CA3066859A1 - Substituted pyrrolopyridine-derivatives - Google Patents

Abstract

The present invention relates to protein-inhibitory substituted pyrrolopyridine derivatives of formula (I) in which X, Y, R1, R2, R3 and R4 are as defined herein, to pharmaceutical compositions and combinations comprising the compounds according to the invention, and to the prophylactic and therapeutic use of the inventive compounds, respectively to the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular for neoplastic disorders, repectively cancer or conditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signaling, as a sole agent or in combina-tion with other active ingredients. The present invention further relates to the use, respectively to the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of protein inhibitors in benign hyperplasias, atherosclerotic disorders, sepsis, autoimmune disorders, vascular disorders, viral infections, in neurodegenerative disorders, in inflammatory disorders, in atherosclerotic disorders and in male fertility control.

Description

DEMANDE OU BREVET VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.

NOTE : Pour les tomes additionels, veuillez contacter le Bureau canadien des brevets JUMBO APPLICATIONS/PATENTS
THIS SECTION OF THE APPLICATION/PATENT CONTAINS MORE THAN ONE
VOLUME

NOTE: For additional volumes, please contact the Canadian Patent Office NOM DU FICHIER / FILE NAME:
NOTE POUR LE TOME / VOLUME NOTE:

Substituted Pyrrolopyridine-Derivatives The present invention relates to protein-inhibitory substituted pyrrolopyridine derivatives, to pharmaceutical compositions and combinations comprising the compounds according to the invention, and to the prophylactic and therapeutic use of the inventive compounds, respectively to the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular for neoplastic disorders, repectively cancer or conditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signaling, as a sole agent or in combination with other active ingredients.
The present invention further relates to the use, respectively to the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of protein inhibitors in benign hyperplasias, atherosclerotic disorders, sepsis, autoimmune disorders, vascular disorders, viral infections, in neurodegenerative disorders, in inflammatory disorders, in atherosclerotic disorders and in male fertility control.
Background Although cancer cell commonly can be recognize by the adaptive immune system, the response generated is evidently not capable of eliminating the tumor. A major reason for this is the presence of immunosuppressive mechanisms in the tumor microenvironment. In this respect, inhibitors of T-cell immune checkpoint such as CTLA-4, PD-1 or PD-L1 were recently shown to result in a remarkable clinical efficacy in subsets of cancer patients. Besides cell surface receptors that act as negative immune regulators, several mediators of intracellular signaling have been identified that also represent potential immunoevasive mechanisms utilized by the tumor.
One of these is MAP4K1, also known as hematopoietic progenitor kinase 1 (HPK1). MAP4K1 (Genel D11184) is a serine/threonine kinase and member of the Germinal Center Kinase family. In the adult organism MAP4K1 expression is restricted to hematopoietic cell types. The MAP4K1 protein consist of a N-terminal kinase domain, followed by a proline-rich domain that can interact with adaptor molecules through SH2 and SH3 domains, and a C-terminal citron homology domain of which the exact function remains to be identified. Through its proline-rich domain, MAP4K1 is capable of binding to a diversity of adaptors in hematopoietic cells, including those involved in T-cell receptor (TCR), B-cell receptor (BCR) and cytokine signaling (Hu et al., Genes Dev. 1996 Sep 15;10(18):2251-64, 2.; Ling et al.,. J Biol Chem. 2001 Jun 1;276(22), Sauer et al., J Biol Chem. 2001 Nov 30;276(48):45207-16., Tsuji et al., J Exp Med.
2001 Aug 20;194(4):529-39, Boomer et al., J Cell Biochem. 2005 May 1;95(1):34-44).

2 The function of MAP4K1 has been studied in greatest detail in the context of TCR signaling.
Upon TCR stimulation, MAP4K1 is phosphorylated on tyrosine 381 (Y-381; Y-379 in mouse) (Di Bartolo et al., J Exp Med. 2007 Mar 19;204(3):681-91). Consequently, MAP4K1 is recruited to the TCR-signaling complex where it induces dissociation of this complex through its serine/threonine kinase function. In particular MAP4K1 phosphorylates the SLP-76 adaptor protein at Serine-376, resulting in downregulation of AP-1 and Erk2 pathways.
As, such, MAPK1 acts as a negative feedback on TCR-signaling (Liou et al., Immunity.

Apr;12(4):399-408; Lasserre et al., J Cell Biol. 2011 Nov 28;195(5):839-53.).
Alternatively, MAP4K1 can be triggered to suppress T cell function by prostaglandin E2 (PGE2), and possibly also by transforming growth factor beta (TGF-beta), factors that are commonly found in the tumor microenvironment. Notably, MAP4K1 activation by these mediators involves protein kinase A (PKA)-dependent phosphorylation of Serine 171 (S-171; also in mouse) (Alzabin et al., Cancer Immunol lmmunother. 2010 Mar;59(3):419-29;
Sawasdikosol et al., J
Biol Chem. 2007 Nov 30;282(48):34693-9.).
Further important insights into the function of MAP4K1 in the regulation of T
cell immunity stem from in vivo and in vitro experiments respectively with MAP4K1 deficient mice produced by two laboratories and with immune cells isolated from these mice (Shui et al., Nat Immunol. 2007 Jan;8(1):84-91; Alzabin et al., Cancer Immunol lmmunother. 2010 Mar;59(3):419-29).
MAP4K1-deficient mice show an apparent normal phenotype, are fertile and exhibit normal lymphocyte development. These animals are prone to develop T-cell dependent autoimmune reactivity as indicated by development of a more severe disease score in the EAE
(experimental autoimmune encephalomyelitis) model of multiple sclerosis (Shui et al., Nat Immunol. 2007 Jan;8(1):84-91). In case of the second strain, a dysregulation of immune function was observed when, at the age of approximately 6 months, MAP4K1-deficient mice develop a spontaneous autoimmune phenotype (Alzabin et al., Cancer Immunol lmmunother.
2010 Mar;59(3):419-29). In vitro studies showed that MAP4K1-/- T-cells display hyper-responsiveness upon TCR-stimulation. These cells proliferate and secrete pro-inflammatory cytokines like IL-2 or IFNg to a significantly greater extent than their wild-type counterparts (Shui et al., Nat Immunol. 2007 Jan;8(1):84-91). Furthermore, MAP4K1-/- T-cells are resistant to PGE2-mediated suppression of T cell proliferation, suppression of IL-2 production and induction of apoptosis (Alzabin et al., Cancer Immunol lmmunother. 2010 Mar;59(3):419-29).
In the context of tumor immunology, in vivo experiments revealed that MAP4K1-/-mice are much more resistant to tumorigenesis by PGE2-producing Lewis lung carcinoma than wild type .. mice, which correlated with increased T-lymphocyte infiltration in the tumor areas. The crucial role of T-cells in tumor rejection was supported by experiments in which MAP4K1-/- T-cells adoptively transferred into T-cell-deficient mice were able to eradicate tumors more efficiently than wild-type T-cells (Alzabin et al., Cancer Immunol lmmunother. 2010 Mar;59(3):419-29).

