyrimidin 3.00 - 3.13 (m, 2H), 3.76 51 N N yl}-N-(pyridin (d, 2H), 3.95 - 4.04 (m, N yl)tetrahydro- 2H), 5.62 (s, 2H), 6.67 - O 2H-pyran 6.75 (m, 2H), 6.99 (t, 1H), carboxamide 7.36 - 7.44 (m, 2H), 7.49 - 7.53 (m, 2H), 7.62 (d, 1H), 7.74 (d, 1H), 8.71 - 8.76 (m, 2H), 8.80 (d, 1H).
LC-MS: retention time: 1.25 min MS ES+: 571.2 [M+H]+ Method B ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 16-4 1H-NMR (300MHz, 3CH N-{2-[1-(4- O ethoxy-2,6- DMSO-d6): δ [ppm]= 1.18 SM = difluorobenzyl)- - 1.31 (m, 3H), 3.12 - 51 N F 1H-indazol 3.16 (m, 3H), 3.34 (dd, N yl]pyrimidin 2H), 3.51 (dd, 2H), 4.00 N yl}(2- (d, 2H), 4.19 (s, 2H), 5.62 N methoxyeth- (s, 2H), 6.71 (d, 2H), 6.95 O oxy)-N-(pyridin- (t, 1H), 7.28 (d, 1H), 7.34 O 4-yl)acetamide - 7.42 (m, 1H), 7.51 - 7.56 (m, 2H), 7.69 - 7.77 O (m, 2H), 8.74 - 8.77 (m, 2H), 8.80 (d, 1H).
LC-MS: retention time: 1.22 min MS ES+: 575.2 [M+H]+ Method B e 17-1 Preparation of 2-[{2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]pyrimidin yl}(pyridinyl)amino]ethanol [Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb F 3 120 mg of 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]-N-(pyridinyl)- pyrimidinamine (51, 0.262 mmol, 1. eq.) were suspended in 12 ml of dry DMF. 426 mg of cesium ate (1.31 mmol, 5 eq.) and 142 mg of 1,3,2- dioxathiolane 2-oxide (1,31 mmol, 5 eq.) were added under nitrogen atmosphere.
The reaction mixture was stirred at 60 °C bath temperature for 18 hours. 142 mg of 1,3,2-dioxathiolane 2-oxide (1,31 mmol, 5 eq.) were added and the mixture was stirred at 60 °C bath temperature for further 22 hours. Then the mixture was partitioned between water and dichloromethane/ isopropanol 4:1. The phases were separated and the aqueous layer was extracted twice with dichloromethane/ isopropanol 4:1. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography and preparative TLC to yield 14,2 mg (0.03 mmol, 10,5%) of the analytically pure target compound. 1H-NMR (300MHz, DMSO-d 6): δ [ppm]= 1.26 (t, 3H), 3.64 - 3.76 (m, 2H), 4.01 (q, 2H), 4.11 (t, 2H), 4.91 (t, 1H), 5.64 (s, 2H), 6.66 - 6.80 (m, 3H), 7.13 (t, 1H), 7.42 (t, 1H), 7.47 - 7.53 (m, 2H), 7.75 (d, 1H), 8.16 (d, 1H), 8.37 (d, 1H), 8.54 - 8.62 (m, 2H).
LC-MS: retention time: 0.96 min MS ES+: 503.1 [M+H]+ Method B [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb The following compounds were prepared according to the same procedure using the indicated starting materials (SM = starting material): 17-2 CH (3-{[{2-[1-(4- 1H-NMR (500MHz, DMSO- F 3 O ethoxy-2,6- d6): δ [ppm]= 1.29 (t, 3H), N difluorobenzyl)- F 3.65 (d, 2H), 4.03 (q, 2H), SM = N 1H-indazol 4.35 (d, 2H), 4.57 (d, 2H), N yl]pyrimidin 4.83 (s, 2H), 5.39 (t, 1H), 51 N yl}(pyridin 5.75 (s, 2H), 6.79 - 6.86 OH yl)amino]methyl} (m, 2H), 7.08 (d, 1H), 7.33 (t, 1H), 7.54 (ddd, 1H), yl)methanol 7.90 (d, 1H), 8.38 - 8.55 (m, 3H), 8.63 (d, 2H), 8.81 (d, 1H), 11.45 (br. s., 1H).
Example 18-1 Preparation of 2-{1-[4-bromofluoro(2,2,2-trifluoroethoxy)benzyl]-1H-indazol- 3-yl}methoxy-N-(pyridinyl)pyrimidinamine O Br N F N N N N O CH 38,2 mg of trifluoroethanol (0.382 mmol, 2 eq.) were dissolved in 1,5 ml of dry DMF under nitrogen atmosphere. 16,8 mg of 60% sodium hydrid in paraffin oil [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb (0.42 mmol, 2.2 eq.) were added. The sion was stirred at room temperature for 15 minutes. 100 mg of 2-[1-(4-bromo-2,6-difluorobenzyl)-1H-indazolyl] methoxy-N-(pyridinyl)pyrimidinamine (21, 0,191 mmol, 1 eq.) were added.
The reaction mixture was stirred at room ature for 18 hours. Water was added dropwise. The sion was filtered off. The precipitate was dried at 50 °C under vacuo. The precipitate was purified by preparative HPLC to yield 34 mg (0.05 mmol, 28%) of the analytically pure target compound. 1H-NMR (400MHz, DMSO-d 6): δ [ppm]= 4.00 (s, 3H), 4.82 (q, 2H), 5.60 (s, 2H), 7.22 (t, 1H), 7.30 (s, 1H), 7.39 - 7.46 (m, 1H), 7.74 (d, 1H), 8.10 - 8.16 (m, 3H), 8.32 (s, 1H), 8.35 - 8.39 (m, 2H), 8.42 (d, 1H), 9.38 (s, 1H).
LC-MS: retention time: 1.05 min MS ES+: 605.0 [M+H]+ As a second product the following compound was obtained: 18-2 F 2-{1-[4-bromo- 1H-NMR (400MHz, DMSO- O Br F 2,6-bis(2,2,2- d6): δ [ppm]= 4.00 (s, 3H), SM = F trifluoroeth- 4.82 (q, 4H), 5.55 (s, 2H), 21 F N O F oxy)benzyl]-1H- 7.16 - 7.22 (t, 1H), 7.26 (s, N N indazolyl} 2H), 7.38 (ddd, 1H), 7.68 methoxy-N- (d, 1H), 8.02 - 8.06 (m, 2H), N N (pyridin 8.29 - 8.34 (m, 3H), 8.41 (d, O CH3 imidin 1H), 9.33 (s, 1H). amine LC-MS: retention time: 1.12 min MS ES+: 685.0 [M+H]+ Method B [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb Example 19-1 Preparation of 2,4-dichloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]- 1H-indazolyl}methyl)benzoic acid O OH N Cl 3 1 g of methyl 2,4-dichloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]- 1H-indazolyl}methyl)benzoate (21, 1.868 mmol, 1. eq.) were dissolved in 19 ml of dry THF and 2.2 ml of ol. 4.67 ml of 2 M aqueous sodium hydroxide solution (9.34 mmol, 5 eq.) were added. The mixture was stirred for three hours at room temperature. The reaction mixture was partitioned n citric acid (pH 3) and ethyl acetate. This process dropped out a white precipitate which was filtered off and dried for three days to yield 992 mg (1.86 mmol, 99,8%) of the analytically pure target compound. 1H-NMR (400MHz, DMSO-d6): δ [ppm]= 3.99 (s, 3H), 5.91 (s, 2H), 7.26 (t, 1H), 7.44 - 7.54 (m, 1H), 7.62 - 7.66 (m, 2H), 7.84 - 7.94 (m, 1H), 8.07 - 8.16 (m, 2H), 8.32 (s, 1H), 8.35 - 8.42 (m, 2H), 8.49 (d, 1H), 9.33 (s, 1H) LC-MS: retention time: 0.96 min MS ES+: 521.1 [M+H]+ [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb The following nd was obtained according to the same procedure using the indicated starting material (SM): 19-2 CH3 F ({2-[1-(4-ethoxy- 1H-NMR (300MHz, DMSO- 2,6- d6): δ [ppm]= 1.24 (t, 3H), SM = 4-14 N F difluorobenzyl)- 4.00 (q, 2H), 5.04 (d, 2H), N azolyl]- 5. 68 (s, 2H), 6. 78 (m, 2H), N 4-(pyridin 7.26 (t, 1H), 7.48 (t, 1H), H yla- 7.83 (d, 1H), 8.39 (d, 1H), mino)pyrimidin 8.51 (s, 1H), 8.53-8.63 (m, OH yl}oxy)acetic acid 4H), 10.58 (s, 1H), 14.33 (br. s, 1H).
LC-MS (Method 1): retention time: 1.03 min MS ES+: 481.4 [ Example 20-1 Preparation of 2,4-dichloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]- 1H-indazolyl}methyl)-N-methylbenzamide [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb O NH N Cl 100 mg of chloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H- indazolyl}methyl)benzoic acid (19-1, 0.192 mmol, 1. eq.) were dissolved in 0,953 ml of dry yl sulfoxide. 80,2 mg of N-[(dimethylamino)(3H- [1,2,3]triazolo[4,5-b]pyridinyloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (0.211 mmol, 1,1 eq.), 67 µl of N-ethyl-N-(propanyl)propan amine (0,384 mmol, 2 eq.) and 96 µl of 2 N methyl amine in tetrahydrofuran were added in this sequence. The reaction mixture was stirred at room temperature for 18 hours. 80,2 mg of N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridinyloxy)- methylidene]-N-methylmethanaminium hexafluorophosphate (0.211 mmol, 1,1 eq.), 67 µl of N-ethyl-N-(propanyl)propanamine (0,384 mmol, 2 eq.) and 96 µl of 2 N methyl amine in tetrahydrofuran were added in this sequence again twice and stirred each time at room temperature for 24 hours. The reaction mixture was stirred at 50 °C bath temperature for further 2 hours. Then the mixture was filtered off purified by ative HPLC to yield 15 mg (0.03 mmol, 14,3%) of the analytically pure target compound. 1H-NMR (300MHz, DMSO-d6): δ [ppm]= 2.68 (d, 3H), 3.99 (s, 3H), 5.91 (s, 2H), 7.19 - 7.32 (m, 1H), 7.42 - 7.51 (m, 2H), 7.63 - 7.72 (m, 1H), 7.87 - 7.98 (m, 1H), 8.07 - 8.23 (m, 2H), 8.32 - 8.50 (m, 5H), 9.33 (s, 1H) [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb LC-MS: retention time: 0.92 min MS ES+: 534.2 [M+H]+ The following compounds were obtained according to the same ure using the ted starting materials (SM): -2 O NH 2 2,4-dichloro 1H-NMR (400MHz, DMSO- Cl ({3-[5-methoxy d6): δ [ppm]= 4.00 (s, 3H), SM = 19-1 (pyridin 5.91 (s, 2H), 7.19 - 7.33 (m, yla- 1H), 7.39 - 7.54 (m, 2H), N Cl N mino)pyrimidin 7.56 - 7.63 (m, 1H), 7.63 - N yl]-1H-indazol 7.71 (m, 1H), 7.85 - 7.97 N yl}methyl)benza (m, 2H), 8.06 - 8.22 (m, H mide 2H), 8.32 (s, 4H), 9.23 - 3 9.42 (m, 1H) LC-MS: retention time: 0.91 min MS ES+: 520.1 [M+H]+ -3 CH3 2,4-dichloro 1H-NMR z, DMSO- O N ({3-[5-methoxy SM = CH3 d6): δ [ppm]= 2.64 (s, 3H), 19-1 Cl (pyridin 2.92 (s, 3H), 3.99 (s, 3H), yla- 5.77 - 6.01 (m, 2H), 7.25 (t, N Cl mino)pyrimidin 1H), 7.40 (d, 1H), 7.44 - N yl]-1H-indazol 7.53 (m, 1H), 7.68 (d, 1H), yl}methyl)-N,N- 7.84 - 7.96 (m, 1H), 8.06 - dimethylben- 8.18 (m, 2H), 8.26 - 8.41 zamide (m, 3H), 8.49 (d, 1H), 9.31 3 (s, 1H) LC-MS: retention time: 0.98min [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb MS ES+: 548.2 [M+H]+ -4 OH 2,4-dichloro-N-(2- 1H-NMR (400MHz, hydroxyethyl) Chloroform-d): δ [ppm]= SM = 19-1 O NH ({3-[5-methoxy 3.62 - 3.73 (m, 2H), 3.81 - Cl (pyridin 3.91 (m, 2H), 4.03 (s, 3H), yla- 5.90 (s, 2H), 6.69 - 6.81 (m, mino)pyrimidin 1H), 7.31 (t, 1H), 7.37 - N Cl N yl]-1H-indazol 7.45 (m, 2H), 7.45 - 7.56 N yl}methyl)benza (m, 2H), 7.66 (d, 1H), 7.97 N mide (d, 2H), 8.18 (s, 1H), 8.48 H (d, 2H), 8.64 (d, 1H) LC-MS: retention time: 0.89 min MS ES+: 564.2 [M+H]+ -5 [2,4-dichloro 1H-NMR (300MHz, DMSO- ({3-[5-methoxy d6): δ [ppm]= 2.99 - 3.11 SM = O N 19-1 Cl in (m, 2H), 3.37 - 3.45 (m, yla- 2H), 3.56 - 3.64 (m, 4H), mino)pyrimidin 4.03 (s, 3H), 5.91 (s, 2H), N Cl yl]-1H-indazol 7.28 (t, 1H), 7.45 (d, 1H), N yl}methyl)phenyl] 7.47 - 7.55 (m, 1H), 7.69 (d, N (morpholin 1H), 7.92 (d, 1H), 8.36 - H hanone 8.44 (m, 2H), 8.46 - 8.50 CH (m, 4H), 10.08 (br. s., 1H) LC-MS: retention time: 0.95 min MS ES+: 590.1 [M+H]+ [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb -6 O 3,5-difluoro({3- 1H-NMR (300MHz, F CH SM = H [5-methoxy METHANOL-d4): δ [ppm]= 19-1 (pyridin 2.91 (s, 3H), 4.13 (s, 3H), N F yla- 5.77 - 5.82 (m, 2H), 7.20 - N mino)pyrimidin 7.28 (m, 1H), 7.44 (td, 1H), N yl]-1H-indazol 7.60 (d, 3H), 8.47 (d, 1H), H yl}methyl)-N- 8.56 (s, 1H), 8.59 - 8.67 (m, 3 methylbenzamide 4H).
LC-MS: retention time: 0.80 min MS ES+: 502.1 [M+H]+ Example 21-1 Preparation of 2-[1-(4-ethynylfluorobenzyl)-1H-indazolyl]methoxy-N- (pyridinyl)pyrimidinamine N F N N N N O CH Step 1: 2-fluoro[(trimethylsilyl)ethynyl]benzyl}-1H-indazolyl)methoxy- N-(pyridinyl)pyrimidinamine 144,7 mg of 2-[1-(2-fluoroiodobenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine , 0,262 mmol, 1 eq.), 6,02 mg of (1E,4E)-1,5- diphenylpenta-1,4-dienone - palladium (2:1) ( 0,01 mmol, 0,04 eq.), 2,0 mg of [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb copper (I) iodide ( 0,01 mmol, 0,04 eq.), and 13,7 mg of triphenylphosphane (0,052 mmol, 0,2 mmol) were suspended in 2,6 ml of dry N,N-diethylethanamine and purged with nitrogen. Then 3,86 ml of ethynyl(trimethyl)silane (1,57 mmol, 6 eq.) were added and the reaction mixture was stirred at 60 °C for 18 hours. The mixture was concentrated under vacuo. The crude product was used without further cation in step 2.
LC-MS: retention time: 1,14 min MS ES+: 523,4 [M+H]+ Method B Step 2: 2-[1-(4-ethynylfluorobenzyl)-1H-indazolyl]methoxy-N-(pyridin imidinamine 37,3 mg of 2-(1-{2-fluoro[(trimethylsilyl)ethynyl]benzyl}-1H-indazolyl) y-N-(pyridinyl)pyrimidinamine (0.071 mmol, 1. eq.) were dissolved in 1,0 ml of dry tetrahydrofuran. 71 µl of a 1 M N,N,N-tributylbutanammonium de in tetrahydrofuran (0,071 mmol, 1 eq.) were added under nitrogen atmosphere and stirred at room temperature for 18 hours. Then the mixture was partitioned between a aqueous half saturated sodium hydrogen carbonate solution and di- chloromethane/ isopropanol 4:1. The phases were separated and the aqueous layer was extracted twice with dichloromethane/ isopropanol 4:1. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative TLC in ethyl acetate/ methanol 7:3 to yield 23,2 mg (0.05 mmol, 68,4%) of the ically pure target compound. 1H-NMR (300MHz, DMSO-d 6): δ [ppm]= 4.01 (s, 3H), 4.28 (s, 1H), 5.79 (s, 2H), 7.20 - 7.31 (m, 3H), 7.34 - 7.48 (m, 2H), 7.80 (d, 1H), 8.07 - 8.13 (m, 2H), 8.33 (s, 1H), 8.35 - 8.40 (m, 2H), 8.44 (d, 1H), 9.41 (s, 1H).
LC-MS: retention time: 0.91 min MS ES+: 451.4 [M+H]+ Method B [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb e 22-1 Preparation of {2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridinyl)-7,8-dihydro- 6H-pyrimido[5,4-b][1,4]oxazinyl}methanol mg of 2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridinylamino)pyrimidinol (3-3, 0.061 mmol, 1. eq.), 28,2 mg of 3-bromopropane-1,2-diol (0,182 mmol, 3 eq.) and 41,9 mg of potassium carbonate (0,303 mmol, 5 eq.) were suspended in 470 µl of dry DMF under nitrogen atmosphere. The reaction mixture was stirred at 100 °C bath temperature for 18 hours. Then the mixture was partitioned between aqueous half saturated sodium chloride on and ethyl acetate. The phases were separated and the aqueous layer was extracted once with ethyl acetate and once with dichloromethane/ isopropanol 4:1. The combined organic layers were dried over magnesium e and concentrated in vacuo. The residue was purified by preparative TLC in romethane/ methanol 9:1 to yield 6,26 mg (0.01 mmol, 19,8%) of the analytically pure target compound. 1H-NMR (300MHz, DMSO-d 6): δ [ppm]= 3.53 - 3.67 (m, 2H), 4.14 - 4.23 (m, 1H), 4.25 - 4.32 (m, 1H), 4.53 - 4.61 (m, 1H), 5.26 - 5.33 (m, 1H), 5.73 (s, 2H), 7.01 - 7.24 (m, 4H), 7.27 - 7.42 (m, 2H), 7.68 - 7.78 (m, 3H), 8.13 (d, 1H), 8.26 (s, 1H), 8.50 - 8.57 (m, 2H).