3 The important role of the kinase enzymatic activity was demonstrated by studies were only wild type MAP4K1, but not the MAP4K1 kinase-dead mutant, could mediate serine-phosphorylation of the TCR-signaling complex component SLP-76 and subsequent binding of SLP-76 to the negative regulator of TCR-signaling 14-3-3-t (Shui et al., Nat lmmunol. 2007 Jan;8(1):84-91).
.. MAP4K1 also regulates the stimulation and activation of dendritic cells.
MAP4K1 deficient Bone marrow derived cells (BMDC) express after maturation and stimulation higher level of costimulatory molecules and produce more proinflammatory cytokines. Also elimination of tumors was observed to be more efficient by MAP4K1 -/- BMDC compared to their wildtype counterparts (Alzabin et al., J lmmunol. 2009 May 15;182(10):6187-94).
Prior art In WO 2016/205942 HPK1, respectively inhibitors and methods of their use in cancer treatment are described. Especially, the application concerns thieno-pyridinones that can be used in anti-cancer therapy. These compounds differ from the instant compounds in their chemical structure.
In WO 2016/195776 inhibitors and methods for leukemia, cancer and diabetes treatment dependent on inhibition the interaction of menin with of MLL1, MLL2 and MLL-fusion oncoproteins are described. These compounds differ from the instant compounds in their chemical structure.
In WO 2006/014325 C-MET modulators and their use in cancer treatment are described.
These compounds differ from the instant compounds in their chemical structur.
In WO 2005/058891 Rho kinase inhibitors and their use in cardiovascular and cancer treatment are described. These compounds differ from the instant compounds in their chemical structure.
In WO 2015/089479 several inhibitors are described that show inhibition of several kinases (e.g., BTK, HCK, TAK1 and HPK1). These compounds differ from the instant compounds in their chemical structure.
In WO 2018/049200 HPK1 kinase inhibitors and their use in cancer treatment are described.
These compounds differ from the instant compounds in their chemical structure.
In WO 2018/049152 HPK1 kinase inhibitors and their use in cancer treatment are described.
These compounds differ from the instant compounds in their chemical structure.

4 In WO 2018/049214 HPK1 kinase inhibitors and their use in cancer treatment are described.
These compounds differ from the instant compounds in their chemical structure.
In WO 2018/049191 HPK1 kinase inhibitors and their use in cancer treatment are described.
These compounds differ from the instant compounds in their chemical structure.
It would therefore be desirable to provide novel compounds having prophylactic and therapeutic properties.
Accordingly, it is an object of the present invention to provide compounds and pharmaceutical compositions comprising these compounds used for prophylactic and therapeutic applications for hyperproliferative disorders, in particular for cancer, respectively tumour disorders, and conditions with dysregulated immune responses, as a sole agent or in combination with other active ingredients.
A further object of the present invention is to provide compounds and pharmaceutical compositions comprising these compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of protein inhibitors in benign hyperplasias, atherosclerotic disorders, sepsis, autoimmune disorders, vascular disorders, viral infections, in neurodegenerative disorders, in inflammatory disorders, in atherosclerotic disorders and in male fertility control.
Surprisingly, the compounds according to the invention inhibit the MAP4K1 protein and inhibit the growth of cancer cells. Accordingly, they provide novel structures for the therapy of human and animal disorders, in particular of cancers.
It has now been found that compounds of formula (I) F NyN,R4 / I
N
(I), in which X represents a nitrogen, a sulphur or an oxygene atom, Y represents a sulphur or an oxygene atom, R1 represents hydrogen, halogen, C1-06-alkyl, halo-CI-Cs-alkyl or cyano, R2 represents fluorine or chlorine,

5 R3 represents hydrogen or C1-06-alkyl, R4 represents hydrogen or represents C1-06-alkyl-, which may optionally be mono-or polysubstituted by identical or different substituents from the group consisting of halogen, cyano, hydroxy, Ci-03-alkoxy-, -N H2, -NH-(Ci-Cs-alkyl), -N(C1-06-alky1)2, -NH-(C1-06-alkyl)-C1-06-alkoxy, C1-06-alkyl-, Ci-Cs-alkoxy-, -S(=0)2NH2, -C(=0)-R9, -C(=0)-NH-Rx, ¨C(=0)-NR5R6, -NH-C(=0)-R9, -NH-S(=0)2-R9, -S(=0)2-R9, -S(=0)(=NRY)-Rx, -S(=0)-Rx, 03-C10-cycloalkyl- which itself may optionally be mono- or polysubstituted by dentical or different substituents from the group consisting of of halogen, cyano, nitro, hydroxy, amino, oxo, carboxy, C1-06-alkyl-, Ci-Cs-alkoxy-, Ci-06-alkoxy-C1-06-alkyl-, hydroxy-Ci-Cs-alkyl-, C1-06-alkylamino-, C1-06-alkylcarbonylamino-, amino-C1-Cs-alkyl-, Ci-Cs-alkylamino-Ci-Cs-alkyl-, halo-CI-Cs-alkyl-, halo-Ci-Cs-alkoxy-, 03-C10-cycloalkyl-, phenyl-, halophenyl-, phenyl-CI-Cs-alkyl-, phenoxy-, pyridinyl-, ¨C(=0)-NR5R6, -NH-C(=0)-R3, ¨C(=0)-R7, -S(=0)2-NR5R6, ¨S(=0)-R3, -S(=0)(=NR5)-R6, -S(=0)2-R3, ¨NH-S(=0)2-R3, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, monocyclic heteroaryl- having 5 or 6 ring atoms which itself may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, cyano, nitro, carboxy, C1-06-alkyl-, Ci-Cs-alkoxy-, 01-06- alkoxy-Ci-Cs-alkyl-, hydroxy-C1-06-alkyl-, C1-06-alkylamino-, amino-C1-06-alkyl-, Ci-Cs-alkylamino-Ci-Cs-alkyl, halo-01-alkyl-, halo-Ci-Cs-alkoxy-, 03-C10-cycloalkyl and a monocyclic heterocyclyl radical having 3 to 8 ring atoms, monocyclic heterocyclyl- having 3 to 8 ring atoms which itself may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, cyano, oxo, carboxy, C1-06-alkyl-, -carboxy-Ci-Cs-alkyl-, Ci-Cs-alkoxy-, Ci-Cs-alkoxy-Ci-Cs-alkyl-, 01-06-alkylamino-, amino-C1-06-alkyl-, Ci-Cs-alkylamino-Ci-Cs-alkyl-, hydroxy-Ci-Cs-alkyl-, halo-CI-Cs-alkyl-, halo-Ci-Cs-alkoxy-, 03-Cio-cycloalkyl-and a monocyclic heterocyclyl radical having 3 to 8 ring atoms, phenyl- which itself may optionally be mono- or polysubstituted by identical or

6 different substituents from the group consisting of halogen, amino, hydroxy, cyano, nitro, carboxy, C1-06-alkyl-, C1-06-alkoxy-, C1-06-alkoxy-C1-06-alkyl-, C1-06-alkyl-amino-, amino-C1-06-alkyl-, C1-06-alkylaminocarbonyl-, C1-06-alkyl-aminosulphonyl-, C1-06-alkylamino-C1-06-alkyl-, hydroxy-C1-06-alkyl-, halo-C1-06-alkyl-, halo-C1-06-alkoxy-, 03-C10-cycloalkyl- and a monocyclic heterocyclyl radical having 3 to 8 ring atoms, spirocycloalkyl, 5 to 12 membered heterospirocycloalkyl, bicycloalkyl-, heterobicycloalkyl-, bridged cycloalkyl or a bridged heterocycloalkyl, naphthyl or bicyclic heteroaryl, or partially saturated bicyclic aryl- or heteroaryl, each of which mentioned supra may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, cyano, nitro, hydroxy, amino, oxo, carboxy, C1-06-alkyl-, C1-06-alkoxy-, C1-06-alkoxy-C1-06-alkyl-, hydroxy-C1-06-alkyl-, C1-06-alkylamino-, C1-06-alkylcarbonylamino-, amino-C1-06-alkyl-, C1-06-alkylamino-C1-06-alkyl-, halo-C1-06-alkyl-, halo-C1-06-alkoxy-, 03-C10-cycloalkyl-, phenyl-, halophenyl-, phenyl-C1-06-alkyl-, phenoxy-, pyridinyl-, -C(=0)-NR5R6, -NH-C(=0)-R8, -C(=0)-R7, -S(=0)2-NR5R6, -S(=0)-R8, -S(=0)(=NR5)-R6, -S(=0)2-R8, -NH-S(=0)2-R8, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, or R4 represents 03-C10-cycloalkyl- which may optionally be mono- or polysubstituted by dentical or different substituents from the group consisting of of of halogen, cyano, nitro, hydroxy, amino, oxo, carboxy, C1-06-alkyl-, C1-06-alkoxy-, C1-06-alkoxy-C1-06-alkyl-, hydroxy-C1-06-alkyl-, C1-06-alkylamino-, C1-06-alkylcarbonylamino-, amino-C1-06-alkyl-, C1-06-alkylamino-C1-06-alkyl-, halo-C1-06-alkyl-, halo-C1-06-alkoxy-, 03-C10-cycloalkyl-, phenyl-, halophenyl-, phenyl-C1-06-alkyl-, phenoxy-, pyridinyl-, -C(=0)-NR5R6, -NH-C(=0)-R8, -C(=0)-R7, -S(=0)2-NR5R6, -S(=0)-R8, -S(=0)(=NR5)-R6, -S(=0)2-R8, -NH-S(=0)2-R8, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, or represents monocyclic heteroaryl- having 5 or 6 ring atoms which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of of halogen, cyano, nitro, hydroxy, amino, carboxy, C1-06-alkyl-, C1-06-alkoxy-, C1-06-alkoxy-C1-06-alkyl-, hydroxy-C1-06-alkyl-, C1-06-alkylamino-, C1-06-alkylcarbonylamino-, amino-C1-06-alkyl-, 01-06-alkylamino-C1-06-alkyl-, halo-CI-Cs-alkyl-, halo-Ci-Cs-alkoxy-, 03-C10-cycloalkyl-, phenyl-, halophenyl-, phenyl-C1-06-alkyl-, phenoxy-, pyridinyl-, -C(=0)-NR5R6, -NH-C(=0)-R8, -C(=0)-R7, -S(=0)2-NR5R6, -S(=0)-R8,

7 -S(=0)(=NR5)-R6, -S(=0)2-R8, -NH-S(=0)2-R8, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, or represents monocyclic heterocyclyl- having 3 to 8 ring atoms which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of of halogen, cyano, nitro, hydroxy, amino, oxo, carboxy, 01-06-alkyl-, 01-06-alkoxy-, 01-06-alkoxy-01-06-alkyl-, hydroxy-01-06-alkyl-, 01-06-alkylamino-, 01-06-alkylcarbonylamino-, amino-C1-06-alkyl-, 01-06-alkylamino-C1-06-alkyl-, halo-C1-06-alkyl-, halo-C1-06-alkoxy-, 03-010-cycloalkyl-, phenyl-, halophenyl-, phenyl-C1-06-alkyl-, phenoxy-, pyridinyl-, -C(=0)-NR5R6, -NH-C(=0)-R8, -C(=0)-R7, -S(=0)2-NR5R6, -S(=0)-R8, -S(=0)(=NR5)-R6, -S(=0)2-R8, -NH-S(=0)2-R8, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, or represents phenyl- which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of of halogen, cyano, nitro, hydroxy, amino, carboxy, 01-06-alkyl-, 01-06-alkoxy-, 01-06-alkoxy-01-alkyl-, hydroxy-01-06-alkyl-, 01-06-alkylamino-, 01-06-alkylcarbonylamino-, amino-C1-06-alkyl-, 01-06-alkylamino-C1-06-alkyl-, halo-C1-06-alkyl-, halo-01-alkoxy-, 03-010-cycloalkyl-, phenyl-, halophenyl-, phenyl-C1-06-alkyl-, phenoxy-, pyridinyl-, -C(=0)-NR5R6, -NH-C(=0)-R8, -C(=0)-R7, -S(=0)2-NR5R6, -S(=0)-R8, -S(=0)(=NR5)-R6, -S(=0)2-R8, -NH-S(=0)2-R8, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, or represents a spirocycloalkyl radical, a 5 to 12 membered heterospirocycloalkyl radical, a bicycloalkyl, a heterobicycloalkyl radical, a bridged cycloalkyl radical or a bridged heterocycloalkyl radical, a naphthyl radical or a bicyclic heteroaryl radical, or a partially saturated bicyclic aryl- or heteroaryl radical, where the radicals mentioned may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of of halogen, cyano, nitro, hydroxy, amino, oxo, carboxy, 01-06-alkyl-, 01-06-alkoxy-, 01-06-alkoxy-01-06-alkyl-, hydroxy-01-06-alkyl-, 01-06-alkylamino-, 01-06-alkylcarbonylamino-, amino-C1-06-alkyl-, 01-06-alkylamino-C1-06-alkyl-, halo-CI-Cs-alkyl-, halo-01-alkoxy-, 03-010-cycloalkyl-, phenyl-, halophenyl-, phenyl-CI-Cs-alkyl-, phenoxy-, pyridinyl-, -C(=0)-NR5R6, -NH-C(=0)-R8, -C(=0)-R7, -S(=0)2-NR5R6, -S(=0)-R8, -S(=0)(=NR5)-R6, -S(=0)2-R8, -NH-S(=0)2-R8, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, or