LC-MS: [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb retention time: 0.89 min MS ES+: 469.0 [M+H]+ Method B Example 23-1 Preparation of 2-[1-(2-fluorobenzyl)-1H-indazolyl]methoxy-N-methyl-N- (pyridinyl)pyrimidinamine N 3 135 mg of 2-[1-(2-fluorobenzyl)-1H-indazolyl]methoxy-N-(pyridinyl)- pyrimidinamine (21, 0.316 mmol, 1. eq.) were ved in 3 ml of 1-methylpyrrolidinone and 514 mg of cesium carbonate (1.58 mmol, 5 eq.) were added.
The reaction mixture was d at 190 °C bath temperature for 18 hours. After cooling at room temperature the mixture was partitioned between water and butan- 2-one. The phases were separated and the aqueous layer was extracted twice with butanone. The combined organic layers were washed with brine and dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography and preparative TLC to yield 10,9 mg (0.02 mmol, 7,2%) of the analytically pure target compound. 1H-NMR (400MHz, DMSO-d 6): δ [ppm]= 3.77 (s, 3H), 3.89 (s, 3H), 5.80 (s, 2H), 7.15 - 7.19 (m, 3H), 7.21 - 7.29 (m, 3H), 7.34 - 7.41 (m, 2H), 7.44 (ddd, 1H), 7.75 (d, 1H), 7.79 (br. s., 1H), 8.23 (s, 1H), 8.50 (d, 1H).
[Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb LC-MS: retention time: 1,02 min MS ES+: 441.53 [M+H]+ Example 24-1 Preparation of 4-({2-[1-(2-fluorobenzyl)-1H-indazolyl]methoxypyrimidin yl}amino)pyridinecarbonitrile N H 3 N 175 mg of 2-[1-(2-fluorobenzyl)-1H-indazolyl]methoxypyrimidinamine (1- 11-1, 0.501 mmol, 1. eq.), 101 mg of 4-bromopyridinecarbonitrile (0.551 mmol, 1.1 eq.), 115 mg of Tris(dibenzylideneacetone)dipalladium (0) (0.125 mmol, 0.25 eq.), 156 mg of 1,1'-binaphthalene-2,2'-diylbis(diphenylphosphane) (0.25 mmol, 0.5 eq), 144 mg of sodium 2-methylpropanolate (97%) (1.503 mmol, 3 eq.) and 52 ml of N,N-dimethylformamide were stirred under nitrogen here for 30 minutes at 100 °C and 300 W in a CEM microwave. The reaction mixture was washed with half-saturated aqueous sodium chloride solution. The organic layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (hexane/ dichloromethane/ ol) and ative HPLC. A crystallisation from dichloromethane/methanol gave 5.8 mg (0.01 mmol, 2,6%) of the analytically pure target compound. ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 1H-NMR (300MHz, DMSO-d 6): δ [ppm]= 4.04 (s, 3H), 5.76 (s, 2H), 7.08 - 7.26 (m, 4H), 7.28 - 7.46 (m, 2H), 7.75 (d, 1H), 8.20 - 8.31 (m, 2H), 8.45 (s, 1H), 8.68 (d, 1H), 8.88 (s, 1H), 9.23 (s, 1H).
LC-MS: retention time: 1.28 min MS ES+: 452.33 [M+H]+ The following compounds were prepared according to the same procedure using the indicated ng materials (SM = starting material), and the respective halopyridines [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb 24-2 F methyl [1- 1H-NMR (300MHz, (2-fluorobenzyl)- DMSO-d6): δ [ppm]= SM = 12 N 1H-indazolyl]- 4.05 (s, 3H), 4.11 (s, - 3H), 5.80 - 5.85 (m, 2H), N O CH3 methoxypyrim- 7.10 - 7.40 (m, 6H), 7.49 N H N O idin - 7.59 (m, 2H), 7.86 (d, O yl}amino)pyridin 1H), 8.06 (d, 1H), 8.39 CH3 N ecarboxylate (dd, 1H), 8.95 - 9.06 (m, 2H).
LC-MS: retention time: 0.91 min MS ES+: 485.11 [M+H]+ 24-3 F 2-[1-(2- 1H-NMR (300MHz, fluorobenzyl)- DMSO-d6): δ [ppm]= SM = 12 1H-indazolyl]- 4.01 (s, 3H), 5.77 (s, N 5-methoxy-N- 2H), 7.10 - 7.49 (m, 6H), (pyridin 7.75 - 7.84 (m, 1H), 8.07 N yl)pyrimidin - 8.17 (m, 2H), 8.33 (s, N amine 1H), 8.35 - 8.40 (m, 2H), 8.40 - 8.48 (m, 1H), 9.35 CH - 9.45 (m, 1H).
LC-MS: retention time: 1.01 min MS ES+: 427.19 [M+H]+ Method B The following compound was also formed during the on leading to 24-3: [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb ation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb 24-4 F 2-[1-(2- 1H-NMR (300MHz, benzyl)-1H- DMSO-d6): δ [ppm]= 3.74 SM = indazolyl] (s, 3H), 5.75 (s, 2H), 6.92 12 N methoxy-N,N- (t, 1H), 6.99 - 7.12 (m, di(pyridin 6H), 7.13 - 7.23 (m, 1H), N yl)pyrimidinamine 7.26 - 7.38 (m, 2H), 7.65 N (dd, 2H), 8.41 - 8.50 (m, O 4H), 8.71 (s, 1H). 3 N LC-MS: retention time: 0.90 min MS ES+: 504.57 [M+H]+ The following compounds were prepared according to the same procedure using the indicated starting materials (SM = starting material), and the respective halopyridines / halopyridones: 24-5 CH3 4-({2-[1-(4-ethoxy- 1H-NMR z, F O 2,6-difluorobenzyl)- DMSO-d6): δ [ppm]= 1.30 SM = 1H-indazolyl] (t, 3H), 4.05 (q, 2H), 4.07 13 N F methoxypyrimidin (s, 3H), 5. 67 (s, 2H), 6.
N N yl}amino)pyridine 80 (m, 2H), 7.22 (t, 1H), N N carbonitrile 7.48 (t, 1H), 7.83 (d, 1H), N 8.32 (d, 1H), 8.45 (br. s, O CH3 1H), 8.68 (br. s, 1H), 8.90 (br. s, 1H), 9.15 (br. s, 1H).
Ein H fehlt LC-MS (Method 5): retention time: 1.43 min MS ES+: 514.2 [5 [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 24-6 CH3 2-[(3-{4-[(2,6- 1H-NMR (400MHz, OH O dimethylpyridin 6): δ [ppm]= 1.24 SM = no] N F CH (t, 3H), 2.36 (s, 6H), 3.90 13 N N CH3 ypyrimidin (q, 2H), 3.99 (s, 3H), 5.
N N yl}-1H-indazol 54 (s, 2H), 6. 20 (br. s, O CH3 yl)methyl]ethoxy- 1H), 6. 24 (br. d, 1H), 3-fluorophenol 7.18 (t, 1H), 7.39 (t, 1H), 7.78 (s, 1H), 7.78 (d, 1H), 8.28 (s, 1H), 8.44 (d, 1H), , 9.09 (s, 1H), 10.26 (br. s, 1H).
LC-MS (Method 5): retention time: 0.68 min MS ES+: 515.2 24-7 O 1H-NMR (300MHz, 3CH 4-({5-methoxy[1- (4-methoxybenzyl)- DMSO-d6): δ [ppm]= 3.65 SM = N 1H-indazol (s, 3H), 4.00 (s, 3H), 5.62 11 H yl]pyrimidin (s, 2H), 6.79 - 6.87 (m, N O yl}amino)pyridin- 3H), 7.13 - 7.27 (m, 2H), H 2(1H)-one 7.27 - 7.45 (m, 4H), 7.76 O CH3 (d, 1H), 8.33 (s, 1H), 8.42 (d, 1H), 9.06 (s, 1H), 11.03 (br. s., 1H).
LC-MS: retention time: 0.97 min MS ES+: 455.2 [M+H]+ [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 24-8 CH3 4-({2-[1-(4-ethoxy- 1H-NMR (300MHz, F O 2,6-difluorobenzyl)- 6): δ [ppm]= 1.25 SM = 1H-indazolyl] (t, 3H), 3.98 (s, 3H), 4.00 13 N F methoxypyrimidin (q, 2H), 5. 63 (s, 2H), 6.
N yl}amino)pyridin- 72 (m, 2H), 6. 97 (br. s, N O 2(1H)-one 1H), 7. 05 (br. d, 1H), H 7.20 (m, 1H), 7.44 (t, 1H), CH3 7.75 (m, 2H), 8.31 (s, 1H), 8.41 (d, 1H), 9.06 (s, 1H), 11.02 (br. s, 1H).
LC-MS (Method 2): retention time: 0.94 min MS ES+: 505.0 24-9 CH 3 4-({5-methoxy[1- (4-propylbenzyl)- LC-MS: SM = 1H-indazol retention time: 1.51min 14 yl]pyrimidin MS ES+: 476.27 [M+H]+ N yl}amino)nicotinonitr N ile CH3 N e 25-1 ation of 4-({2-[1-(2-fluorobenzyl)-1H-indazolyl]methoxypyrimidin yl}amino)pyridinecarboxamide [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb N H N NH 3 N 54 mg of [1-(2-fluorobenzyl)-1H-indazolyl]methoxypyrimidin yl}amino)pyridinecarbonitrile (24-1, 0.12 mmol, 1. eq.) were ved in 1.6 ml of dimethyl sulfoxide under nitrogene atmosphere. 42 µl of 3 M aqueous sodium hydroxide solution (0.126 mmol, 1.05 eq.) were added. The mixture was oilbath heated to 63 °C bath ature. At this temperature 302µl hydrogen peroxide (30% in water) (9.87 mmol, 82.2 eq.) were added dropwise. The reaction mixture was stirred at 65 °C bath temperature for 3 hours and at room temperature for 24 hours. After stirring the mixture one hour with ice-water it was extracted three times with dichloromethane/ isopropanol 4:1. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative TLC (dichloromethane/ methanol 9:1) to yield 12.0 mg (0.02 mmol, 20.5%) of the analytically pure target compound. 1H-NMR (300MHz, DMSO-d 6): δ [ppm]= 4.01 (s, 3H), 5.79 (s, 2H), 7.10 - 7.39 (m, 5H), 7.45 (t, 1H), 7.81 (d, 2H), 8.34 - 8.55 (m, 4H), 8.91 (s, 1H), 9.22 (d, 1H), 12.10 - 12.19 (m, 1H).
LC-MS: retention time: 1.01 min MS ES+: 470.1 [M+H]+ Method B [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb The following compounds were obtained according to the same procedure using the indicated ng materials (SM = ng al): -2 CH 1H-NMR (400MHz, 3 4-({5-methoxy[1- (4-propylbenzyl)- DMSO-d6): δ [ppm]= 0.81 SM = 1H-indazol (t, 3H), 1.43 - 1.55 (m, yl]pyrimidin 2H), 2.44 – 2.56 (m, 2H), 24-9 N yl}amino)pyridine 4.02 (s, 3H), 5.70 (s, 2H), N carboxamide 7.12 (d, 2H), 7.21 - 7.29 N (m, 3H), 7.41 (ddd, 1H), NH2 7.78 (d, 1H), 7.86 (br. s., O O 1H), 8.38 - 8.46 (m, 3H), 8.54 (d, 1H), 8.92 (s, 1H), 9.25 (d, 1H), 12.19 (s, 1H).
LC-MS: retention time: 1.24 min MS ES+: 494.3 [M+H]+ The following compound was prepared according to the following alternative method: 105 mg of 4-({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl] methoxypyrimidinyl}amino)pyridinecarbonitrile (24-5, 0,204 mmol) was dissolved in 311 µl conc. sulphuric acid (5,83 mmol) and stirred at room temperature for 18 hours. The mixture was poured in ice water and then 2M sodium hydroxid was added until a basic pH was reached. The aqueous phase was extracted 3 times with CH2Cl2/isopropanol 4:1, dried over magnesium sulphate, ed off and concentrated in vacuo. The residue was purified by preparative TLC oromethane / methanol 9:1) to yield 6.9 mg (0.01 mmol, 6.3%) of the analytically pure target compound.
[Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb -3 CH 4-({2-[1-(4-ethoxy- 1H-NMR (400MHz, F O 2,6-difluorobenzyl)- DMSO-d6): δ [ppm]= 1.26 SM = 1H-indazolyl] (t, 3H), 3.94 - 4.08 (m, N F 24-5 N N methoxypyrimidin 5H), 5.65 (s, 2H), 6.77 (d, N yl}amino)pyridine 2H), 7.19 - 7.32 (m, 1H), N N NH H 2 O carboxamide 7.40 - 7.53 (m, 1H), 7.74 O CH 3 - 7.87 (m, 2H), 8.29 - 8.55 (m, 4H), 8.92 (s, 1H), 9.20 - 9.30 (m, 1H), 12.17 (s, 1H).
LC-MS: retention time: 1.13 min MS ES+: 532.3 [M+H]+ The following compound was also formed during the same reaction: -4 F OH 4-({2-[1-(2,6- 1H-NMR (500MHz, difluoro DMSO-d6): δ [ppm]= 4.05 SM = N F N N hydroxybenzyl)-1H- (s, 3H), 5.66 (s, 2H), 6.54 24-5 N indazolyl] (m, 2H), 7.30 (t, 1H), 7.51 N N NH H 2 O methoxypyrimidin (t, 1H), 7.85-7.88 (m, 2H), O no)pyridine 8.42 (s, 1H), 8.46 (br. s, carboxamide 1H), 8.48 (s, 1H), 8.49 (s, 1H), 8.53 (d, 1H), 8.96 (s, 1H), 9.33 (d, 1H), 10.56 (br. s, 1H).
LC-MS (Method 5): retention time: 0.75 min MS ES+: 504.2 [M+H]+ [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb e 26-1 Preparation of 4-({2-[1-(2-fluorobenzyl)-1H-indazolyl]hydroxypyrimidin yl}amino)pyridinecarbonitrile N N N 50 mg of 4-amino[1-(2-fluorobenzyl)-1H-indazolyl]pyrimidinol 1, 0.149 mmol, 1. eq.) were dissolved in 3 ml of N,N-dimethylformamide. 103 mg of potassium carbonate (0.746 mmol, 5 eq.) and 32.8 mg of 4-bromopyridine itrile (0.179 mmol, 1.2 eq.) were added. The reaction mixture was stirred at 100 °C bath temperature for 18 hours. After cooling at room temperature the mixture was filtered off and washed with dichloromethane. The filtrate was concentrated in vacuo. The residue was ed by preparative HPLC and preparative TLC to yield 4.21 mg (0.01 mmol, 6.1%) of the analytically pure target compound. 1H-NMR (400MHz, DMSO-d 6): δ [ppm]= 5.75 (s, 2H), 7.10 - 7.25 (m, 4H), 7.29 - 7.37 (m, 1H), 7.41 (ddd, 1H), 7.76 (d, 1H), 8.21 (s, 1H), 8.30 (d, 1H), 8.48 (d, 1H), 8.65 (d, 1H), 8.86 (s, 1H), 8.90 - 9.03 (m, 1H), 11.09 - 11.44 (m, 1H).
LC-MS: retention time: 1.13 min MS ES+: 438.32 [M+H]+ [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb The following compound was formed during the same procedure using the indicated starting material (SM = starting material): 26-2 F 4-({4-[(3- LC-MS: cyanopyridin retention time: 1.10 min SM = N yl)amino][1-(2- 11 N fluorobenzyl)-1H- MS ES+: 540.30 [M+H]+ N indazol N H N yl]pyrimidin yl}oxy)pyridine N carbonitrile N N e 27-1 ation of 5-methoxy[1-(4-methoxybenzyl)-1H-indazolyl]-N-[3- (trifluoromethyl)pyridinyl]pyrimidinamine NN N CH FF 3 F 1 g of 5-methoxy[1-(4-methoxybenzyl)-1H-indazolyl]pyrimidinamine , 2.77 mmol, 1. eq.), 938 mg of 4-bromo(trifluoromethyl)pyridine (4.15 mmol, 1.5 eq.), 127 mg of Tris(dibenzylideneacetone)dipalladium (0) (0.138 mmol, 0.05 eq.), [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 345 mg of 1,1'-binaphthalene-2,2'-diylbis(diphenylphosphane) (0.553 mmol, 0.2 eq), 1.06 g of sodium 2-methylpropanolate (97%) (11.1 mmol, 4 eq.) and 15 ml of N,N-dimethylformamide were stirred under nitrogen atmosphere for 24 hours at 100 °C bath temperature in a pressure pipe. The reaction mixture was washed with half-saturated aqueous ammonium chloride solution. The organic layer was extracted three times with dichloromethane. The combined organic layers were washed with brine and dried over magnesium e and trated in vacuo.
The residue was purified twice by flash tography (hexane/ ethyl acetate/ methanol) and preparative TLC. A crystallisation gave 56.9 mg (0.1 mmol, 3.73%) of the ically pure target compound. 1H-NMR (400MHz, DMSO-d 6): δ [ppm]= 3.66 (s, 3H), 4.05 (s, 3H), 5.65 (s, 2H), 6.81 - 6.89 (m, 2H), 7.17 (t, 1H), 7.28 (d, 2H), 7.34 - 7.42 (m, 1H), 7.76 (d, 1H), 8.18 - 8.28 (m, 2H), 8.45 (s, 1H), 8.76 - 8.89 (m, 3H).