8 R3 and R4 together with the nitrogen atom form a 4 to 10 membered heterocycloalkyl or a to 12 membered heterospirocycloalkyl, which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of of halogen, cyano, nitro, hydroxy, amino, oxo, carboxy, 01-06-alkyl-, 5 01-06-alkoxy-, 01-06-alkoxy-01-06-alkyl-, hydroxy-01-06-alkyl-, 01-06-alkylamino-, 01-06-alkylcarbonylamino-, amino-C1-06-alkyl-, 01-06-alkylamino-C1-06-alkyl-, halo-C1-06-alkyl-, halo-C1-06-alkoxy-, 03-010-cycloalkyl-, phenyl-, halophenyl-, phenyl-C1-06-alkyl-, phenoxy-, pyridinyl-, -C(=0)-NR5R6, -NH-C(=0)-R3, -C(=0)-R7, -S(=0)2-NR5R6, -S(=0)-R3, -S(=0)(=NR5)-R6, -S(=0)2-R3, -NH-S(=0)2-R3, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, R5 and R6 independently of one another represent hydrogen, 01-03-alkyl-, cyclopropyl- or di-C1-03-alkylamino-C1-03-alkyl-, or R5 and R6 together with the nitrogen atom form a monocyclic heterocyclyl-having 3 to 8 ring atoms which itself may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, cyano, oxo, 01-06-alkyl-, 01-06-alkoxy-, 01-06-alkylamino-, halo-C1-06-alkyl-, halo-C1-06-alkoxy-, R7 represents hydroxy, 01-06-alkyl-, 01-06-alkoxy-, halo-C1-03-alkyl-, hydroxy-Ci-03-alkyl-, 01-03-alkoxy-01-03-alkyl-, 03-08-cycloalkyl-, phenyl-, monocyclic heterocyclyl- having 3 to 8 ring atoms or monocyclic heteroaryl- having 5 or 6 ring atoms where phenyl-, heteroaryl- and heterocyclyl- may optionally be mono- or disubstituted by halogen, 01-03-alkoxy- or 01-03-alkyl-, R3 represents 01-06-alkyl-, R9 represents 01-06-alkyl-, -N H2, -NH-CI-Cs-alkyl, -N(01-06-alky1)2, or 01-06-alkoxy-01-06-alkyl-, or represents monocyclic heterocyclyl- having 3 to 8 ring atoms which itself may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of of halogen, cyano, nitro, hydroxy, amino, oxo, carboxy, 01-06-alkyl-, 01-06-alkoxy-, 01-06-alkoxy-01-06-alkyl-, hydroxy-01-06-alkyl-, 01-06-alkylamino-, 01-06-alkylcarbonylamino-, amino-C1-06-alkyl-, 01-06-alkylamino-C1-06-alkyl-, halo-CI-Cs-alkyl-, halo-C1-06-alkoxy-, 03-010-cycloalkyl-, phenyl-, halophenyl-, phenyl-C1-06-alkyl-, phenoxy-, pyridinyl-, -C(=0)-NR5R6, -NH-C(=0)-R3, -C(=0)-R7, -S(=0)2-NR5R6, -S(=0)-R3, -S(=0)(=NR5)-R6, -S(=0)2-R3, -NH-S(=0)2-R3, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms,

9 IR' represents Ci-Cs-alkyl- or Ci-Cs-alkoxy-Ci-Cs-alkyl-, RY represents hydrogen, halo-CI-Cs-alkyl, C1-06-alkyl, C1-06-alkyl substituted with 03-06-cycloalkyl, and their polymorphs, enantiomers, diastereomers, racemates, tautomers, solvates, physiologically acceptable salts and solvates of these salts are particularly suitable for a large number of prophylactic and therapeutic applications, in particular for hyperproliferative disorders, for tumour disorders and as proteine inhibitors and further for viral infections, for neurodegenerative disorders, for inflammatory disorders, for atherosclerotic disorders and for male fertility control.
Further, it covers their use in combination with other anti cancer medications such as immunotherapeutics, targeted anti cancer agents, radiation or chemotherapy.
DEFINITIONS
The term "substituted" means that one or more hydrogen atoms on the designated atom or group are replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded.
Combinations of substituents and/or variables are permissible.
.. The term "optionally substituted" means that the number of substituents can be equal to or different from zero. Unless otherwise indicated, it is possible that optionally substituted groups are substituted with as many optional substituents as can be accommodated by replacing a hydrogen atom with a non-hydrogen substituent on any available carbon atom.
Commonly, it is possible for the number of optional substituents, when present, to be 1, 2 or 3.
The term "comprising" when used in the specification includes "consisting of".
If within the present text any item is referred to as "as mentioned herein", it means that it may be mentioned anywhere in the present text.
The terms as mentioned in the present text have the following meanings:
The term "halogen" means a fluorine, chlorine, bromine or iodine, particularly a fluorine, chlorine or bromine atom.
The term "C1-C6-alkyl" means a linear or branched, saturated, monovalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neo-pentyl, 1,1-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2,3-dimethylbutyl, 1,2-dimethylbutyl or 1,3-dimethylbutyl group, or an isomer thereof. Particularly, said group has 1, 2, 3 or 4 carbon atoms ("CI-Ca-alkyl"), e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl isobutyl, or tert-butyl group, more particularly 1, 2 or 3 carbon atoms ("C1-03-alkyl"), e.g. a methyl, ethyl, n-propyl or isopropyl group.
5 The term "hydroxy-C1-06-alkyl" means a linear or branched, saturated, monovalent hydrocarbon group in which the term "C1-06-alkyl" is defined supra, and in which 1 or 2 hydrogen atoms are replaced with a hydroxy group, e.g. a hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropyl, 1-hydroxypropan-2-yl, 2-hydroxypropan-2-yl, 2,3-dihydroxypropyl, 1,3-dihydroxypropan-2-yl,

10 3-hydroxy-2-methyl-propyl, 2-hydroxy-2-methyl-propyl, 1-hydroxy-2-methyl-propyl group.
The term "C1-06-alkoxy" means a linear or branched, saturated, monovalent group of formula (C1-06-alkyl)-O-, which means methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy.
The term "C1-06-alkoxy-C1-06-alkyl-" means a linear or branched, saturated, monovalent group of formula (C1-06-alkyl)-0-(C1-06-alkyl), in which the term "C1-06-alkyl" is defined supra, and in which 1 to 3 hydrogen atoms of the C1-06-alkyl group are replace by C1-06-alkoxy.
The term "C1-06-alkylamino-" means an amino radical having one or two alkyl substituents (selected independently of one another) having generally 1 to 6 (C1-06-alkylamino) and preferably 1 to 3 (C1-03-alkylamino) carbon atoms. (C1-03)-Alkylamino represents, for example, a monoalkylamino radical having 1 to 3 carbon atoms or a dialkylamino radical having 1 to 3 carbon atoms each per alkyl substituent.
The following may be mentioned by way of example:
methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino, n-hexylamino, N,N-dimethylamino, N,N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino, N-isopropyl-N-n-propylamino, N-tert-butyl-N-methylamino, N-ethyl-N-n-pentylamino and N-n-hexyl-N-methylamino.
The term "amino-C1-06-alkyl-" means a linear or branched, saturated, monovalent hydrocarbon group in which the term "C1-06-alkyl" is defined supra, and in which 1 or 2 hydrogen atoms are replaced with an amino group, e.g. a aminomethyl, 1-aminoethyl, 2-aminoethyl, 1,2-diaminoethyl, 3-aminopropyl, 2-aminopropyl, 1-aminopropyl, 1-aminopropan-2-yl, 2-aminopropan-2-yl, 2,3-diaminopropyl, 1,3-diaminopropan-2-yl, 3-amino-2-methyl-propyl, 2-amino-2-methyl-propyl, 1-amino-2-methyl-propyl group.