LC-MS: retention time: 1.39 min MS ES+: 507.0 [M+H]+ Example 28-1 Preparation of 3-chloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H- indazolyl}methyl)benzoic acid [Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb 150 mg of methyl 3-chloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]- 1H-indazolyl}methyl)benzoate (21, 0.299 mmol, 1. eq.) were dissolved in 0,364 ml of methanol. 60 mg of sodium hydroxid (1.50 mmol, 5 eq.) were added.
The reaction mixture was d at room temperature for 3 hours. The resulting suspension was neutralised with acetic acid. The solution was diluted with ethyl acetate. The occurred precipitate was filtered off and washed with ethyl acetate and was dried in vacuo at 50 °C to yield 138 mg (0.28 mmol, 92,8%) of the analytically pure target compound. 1H-NMR (400MHz, DMSO-d 6): δ [ppm]= 4.01 (s, 3H), 5.88 (s, 2H), 7.20 (d, 1H), 7.26 (t, 1H), 7.45 (td, 1H), 7.76 - 7.85 (m, 2H), 7.95 (d, 1H), 8.07 - 8.11 (m, 2H), 8.32 - 8.37 (m, 3H), 8.48 (d, 1H), 9.39 (s, 1H).
LC-MS: ion time: 0.93 min MS ES+: 487.2 [M+H]+ Example 29-1 Preparation of formic acid - 3-chloro({3-[5-methoxy(pyridin ylamino)pyrimidinyl]-1H-indazolyl}methyl)-N-methylbenzamide (1:1) N CH3 O CH x HCOOH 130.9 mg of 3-chloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H- indazolyl}methyl)benzoic acid (28-1, 0.269 mmol, 1. eq.), 1,1 ml of dimethyl- [Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb sulfoxide, 269 µl of 2 M methanamine in tetrahydrofuran (0.538 mmol, 2 eq.), 225 mg of N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridinyloxy)methylidene]-N- methylmethanaminium hexafluorophosphate (HATU; 0.591 mmol, 2.2 eq.) and 140 µl of N-ethyl-N-(propanyl)propanamine (0.806 mmol, 3eq.) were stirred at 50 °C bath temperature for 5 hours. The reaction mixture was ed off and purified by preparative HPLC to yield 91 mg (0.17 mmol, 62%) of the analytically pure target nd. 1H-NMR (300MHz, DMSO-d 6): δ [ppm]= 2.72 (d, 3H), 4.01 (s, 3H), 5.85 (s, 2H), 7.19 - 7.29 (m, 2H), 7.40 - 7.48 (m, 1H), 7.73 (dd, 1H), 7.79 (d, 1H), 7.92 (d, 1H), 8.06 - 8.13 (m, 3H), 8.31 - 8.39 (m, 3H), 8.44 - 8.54 (m, 2H), 9.39 (s, 1H).
LC-MS: retention time: 0.82 min MS ES+: 500.1 [M+H]+ Method B The compound was treated with base to form the salt free analogon: 29-2 O 3-chloro({3-[5- 1H-NMR (300MHz, N 3 methoxy(pyridin- DMSO-d6): δ [ppm]= 2.72 SM = N Cl 4-ylamino)pyrimidin- (d, 3H), 4.01 (s, 3H), 5.85 28-1 N 2-yl]-1H-indazol (s, 2H), 7.20 - 7.28 (m, N yl}methyl)-N- 2H), 7.44 (td, 1H), 7.73 H methylbenzamide (dd, 1H), 7.79 (d, 1H), CH3 7.92 (d, 1H), 8.10 (dd, 2H), 8.32 - 8.39 (m, 3H), 8.45 - 8.54 (m, 2H), 9.38 (s, 1H).
Example 30-1 ation of 4-({2-[1-(2-fluorobenzyl)-1H-indazolyl]hydroxypyrimidin yl}amino)pyridinecarboxamide [Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb N H N NH mg of o[1-(2-fluorobenzyl)-1H-indazolyl]pyrimidinol (11, 0.075 mmol, 1. eq.) were dissolved in 1.5 ml of N,N-dimethylformamide. 51.52 mg of potassium carbonate (0.373 mmol, 5 eq.) and 23.35 mg of ropyridine carboxamide (0.149 mmol, 2 eq.) were added. The reaction mixture was stirred at 100 °C bath temperature in a pressure pipe for 48 hours. The reaction mixture was filtered off. The residue was purified by preparative HPLC to yield 2.07 mg (0.004 mmol, 5.6%) of the ically pure target compound. 1H-NMR (300MHz, DMSO-d 6): δ [ppm]= 5.77 (s, 2H), 7.11 - 7.37 (m, 5H), 7.40 - 7.48 (m, 1H), 7.74 - 7.83 (m, 2H), 8.18 (s, 1H), 8.38 (br. s., 1H), 8.41 - 8.50 (m, 2H), 8.89 (s, 1H), 9.20 (d, 1H), 10.90 (br. s., 1H), 11.94 (s, 1H).
LC-MS: retention time: 0.94 min MS ES+: 456.2 [M+H]+ The following compound was formed during the same procedure using the indicated starting material (SM = starting material): [Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb -2 F 4-({2-[1-(2- 1H-NMR (300MHz, fluorobenzyl)-1H- DMSO-d6): δ [ppm]= 5.78 SM = N indazolyl] (s, 2H), 7.12 - 7.39 (m, 11 hydroxypyrimidin 6H), 7.44 (t, 1H), 7.79 (d, N O yl}amino)pyridine 1H), 8.23 (s, 1H), 8.44 (d, N OH carboxylic acid 1H), 8.50 (d, 1H), 8.98 (s, 1H), 9.33 (d, 1H), 11.02 (br. s., 1H), 13.66 - 14.11 (br. s., 1H).
LC-MS: retention time: 0.95 min MS ES+: 456.9 [M+H]+ Method B -3 F ethyl 4-({2-[1-(2- 1H-NMR (300MHz, fluorobenzyl)-1H- DMSO-d6): δ [ppm]= 1.36 SM = N indazolyl] (t, 3H), 4.35 (q, 2H), 5.68 11 hydroxypyrimidin (s, 2H), 7.07 - 7.38 (m, N O N H N O yl}amino)pyridine 7H), 7.47 (s, 1H), 7.63 (d, OH ylate 1H), 8.32 - 8.42 (m, 1H), 8.43 - 8.53 (m, 1H), 8.90 (s, 1H), 9.43 (d, 1H), 11.26 (s, 1H).
LC-MS: retention time: 1.09 min MS ES+: 485.21 [M+H]+ e 31-1 Preparation of 2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinecarbonitrile [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb N N N N 73 mg of 4-chloro[1-(2-fluorobenzyl)-1H-indazolyl]pyrimidinecarbonitrile (11, 0.201 mmol, 1. eq.), 22.66 mg of pyridinamine (0.241 mmol, 1.2 eq.), 42 µl of N-ethyl-N-(propanyl)propanamine (0.241 mmol, 1.2 eq.) and 1 ml of N,N-dimethylformamide were stirred at room temperature for 24 hours. The reaction mixture was partitioned between half-saturated aqueous sodium hydrogen carbonate on and dichloromethane/ panol 4:1. The aqueous layer was extracted twice with dichloromethane/ isopropanol 4:1. The combined organic layers were washed with brine, dried over a silicon filter and concentrated in vacuo.
The residue was purified by flash chromatography and preparative HPLC to yield 24.4 mg (0.06 mmol, 28.9%) of the analytically pure target compound. 1H-NMR (300MHz, DMSO-d 6): δ [ppm]= 5.83 (s, 2H), 7.08 - 7.40 (m, 5H), 7.47 (td, 1H), 7.82 - 7.92 (m, 3H), 8.34 (d, 1H), 8.46 (d, 2H), 8.99 (s, 1H), 10.16 - 10.37 (m, 1H).
LC-MS: retention time: 1.00 min MS ES+: 422.2 [M+H]+ Example 32-1 Preparation of 2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinecarboxamide [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb N N N N ,7 mg of 2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridinylamino)pyrimidine- -carbonitrile (31-1, 0.049 mmol, 1 eq.) were added to ice bath cooled conc. sulfuric acid (1.84 mmol, 37.5 eq.) and stirred for five minutes at 5 °C and further 24 hours at room temperature. Ice was added to the suspension. The suspension was ed off, washed with water and the filter cake was dried under vacuo at 50 °C to yield 23.0 mg (0.05 mmol, 106%) of the analytically pure target compound. 1H-NMR (300MHz, DMSO-d 6): δ [ppm]= 5.86 (s, 2H), 7.13 - 7.27 (m, 2H), 7.29 - 7.41 (m, 3H), 7.46 - 7.55 (m, 1H), 7.88 (d, 1H), 8.07 (br. s., 1H), 8.28 (d, 2H), 8.46 (d, 1H), 8.57 (d, 3H), 9.19 (s, 1H), 12.07 (s, 1H).
LC-MS: retention time: 1.02 min MS ES+: 440.37 [M+H]+ Example 33-1 ation of 4-({2-[1-(2-fluorobenzyl)-1H-indazolyl](2- hydroxyethoxy)pyrimidinyl}amino)pyridinecarboxylic acid hydrochloride (1:1) [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb N x HCl N O N H N OH 183 mg of 4-({5-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)[1-(2-fluorobenzyl)-1H- indazolyl]pyrimidinyl}amino)pyridinecarboxylic acid (derived from 30-3 as SM via step 1 of the procedure described in 13-1 and subsequent ester hydrolysis) 0.297 mmol, 1. eq.) were dissolved in 10 ml of 4 M hydrogen chloride solution in dioxane and d at room temperature for 24 hours. The precipitate was filtered off, washed with dichloromethane and the filter cake was dried under vacuo to yield 157 mg (0.26 mmol, 88.4%) of the analytically pure target nd. 1H-NMR (300MHz, DMSO-d 6): δ [ppm]= 3.52 (s, 2H), 3.79 - 3.88 (m, 2H), 4.35 (t, 2H), 5.82 (s, 2H), 7.08 - 7.38 (m, 5H), 7.46 (t, 1H), 7.81 (d, 1H), 8.43 (d, 1H), 8.65 - 8.70 (m, 1H), 8.76 (d, 1H), 9.11 (s, 1H), 9.66 (d, 1H), 12.53 (s, 1H).
LC-MS: retention time: 0.98 min MS ES+: 501.33 [M+H]+ Example 34-1 Preparation of N-(2-fluoropyridinyl)methoxy[1-(4-methoxybenzyl)-1H- indazolyl]pyrimidinamine [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb N H O F 3 N 100 mg of oxy[1-(4-methoxybenzyl)-1H-indazolyl]pyrimidinamine (11, 0.277 mmol, 1. eq.), 78.0 mg of (2-fluoropyridinyl)boronic acid (0.553 mmol, 2 eq.) and 205 mg of copper (II) acetate were suspended in 4 ml of tri- chloromethane. 154 µl of triethylamine (1.11 mmol, 4 eq.) and 16.9 mg of N,N- dimethylpyridinamine (138 mmol, 0.5 eq.) were added. The reaction mixture was stirred at room temperature for 24 The reaction mixture was filtered off over Celite 545 and washed with dichloromethane. The filtrate was concentrated in vacuo. The residue was ed by flash chromatography and preparative HPLC to yield 13 mg (0.03 mmol, 10.9%) of the analytically pure target compound. 1H-NMR (300MHz, DMSO-d6): δ [ppm]= 3.66 (s, 3H), 4.03 (s, 3H), 5.63 (br. s., 2H), 6.85 (d, 2H), 7.23 (d, 1H), 7.29 - 7.48 (m, 3H), 7.75 - 7.92 (m, 2H), 8.05 (d, 1H), 8.26 (s, 1H), 8.42 (d, 2H), 9.75 (s, 1H).
LC-MS: retention time: 1.25 min MS ES+: 457.2 [M+H]+ The following compound was formed according to the same procedure using the indicated starting material (SM): [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 34-2 1H-NMR (400MHz, O N-(2,6- 3 difluoropyridinyl)- DMSO-d6): δ [ppm]= 3.66 SM = N 5-methoxy[1-(4- (s, 3H), 4.04 (s, 3H), 5.63 11 methoxybenzyl)-1H- (s, 2H), 6.84 (d, 2H), 7.22 N H N indazol (t, 1H), 7.36 (d, 2H), 7.40 O F yl]pyrimidinamine (d, 1H), 7.83 (d, 1H), 7.98 3 N (s, 2H), 8.38 - 8.49 (m, 2H), 10.04 (s, 1H).
LC-MS: retention time: 1.40 min MS ES+: 475.3 [M+H]+ Method B 34-3 1H-NMR z, O N-(3-fluoropyridin 3 yl)methoxy[1- DMSO-d6): δ [ppm]= 3.65 SM = N (4-methoxybenzyl)- (s, 3H), 4.02 (s, 3H), 5.62 11 1H-indazol (br. s., 2H), 6.83 (d, 2H), N H F N yl]pyrimidinamine 7.07 - 7.18 (m, 1H), 7.24 O (br. s., 2H), 7.38 (t, 1H), 3 N 7.74 (d, 1H), 8.22 (d, 1H), 8.29 - 8.79 (m, 5H).
LC-MS: retention time: 1.17 min MS ES+: 457.43 [M+H]+ Method B 34-4 5-methoxy[1-(4- 1H-NMR z, CH3 O methoxybenzyl)-1H- DMSO-d6): δ [ppm]= 2.41 SM = N N indazolyl]-N-(2- (s, 3H), 3.66 (s, 3H), 4.01 11 N N methylpyridin (s, 3H), 5.65 (br. s., 2H), N CH H yl)pyrimidinamine 6.85 (d, 2H), 7.20 (t, 1H), O CH 3 7.31 (d, 2H), 7.40 (t, 1H), 7.72 (br. d, 1H), 7.79 (d, [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb 1H), 8.23-8.27 (m, 2H), 8.32 (s, 1H) 8.44 (d, 1H), 9.30 (m, 1H).
LC-MS (Method 2): retention time: 0.96min MS ES+: 453.1 [M+H]+ Example 35-1 Preparation of N-(difluoromethyl)[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazol yl]-N-(pyridinyl)pyrimidinamine F 3 119.176 mg of 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]-N-(pyridin yl)pyrimidinamine (5-1, 0.260 mmol, 1. eq.) were dissolved in 2 ml of dry N,N- ylformamide. 254.09 mg of cesium carbonate and 39.63 mg of sodium chlo- ro(difluoro)acetate were added and stirred for two hours at 100 °C bath temperature under nitrogen atmosphere. Then the mixture was portioned between water and romethane/ isopropanol 4:1. The phases were separated and the aqueous layer (slightly brown) was extracted twice with romethane/ isopropanol 4:1. The combined organic layers were washed with brine, dried over a silicone filter and concentrated in vacuo. The residue was purified by flash chromatography to yield 9 mg (0.02 mmol, 6.13%) of the analytically pure target compound.
[Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb 1H-NMR (500MHz, DMSO-d 6): δ [ppm]= 1.27 - 1.31 (t, 3H), 4.04 (q, 2H), 5.69 (s, 2H), 6.70 - 6.82 (m, 5H), 7.24 (t, 1H), 7.42 - 7.68 (m, 1H), 7.47 (ddd, 1H), 7.79 (dd, 3H), 8.47 (d, 1H), 8.60 (d, 1H).
LC-MS: retention time: 1.09 min MS ES+: 509.1 [M+H]+ Method B e 36-1 Preparation of 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl][2- (methylsulfinyl)ethoxy]-N-(pyridinyl)pyrimidinamine F O N F N N N N To a solution of 1.24 g 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl][2- (methylsulfanyl) ethoxy]-N-(pyridinyl)pyrimidinamine (4-16, 2.26 mmol, 1. eq.) in 2.15 ml of dry chloroform, was added slowly at 0 °C a solution of 557 mg 2- chlorobenzenecarboperoxoic acid (77%, 2.49 mmol, 1.1 eq.) in 2.15 ml chloroform.
After 30 min dichloromethane and sodium thiosulfate-solution (10 %) were [Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb added. The slurry was stirred for 5 min.. After separating the solid (product) the aqueous layer was washed with dichloromethane twice. The organic layers were dried with sodium sulphate and concentrated in vacuo. The residue was purified by flash chromatography and combined the former ed solid to yield 1.22 g (2.05 mmol, 91%) of the analytically pure target compound. 1H-NMR (400MHz, DMSO-d 6): δ [ppm]= 1.29 (t, 3H), 2.72 (s, 3H), 3.18 - 3.28 (m, 1H), 3.34 - 3.47 (m, 1H), 4.04 (q, 2H), 4.58 - 4.78 (m, 2H), 5.69 (s, 2H), 6.73 - 6.87 (m, 2H), 7.21 - 7.34 (m, 1H), 7.43 - 7.56 (m, 1H), 7.80 - 7.92 (m, 1H), 8.08 - 8.17 (m, 2H), 8.39 - 8.52 (m, 4H), 9.40 (s, 1H) LC-MS: retention time: 0.98 min MS ES+: 564.0 [M+H]+ Example 36-1 was separated into its enantiomers via chiral HPLC separation (Method: Column: pak AD-H 5≥ 150x4,6 Channel: UV_VIS_3 Solvent: A:Hexan C:EtOH Wavelength (nm): 280 Puffer: 0.1% DEA Flow (ml/min): 1,000 Gradient: Iso_70%A+30%C Run Time (min): 15,00 Solution: 1 mg/mL eOH 2:1 Vial Number: 6 Comment: 25°C Injection Volume: 10,0) 36-2 2-[1-(4-ethoxy-2,6- 1H-NMR (400MHz, difluorobenzyl)-1H- DMSO-d 6): δ [ppm]= SM = indazolyl][2- 1.29 (t, 3H), 2.72 (s, 3H), 36-1 lsulfinyl)ethox 3.18 - 3.28 (m, 1H), 3.34 y]-N-(pyridin - 3.47 (m, 1H), 4.04 (q, yl)pyrimidinamine 2H), 4.58 - 4.78 (m, 2H), (Enantiomer 1) 5.69 (s, 2H), 6.73 - 6.87 (m, 2H), 7.21 - 7.34 (m, 1H), 7.43 - 7.56 (m, 1H), 7.80 - 7.92 (m, 1H), 8.08 [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb - 8.17 (m, 2H), 8.39 - 8.52 (m, 4H), 9.40 (s, 1H). retention time: 10.08 min specific rotation: 18.5° +/- 0.08° 36-3 4-ethoxy-2,6- 1H-NMR (400MHz, difluorobenzyl)-1H- DMSO-d 6): δ [ppm]= SM = indazolyl][2- 1.29 (t, 3H), 2.72 (s, 3H), 36-1 (methylsulfi- 3.18 - 3.28 (m, 1H), 3.34 nyl)ethoxy]-N- - 3.47 (m, 1H), 4.04 (q, (pyridin 2H), 4.58 - 4.78 (m, 2H), yl)pyrimidinamine 5.69 (s, 2H), 6.73 - 6.87 (Enantiomer 2) (m, 2H), 7.21 - 7.34 (m, 1H), 7.43 - 7.56 (m, 1H), 7.80 - 7.92 (m, 1H), 8.08 - 8.17 (m, 2H), 8.39 - 8.52 (m, 4H), 9.40 (s, 1H) retention time: 12.87 min specific rotation: -14.7° +/- 0.15° Example 37-1 Preparation of 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazol yl][2-(methylsulfonyl)ethoxy]-N-(pyridinyl)pyrimidinamine [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb F O N F N N N N 100 mg of 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl][2- (methylsulfinyl)ethoxy]-N-(pyridinyl)pyrimidinamine (36-1, 0.177 mmol, 1.0 eq.) were dissolved in 0.9 ml of anhydrous tetrahydrofuran. 0.09 ml of aqueous hydrogen peroxide (30 %, 0.886 mmol, 5.0 eq.) and 37.0 mg Diethylazodicarboxylate were added. The reaction mixture was d at 50 °C for 2 h. A white precipitate was filtered off and ed by flash chromatography to yield 18.1 mg (0.03 mmol, 17.6%) of the analytically pure target compound. 1H-NMR (300MHz, DMSO-d 6): δ [ppm]= 1.28 (t, 3H), 3.14 (s, 3H), 3.78 (t, 2H), 4.03 (q, 2H), 4.66 (t, 2H), 5.69 (s, 2H), 6.72 - 6.95 (m, 2H), 7.27 (t, 1H), 7.49 (t, 1H), 7.86 (d, 1H), 8.05 - 8.13 (m, 2H), 8.36 - 8.55 (m, 4H), 9.06 (s, 1H).
LC-MS (Method 1): retention time: 1.03 min MS ES+: 581.2 [M+H]+ [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb Example 38-1 Preparation of 5-(2-aminoethoxy)[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazol yl]-N-(pyridinyl)pyrimidinamine F O N F N N N N 28.6 mg of tert-butyl [2-({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl] (pyridinylamino)pyrimidinyl}oxy)ethyl]carbamate (4-23, 0.046 mmol, 1.0 eq.) were dissolved in 2 ml of dry dichloromethane. 0.071 ml of trifluoroacetic acid (0.926 mmol, 20.0 eq.) were added at 0 °C. The reaction mixture was stirred over night at room temperature. Then a mixture 2 N sodium carbonate and romethane / isopropanol 4:1 was added and the mixture was d for 30 min. The phases were separated and the aqueous layer (slightly brown) was extracted twice with dichloromethane/ isopropanol 4:1. The combined organic layers were dried over a magnesium e and concentrated in vacuo. The residue was purified by crystallization from ethylacetate to yield 6.8 mg (0.01 mmol, 27.0 %) of the analytically pure target compound. 1H-NMR (600MHz, DMSO-d 6): δ [ppm]= 1.29 (t, 3H), 2.98 (t, 2H), 4.05 (q, 2H), 4.15 (t, 2H), 5.68 (s, 2H), 6.75 - 6.82 (m, 2H), 7.23 - 7.29 (m, 1H), 7.47 – 7.50 (m, 1H), 7.85 (d, 1H), 8.13 - 8.17 (m, 2H), 8.31 (s, 1H), 8.35 (s, 1H), 8.42 - 8.45 (m, 2H), 8.46 (d, 1H).
[Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb LC-MS (Method 5): retention time: 1.24 min MS ES+: 518.2 [M+H]+ The following compounds were prepared ing to the same procedure using the indicated starting materials (SM = starting material): 38-2 CH 1H-NMR (400MHz, F 3 2-[1-(4-ethoxy-2,6- O difluorobenzyl)-1H- DMSO-d6): δ [ppm]= SM = 4-11 N indazolyl] 1.28 (t, 3H), 2.51 - 2.57 (morpholin (m, 1H), 2.64 - 2.71 (m, N oxy)-N- 2H), 2.94 - 3.02 (m, 1H), H (pyridin 3.45 - 3.56 (m, 1H), yl)pyrimidinamine 3.74 - 3.81 (m, 1H), O 3.83 - 3.92 (m, 1H), 4.02 (q, 2H), 4.12 - 4.27 (m, 2H), 5.67 (s, 2H), 6.73 - 6.84 (m, 2H), 7.20 - 7.30 (m, 1H), 7.43 - 7.53 (m, 1H), 7.80 - 7.87 (m, 1H), 8.10 - 8.17 (m, 2H), 8.38 (s, 1H), 8.39 - 8.47 (m, 3H), 9.14 (s, 1H).
LC-MS (Method 5): retention time: 1.24 min MS ES+: 574.5 [M+H]+ Example 39-1 [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb ation of ethyl 4-({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl] methoxypyrimidinyl}amino)pyridinecarboxylate H CH3 150 mg of 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]methoxypyrimidin- 4-amine (13, 0.365 mmol, 1.0 eq.), 89 mg of commercial ethyl 4- chloronicotinate (0.401 mmol, 1.1 eq.), 31.6 mg of (9,9-dimethyl-9H-xanthene-4,5- diyl)bis(diphenylphosphine) (0.055 mmol, 0.15 eq.), 356 mg of caesium carbonate (1.09 mmol, 3.0 eq.) and 8.2 mg of palladium diacetate (0.036 mmol, 0.1 eq.) were ded in 4.7 mL of dry dioxane and d under nitrogen atmosphere at 105°C bath temperature for 3 h. Solids were filtered off, washed with dioxane and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography yielding 77 mg from which only 15.7 mg were further purified by crystallization from THF to yield 3.1 mg (0.01 mmol, 1.44 %) of analytically pure target compound. 1H-NMR (300MHz, DMSO-d 6): δ [ppm]= 1.26 (t, 3H), 1.36 (t, 3H), 3.95 – 4.10 (m, 5H), 4.37 (q, 2H), 5.68 (s, 2H), 6.71 - 6.87 (m, 2H), 7.19 - 7.33 (m, 1H), 7.41 - 7.54 (m, 1H), 7.83 (d, 1H), 8.37 - 8.48 (m, 2H), 8.59 (d, 1H), 9.07 (s, 1H), 9.39 (d, 1H), 11.29 (s, 1H).
LC-MS: ion time: 1.55min MS ES+: 560.0 [M+H]+ [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb The following compounds were prepared ing to the same procedure using the indicated starting materials (SM = starting material): 39-2 CH - 1H-NMR (400MHz, F O difluoropyridinyl)- 6): δ [ppm]= 1.26 SM = 13 2-[1-(4-ethoxy-2,6- (t, 3H), 3.90 - 4.12 (m, N F difluorobenzyl)-1H- 5H), 5.58 (s, 2H), 6.62 - N N F indazolyl] 6.79 (m, 2H), 6.94 - 7.04 N N F methoxypyrimidin (m, 1H), 7.25 - 7.40 (m, O CH amine 1H), 7.65 - 7.74 (m, 1H), 7.76 - 7.85 (m, 1H), 8.24 (s, 1H), 8.59 (s, 2H), 9.36 (s, 1H).
LC-MS (Method 5): retention time: 1.34 min MS ES+: 525.2 [M+H]+ Example 40-1 Preparation of 2-[1-(3-amino-2,6-dichlorobenzyl)-1H-indazolyl]methoxy-N- (pyridinyl)pyrimidinamine N Cl [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb 52 mg of 2-[1-(2,6-dichloronitrobenzyl)-1H-indazolyl]methoxy-N-(pyridin imidinamine (21, 0.10 mmol, 1.0 eq.) were dissolved in 5.2 ml of dry methanol. 23.4 mg raney nickel (50 %, 0.199 mmol, 2.0 eq.) and 0.045 ml hydrazine (35 %, 0.498 mmol, 5.0 eq) were added. The reaction mixture was stirred at room temperature vigorously over night. The slurry was filtered over celite and washed with methanol twice. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography to yield 19.2 mg (0.04 mmol, 38%) of the analytically pure target compound. 1H-NMR (300MHz, DMSO-d 6): δ [ppm]= 4.00 (s, 3H), 5.62 (s, 2H), 5.78 (s, 2H), 6.82 (d, 1H), 7.22 (t, 2H), 7.46 (t, 1H), 7.86 (d, 1H), 8.14 (d, 2H), 8.32 (s, 1H), 8.38 (d, 2H), 8.47 (d, 1H), 9.34 (s, 1H).
LC-MS: retention time: 0.97 min MS ES+: 492.1 [M+H]+ Example 41-1 ation of N-[2,4-dichloro({3-[5-methoxy(pyridinylamino)pyrimidin yl]-1H-indazolyl}methyl)phenyl]acetamide N CH N Cl H 3 50 mg of 2-[1-(3-amino-2,6-dichlorobenzyl)-1H-indazolyl]methoxy-N-(pyridin- 4-yl)pyrimidinamine (40-1, 0.102 mmol, 1.0 eq.) were dissolved in 0.6 ml of dry [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb N,N-dimethylformamide. 0.014 ml ethylethanamine (0.102 mmol, 1.0 eq.) and 0.010 ml acetic anhydride (0.102 mmol, 1.0 eq.) were added at 0 °C and stirred for 3.5 h Then again 0.014 ml ethylethanamine (0.102 mmol, 1.0 eq.) and 0.010 ml acetic anhydride (0.102 mmol, 1.0 eq.) were added at 0 °C and stirred over night at room temperature. Saturated sodium hydrogen carbonate on and ethyl e were added and the reaction mixture was stirred for 30 min. The organic layer was washed with ethyl acetate twice. The combined organic layers were dried over a silicone filter and concentrated in vacuum. The residue was purified by flash chromatography to yield 17.3 mg (0.03 mmol, 30%) of the analytically pure target compound. 1H-NMR (400MHz, DMSO-d 6): δ [ppm]= 2.07 (s, 3H), 3.99 (s, 3H), 5.89 (s, 2H), 7.22 - 7.29 (m, 1H), 7.44 - 7.52 (m, 1H), 7.58 (d, 1H), 7.79 (d, 1H), 7.90 (d, 1H), 8.09 - 8.16 (m, 2H), 8.31 (s, 1H), 8.34 - 8.39 (m, 2H), 8.48 (d, 1H), 9.32 (s, 1H), 9.60 (s, 1H).
LC-MS (Method 1): retention time: 0.97 min MS ES+: 534.1 [M+H]+ Example 42-1 Preparation of 2-[1-(4-ethoxy-2,6-difluorobenzyl)methyl-1H-indazolyl] methoxy-N-(pyridinyl)pyrimidinamine [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb F O N F 3 N O CH 100 mg of 4-ethoxy-2,6-difluorobenzyl)methyl-1H-indazolyl] methoxypyrimidinamine , 0.236 mmol, 1.0 eq.) and 94.2 mg 4- Fluoropyridin hydrochloride (0.705 mmol, 3.0 eq.) were dissolved in 1.1 ml of dry N,N-dimethylformamide. 113 mg sodium hydride (60 %, 2.82 mmol, 12 eq.) were added. The reaction mixture was stirred at 90 °C for 2 h. Water and ethyl acetate were added and the aqueous layer was washed with ethyl acetate twice. The ed organic layers were dried over a silicone filter and concentrated in vacuum.
The residue was purified by HPLC to yield 46 mg (0.09 mmol, 38%) of the analytically pure target compound. 1H-NMR (300MHz, DMSO-d 6): δ [ppm]= 1.26 (t, 3H), 2.42 (s, 3H), 3.93 - 4.07 (m, 5H), 5.59 (s, 2H), 6.68 - 6.78 (m, 2H), 6.94 (d, 1H), 7.32 (t, 1H), 7.59 (d, 1H), 7.91 - 8.02 (m, 2H), 8.22 - 8.36 (m, 3H), 9.36 (s, 1H).
LC-MS (Method B): retention time: 1.32 min MS ES+: 503.03 [M+H]+ [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb Biological investigations The ing assays can be used to illustrate the commercial utility of the compounds according to the present invention.
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 e 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 calculated utilizing data sets obtained from testing of one or more synthetic batch.
Biological Assay 1.0: Bub1 kinase assay Bub1-inhibitory ties of compounds bed in the present invention were quantified using a time-resolved fluorescence energy transfer (TR-FRET) kinase assay which es phosphorylation of the tic peptide Biotin-Ahx- VLLPKKSFAEPG (C-terminus in amide form), purchased from e.g. Biosyntan n, Germany) by the (recombinant) catalytic domain of human Bub1 (amino acids 704-1085), expressed in Hi5 insect cells with an N-terminal His6-tag and purified by affinity- (Ni-NTA) and size exclusion chromatography.
In a typical assay 11 different concentrations of each compound (0.1 nM, 0.33 nM, 1.1 nM, 3.8 nM, 13 nM, 44 nM, 0.15 µM, 0.51 µM, 1.7 µM, 5.9 µM and 20 µM) [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb were tested in duplicate within the same microtiter plate. To this end, 100-fold concentrated compound solutions (in DMSO) were usly prepared by serial dilution (1:3.4) of 2 mM stocks in a clear low volume 384-well source microtiter plate (Greiner Bio-One, Frickenhausen, Germany), from which 50 nl of compounds were transferred into a black low volume test microtiter plate from the same supplier.
Subsequently, 2 µl of Bub1 (the final concentration of Bub1 was adjusted depending on the activity of the enzyme lot in order to be within the linear dynamic range of the assay: typically ~ 200 µg/ml were used) in aqueous assay buffer [50 mM Tris/HCl pH 7.5, 10 mM magnesium de (MgCl2), 200 mM potassium chloride (KCl), 1.0 mM dithiothreitol (DTT), 0.1 mM sodium ortho-vanadate, 1% (v/v) glycerol, 0.01 % (w/v) bovine serum albumine (BSA), 0.005% (v/v) Trition X- 100 (Sigma), 1x Complete EDTA-free protease inhibitor mixture )] were added to the nds in the test plate and the mixture was ted for 15 min at 22°C to allow pre-equilibration of the ve enzyme-inhibitor complexes before the start of the kinase reaction, which was initiated by the addition of 3 µl 1.67-fold concentrated solution (in assay buffer) of adenosine-tri-phosphate (ATP, µM final concentration) and peptide substrate (1 µM final concentration). The resulting mixture (5 µl final ) was incubated at 22°C during 60 min., and the reaction was stopped by the on of 5 µl of an aqueous EDTA-solution (50 mM EDTA, in 100 mM HEPES pH 7.5 and 0.2 % (w/v) bovine serum albumin) which also contained the TR-FRET detection reagents (0.2 µM streptavidin-XL665 [Cisbio Bioassays, Codolet, France] and 1 nM hosho-Serine antibody [Merck Millipore, cat. # 35-001] and 0.4 nM LANCE EU-W1024 labeled anti-mouse IgG antibody [Perkin-Elmer, product no. AD0077, alternatively a Terbium-cryptate- labeled anti-mouse IgG antibody from Cisbio Bioassays can be used]). The stopped reaction mixture was further incubated 1 h at 22°C in order to allow the formation of complexes between es and detection reagents. Subsequently, the amount of product was evaluated by ement of the resonance energy transfer from the late-antibody complex recognizing the Phosphoserine res- idue to the streptavidin-XL665 bound to the biotin moiety of the peptide. To this end, the fluorescence emissions at 620 nm and 665 nm after excitation at 330-350 nm were measured in a TR-FRET plate reader, e.g. a Rubystar or Pherastar (both from BMG Labtechnologies, urg, Germany) or a Viewlux (Perkin-Elmer) and [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb the ratio of the emissions (665 nm/622 nm) was taken as indicator for the amount of phosphorylated ate. The data were normalised using two sets of (typically 32-) control wells for high- (= enzyme reaction without inhibitor = 0 % = Minimum inhibition) and low- (= all assay components t enzyme = 100 % = Maximum inhibition) Bub1 activity. IC50 values were calculated by g the ized inhibition data to a 4-parameter logistic equation (Minimum, Maximum, IC50, Hill; Y = Max + (Min - Max) / (1 + (X/IC50)Hill)) using a Bayer-proprietary analysis software. ical Assay 2.0: Proliferation Assay: ated tumor cells (cells were ordered from ATCC, except HeLa-MaTu and HeLa-MaTu-ADR, which were ordered from EPO-GmbH, ) were plated at a density of 1000 to 5000 cells/well, depending on the growth rate of the respective cell line, in a 96-well multititer plate in 200 ≥L of their respective growth medium supplemented 10% fetal calf serum. After 24 hours, the cells of one plate oint plate) were stained with crystal violet (see below), while the medium of the other plates was replaced by fresh culture medium (200 ≥l), to which the test sub- stances were added in various concentrations (0 ≥M, as well as in the range of 0.001-10 ≥M; the final concentration of the solvent dimethyl sulfoxide was 0.5%).
The cells were incubated for 4 days in the presence of test substances. Cell proliferation was determined by staining the cells with crystal violet: the cells were fixed by adding 20 ≥l/measuring point of an 11% glutaric aldehyde solution for 15 minutes at room temperature. After three washing cycles of the fixed cells with water, the plates were dried at room temperature. The cells were stained by adding 100 ≥l/measuring point of a 0.1% crystal violet solution (pH 3.0). After three washing cycles of the stained cells with water, the plates were dried at room temperature.