11 The term "C1-06-alkylamino-C1-06-alkyl means that the alkylaminoalkyl group is attached via the alkyl moiety to the remainder of the molecule, e.g. N,N-dimethylaminoethyl-, N,N-dimethylaminomethyl-, N,N-diethylaminoethyl-, N,N-dimethylaminopropyl-, N-methylaminoethyl-, N-methylaminomethyl-.
The term "halo-C1-06-alkyl-" means an alkyl radical having at least one halogen substituent. The term "C1-06-alkyl-" is as defined supra.
A halo-C1-06-alkyl radical is an alkyl radical having 1-6 carbon atoms and at least one halogen substituent. If a plurality of halogen substituents is present, these may also be different from one another. Preference is given to fluoro-C1-06-alkyl, fluoro-C1-04-alkyl, fluoro-C1-03-alkyl, chloro-C1-06-alkyl, chloro-C1-04-alkyl, chloro-C1-03-alkyl, bromo-C1-06-alkyl, bromo-C1-04-alkyl and bromo-C1-03-alkyl radicals.
In this regard preferred are difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 4,4,5,5,5-pentafluoropentyl or 3,3,4,4,5,5,5-heptafluoropentyl.
Preference is given to perfluorinated alkyl radicals such as trifluoromethyl or 2,2,2-trifluoroethyl.
The term "haloalkoxy" means an alkoxy radical having at least one halogen substituent.
A halo-C1-06-alkoxy radical is an alkoxy radical having 1-6 carbon atoms and at least one halogen substituent. If a plurality of halogen substituents is present, these may also be different from one another. Preference is given to fluoro-C1-06-alkoxy, fluoro-C1-04-alkoxy, fluoro-C1-03-alkoxy, chloro-C1-06-alkoxy, chloro-C1-04-alkoxy, chloro-C1-03-alkoxy, bromo-Ci-Cs-alkoxy, bromo-C1-04-alkoxy and bromo-Ci-03-alkoxy radicals.
In this regard preferred are trifluoromethoxy and 2,2,2-trifluoroethoxy radicals.
The term "halophenyl" means a phenyl radical which is mono- or polysubstituted by identical or different substituents from the group consisting of fluorine, chlorine and bromine.
The term "03-Cio-cycloalkyl" means a saturated, monovalent, monocyclic hydrocarbon ring which contains 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms ("03-Cio-cycloalkyl").
Said 03-010-cycloalkyl group is a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecanyl. Preferred are 3 to 8 (03-08-cycloalkyl) and particularly preferably 3 to 7 (03-07-cycloalkyl) carbon atoms.
The term "C1-06-alkylcarbonylamino" means the group alkyl-C(=0)-NH¨ having generally 1 to 6 (C1-06-alkylcarbonylamino), preferably 1 to 4 and particularly preferably 1 to 3 carbon atoms in the alkyl moiety.

12 The term "phenyl-C1-06-alkyl-" is understood to mean a group composed of an optionally substituted phenyl radical and a C1-06-alkyl group, and bonded to the rest of the molecule via the C1-06-alkyl group. Here, the C1-06-alkyl is as defined supra.
Examples which may be mentioned include benzyl, phenethyl, phenylpropyl, phenylpentyl, with benzyl being preferred.
The term "monocyclic heterocyclyl-" means a non-aromatic monocyclic ring system having one, two or three heteroatoms which may be identical or different. The heteroatoms may be nitrogen atoms, oxygen atoms or sulphur atoms. The sulphur atom may be substituted with oxygene to form a -S(=0)- or ¨S(=0)2- group in the ring.
A monocyclic heterocyclyl ring according to the present invention may have 3 to 8, preferably 4 to 7, particularly preferably 5 or 6 ring atoms.
By way of example and with preference, the following may be mentioned for monocyclic heterocyclyl radicals having 3 ring atoms:
aziridinyl-.
By way of example and with preference, the following may be mentioned for monocyclic heterocyclyl radicals having 4 ring atoms:
azetidinyl-, oxetanyl- and 1,1-dioxidothietanyl-.
By way of example and with preference, the following may be mentioned for monocyclic heterocyclyl radicals having 5 ring atoms:
.. pyrrolidinyl-, imidazolidinyl-, pyrazolidinyl-, pyrrolinyl-, dioxolanyl-, 1,1-dioxidotetrahydro-thiophen-y1-, oxopyrrolidinyl- and tetrahydrofuranyl-.
By way of example and with preference, the following may be mentioned for monocyclic heterocyclyl radicals having 6 ring atoms:
piperidinyl-, piperazinyl-, morpholinyl-, dioxanyl-, tetrahydropyranyl-, 1,1-dioxidotetrahydro-2H-thiopyranyl-, oxopiperidinyl- and thiomorpholinyl-.
By way of example and with preference, the following may be mentioned for monocyclic heterocyclyl radicals having 7 ring atoms:
azepanyl-, oxepanyl-, 1,3-diazepanyl-, 1,4-diazepanyl-.

13 By way of example and with preference, the following may be mentioned for monocyclic heterocyclyl radicals having 8 ring atoms:
oxocanyl-, azocanyl-.
From among the monocyclic heterocyclyl radicals, preference is given to 4- to 7-membered saturated heterocyclyl radicals having up to two heteroatoms from the group consisting of 0, N
and S.
Particular preference is given to morpholinyl-, piperidinyl- and pyrrolidinyl-.
The term "4- to 10-membered heterocycloalkyl" means a monocyclic, saturated heterocycle with 4, 5, 6, 7, 8, 9 or 10 ring atoms in total, which contains one or two identical or different ring heteroatoms from the series N and 0, it being possible for said heterocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, a nitrogen atom. The term "heterocycloalkyl" is as defined supra.
Said heterocycloalkyl group, without being limited thereto, can be a 4-membered ring, such as azetidinyl or oxetanyl, for example; or a 5-membered ring, such as tetrahydrofuranyl, 1,3-dioxolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1,2-oxazolidinyl or 1,3-oxazolidinyl, for example; or a 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, 1,3-dioxanyl, 1,4-dioxanyl or 1,2-oxazinanyl, for example.
Particularly, "4- to 6-membered heterocycloalkyl" means a 4- to 6-membered heterocycloalkyl as defined supra containing one ring oxygen atom and optionally one further ring heteroatom from the series: N, 0. More particularly, "5- or 6-membered heterocycloalkyl"
means a monocyclic, saturated heterocycle with 5 or 6 ring atoms in total, containing one ring oxygen atom.
The term "heteroaryl" means a monovalent, monocyclic aromatic ring or bicyclic aromatic ring system having 5 to 10 ring atoms (a "5- or 10-membered heteroaryl" group), which contains at least one ring heteroatom and optionally one or two further ring heteroatoms from the series:
N, 0 and/or S, and which is bound via a ring carbon atom or optionally via a ring nitrogen atom (if allowed by valency).
The term "monocyclic heteroaryl" means a monovalent, aromatic ring having 5 or 6 ring atoms (a "5- or 6-membered heteroaryl" group), which contains at least one ring heteroatom and optionally one or two further ring heteroatoms from the series: N, 0 and/or S, and which is bound via a ring carbon atom or optionally via a ring nitrogen atom (if allowed by valency).