The dye was dissolved by adding 100 ≥l/measuring point of a 10% acetic acid solution. Absorbtion was determined by photometry at a wavelength of 595 nm. The change of cell , in percent, was calculated by ization of the measured values to the aborbtion values of the zero-point plate (=0%) and the ab- [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb sorbtion of the untreated (0 ≥m) cells (=100%). The IC50 values were determined by means of a 4 parameter fit using the company’s own software.
Tab.1. Compounds had been ted in the following cell lines, which examplify the sub-indications listed Tumor indication Cell line Cervical cancer HeLa HeLa-MaTu-ADR Breast cancer MDA-MB 453 HCC-70 MCF7 MDA MB231 MDA-MB-468 Ovarian cancer SKBR-3 A2780 COLO-704 Caov-3 ES-2 SK-OV-3 IGROV-1 OVCAR8 Non-small cell lung A549 cancer (NSCLC) NCI-H460 NCI-H1299 Prostate cancer DU145 Colon cancer Caco2 HCT15 HT29 Pancreas cancer a2 Osteo sacroma U2OS Acute myelogenous KG1 leucemia MOLM-13 Burkitt lymphoma RAMOS Multiple myeloma OPM-2 Melanoma B16F10 [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb ation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb The following table gives the data regarding Bub1 kinase tion, and inhibition of HeLa cell proliferation, for the examples of the present invention for the biological assays 1 and 2: ical Assay 2: Biological Assay 1: Proliferation assay Example Nr. Bub1 kinase assay (HeLa cell line) median IC50 [mol/l] median IC50 [mol/l] 21 2.6e-009 3.8e-006 23 1.2e-007 not tested 21 6.7e-009 ≥1.0e-005 22 1.2e-006 not tested 21 7.1e-009 2.9e-007 22 5.4e-007 3.4e-006 21 09 1.6e-006 21 8.0e-009 3.8e-006 21 8.3e-009 4.7e-006 22 7.3e-007 not tested 21 3.8e-008 4.7e-006 22 3.2e-006 not tested 21 8.4e-009 1.6e-006 21 8.8e-009 ≥1.0e-005 22 8.9e-007 not tested 21 1.3e-008 9.3e-006 21 1.0e-008 06 21 2.6e-009 3.4e-006 23 2.5e-008 not tested 21 1.1e-008 7.3e-006 21 1.2e-008 ≥1.0e-005 [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb Biological Assay 2: Biological Assay 1: Proliferation assay Example Nr. Bub1 kinase assay (HeLa cell line) median IC50 [mol/l] median IC50 [mol/l] 22 2.0e-005 not tested 21 3.2e-006 not tested 21 1.3e-008 9.3e-006 21 1.4e-008 3.1e-006 21 1.5e-008 9.8e-006 21 1.6e-008 5.6e-007 22 8.4e-007 2.9e-006 21 2.0e-008 ≥1.0e-005 21 2.2e-008 8.1e-006 21 08 06 21 4.4e-009 06 23 3.6e-007 8.5e-006 21 2.3e-008 2.2e-006 21 2.8e-008 ≥1.0e-005 21 2.9e-008 4.2e-006 21 08 ≥1.0e-005 22 1.1e-006 not tested 21 3.8e-008 1.6e-006 21 5.2e-008 ≥1.0e-005 21 5.8e-008 ≥1.0e-005 21 7.1e-008 ≥1.0e-005 21 08 ≥1.0e-005 21 5.6e-009 3.6e-006 22 6.9e-006 not tested 21 4.5e-009 3.5e-006 [Annotation] jessb None set by jessb ation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb Biological Assay 2: Biological Assay 1: Proliferation assay Example Nr. Bub1 kinase assay (HeLa cell line) median IC50 [mol/l] median IC50 [mol/l] 22 3.5e-006 not tested 23 1.4e-008 3.9e-006 21 1.2e-007 5.6e-006 21 1.5e-007 7.9e-006 21 1.9e-007 ≥1.0e-005 21 1.2e-006 ≥1.0e-005 21 4.1E-8 not tested 21 1.1E-7 not tested 21 1.6e-008 1.4e-006 21 2.4E-6 not tested 21 5.5E-9 ≥1.0e-005 21 1.5E-6 not tested 21 4.6e-009 2.1e-006 22 9.3e-006 not tested 23 2.1e-008 ≥1.0e-005 21 08 ≥1.0e-005 21 1.0E-8 2.7E-6 21 1.1E-8 2.1E-6 21 8.3e-008 3.4e-006 21 4.7e-009 3.8e-006 23 5.9e-008 ≥1.0e-005 21 4.8e-009 ≥1.0e-005 22 2.1e-007 not tested 23 4.3e-007 ≥1.0e-005 [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb Biological Assay 2: ical Assay 1: Proliferation assay Example Nr. Bub1 kinase assay (HeLa cell line) median IC50 [mol/l] median IC50 [mol/l] 21 6.7e-009 ≥1.0e-005 22 2.9e-007 not tested 23 5.7e-008 1.0e-005 21 6.7e-009 ≥1.0e-005 22 2.4e-007 not tested 23 2.0e-005 not tested 3-1 4.7e-009 005 3-2 9.8e-009 ≥1.0e-005 3-3 1.5e-008 005 3-4 4.8e-008 ≥1.0e-005 4-1 2.4e-009 3.5e-006 4-10 9.0e-009 4.4e-006 4-11 2.4e-008 not tested 4-12 7.8e-009 9.0e-006 4-13 7.6e-009 8.0e-006 4-14 1.2e-008 ≥1.0e-005 4-15 8.0e-009 3.9e-006 4-16 1.4e-008 4.4e-006 4-17 7.4E-9 4.8E-6 4-18 1.2E-8 not tested 4-19 1.0E-8 1.2E-6 41 3.3e-009 06 42 4.3e-007 not tested 43 9.3E-9 4.9E-6 [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb Biological Assay 2: Biological Assay 1: Proliferation assay Example Nr. Bub1 kinase assay (HeLa cell line) median IC50 [mol/l] median IC50 [mol/l] 4-20 2.1E-7 not tested 4-21 7.8E-9 3.8E-6 4-22 5.8E-9 1.9E-6 4-23 not tested not tested 4-3 7.5e-009 1.4e-005 4-4 1.4e-008 06 4-5 1.8e-008 ≥1.0e-005 42 3.3e-007 not tested 4-6 2.9e-008 3.6e-006 4-7 3.5e-008 ≥1.0e-005 4-8 8.0e-009 1.3E-6 4-9 5.4E-9 1.7E-6 4-10 9.0E-9 4.4E-6 4-11 2.4E-8 not tested 4-12 7.8E-9 9.0E-6 4-13 7.6E-8 8.0E-6 4-14 1.2E-8 ≥1.0e-005 4-15 8.0E-9 3.9E-6 4-16 1.4E-8 4.4E-6 4-17 7.4E-9 4.8E-6 4-18 1.2E-8 not tested 4-19 1.0E-8 1.2E-6 4-20 2.1E-7 not tested 4-21 7.8E-9 3.8E-6 4-22 5.8E-9 1.9E-6 [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb ed set by jessb Biological Assay 2: Biological Assay 1: Proliferation assay Example Nr. Bub1 kinase assay (HeLa cell line) median IC50 ] median IC50 [mol/l] 4-23 9.3E-9 4.9E-6 -1 5.2e-009 1.4e-006 -2 2.7e-008 7.1e-007 -3 2.8e-008 7.4e-006 6-1 3.9e-009 3.1e-006 6-2 7.4e-009 1.4e-006 7-1 3.0e-009 4.4e-006 8-1 7.4e-009 3.2e-006 8-2 2.1e-008 5.5e-006 8-3 2.4e-007 ≥1.0e-005 8-4 1.3E-8 5.0E-6 9-1 9.8e-009 not tested 9-2 2.1e-008 ≥1.0e-005 9-3 2.3e-008 7.0e-006 -1 1.2e-008 2.0e-006 -2 4.2e-007 1.7e-006 -3 3.6e-007 9.6e-006 11-1 1.8e-008 8.1e-006 11-2 1.0e-008 ≥1.0e-005 12-1 1.1e-008 ≥1.0e-005 12-2 4.6e-009 ≥1.0e-005 12-3 4.8e-009 ≥1.0e-005 13-1 3.3e-009 06 13-2 7.2e-009 9.6e-006 13-3 1.7e-008 ≥1.0e-005 [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb Biological Assay 2: Biological Assay 1: Proliferation assay Example Nr. Bub1 kinase assay (HeLa cell line) median IC50 [mol/l] median IC50 [mol/l] 13-4 4.7e-009 8.0e-006 13-5 6.5e-009 ≥1.0e-005 13-6 8.6e-009 ≥1.0e-005 14-1 3.3e-006 005 -1 5.2e-009 1.4e-006 -2 5.5e-009 005 -3 5.7e-009 1.7e-006 -4 09 ≥1.0e-005 -5 1.2e-008 9.9e-006 -6 4.6e-009 005 16-1 1.7e-007 2.8e-006 16-2 2.3e-008 3.5e-006 16-3 2.1e-007 4.1e-006 16-4 2.0e-008 2.7e-006 17-1 1.7e-007 ≥1.0e-005 17-2 2.4e-006 ≥1.0e-005 18-1 1.6e-008 1.4e-006 18-2 2.8e-006 06 19-1 2.0e-005 not tested 19-2 6.3E-9 5 -1 2.0e-007 1.9e-007 -2 4.0e-008 3.3e-006 -3 1.2e-006 4.1e-006 -4 7.5e-007 ≥1.0e-005 -5 8.8e-006 5.9e-006 [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb Biological Assay 2: Biological Assay 1: Proliferation assay Example Nr. Bub1 kinase assay (HeLa cell line) median IC50 [mol/l] median IC50 [mol/l] -6 6.7e-006 not tested 21-1 2.8e-008 3.8e-006 22-1 7.7e-007 not tested 23-1 1.4e-006 ≥1.0e-005 24-1 6.2e-008 ≥1.0e-005 24-2 2.0e-005 not tested 24-3 1.3e-008 9.3e-006 24-4 4.28e-006 not tested 24-5 1.1E-8 not tested 24-6 9.4E-7 not tested 24-7 1.2E-6 1.0e-005 24-8 2.6E-8 05 24-9 not tested not tested -1 1.3e-008 ≥1.0e-005 -2 5.4e-009 005 -3 8.8E-9 4.4E-6 -4 5.03E-9 1.0e-005 26-1 1.7e-008 9.2e-006 26-2 2.4e-006 not tested 27-1 08 3.9e-006 28-1 3.7e-006 not tested 29-1 1.1e-008 005 29-2 8.9e-009 005 -1 1.7e-008 ≥1.0e-005 -2 2.0e-008 ≥1.0e-005 ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb Biological Assay 2: Biological Assay 1: Proliferation assay Example Nr. Bub1 kinase assay (HeLa cell line) median IC50 [mol/l] median IC50 [mol/l] -3 8.4e-009 ≥1.0e-005 31-1 4.7e-006 not tested 32-1 1.2e-007 ≥1.0e-005 33-1 1.1e-008 ≥1.0e-005 34-1 2.3e-007 ≥1.0e-005 34-2 6.2E-6 ≥1.0e-005 34-3 2.8e-008 06 34-4 1.2E-7 not tested -1 1.3e-006 not tested 36-1 4.91E-9 3.3E-6 36-2 6.2E-9 4.4E-7 36-3 6.3E-9 4.3E-7 37-1 5.7E-9 4.2E-6 38-1 3.4E-9 1.4E-6 38-2 3.8E-9 1.2E-6 39-1 under evaluation under evaluation 39-2 6.7E-7 ≥1.0e-005 40-1 3.9E-8 not tested 41-1 1.9E-8 6.0E-6 42-1 6.7E-9 3.6E-6 [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb Inhibition of proliferation of HeLa-MaTu-ADR, NCI-H460, DU145, Caco-2 and B16F10 cells by compounds according to the present invention, determined as described under Biological Assays 2.0. All IC50 (inhibitory concentration at 50% of maximal effect) values are indicated in [mol/L].
Biological Biological Biological Biological Biological Biological Assay 2: Assay 2: Assay 2: Assay 2: Assay 2: Assay 2: Prolifera- Prolifera- Prolifera- Prolifera- Prolifera- Proliferation tion tion tion tion tion assay assay assay assay assay assay (HeLa- (MCF7 (H460 cell (DU145 (Caco2 (B16F10 MaTu- cell line) line) cell line) cell line) cell line) ADR median median median median median cell line) IC50 IC50 IC50 IC50 IC50 median [mol/l] [mol/l] ] [mol/l] [mol/l] Example IC50 Nr. [mol/l] 21 1,3E-06 tested 4,2E-06 3,3E-06 1,4E-06 1,2E-06 21 1,2E-06 6 1,4E-06 1,7E-06 1,2E-06 1,1E-06 21 8,1E-06 tested 1,0E-05 1,0E-05 1,0E-05 9,5E-06 21 3,0E-06 tested 3,0E-06 3,0E-06 6 2,9E-06 21 1,3E-06 tested 1,5E-06 1,6E-06 1,4E-06 1,4E-06 21 1,2E-06 2,0E-06 2,9E-06 2,0E-06 2,6E-06 9,9E-07 21 1,3E-06 tested 2,0E-06 1,3E-06 1,5E-06 1,4E-06 21 1,0E-05 tested 1,0E-05 1,0E-05 1,0E-05 1,0E-05 21 3,9E-07 tested 1,0E-06 5,3E-07 3,8E-07 4,2E-07 21 6 tested 8,5E-06 6 2,4E-06 1,3E-06 21 1,2E-06 tested 6,6E-06 6 3,4E-06 1,2E-06 21 3,8E-07 tested 8,8E-07 8,5E-07 9,0E-07 7 22 1,0E-05 tested 6 3,6E-06 8,0E-06 2,1E-06 23 1,0E-07 tested 6 2,5E-06 1,9E-06 1,5E-06 41 5,8E-06 tested 6 5 9,9E-06 3,7E-06 4-4 1,2E-06 tested 3,5E-06 4,5E-06 9,0E-07 5,0E-07 [Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb Biological Biological Biological Biological Biological Biological Assay 2: Assay 2: Assay 2: Assay 2: Assay 2: Assay 2: Prolifera- Prolifera- Prolifera- Prolifera- Prolifera- Proliferation tion tion tion tion tion assay assay assay assay assay assay (HeLa- (MCF7 (H460 cell (DU145 (Caco2 (B16F10 MaTu- cell line) line) cell line) cell line) cell line) ADR median median median median median cell line) IC50 IC50 IC50 IC50 IC50 median [mol/l] [mol/l] [mol/l] [mol/l] [mol/l] e IC50 Nr. [mol/l] 4-8 3,6E-07 tested 1,1E-06 1,2E-06 7,6E-07 5,7E-07 4-9 8,6E-07 tested 1,3E-06 1,3E-06 7,8E-07 5,3E-07 4-19 1,0E-05 tested 2,2E-06 2,3E-06 1,0E-05 5,3E-07 4-22 1,0E-05 tested 2,1E-06 3,6E-06 9,5E-06 1,2E-06 -2 3,0E-06 tested 6 3,0E-06 3,0E-06 3,0E-06 6-2 1,6E-06 tested 1,7E-06 1,4E-06 6 6 -2 5,9E-07 tested 1,5E-06 1,4E-06 1,1E-06 9,0E-07 12-1 1,0E-05 tested 1,0E-05 1,0E-05 1,0E-05 1,0E-05 13-1 1,3E-06 tested 1,3E-06 1,6E-06 1,2E-06 7,9E-07 -1 1,2E-06 tested 6 6 1,2E-06 7,6E-07 -1 3,0E-06 tested 3,0E-06 3,0E-06 3,0E-06 6 38-2 1,1E-06 tested 1,1E-06 1,3E-06 6,0E-07 6,0E-07 41-1 1,0E-05 tested 1,0E-05 1,0E-05 3,3E-06 1,8E-06 It is to be tood that, if any prior art publication is ed to herein, such reference does not constitute an admission that the publication forms a part of the common general knowledge in the art.
[Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb

Claims (5)

Claims 1. A compound of a (I) (R4) N (R8) R6 (I) in which 5 R1 is hydrogen, halogen, 1-3C-alkyl, R2/R3 are independently from each other hydrogen, halogen, cyano, hydroxy 1-6C-haloalkyl, 1-6C-haloalkoxy, 1-6C-alkoxy, R4 is independently hydrogen, hydroxy, halogen, cyano, NO2, 1-6C-alkyl, 2-6C- alkenyl, 2-6C-alkynyl, 1-6C-haloalkyl, 1-6C-hydroxyalkyl, 1-6C-alkoxy, 10 -O-(2-6C-alkylen)-O-C(O)-(1-6C-alkyl), 1-6C-haloalkoxy, -C(O)OR9, -(1-6C- alkylen)-C(O)OR9, -C(O)-(1-6C-alkyl), R10R11, 3-7C-cycloalkyl, -S-(1- 6C-haloalkyl), SF5, -SO2NH-(3-7C-cycloalkyl), -SO2NR10R11, NR10R11, heteroaryl which optionally is substituted independently one or more times with cyano, 1-4C-alkyl, 1-6C-haloalkyl, 1-6C-haloalkoxy, C(O)OR9, 15 C(O)NR10R11, whereby two of R2, R3 (R4)n, when positioned ortho to each other, may form together with the two carbon atoms to which they are attached, a heterocyclic 5-, 6- or 7-membered ring containing 1 or 2 heteroatoms selected from O or N, and optionally containing an additional double bond and/or optional- 20 ly substituted by an oxo (=O) group and/or an 1-4C-alkyl group, n 0 - 3 R6 is (a) hydrogen; (b) y; (c) cyano; 25 (d) 1-6C-alkoxy optionally substituted independently one or more times with ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb (d1) OH, (d2) –O-(1-6C-alkyl) (d3) C(O)OR9, (d4) C(O)NR10R11, 5 (d5) NR10R11, (d6) –S-(1-6C-alkyl), (d7) –S(O)-(1-6C-alkyl), (d8) –SO2-(1-6C-alkyl) (d9) SO2NR10R11, 10 (d10) heterocyclyl, which is optionally substituted with C(O)OR9, or oxo (=O), (d11) heteroaryl, which is optionally substituted independently one or more times with cyano, 1-4C-alkyl, 1-6C-haloalkyl, 1-6C-haloalkoxy, C(O)OR9, 10R11, (1-6C-alkylen)-O-(1-6C-alkyl), 15 (e) SO2NR10R11, (f) 3-7C-cycloalkoxy, (g) 1-6C-haloalkoxy, (h) COOR9, (i) -C(O)NR10R11, 20 (j) eroaryl optionally substituted with CN * O O H (k) O , whereby the * is the point of attachment, (l) –O-(2-6C-alkylen)-O-(1-6C-alkyl) which is optionally substituted with hydroxy , NH(CO)OR9, R7 is 25 (a) hydrogen, C-alkyl, which is optionally substituted with heteroaryl (c) 1-6C-haloalkyl, (d) 1-6C-hydroxyalkyl, 2 O H (e) O , whereby the * is the point of attachment, [Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb (f) -C(O)-(1-6C-alkyl), (g) –C(O)-(1-6C-alkylen)-O-(1-6C-alkyl), (h) –C(O)-(1-6C-alkylen)-O-(2-6C-alkylen)-O-(1-6C-alkyl), (i) –C(O)-heterocyclyl, 5 (j) benzyl whereby the phenyl ring is optionally substituted with 1-5 substituents independently selected from the group ting of hydrogen, halogen, 1-4C-alkyl, aloalkyl, 1-4C-alkoxy, 1-4C-haloalkoxy, cyano, C(O)OR9, 10 (k) aryl optionally, R6 and R7 together with the nitrogen atom to which R7 is attached form a 6-membered ring which may contain one further heteroatom selected from the group consisting of O, S, N, 15 and which is optionally substituted by (1-6C-alkyl)-OH, (1-6C-alkyl)-NR10R11, R8 is en, halogen, hydroxy, cyano, 1-6C-alkyl, 1-6C-hydroxyalkyl, 1-6C- haloalkyl, 1-6C-haloalkoxy, C(O)OR9, C(O)NR10R11, m is 0-4 20 R9 is (a) en, (b) 1-6C-alkyl which optionally is substituted with hydroxy, R10, R11 are independently from each other hydrogen, 1-4C-alkyl, 1-4C- hydroxyalkyl, 1-4C-alkoxy, -(CO)-(1-6C-alkyl), CHO, COOR9, or er with the nitrogen atom to which they are attached form a 4 25 membered heterocyclic ring optionally ning one further heteroatom selected from the group consisting of O, S or N, and which is optionally substituted with 1-2 fluorine atoms or COOR9, or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer. 2. The compound of formula (I) ing to claim 1, wherein R1 is hydrogen, halogen, 1-3C-alkyl, [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb R2/R3 are independently from each other hydrogen, halogen, cyano, 1-6C- haloalkyl, aloalkoxy, R4 is independently hydrogen, halogen, cyano, 1-6C-alkyl, 2-6C-alkenyl, 1-6C- 5 haloalkyl, ydroxyalkyl, 1-6C-alkoxy, 1-6C-haloalkoxy, -C(O)OR9, -(1- 6C-alkylen)-C(O)OR9, -C(O)-(1-6C-alkyl), R10R11, 3-7C-cycloalkyl, - S-(1-6C-haloalkyl), SF5, -SO2NH-(3cycloalkyl), -SO2NR10R11, heteroaryl which optionally is substituted independently one or more times with cyano, 1-4C-alkyl, 1-6C-haloalkyl, 1-6C-haloalkoxy, C(O)OR9, 10 C(O)NR10R11, whereby two of R2, R3 (R4)n, when oned ortho to each other, may form together with the two carbon atoms to which they are attached, a heterocyclic 5-, 6- or 7-membered ring containing 1 or 2 heteroatoms selected from O or N, and optionally an additional double bond and/or a carbonyl group 15 and/or an 1-4C-alkyl group, n 0 - 3 R6 is (a) hydrogen; (b) hydroxy; (c) cyano; 20 (d) 1-6C-alkoxy optionally substituted with (d1) 1-2 OH, (d2) NR10R11, (d3) SO2NR10R11, (d4) heterocyclyl, 25 (d5) heteroaryl, which is optionally substituted ndently one or more times with cyano, 1-4Calkyl, 1-6C-haloalkyl, 1-6C-haloalkoxy, C(O)OR9, C(O)NR10R11, (e) SO2NR10R11, ; (f) ycloalkoxy, 30 (g) 1-6C-haloalkoxy, (h) -C(O)NR10R11, [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb (i) -O-heteroaryl optionally substituted with CN * O O H (j) O , whereby the * is the point of attachment, R7 is (a) hydrogen, 5 (b)1-6C-alkyl, which is optionally substituted with aryl (c) 1-6C-haloalkyl, (d) 1-6C-hydroxyalkyl, 2 O H (e) O , whereby the * is the point of attachment, (f) -C(O)-(1-6C-alkyl) 10 (g) –C(O)-(1-6C-alkylen)-O-(1-6C-alkyl) (h) –C(O)-(1-6C-alkylen)-O-(1-6C-alkylen)-O-(1-6C-alkyl) (i) –C(O)-heterocyclyl, (j) benzyl whereby the phenyl ring is optionally substituted with 1-5 substituents independently ed from the group consisting of 15 en, halogen, 1-4Calkyl, aloalkyl, 1-4C-alkoxy, 1-4C- koxy, cyano, C(O)OR9, (k) heteroaryl 20 optionally R6 and R7 together with the en atom to which they are attached form a 6-membered ring which may contain one further heteroatom selected from the group consisting of O, S, N, and which is optionally substituted by hydroxy-(1-6alkyl), 25 R8 is hydrogen, halogen, cyano, 1-6C-haloalkyl, 1-6C-haloalkoxy, C(O)OR9, C(O)NR10R11, m is 0-4 R9 is (a) hydrogen, (b) 1-6C-alkyl which optionally may be substituted with hydroxy, [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb R10, R11 are independently from each other hydrogen, 1-4C-alkyl, 1-4C- yalkyl, 1-4C-alkoxy, or together with the nitrogen atom to which they are attached form a 5 membered heterocyclic ring ally containing one further atom 5 selected from the group consisting of O, S or N, or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer. 3. The nd of formula (I) according to claim 1, 10 wherein R1 is hydrogen, halogen, 1-3C-alkyl, R2/R3 are independently from each other hydrogen, halogen, cyano, hydroxy, 1-3C-haloalkyl, 1-3C-haloalkoxy, 1-3C-alkoxy, R4 is independently hydrogen, hydroxy, halogen, cyano, NO2, 1-3C-alkyl, 2-3C- 15 alkenyl, 2-3C-alkynyl, 1-3C-haloalkyl, 1-3C-hydroxyalkyl, 1-3C-alkoxy, -O-(2-3C-alkylen)-O-C(O)-(1-3C-alkyl), 1-3C-haloalkoxy, R9, - alkylen)-C(O)OR9, -C(O)-(1-3C-alkyl), -C(O)NR10R11, 3-7C-cycloalkyl, -S-(1- 3C-haloalkyl), SF5, -SO2NH-(3-7C-cycloalkyl), 10R11, NR10R11, heteroaryl which optionally is substituted independently one or more times 20 with cyano, 1-3C-alkyl, 1-3C-haloalkyl, 1-3C-haloalkoxy, C(O)OR9, C(O)NR10R11, whereby two of R2, R3 (R4)n, when positioned ortho to each other, may form together with the two carbon atoms to which they are attached, a heterocyclic 5-, 6- or 7-membered ring containing 1 or 2 atoms selected from 25 O or N, and optionally containing an additional double bond and/or optionally substituted by an oxo (=O) group and/or an 1-3C-alkyl group, n 0 - 3 R6 is (a) en; (b) y; 30 (c) cyano; (d) 1-6C-alkoxy optionally substituted independently one or more times with (d1) OH, (d2) –O-(1-3C-alkyl) [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb (d3) C(O)OR9, (d4) 10R11, (d5) NR10R11, (d6) –S-(1-3C-alkyl), 5 (d7) –S(O)-(1-3C-alkyl), (d8) –SO2-(1-3C-alkyl), (d9) SO2NR10R11, (d10) heterocyclyl, which is optionally substituted with C(O)OR9, or oxo (=O), 10 (d11) heteroaryl, which is optionally substituted independently one or more times with cyano, 1-3C-alkyl, aloalkyl, 1-3C-haloalkoxy, C(O)OR9, C(O)NR10R11, alkylen)-O-(1-3C-alkyl), (e) SO2NR10R11, (f) 3-7C-cycloalkoxy, 15 (g) 1-6C-haloalkoxy, (h) COOR9, (i) -C(O)NR10R11, (j) -O-heteroaryl optionally substituted with CN * O O H (k) O , whereby the * is the point of attachment, 20 (l) –O-(2-3C-alkylen)-O-(1-3C-alkyl) which is optionally substituted with hydroxy , NH(CO)OR9, R7 is (a) hydrogen, (b)1-3C-alkyl, which is ally substituted with heteroaryl 25 (c) 1-3C-haloalkyl, (d) 1-3C-hydroxyalkyl, 2 O H (e) O , whereby the * is the point of attachment, (f) -C(O)-(1-3C-alkyl) (g) –C(O)-(1-3C-alkylen)-O-(1-3C-alkyl) [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb (h) –C(O)-(1-3C-alkylen)-O-(2-3C-alkylen)-O-(1-3C-alkyl) (i) –C(O)-heterocyclyl, (j) benzyl whereby the phenyl ring is optionally substituted with 1-5 substituents 5 independently selected from the group consisting of hydrogen, halogen, lkyl, 1-4C-alkoxy, 1-4C-haloalkoxy, cyano, C(O)OR9, (k) heteroaryl 10 ally, R6 and R7 er with the nitrogen atom to which R7 is attached form a 6-membered ring which may contain one further heteroatom selected from the group consisting of O, S, N, and which is optionally substituted by (1-3C-alkyl)-OH, (1-3C-alkyl)-NR10R11, R8 is hydrogen, halogen, y, cyano, 1-3C-alkyl, ydroxyalkyl, 1-3C- haloalkyl, 1-3C-haloalkoxy, C(O)OR9, C(O)NR10R11, m is 0-4 R9 is (a) hydrogen, 20 (b) 1-3C-alkyl which optionally is substituted with hydroxy, R10, R11 are independently from each other hydrogen, 1-3C-alkyl, 1-3C- hydroxyalkyl, 1-3C-alkoxy, -(CO)-(1-3C-alkyl), CHO, COOR9 or together with the nitrogen atom to which they are attached form a 4 membered heterocyclic ring optionally containing one further heteroatom 25 selected from the group consisting of O, S or N, which is optionally substituted with 1-2 fluorine atoms or COOR9, or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said e, tautomer or stereoisomer. 30 4. The compound of formula (I) according to claim 1, in which R1 is en, 1-3C-alkyl, [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb R2/R3 are independently from each other hydrogen, halogen, cyano, hydroxy, 1-4C-haloalkyl, 1-4C-alkoxy, R4 is ndently hydrogen, hydroxy, halogen, cyano, 1-4C-alkyl, 2-4C- alkenyl, lkynyl, 1-4C-haloalkyl, 1-4C-hydroxyalkyl, 1-4C-alkoxy, 5 -O-(2-4C-alkylen)-O-C(O)-(1-4C-alkyl), 1-4C-haloalkoxy, -C(O)OR9, -(1-4C- alkylen)-C(O)OR9, -C(O)-(1-4C-alkyl), -C(O)NR10R11, 3-7C-cycloalkyl, -S-(1- 4C-haloalkyl), SF5, -(3-7C-cycloalkyl), -SO2NR10R11, NR10R11, aryl which optionally is tuted independently one or more times with cyano, 1-4C-alkyl, 1-4C-haloalkyl, 1-4C-haloalkoxy, C(O)OR9, 10 C(O)NR10R11, whereby two of R2, R3 (R4)n, when positioned ortho to each other, may form together with the two carbon atoms to which they are attached, a heterocyclic 5-, 6- or 7-membered ring containing 1 or 2 heteroatoms selected from O or N, and optionally containing an additional double bond and/or optional- 15 ly substituted by an oxo (=O) group and/or an 1-4C-alkyl group, n 0 - 3 R6 is (a) en; (b) hydroxy; (d) 1-4C-alkoxy optionally substituted independently one or more times with 20 (d1) OH, (d2) –O-(1-4C-alkyl) (d3) C(O)OR9, (d4) C(O)NR10R11, (d5) NR10R11, 25 (d6) –S-(1-4C-alkyl), (d7) (1-4C-alkyl), (d8) –SO2-(1-4C-alkyl) (d9) SO2NR10R11, (d10) heterocyclyl, which is optionally substituted with C(O)OR9, 30 or oxo (=O), (d11) aryl, which is optionally substituted ndently one or more times with cyano, 1-4C-alkyl, 1-4C-haloalkyl, 1-4C-haloalkoxy, C(O)OR9, C(O)NR10R11, (1-4C-alkylen)-O-(1-4C-alkyl), [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb (e) SO2NR10R11, (f) 3-7C-cycloalkoxy, (g) 1-6C-haloalkoxy, (h) COOR9, 5 (i) R10R11, (j) -O-heteroaryl optionally substituted with CN * O O H (k) O , whereby the * is the point of attachment, (l) –O-(2-4C-alkylen)-O-(1-4C-alkyl) which is optionally substituted with hydroxy , NH(CO)OR9, 10 R7 is (a) hydrogen, (b) alkyl)-heteroaryl (c) 1-4C-haloalkyl, (d) 1-4C-hydroxyalkyl, * C H 2 O H 15 (e) O , whereby * is the point of attachment, (f) -C(O)-(1-4C-alkyl) (g) –C(O)-(1-4C-alkylen)-O-(1-4C-alkyl) (h) –C(O)-(1-4C-alkylen)-O-(2-4C-alkylen)-O-(1-4C-alkyl) (i) –C(O)-heterocyclyl, 20 (j) benzyl whereby the phenyl ring is optionally substituted with 1-5 substituents independently selected from the group ting of hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-haloalkoxy, cyano, C(O)OR9, (k) heteroaryl 25 or optionally, R6 and R7 together with the nitrogen atom to which R7 is attached form a ered ring which may contain one further heteroatom selected from the group consisting of O, S, N, [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb and which is optionally substituted by alkyl)-OH, (1-4C-alkyl)-NR10R11, R8 is hydrogen, halogen, hydroxy, cyano, C(O)NR10R11, 1-4C-alkyl, 1-4C- hydroxyalkyl, 1-4C-haloalkyl, 1-4C-haloalkoxy, 5 m is 0-2, R9 is hydrogen, 1-4C-alkyl which optionally is substituted with hydroxy, R10, R11 are independently from each other hydrogen, 1-4C-alkyl, 1-4C- yalkyl, 1-4C-alkoxy, -C(O)-(1-4C-alkyl), or COOR9 or together with the nitrogen atom to which they are attached form a 4 10 membered heterocyclic ring optionally containing one further heteroatom selected from the group consisting of O, S or N, which is optionally substituted with 1-2 fluorine atoms or COOR9, or an N-oxide, a salt, a tautomer or a stereoisomer of said nd, or a salt of said N-oxide, tautomer or stereoisomer. 5. The compound of formula (I) according to claim 1, wherein, R1 is hydrogen, 20 R2/R3 is independently hydrogen, fluorine, ne, bromine, cyano, hydroxy, CF3, -O-CH3 or -O-CH2-CF3, R4 is independently of each other hydrogen, fluorine, ne, bromine or iodine , cyano, NO2, hydroxy, -CH3, -C3H7, cyclopropyl, enyl, -C≡CH, -CF3, -CH2-OH, -CH2-CH2-OH, -C(CH3)2-OH, -CH2-C(CH3)2-OH, -C(CH3)2- 25 CH2-OH, -OCH3, -O-CH2-CH3, -OCF3, -OCF2H, -OCH2CF3, -O-(CH2)-OC (O)-CH3, -C(O)CH3, -COOH, -C(O)OCH3, -C(O)OC2H5, -C(O)OC(CH3)3, -CH2-COOH, -CH2-COOC2H5, -C(CH3)2-COOC2H5, -C(O)NH2, -C(O)NH(CH3), -C(O)N(CH3)2, -C(O)NH-(CH2)2-OH, -C(O)-(N-morpholinyl), -SO2-NH-cyclopropyl, -SO2-(N-morpholino), NH2, NH-C(O)(CH3), yl- 30 oxa-diazolyl, N-pyrrolyl, N-pyrazolyl, , SF5, whereby two of R2, R3 (R4)n, when positioned ortho to each other, form together -CH2-CH2-O-, -O-CH2-CH2-, -(CH3)C=CH-(C=O)-O-, [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb -CH2-(C=O)-O-, -(CH2)2-(C=O)-NH-, which together with the two carbon atoms to which they are attached form a 5-, 6- or 7-membered ring, n is 0, 1, 2, 3, R6 is hydrogen, hydroxy, cyano, -O-cyclopropyl, -OCH3, -OCF3, , 5 F3, -O-(CH2)2-OH, 2)2-NH2, )2-N(CH3)2, -O-(CH2)2-OCH3 , -O-(CH2)2-O-(CH2)2-OH, -O-CH2-CH(OH)-CH2OH, -O-CH2-CH(OH)- CH2-NH-C(O)OC(CH3)3, -O-CH2-COOH, -O-CH2-COOC2H5, C(O)NH2, -OCH2-C (O)-(3-fluoro-N-azetidine), -O-CH2-C(O)-(3,3-difluoro-N-azetidine), - O-CH2-CH(OH)-CH2-N-piperidinyl, -O-(CH2)2(morpholineyl), -O-CH2- 10 (morpholineyl), -(morpholineyltert.