14 Said heteroaryl group can be a 5-membered heteroaryl group, such as, for example, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl or tetrazolyl; or a 6-membered heteroaryl group, such as, for example, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl.
In general, and unless otherwise mentioned, the heteroaryl or heteroarylene groups include all possible isomeric forms thereof, e.g.: tautomers and positional isomers with respect to the point of linkage to the rest of the molecule. Thus, for some illustrative non-restricting examples, the term pyridinyl includes pyridin-2-yl, pyridin-3-y1 and pyridin-4-y1; or the term thienyl includes thien-2-y1 and thien-3-yl.
Particularly, the heteroaryl group is a isothiazolyl, pyrazolyl, pyridinyl, pyridazinyl or pyrimidinyl group.
The term "spirocycloalkyl" means a 05- to 012-membered bicyclic, saturated ring system with 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms in total which rings are fused in a way that they share one common ring carbon atom, it being possible for said spirocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms, except the spiro carbon atom.
The term "heterospirocycloalkyl" means a 5 to 12 -membered bicyclic, saturated ring system with 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms in total whereas one, two, three or four ring atoms are heteroatoms as defined above, the remaining ring atoms are carbon atoms and which rings are fused in a way that they share one common ring carbon atom, it being possible for said heterospirocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms, except the spiro carbon atom, or, if present, a nitrogen atom.
Examples are spiro[2.2]pentyl, spiro[2.3]hexyl, azaspiro[2.3]hexyl, spiro[3.3]heptyl, azaspiro[3.3]heptyl, oxaazaspiro[3.3]heptyl, thiaazaspiro[3.3]heptyl, oxaspiro[3.3]heptyl, oxazaspiro[3.5]nonyl, oxazaspiro[3.4]octyl, oxazaspiro[5.5]undecyl, diazaspiro[3.3]heptyl, thiazaspiro[3.3]heptyl, thiazaspiro[3.4]octyl, azaspiro[5.5]decyl, and the further homologous spiro[3.4], spiro[4.4], spiro[5.5], spiro[6.6], spiro[2.4], spiro[2.5], spiro[2.6], spiro[3.5], spiro[3.6], spiro[4.5], spiro[4.6] and spiro[5.6] systems including the variants modified by heteroatoms as per the definition. Preference is given to 06-Cio-heterospirocycloalkyl-, by way of example and with particular preference 2-azaspiro[3.3]heptyl-, 2,2-dioxido-2-thia-6-azaspiro[3.3]heptyl.
1,1-dioxido-1-thia-6-azaspiro[3.3]heptyl, 1-thia-6-azaspiro[3.3]heptyl-, 2-thia-6-azaspiro[3.3]heptyl-, 2-oxa-6-azaspiro[3.3]heptyl-,2,6-diazaspiro[3.3]heptyl-, 2-oxa-6-azaspiro[3.4]octyl-, 2-oxa-6-azaspiro[3.5]nonyl-,2-oxa-7-azaspiro[3.5]nonyl-, azaspiro[4.5]decyl-, 2,8-diazaspiro[4.5]decyl- or 3-oxa-1,8-diazaspiro[4.5]decyl-.

The terms "bicycloalkyl" and "heterobicycloalkyl" mean 06-012-bicycloalkyl or heterobicycloalkyl where one, two, three or four carbon atoms are replaced by heteroatoms as defined above in any combination is understood to mean a fusion of two saturated ring 5 systems which share two directly adjacent atoms.
Examples are radicals derived from bicyclo[2.2.0]hexyl-, bicyclo[3.3.0]octyl-, bicyclo[4.4.0]decyl-, bicyclo[5.4.0]undecyl-, bicyclo[3.2.0]heptyl-, bicyclo[4.2.0]octyl-, bicyclo[5.2.0]nonyl-, bicyclo[6.2.0]decyl-, bicyclo[4.3.0]nonyl-, bicyclo[5.3.0]decyl-, 10 bicyclo[6.3.0]undecyl- and bicyclo[5.4.0]undecyl-, including the variants modified by heteroatoms, for example azabicyclo[3.3.0]octyl-, azabicyclo[4.3.0]nonyl-, diazabicyclo[4.3.0]nonyl-, oxazabicyclo[4.3.0]nonyl-, thiazabicyclo[4.3.0]nonyl- or azabicyclo[4.4.0]decyl-, and the further possible combinations as per the definition. Preference is given to 06-Cio-heterobicycloalkyl-, by way of example and with particular preference

15 perhydrocyclopenta[c]pyrroly1-, perhydrofuro[3,2-c]pyridinyl-, perhydropyrrolo[1,2-a]pyrazinyl-, perhydropyrrolo[3,4-c]pyrroly1-.
Preferred examples of 06-012-bicycloalkyl- are perhydronaphthalenyl-(decalinyl-), perhydrobenzoannulenyl-, perhydroazulenyl-, perhydroindanyl-, perhydropentalenyl-.
The terms "bridged cycloalkyl" and "bridged heterocycloalkyl" mean a bridged 06-012 ring system such as bridged 06-012-cycloalkyl- or bridged 06-012-heterocycloalkyl-is understood to mean a fusion of at least two saturated rings which share two atoms that are not directly adjacent to one another. This may give rise either to a bridged carbocycle (bridged cycloalkyl-) or to a bridged heterocycle (bridged heterocycloalkyl-) where one, two, three or four carbon atoms are replaced by heteroatoms as defined above in any combination.
Examples are bicyclo[2.2.1]heptyl-, azabicyclo[2.2.1]heptyl-, oxazabicyclo[2.2.1]heptyl-, thiazabicyclo[2.2.1]heptyl-, diazabicyclo[2.2.1]heptyl-, bicyclo[2.2.2]octyl-, azabicyclo[2.2.2]octyl-, diazabicyclo[2.2.2]octyl-, oxazabicyclo[2.2.2]octyl-, thiazabicyclo[2.2.2]octyl-, bicyclo[3.2.1]octyl-, azabicyclo[3.2.1]octyl-, diazabicyclo[3.2.1]octyl-, oxazabicyclo[3.2.1]octyl-, thiazabicyclo[3.2.1]octyl-, bicyclo[3.3.1]nonyl-, azabicyclo[3.3.1]nonyl-, diazabicyclo[3.3.1]nonyl- oxazabicyclo[3.3.1]nonyl-, thiazabicyclo[3.3.1]nonyl-, bicyclo[4.2.1]nonyl-, azabicyclo[4.2.1]nonyl-, diazabicyclo[4.2.1]nonyl-, oxazabicyclo[4.2.1]nonyl-, thiazabicyclo[4.2.1]nonyl-, bicyclo[3.3.2]decyl-, azabicyclo[3.3.2]decyl-, diazabicyclo[3.3.2]decyl-, oxazabicyclo[3.3.2]decyl-, thiazabicyclo[3.3.2]decyl- or azabicyclo[4.2.2]decyl- and the further possible combinations according to the definition.

16 Preference is given to bridged 06-C10-heterocycloalkyl-, by way of example and with particular preference 2-azabicyclo[2.2.1]heptyl-, 2,5-diazabicyclo[2.2.1]heptyl-, 2-oxa-5-azabicyclo[2.2.1]heptyl-, 8-azabicyclo[3.2.1]octyl-, 8-oxa-3-azabicyclo[3.2.1]octyl-, 3,9-diazabicyclo[4.2.1]nonyl-.
Where the plural form of the word compounds, salts, polymorphs, hydrates, solvates and the like, is used herein, this is taken to mean also a single compound, salt, polymorph, isomer, hydrate, solvate or the like.
By "stable compound' or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The compounds of the present invention optionally contain one or more asymmetric centres, depending upon the location and nature of the various substituents desired. It is possible that one or more asymmetric carbon atoms are present in the (R) or (S) configuration, which can result in racemic mixtures in the case of a single asymmetric centre, and in diastereomeric mixtures in the case of multiple asymmetric centres. In certain instances, it is possible that asymmetry also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds.
Preferred compounds are those which produce the more desirable biological activity.
Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of the present invention are also included within the scope of the present invention. The purification and the separation of such materials can be accomplished by standard techniques known in the art.
Preferred isomers are those which produce the more desirable biological activity. These separated, pure or partially purified isomers or racemic mixtures of the compounds of this invention are also included within the scope of the present invention. The purification and the separation of such materials can be accomplished by standard techniques known in the art.
The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers. Examples of appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, for example, by

17 chromatography or fractional crystallisation. The optically active bases or acids are then liberated from the separated diastereomeric salts. A different process for separation of optical isomers involves the use of chiral chromatography (e.g., H PLC columns using a chiral phase), with or without conventional derivatisation, optimally chosen to maximise the separation of the enantiomers. Suitable H PLC columns using a chiral phase are commercially available, such as those manufactured by Daicel, e.g., Chiracel OD and Chiracel OJ, for example, among many others, which are all routinely selectable. Enzymatic separations, with or without derivatisation, are also useful. The optically active compounds of the present invention can likewise be obtained by chiral syntheses utilizing optically active starting materials.
In order to distinguish different types of isomers from each other reference is made to IUPAC
Rules Section E (Pure Appl Chem 45, 11-30, 1976).
The present invention includes all possible stereoisomers of the compounds of the present invention as single stereoisomers, or as any mixture of said stereoisomers, e.g. (R)- or (5)-isomers, in any ratio. Isolation of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound of the present invention is achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example.
Further, the compounds of the present invention can exist as N-oxides, which are defined in that at least one nitrogen of the compounds of the present invention is oxidised. The present invention includes all such possible N-oxides.
The present invention also covers useful forms of the compounds of the present invention, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and/or co-precipitates.
The compounds of the present invention can exist as a hydrate, or as a solvate, wherein the compounds of the present invention contain polar solvents, in particular water, methanol or ethanol for example, as structural element of the crystal lattice of the compounds. It is possible for the amount of polar solvents, in particular water, to exist in a stoichiometric or non-stoichiometric ratio. In the case of stoichiometric solvates, e.g. a hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta- etc. solvates or hydrates, respectively, are possible. The present invention includes all such hydrates or solvates.

18 Further, it is possible for the compounds of the present invention to exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or to exist in the form of a salt. Said salt may be any salt, either an organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt, which is customarily used in pharmacy, or which is used, for example, for isolating or purifying the compounds of the present invention.
The term "pharmaceutically acceptable salt" refers to an inorganic or organic acid addition salt of a compound of the present invention. For example, see S. M. Berge, etal.
"Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19.
A suitable pharmaceutically acceptable salt of the compounds of the present invention may be, for example, an acid-addition salt of a compound of the present invention bearing a nitrogen atom, in a chain or in a ring, for example, which is sufficiently basic, such as an acid-addition salt with an inorganic acid, or "mineral acid", such as hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, bisulfuric, phosphoric, or nitric acid, for example, or with an organic acid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2-(4-hydroxybenzoyI)-benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nicotinic, pamoic, pectinic, 3-phenylpropionic, pivalic, 2-hydroxyethanesulfonic, itaconic, trifluoromethanesulfonic, .. dodecylsulfuric, ethanesulfonic, benzenesulfonic, para-toluenesulfonic, methanesulfonic, 2-naphthalenesulfonic, naphthalinedisulfonic, camphorsulfonic acid, citric, tartaric, stearic, lactic, oxalic, malonic, succinic, malic, adipic, alginic, maleic, fumaric, D-gluconic, mandelic, ascorbic, glucoheptanoic, glycerophosphoric, aspartic, sulfosalicylic, or thiocyanic acid, for example.
Further, another suitably pharmaceutically acceptable salt of a compound of the present invention which is sufficiently acidic, is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium, magnesium or strontium salt, or an aluminium or a zinc salt, or an ammonium salt derived from ammonia or from an organic primary, secondary or tertiary amine having 1 to 20 carbon atoms, such as ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, diethylaminoethanol, tris(hydroxymethyl)aminomethane, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, 1,2-ethylenediamine, N-methylpiperidine, N-methyl-glucamine, N,N-dimethyl-glucamine, N-ethyl-glucamine, 1,6-hexanediamine, glucosamine, sarcosine, serinol, 2-amino-1,3-propanediol, 3-amino-1,2-propanediol, 4-amino-1,2,3-butanetriol, or a salt with a quarternary ammonium ion having 1 to 20 carbon atoms, such as tetramethylammonium,

19

20 tetraethylammonium, tetra(n-propyl)ammonium, tetra(n-butyl)ammonium, N-benzyl-N,N,N-trimethylammonium, choline or benzalkonium.
Those skilled in the art will further recognise that it is possible for acid addition salts of the claimed compounds to be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods. Alternatively, alkali and alkaline earth metal salts of acidic compounds of the present invention are prepared by reacting the compounds of the present invention with the appropriate base via a variety of known methods.
The present invention includes all possible salts of the compounds of the present invention as single salts, or as any mixture of said salts, in any ratio.
In the present text, in particular in the Experimental Section, for the synthesis of intermediates and of examples of the present invention, when a compound is mentioned as a salt form with the corresponding base or acid, the exact stoichiometric composition of said salt form, as obtained by the respective preparation and/or purification process, is, in most cases, unknown.
Unless specified otherwise, suffixes to chemical names or structural formulae relating to salts, such as "hydrochloride", "trifluoroacetate", "sodium salt", or "x HCI", "x CF3000H", "x Na", for example, mean a salt form, the stoichiometry of which salt form not being specified.
This applies analogously to cases in which synthesis intermediates or example compounds or salts thereof have been obtained, by the preparation and/or purification processes described, as solvates, such as hydrates, with (if defined) unknown stoichiometric composition.
Furthermore, the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as single polymorph, or as a mixture of more than one polymorph, in any ratio.
Moreover, the present invention also includes prodrugs of the compounds according to the invention. The term "prod rugs" here designates compounds which themselves can be biologically active or inactive, but are converted (for example metabolically or hydrolytically) into compounds according to the invention during their residence time in the body.
The invention further includes all possible crystallized and polymorphic forms of the inventive compounds, whereby the polymorphs are existing either as a single polymorph form or are existing as a mixture of several polymorphs in all concentrations.