-butoxycarboxylate), -OCH2- (pyrrolidinoneyl), -O-(CH2)2-S-CH3, -O-(CH2)2-SO-CH3, -O- * O O H (CH2)2-SO2-CH2, -O-CH2-SO2NH2, -SO2-CH(CH3)2, O , whereby * is the point of attachment, -O-(CH2)2-tetrazolyl, -O-CH2-tetrazolyl, -O-pyridineyl, -O-(3-cyano- 15 pyridineyl), or - (oxadiazole)-CH2-O-CH3, C H 2 R7 is en, methyl, difluoromethyl, hydroxyethyl, O , whereby * is the point of attachment, -(CH2)2-tetrazolyl, pyridineyl, -C(O)-tetrahydropyranyl, -C(O)-CH2-O- 20 CH3, -C(O)-CH3, -C(O)CH2-O-(CH2)2-O-CH3, C(O)OCH2-CH=CH2, or benzyl which is optionally substituted one or more times with fluorine, chlorine, bromine, cyano, methyl, difluoromethyl, methoxy, ethoxy, difluormethoxy, trifluoromethoxy, -O-CH2-CF3, -C(O)OCH3, or optionally, R6 and R7 er with the nitrogen atom to which R7 is at- 25 tached form a 6-membered ring which may contain one further heteroatom selected from the group consisting of O, S, N and which in addition is optionally substituted by -CH2-OH or -CH2-NH-CHO R8 is hydrogen, fluorine, y, cyano, CH3, CF3, CH2-OH, OCH3, C(O)OH, C(O)OCH3, C(O)OC2H5, C(O)O(CH2)2-OH, C(O)NH2, C(O)NHCH3, 30 m is 0, 1 or 2 [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer. 6. Compounds of formula (I) according to claim 1, which is selected from the group 5 consisting of: 2-[1-(6-chlorofluoromethylbenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, 2-[1-(6-chlorofluoromethoxybenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, 5-methoxy{1-[3-(5-methyl-1,2,4-oxadiazolyl)benzyl]-1H-indazolyl}-N- (pyridinyl)pyrimidinamine, 2-[1-(2-chloro-4,5-dimethylbenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, 5-methoxy{1-[4-(pentafluoro-λ6-sulfanyl)benzyl]-1H-indazolyl}-N-(pyridin yl)pyrimidinamine, 2-[1-(2,6-difluoromethoxybenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, N-(2,6-difluoromethoxybenzyl)[1-(2,6-difluoromethoxybenzyl)-1H-indazol- 3-yl]methoxy-N-(pyridinyl)pyrimidinamine, 2-{1-[(6-bromo-1,3-benzodioxolyl)methyl]-1H-indazolyl}methoxy-N- (pyridinyl)pyrimidinamine, 4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, N-(4-ethoxy-2,6-difluorobenzyl)[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]- 5-methoxy-N-(pyridinyl)pyrimidinamine, 2-({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol hyl)benzonitrile, 2-[1-(2-chloromethoxybenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, 2-[1-(3,4-dihydro-2H-1,5-benzodioxepinylmethyl)-1H-indazolyl]methoxy-N- (pyridinyl)pyrimidinamine, 2-[1-(2,6-difluorobenzyl)-1H-indazolyl]methoxy-N-(pyridinyl)pyrimidin amine, N-(2,6-difluorobenzyl)[1-(2,6-difluorobenzyl)-1H-indazolyl]methoxy-N- (pyridinyl)pyrimidinamine, 5-methoxy-N-(pyridinyl)(1-{3-[(trifluoromethyl)sulfanyl]benzyl}-1H-indazol yl)pyrimidinamine, 2-[1-(2,3-difluoromethylbenzyl)-1H-indazolyl]methoxy-N-(pyridin imidinamine, N-(2,3-difluoromethylbenzyl)[1-(2,3-difluoromethylbenzyl)-1H-indazolyl]- [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb oxy-N-(pyridinyl)pyrimidinamine, 5-methoxy{1-[4-(1H-pyrazolyl)benzyl]-1H-indazolyl}-N-(pyridin yl)pyrimidinamine 2,6-dichlorobenzyl)-1H-indazolyl]methoxy-N-(pyridinyl)pyrimidin amine, N-(2,6-dichlorobenzyl)[1-(2,6-dichlorobenzyl)-1H-indazolyl]methoxy-N- (pyridinyl)pyrimidinamine, 5-methoxy-N-(pyridinyl)(1-{4-[(trifluoromethyl)sulfanyl]benzyl}-1H-indazol yl)pyrimidinamine, 2-[1-(2-chlorobenzyl)-1H-indazolyl]methoxy-N-(pyridinyl)pyrimidin amine, N-(2-chlorobenzyl)[1-(2-chlorobenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, methyl 3-chloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol- ethyl)benzoate, methyl 3-chloro{[(2-{1-[2-chloro(methoxycarbonyl)benzyl]-1H-indazolyl} methoxypyrimidinyl)(pyridinyl)amino]methyl}benzoate, 2-[1-(4-bromo-2,6-difluorobenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, 2-[1-(2-chlorofluoromethoxybenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, 2-[1-(4-ethoxy-2,3-difluorobenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, N-(4-ethoxy-2,3-difluorobenzyl)[1-(4-ethoxy-2,3-difluorobenzyl)-1H-indazolyl]- 5-methoxy-N-(pyridinyl)pyrimidinamine, 5-methoxy-N-(pyridinyl){1-[2,3,5,6-tetrafluoro(2,2,2-trifluoroethoxy)benzyl]- 1H-indazolyl}pyrimidinamine, 5-methoxy-N-(pyridinyl)-N-[2,3,5,6-tetrafluoro(2,2,2-trifluoroethoxy)benzyl] {1-[2,3,5,6-tetrafluoro(2,2,2-trifluoroethoxy)benzyl]-1H-indazolyl}pyrimidin amine, methyl 2,4-dichloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H- indazolyl}methyl)benzoate, 5-methoxy-N-(pyridinyl)[1-(2,4,6-trifluorobenzyl)-1H-indazolyl]pyrimidin amine, 5-methoxy-N-(pyridinyl)-N-(2,4,6-trifluorobenzyl)[1-(2,4,6-trifluorobenzyl)-1H- indazolyl]pyrimidinamine, 2-[1-(2-fluorobenzyl)-1H-indazolyl]methoxy-N-(pyridinyl)pyrimidinamine 2-[1-(2,4-dichlorobenzyl)-1H-indazolyl]methoxy-N-(pyridinyl)pyrimidin amine, 2-[1-(2-fluoroiodobenzyl)-1H-indazolyl]methoxy-N-(pyridinyl)pyrimidin- 4-amine, ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 2-bromobenzyl)-1H-indazolyl]methoxy-N-(pyridinyl)pyrimidin amine, N-(2-bromobenzyl)[1-(2-bromobenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, [3-fluoro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)phenyl]acetic acid, 5-methoxy-N-(pyridinyl)[1-(2,3,5,6-tetrafluoromethoxybenzyl)-1H-indazol- 3-yl]pyrimidinamine, 5-methoxy[1-(4-propylbenzyl)-1H-indazolyl]-N-(pyridinyl)pyrimidin amine, 2-{1-[2,6-dichloro(trifluoromethoxy)benzyl]-1H-indazolyl}methoxy-N- (pyridinyl)pyrimidinamine, N-[2,6-dichloro(trifluoromethoxy)benzyl]{1-[2,6-dichloro (trifluoromethoxy)benzyl]-1H-indazolyl}methoxy-N-(pyridinyl)pyrimidin amine, [5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazolyl}methyl)-3,4- dihydroquinolin-2(1H)-one, 2-[1-(2-chloroiodobenzyl)-1H-indazolyl]methoxy-N-(pyridinyl)pyrimidin- 4-amine, 3,5-dimethoxybenzyl)-1H-indazolyl]methoxy-N-(pyridinyl)pyrimidin amine, 2-{1-[2-chloro(trifluoromethyl)benzyl]-1H-indazolyl}methoxy-N-(pyridin yl)pyrimidinamine, 2-[1-(2-chlorofluorobenzyl)-1H-indazolyl]methoxy-N-(pyridinyl)pyrimidin- 4-amine, 7-({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazolyl}methyl) methyl-2H-chromenone, 3-fluoro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)benzonitrile, 4-{[{2-[1-(4-cyanofluorobenzyl)-1H-indazolyl]methoxypyrimidin yl}(pyridinyl)amino]methyl}fluorobenzonitrile, 2-{1-[2,6-dichloro(trifluoromethyl)benzyl]-1H-indazolyl}methoxy-N-(pyridin- 4-yl)pyrimidinamine, ethyl [3-({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)phenyl]acetate, 2-[1-(4-fluorobenzyl)-1H-indazolyl]methoxy-N-(pyridinyl)pyrimidinamine, N-cyclopropyl({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)benzenesulfonamide, 6-({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazolyl}methyl) benzofuran-2(3H)-one, [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 4-(difluoromethoxy)-2,6-difluorobenzyl]-1H-indazolyl}methoxy-N- (pyridinyl)pyrimidinamine, tert-butyl 3-chloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H- indazolyl}methyl)benzoate, ethyl 2-[3-({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)phenyl]methylpropanoate, 4-({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)benzonitrile, 5-methoxy{1-[4-(morpholinylsulfonyl)benzyl]-1H-indazolyl}-N-(pyridin yl)pyrimidinamine, 2-[1-(2,6-dichloronitrobenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, 3-({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol hyl)benzonitrile, N-[4-(difluoromethoxy)-2,6-difluorobenzyl]{1-[4-(difluoromethoxy)-2,6- difluorobenzyl]-1H-indazolyl}methoxy-N-(pyridinyl)pyrimidinamine, 5-methoxy-N-(pyridinyl){1-[3-(1H-pyrrolyl)benzyl]-1H-indazol yl}pyrimidinamine, 3,5-difluoro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)benzonitrile 5-methoxy{1-[2-methoxy(trifluoromethyl)benzyl]-1H-indazolyl}-N-(pyridin- 4-yl)pyrimidinamine, 2-[1-(2,6-difluoromethylbenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, 2-[1-(2-fluoromethoxybenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, 3,5-difluoro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)benzamide, 2-[3,5-difluoro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)phenoxy]ethyl acetate, 2-[1-(2,6-difluoropropoxybenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, 2-[1-(4-ethoxyfluoromethoxybenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridinylamino)pyrimidin- 5-ol 2-[1-(4-methoxybenzyl)-1H-indazolyl](pyridinylamino)pyrimidinol, 2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridinylamino)pyrimidinol, 2-[1-(4-fluorobenzyl)-1H-indazolyl](pyridinylamino)pyrimidinol, {3-[({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb ylamino)pyrimidinyl}oxy)methyl]oxetanyl}methanol, {3-[({2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridinylamino)pyrimidin yl}oxy)methyl]oxetanyl}methanol, (3-{[(2-[1-(2-fluorobenzyl)-1H-indazolyl]{[3-(hydroxymethyl)oxetan yl]methoxy}pyrimidinyl)(pyridinyl)amino]methyl}oxetanyl)methanol, 1-({2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridinylamino)pyrimidin yl}oxy)methanesulfonamide, 5-[2-(dimethylamino)ethoxy][1-(2-fluorobenzyl)-1H-indazolyl]-N-(pyridin yl)pyrimidinamine, 2-[1-(2-fluorobenzyl)-1H-indazolyl]-N-(pyridinyl)[2-(1H-tetrazol yl)ethoxy]pyrimidinamine, 2-[1-(2-fluorobenzyl)-1H-indazolyl]-N-(pyridinyl)[2-(1H-tetrazol yl)ethoxy]-N-[2-(1H-tetrazolyl)ethyl]pyrimidinamine, 5-[2-(dimethylamino)ethoxy][1-(4-fluorobenzyl)-1H-indazolyl]-N-(pyridin yl)pyrimidinamine, 2-[1-(2-fluorobenzyl)-1H-indazolyl]-N-(pyridinyl)(1H-tetrazol ylmethoxy)pyrimidinamine, 5-[2-(dimethylamino)ethoxy][1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]-N- (pyridinyl)pyrimidinamine, 1-({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)(piperidinyl)propanol, 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](2-methoxyethoxy)-N- (pyridinyl)pyrimidinamine, tert-butyl 2-[({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)methyl]morpholinecarboxylate, 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl][2-(morpholinyl)ethoxy]-N- (pyridinyl)pyrimidinamine, 2-[1-(2-fluorobenzyl)-1H-indazolyl]{[3-(methoxymethyl)-1,2,4-oxadiazol yl]methoxy}-N-(pyridinyl)pyrimidinamine, ethyl ({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)acetate, -difluoroazetidinyl)({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]- 4-(pyridinylamino)pyrimidinyl}oxy)ethanone, 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl][2-(methylsulfanyl)ethoxy]-N- (pyridinyl)pyrimidinamine, 2-[2-({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)ethoxy]ethanol, formic acid - -[({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl] inylamino)pyrimidinyl}oxy)methyl]pyrrolidinone (1:1), (5R)[({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)methyl]pyrrolidinone, [Annotation] jessb None set by jessb [Annotation] jessb ionNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb tert-butyl {2-[2-({2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)ethoxy]ethyl}carbamate, 2-({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)(3-fluoroazetidinyl)ethanone, (5S)[({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin o)pyrimidinyl}oxy)methyl]pyrrolidinone, tert-butyl [2-({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)ethyl]carbamate, N-({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridinyl)-7,8-dihydro- 6H-pyrimido[5,4-b][1,4]oxazinyl}methyl)formamide, 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]-N-(pyridinyl)pyrimidin amine, 2-[1-(4-methoxybenzyl)-1H-indazolyl]-N-(pyridinyl)pyrimidinamine, 2-[1-(2-fluorobenzyl)-1H-indazolyl]-N-(pyridinyl)pyrimidinamine, 2-[1-(4-cyclopropyl-2,6-difluorobenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, 2-(1-{2,6-difluoro[(1E)-propenyl]benzyl}-1H-indazolyl)methoxy-N- (pyridinyl)pyrimidinamine, 1-[3,5-difluoro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)phenyl]ethanone, [2,4-dichloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)phenyl]methanol, 2-[3-({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)phenyl]ethanol, 2-[3-({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)phenyl]methylpropanol, [4-({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]methoxypyrimidin yl}amino)pyridinyl]methanol, 2-[3-chloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)phenyl]propanol, 1-[3-({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)phenyl]methylpropanol, 2-[2,4-dichloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)phenyl]propanol, 5-(difluoromethoxy)[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]-N-(pyridin- 4-yl)pyrimidinamine, luoromethoxy)-N-(difluoromethyl)[1-(4-ethoxy-2,6-difluorobenzyl)-1H- indazolyl]-N-(pyridinyl)pyrimidinamine, fluoromethyl)(pyridinyl)amino][1-(4-ethoxy-2,6-difluorobenzyl)-1H- indazolyl]pyrimidinol, [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb ed set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb 2-[1-(4-methoxybenzyl)-1H-indazolyl]-N-(pyridinyl)(2,2,2- trifluoroethoxy)pyrimidinamine, 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]-N-(pyridinyl)(2,2,2- trifluoroethoxy)pyrimidinamine, 3-({2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridinylamino)pyrimidin yl}oxy)propane-1,2-diol, (2S)({2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridinylamino)pyrimidin yl}oxy)propane-1,2-diol, (2R)({2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridinylamino)pyrimidin yl}oxy)propane-1,2-diol, 2-({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)ethanol, [1-(2-fluorobenzyl)-1H-indazolyl](pyridinylamino)pyrimidin yl}oxy)ethanol, ethyl 4-({2-[1-(2-fluorobenzyl)-1H-indazolyl](2-hydroxyethoxy)pyrimidin yl}amino)pyridinecarboxylate, 4-({2-[1-(2-fluorobenzyl)-1H-indazolyl](2-hydroxyethoxy)pyrimidin yl}amino)-N-methylpyridinecarboxamide, 4-({2-[1-(2-fluorobenzyl)-1H-indazolyl](2-hydroxyethoxy)pyrimidin yl}amino)pyridinecarboxamide, 2-hydroxyethyl 4-({2-[1-(2-fluorobenzyl)-1H-indazolyl](2- hydroxyethoxy)pyrimidinyl}amino)pyridinecarboxylate, 5-(cyclopropyloxy)[1-(4-methoxybenzyl)-1H-indazolyl]-N-(pyridin yl)pyrimidinamine, 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine hydrochloride (1:1), (2S)({2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridinylamino)pyrimidin yl}oxy)propane-1,2-diol hydrochloride (1:1), 2-({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)ethanol hydrochloride (1:1), 2-[1-(2,6-dichlorobenzyl)-1H-indazolyl]methoxy-N-(pyridinyl)pyrimidin amine hydrochloride (1:1), [2,4-dichloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)phenyl]methanol hydrochloride (1:1), (2R)({2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridinylamino)pyrimidin )propane-1,2-diol hydrochloride (1:1), N-{2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]pyrimidinyl}-N-(pyridin yl)acetamide, N-{2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]pyrimidinyl}methoxy-N- (pyridinyl)acetamide, ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb N-{2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]pyrimidinyl}-N-(pyridin yl)tetrahydro-2H-pyrancarboxamide, N-{2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]pyrimidinyl}(2- methoxyethoxy)-N-(pyridinyl)acetamide, [1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]pyrimidinyl}(pyridin yl)amino]ethanol, (3-{[{2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]pyrimidinyl}(pyridin yl)amino]methyl}oxetanyl)methanol, 2-{1-[4-bromofluoro(2,2,2-trifluoroethoxy)benzyl]-1H-indazolyl}methoxy- N-(pyridinyl)pyrimidinamine, 2-{1-[4-bromo-2,6-bis(2,2,2-trifluoroethoxy)benzyl]-1H-indazolyl}methoxy-N- (pyridinyl)pyrimidinamine, 2,4-dichloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)benzoic acid, -(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](pyridin ylamino)pyrimidinyl}oxy)acetic acid, 2,4-dichloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)-N-methylbenzamide, 2,4-dichloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)benzamide, 2,4-dichloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)-N,N-dimethylbenzamide, 2,4-dichloro-N-(2-hydroxyethyl)({3-[5-methoxy(pyridinylamino)pyrimidin yl]-1H-indazolyl}methyl)benzamide, [2,4-dichloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)phenyl](morpholinyl)methanone, 3,5-difluoro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)-N-methylbenzamide, 2-[1-(4-ethynylfluorobenzyl)-1H-indazolyl]methoxy-N-(pyridin imidinamine, {2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridinyl)-7,8-dihydro-6H-pyrimido[5,4- b][1,4]oxazinyl}methanol, 2-[1-(2-fluorobenzyl)-1H-indazolyl]methoxy-N-methyl-N-(pyridin yl)pyrimidinamine, 4-({2-[1-(2-fluorobenzyl)-1H-indazolyl]methoxypyrimidinyl}amino)pyridine- 3-carbonitrile, 2-[1-(2-fluorobenzyl)-1H-indazolyl]methoxy-N,N-di(pyridinyl)pyrimidin amine, methyl 4-({2-[1-(2-fluorobenzyl)-1H-indazolyl]methoxypyrimidin yl}amino)pyridinecarboxylate, [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb 2-[1-(2-fluorobenzyl)-1H-indazolyl]methoxy-N-(pyridinyl)pyrimidinamine, 4-({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]methoxypyrimidin yl}amino)pyridinecarbonitrile, 2-[(3-{4-[(2,6-dimethylpyridinyl)amino]methoxypyrimidinyl}-1H-indazol yl)methyl]ethoxyfluorophenol, 4-({5-methoxy[1-(4-methoxybenzyl)-1H-indazolyl]pyrimidin yl}amino)pyridin-2(1H)-one, 4-({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]methoxypyrimidin yl}amino)pyridin-2(1H)-one, methoxy[1-(4-propylbenzyl)-1H-indazolyl]pyrimidin yl}amino)nicotinonitrile, 4-({2-[1-(2-fluorobenzyl)-1H-indazolyl]methoxypyrimidinyl}amino)pyridine- 3-carboxamide, 4-({5-methoxy[1-(4-propylbenzyl)-1H-indazolyl]pyrimidinyl}amino)pyridine- 3-carboxamide, 4-({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]methoxypyrimidin yl}amino)pyridinecarboxamide, 4-({2-[1-(2,6-difluorohydroxybenzyl)-1H-indazolyl]methoxypyrimidin yl}amino)pyridinecarboxamide, 4-({2-[1-(2-fluorobenzyl)-1H-indazolyl]hydroxypyrimidinyl}amino)pyridine- onitrile, 4-({4-[(3-cyanopyridinyl)amino][1-(2-fluorobenzyl)-1H-indazolyl]pyrimidin- 5-yl}oxy)pyridinecarbonitrile, 5-methoxy[1-(4-methoxybenzyl)-1H-indazolyl]-N-[3-(trifluoromethyl)pyridin yl]pyrimidinamine, 3-chloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)benzoic acid, formic acid - 3-chloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H- indazolyl}methyl)-N-methylbenzamide (1:1), 3-chloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)-N-methylbenzamide, [1-(2-fluorobenzyl)-1H-indazolyl]hydroxypyrimidinyl}amino)pyridine- 3-carboxamide, 4-({2-[1-(2-fluorobenzyl)-1H-indazolyl]hydroxypyrimidinyl}amino)pyridine- 3-carboxylic acid, ethyl [1-(2-fluorobenzyl)-1H-indazolyl]hydroxypyrimidin yl}amino)pyridinecarboxylate, 2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridinylamino)pyrimidinecarbonitrile 2-[1-(2-fluorobenzyl)-1H-indazolyl](pyridinylamino)pyrimidine carboxamide, [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb 4-({2-[1-(2-fluorobenzyl)-1H-indazolyl](2-hydroxyethoxy)pyrimidin yl}amino)pyridinecarboxylic acid hydrochloride (1:1), N-(2-fluoropyridinyl)methoxy[1-(4-methoxybenzyl)-1H-indazol yl]pyrimidinamine, N-(2,6-difluoropyridinyl)methoxy[1-(4-methoxybenzyl)-1H-indazol yl]pyrimidinamine, N-(3-fluoropyridinyl)methoxy[1-(4-methoxybenzyl)-1H-indazol yl]pyrimidinamine, 5-methoxy[1-(4-methoxybenzyl)-1H-indazolyl]-N-(2-methylpyridin yl)pyrimidinamine, N-(difluoromethyl)[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]-N-(pyridin yl)pyrimidinamine, 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl][2-(methylsulfinyl)ethoxy]-N- (pyridinyl)pyrimidinamine, 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl][2-(methylsulfinyl)ethoxy]-N- (pyridinyl)pyrimidinamine (Enantiomer 1), 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl][2-(methylsulfinyl)ethoxy]-N- inyl)pyrimidinamine (Enantiomer 2), 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl][2-(methylsulfonyl)ethoxy]-N- (pyridinyl)pyrimidinamine, 5-(2-aminoethoxy)[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl]-N-(pyridin yl)pyrimidinamine, 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl](morpholinylmethoxy)-N- (pyridinyl)pyrimidinamine, Preparation of ethyl 4-({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl] methoxypyrimidinyl}amino)pyridinecarboxylate, N-(3,5-difluoropyridinyl)[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazolyl] methoxypyrimidinamine, 2-[1-(3-amino-2,6-dichlorobenzyl)-1H-indazolyl]methoxy-N-(pyridin yl)pyrimidinamine, N-[2,4-dichloro({3-[5-methoxy(pyridinylamino)pyrimidinyl]-1H-indazol yl}methyl)phenyl]acetamide, 2-[1-(4-ethoxy-2,6-difluorobenzyl)methyl-1H-indazolyl]methoxy-N-(pyridin- 4-yl)pyrimidinamine, or an N-oxide, a salt, a tautomer or a isomer of said nd, or a salt of said N-oxide, tautomer or stereoisomer. 5 7. A compound of formula (I), [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb ed set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb (R4) N (R8) R6 (I) wherein, R1 is hydrogen, R2/R3 is independently hydrogen, fluorine, chlorine, bromine, cyano, hydroxy, CF3, 5 -O-CH3 or -O-CH2-CF3, R4 is independently of each other hydrogen, fluorine, ne, bromine or iodine , cyano, NO2, hydroxy, -CH3, -C3H7, cyclopropyl, 1-propenyl, -C≡CH, -CF3, -CH2-OH, -CH2-CH2-OH, -C(CH3)2-OH, -CH2-C(CH3)2-OH, -C(CH3)2- CH2-OH, -OCH3, -O-CH2-CH3 optionally substituted one or more times with 10 hydroxy, -OCF3, -OCF2H, F3, -O-(CH2)-O-C(O)-CH3, -C(O)CH3, -COOH, CH3, -C(O)OC2H5, -C(O)OC(CH3)3, -CH2-COOH, -CH2- COOC2H5, -C(CH3)2-COOC2H5, -C(O)NH2, -C(O)NH(CH3), -C(O)N(CH3)2, -C(O)NH-(CH2)2-OH, -C(O)-(N-morpholinyl), -SO2-NH-cyclopropyl, -SO2-(N- morpholino), NH2, NH-C(O)(CH3), 5-methyl-oxa-diazolyl, N-pyrrolyl, N- 15 pyrazolyl, -S-CF3, SF5, whereby two of R2, R3 (R4)n, when positioned ortho to each other, form together -O-CH2-CH2-CH2-O-, -CH2-, -(CH3)C=CH-(C=O)-O-, -CH2-(C=O)-O-, -(CH2)2-(C=O)-NH-, which together with the two carbon at- 20 oms to which they are ed form a 5-, 6- or 7-membered ring, n is 0, 1, 2, 3, R6 is hydrogen, hydroxy, cyano, lopropyl, -OCH3, -OCF3, -OCF2H, -OCH2CF3, -O-(CH2)2-OH, -O-(CH2)2-NH2, )2-N(CH3)2, -O-(CH2)2-OCH3 , -O-(CH2)2-O-(CH2)2-OH, -O-CH2-CH(OH)-CH2OH, -O-CH2-CH(OH)- 25 CH2-NH-C(O)OC(CH3)3, -O-CH2-COOH, -O-CH2-COOC2H5, C(O)NH2, -O- [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb CH2-C(O)-(3-fluoro-N-azetidine), -O-CH2-C(O)-(3,3-difluoro-N-azetidine), - O-CH2-CH(OH)-CH2-N-piperidinyl, -O-(CH2)2(morpholineyl), -O-CH2- (morpholineyl), -O-CH2-(morpholineyltert.-butoxycarboxylate), -OCH2- (pyrrolidinoneyl), -O-(CH2)2-S-CH3, -O-(CH2)2-SO-CH3, -O- * O O H 5 (CH2)2-SO2-CH2, -O-CH2-SO2NH2, -SO2-CH(CH3)2, O , whereby * is the point of attachment, -O-(CH2)2-tetrazolyl, -O-CH2-tetrazolyl, -O-pyridineyl, cyano- pyridineyl), or - O-CH2-(oxadiazole)-CH2-O-CH3, C H 2 10 R7 is hydrogen, methyl, difluoromethyl, hydroxyethyl, O , whereby * is the point of attachment, -(CH2)2-tetrazolyl, pyridineyl, tetrahydropyranyl, -C(O)-CH2-OCH3 , CH3, -C(O)CH2-O-(CH2)2-O-CH3, H2-CH=CH2, or benzyl which is optionally substituted one or more times with fluorine, ne, 15 bromine, cyano, methyl, difluoromethyl, methoxy, ethoxy, difluormethoxy, trifluoromethoxy, -O-CH2-CF3, -C(O)OCH3, or optionally, R6 and R7 together with the nitrogen atom to which R7 is attached form a ered ring which may contain one further heteroatom selected from the group consisting of O, S, N and which in addition is op- 20 tionally substituted by -CH2-OH or -CH2-NH-CHO R8 is hydrogen, fluorine, hydroxy, cyano, CH3, CF3, CH2-OH, OCH3, C(O)OH, C(O)OCH3, C(O)OC2H5, CH2)2-OH, C(O)NH2, C(O)NHCH3, m is 0, 1 or 2 or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of 25 said N-oxide, tautomer or stereoisomer. 8. A compound of formula (I) ation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb (R4) N (R8) R6 (I) in which R1, R2, R3, n, R6, R7, R8 and m have the meanings ing to claim 7, and 5 R4 is independently of each other hydrogen, fluorine, chlorine, e or iodine, cyano, NO2, hydroxy, -CH3, -C3H7, cyclopropyl, 1-propenyl, -C≡CH, -CF3, -CH2-OH, -CH2-CH2-OH, -C(CH3)2-OH, -CH2-C(CH3)2-OH, )2-CH2-OH, -OCH3, -O-CH2-CH3, -OCF3, -OCF2H, -OCH2CF3, -O-(CH2)-O-C(O)-CH3, -C(O)CH3, -COOH, -C(O)OCH3, -C(O)OC2H5, -C(O)OC(CH3)3, -CH2-COOH, 10 -CH2-COOC2H5, -C(CH3)2-COOC2H5, -C(O)NH2, -C(O)NH(CH3), -C(O)N(CH3)2, -C(O)NH-(CH2)2-OH, -C(O)-(N-morpholinyl), -SO2-NH- cyclopropyl, -SO2-(N-morpholino), NH2, NH-C(O)(CH3), 5-methyl-oxa-diazol- 3-yl, N-pyrrolyl, N-pyrazolyl, and -S-CF3, SF5, said group being optionally substituted, one or more times, identically or different- 15 ly, with a substituent selected from: hydroxy, halogen, cyano, 1-6C-alkyl, aloalkyl, and 1-6C-alkoxy, whereby two of R2, R3 (R4)n, when positioned ortho to each other, form together 20 -O-CH2-CH2-CH2-O-, -O-CH2-CH2-, C=CH-(C=O)-O-, -CH2-(C=O)-O-, 2-(C=O)-NH-, which together with the two carbon atoms to which they are attached form a 5-, 6- or 7-membered ring, or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of 25 said N-oxide, tautomer or stereoisomer. [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 9. A nd of formula (I) (R4) N (R8) R6 (I) in which 5 R1, R2, R3, n, R6, R7, R8 and m have the meanings according to claim 7, and R4 is selected from the group consisting of hydrogen, halogen, cyano, 1-3C-alkyl, 3-6C-cycloalkyl, lkenyl, 1-3C-haloalkyl, 1-3C-hydroxyalkyl, 1-3C-alkoxy, 1- 3C-haloalkoxy, -C(O)-(1-3C-alkyl), COOH, (1-3C-alkylen)-COOH, -(1-3C-alkylen)3C-alkyl), -COO-(1-4C-alkyl), -C(O)NH2, -C(O)NH(1-3C-alkyl), -C(O)N(1-3C-alkyl)2, -C(O)NH-(1-3C-alkyl)-OH, -C(O)-(N-heterocyclyl), -SO2-NH- (3-6C-cycloalkyl), -SO2-(N-heterocyclyl), said group being optionally substituted, one or more times, identically or different- 15 ly, with a substituent selected from: hydroxy, halogen, cyano, 1-6C-alkyl, 1-4C-haloalkyl, and 1-6C-alkoxy, or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer. 10. Process for the manufacture of compounds of general formula (I) according to claim 1, wherein R7 is en as reflected in a (Ia), characterized in that a compound of formula (1-4) [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb ation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb (R4) N R3 N 2 whereby R1, R2, R3, R4, R6 and n have the meaning according to claim 1, is reacted with a compound of formula (C) (R8) 5 X' C whereby R8 and m have the g according to claim 1, and X’ represents F, Cl, Br, I, boronic acid or a boronic acid ester in the ce of a suitable base, and a suitable palladium catalyst, optionally in the presence of a suitable ligand, 10 g a compound of formula (Ia) (R4)n N R3 N R1 (R8) N m N H (Ia) which is optionally subsequently deprotected to form a compound of general formula (I) wherein R7 is hydrogen and R1, R2, R3, R4, R6, R8 and n and m have the meaning as defined in claim 1. 11. Process for the manufacture of compounds of general formula (I) according to claim 1, wherein [Annotation] jessb None set by jessb ation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb a compound of formula (Ib) R2 O N R3 N R1 (R8) N m (Ib) R6 whereby R1, R2, R3, R6, R7, R8 and m have the meaning according to claim 1 and R’ is 1-6C-alkyl or benzyl, 5 is treated with a suitable acid system to cleave the benzylic group in order to obtain a compound of a 1-5 N N R1 (R8) N m 1-5 R6 followed by reacting the compound of formula 1-5 with a compound of general formula (B), X R3 10 B wherein R2, R3, R4 and n have the meaning ing to claim 1 and X represents a leaving group, in a suitable solvent system, in the presence of a suitable base, in a temperature range from room temperature to the boiling point of the tive solvent, to fur- 15 nish compounds of general formula (I). [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 12. An intermediate nd of general formula (1-5), N N R1 (R8) N m
1.-5 R6 whereby R1, R6, R7, R8 and m have the g according to any one of claims 1 to 5. 13. Use of a compound of formula 1-5 according to claim 12 for the cture of a compound of formula (I) according to any one of claims 1 to 9. 14. An intermediate compound of general formula (1-4), (R4) N R3 N 2 10 1-4 whereby R1, R2, R3, R4, R6 and n have the meaning according to any one of claims 1 to 5 or 7 to 9 and R2 and R3 are halogen. 15. The ediate compound of general a (1-4) according to claim 14, 15 wherein R² and R³ are fluorine, chlorine or bromine. 16. The intermediate compound of general formula (1-4) according to claim 14, wherein R² and R³ are fluorine or chlorine. 20 17. Use of a compound of formula (1-4) [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb (R4) N R3 N 2 whereby R1, R2, R3, R4, R6 and n have the meaning ing to any one of claims 1 to 5 or 7 to 9, for the manufacture of a compound of formula (I) ing to any one of claims 1 5 to 9. 18. Use of a compound of general formula (I) according to any one of claims 1 to 9 for the manufacture of a medicament for the treatment or prophylaxis of diseases. 10 19. Use of a compound of l formula (I) ing to claim 18, whereby the diseases are hyperproliferative diseases and/or disorders responsive to induction of apoptosis. 20. Use of a compound of general formula (I) according to according to claim 19, 15 y the hyperproliferative diseases and/or disorders responsive to induction of apoptosis are haemotological tumours, solid tumours and/or metastases f. 21. Use of a nd of formula (I) according to claim 20, whereby the tumors 20 are cervical -, breast -, non-small cell lung -, prostate -, colon – or melanoma tumors and/or metastases thereof. 2
2. A pharmaceutical composition comprising at least one compound of general formula (I) according to any one of claims 1 to 9, together with at least one phar- 25 maceutically acceptable auxiliary. [Annotation] jessb None set by jessb [Annotation] jessb MigrationNone set by jessb [Annotation] jessb Unmarked set by jessb 2
3. A composition according to claim 22 for the treatment of haemotological tumours , solid tumours and/or metastases f. 2
4. A combination comprising one or more first active ingredients selected from a 5 compound of general formula (I) according to any one of claims 1 to 9, and one or more second active ingredients selected from chemotherapeutic anti-cancer agents and -specific ancer agents. 2
5. The compound of formula (I) according to claim 1, 7, 8 or 9, the process ac- 10 cording to claim 10 or 11, the intermediate compound of general formula (1-5) according to claim 12, the ediate compound of general formula (1-4) according to claim 14, the use according to claim 18, the composition ing to claim 23 or the combination according to claim 24, substantially as herein described with reference to any one of the Examples.
NZ623098A 2011-10-06 2012-10-04 Substituted benzylindazoles for use as bub1 kinase inhibitors in the treatment of hyperproliferative diseases. NZ623098B2 (en)

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EP11184061.7 2011-10-06
EP11184061 2011-10-06
PCT/EP2012/069562 WO2013050438A1 (en) 2011-10-06 2012-10-04 Substituted benzylindazoles for use as bub1 kinase inhibitors in the treatment of hyperproliferative diseases.

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NZ623098A NZ623098A (en) 2016-09-30
NZ623098B2 true NZ623098B2 (en) 2017-01-05

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