The invention further includes all possible cyclodextrin clathrates, i.e alpha-, beta-, or gamma-cyclodextrins, hydroxypropyl-beta-cyclodextrins, methylbetacyclodextrins.
In accordance with a further embodiment, the present invention covers compounds of general 5 formula (I), in which X represents an oxygene atom.
In accordance with a further embodiment, the present invention covers compounds of general formula (I), in which Y represents a sulphur or an oxygene atom.
10 In accordance with a further embodiment, the present invention covers compounds of general formula (I), in which X represents a sulphur or an oxygene atom.
In accordance with a further embodiment, the present invention covers compounds of general formula (I), in which Y represents a sulphur or an oxygene atom.
In accordance with a further embodiment, the present invention covers compounds of general formula (I), in which X represents a sulphur and Y an oxygene atom.
In accordance with a further embodiment, the present invention covers compounds of general formula (I), in which Y represents a sulphur and X an oxygene atom.
In accordance with a further embodiment, the present invention covers compounds of general formula (I), in which R1 represents hydrogen, halogen, C1-06-alkyl, halo-C1-06-alkyl and cyano.
In accordance with a further embodiment, the present invention covers compounds of general formula (I), in which R2 represents fluorine.
In accordance with a further embodiment, the present invention covers compounds of general formula (I), in which R3 represents hydrogen or C1-06-alkyl.
In accordance with a further embodiment, the present invention covers compounds of general formula (I), in which R3 represents hydrogen or C1-03-alkyl.
In accordance with a further embodiment, the present invention covers compounds of general formula (I), in which R3 represents hydrogen or methyl.

21 In accordance with a further embodiment, the present invention covers compounds of general formula (I), in which R4 represents hydrogen or represents C1-06-alkyl-, which may optionally be mono-or polysubstituted by identical or different substituents from the group consisting of halogen, cyano, hydroxy, C1-03-alkoxy-, -N(C1-06-alky1)2, -C(=0)-R9, -C(=0)-NH-Rx, ¨C(=0)-NR5R6, -NH-C(=0)-R9, -NH-S(=0)2-R9 or -S(=0)2-R9, or a 03-C10-cycloalkyl- which itself may optionally substituted by hydroxyl, or a monocyclic heteroaryl- having 5 or 6 ring atoms which itself may optionally be mono-or polysubstituted by identical or different substituents from the group consisting of cyano, C1-06-alkyl-, C1-06-alkoxy- or C1-06-alkoxy-C1-06-alkyl-, or a monocyclic heterocyclyl- having 3 to 8 ring atoms which itself may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, hydroxyl, carboxy, C1-06-alkyl- or hydroxy-C1-06-alkyl-, or a phenyl, 5 to 12 membered heterospirocycloalkyl or partially saturated bicyclic heteroaryl, each of which mentioned supra may optionally be substituted by ¨C(=0)-NR5R6, or R4 represents a 03-C10-cycloalkyl- which may optionally substituted by ¨C(=0)-NR5R6 or C1-06-alkoxy-C1-06-alkyl-or represents a monocyclic heteroaryl- having 5 or 6 ring atoms which may optionally be mono-or polysubstituted by identical or different substituents from the group consisting of halogen, C1-06-alkyl-, halo-C1-06-alkyl-, 03-Cio-cycloalkyl-,¨C(=0)-NR5R6, -S(=0)2-R8 or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, or represents a monocyclic heterocyclyl- having 3 to 8 ring atoms which may optionally be mono-or polysubstituted by identical or different substituents from the group consisting of halogen, oxo, C1-06-alkylamino-C1-06-alkyl or monocyclic heterocyclyl radical having 3 to 8 ring atoms or represents a phenyl- which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, C1-06-alkoxy- or halo-C1-06-alkyl-, or represents a 5 to 12 membered heterospirocycloalkyl radical, or a bridged heterocycloalkyl radical,

22 or R3 and R4 together with the nitrogen atom form a 4 to 10 membered heterocycloalkyl or a 5 to 12 membered heterospirocycloalkyl, which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, C1-06-alkyl-, C1-06-alkoxy- or hydroxy-C1-06-alkyl-.
In accordance with a further embodiment, the present invention covers compounds of general formula (I), in which R4 represents hydrogen or represents C1-06-alkyl-, which may optionally be mono-or polysubstituted by identical or different substituents from the group consisting of halogen, cyano, hydroxy, C1-03-alkoxy-, -N(C1-03-alky1)2, -C(=0)-R9, -C(=0)-NH-Rx, ¨C(=0)-NR5R6, -NH-C(=0)-R9, -NH-S(=0)2-R9, -S(=0)2-R9, or a 03-07-cycloalkyl- which itself may optionally substituted by hydroxy, or a monocyclic heteroaryl- having 5 or 6 ring atoms which itself may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of cyano, C1-06-alkyl-, C1-06-alkoxy- or C1-06-alkoxy-C1-06-alkyl-, or a monocyclic heterocyclyl- having 4 to 6 ring atoms which itself may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, hydroxyl, carboxy, C1-06-alkyl- or hydroxy-C1-06-alkyl-, or a phenyl, 7 to 9 membered heterospirocycloalkyl or partially saturated bicyclic heteroaryl, each of which mentioned supra may optionally be substituted by ¨C(=0)-NR5R6, or R4 represents a 03-07-cycloalkyl- which may optionally substituted by ¨C(=0)-NR5R6or C1-06-alkoxy-C1-06-alkyl-or represents a monocyclic heteroaryl- having 5 or 6 ring atoms which may optionally be mono-or polysubstituted by identical or different substituents from the group consisting of halogen, C1-03-alkyl-, halo-C1-03-alkyl-, 03-07-cycloalkyl-, ¨C(=0)-NR5R6, -S(=0)2-R3 or a monocyclic heterocyclyl radical having 4 to 6 ring atoms, or

23 wo 2018/228920 represents a monocyclic heterocyclyl- having 4 to 6 ring atoms which may optionally be mono-or polysubstituted by identical or different substituents from the group consisting of halogen, oxo, C1-03-alkylamino-C1-03-alkyl or monocyclic heterocyclyl radical having 4 to 6 ring atoms, or represents a phenyl- which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, C1-03-alkoxy- or halo-C1-03-alkyl-, or represents a 7 to 9 membered heterospirocycloalkyl radical, or a bridged heterocycloalkyl radical, or R3 and R4 together with the nitrogen atom form a 4 to 6 membered heterocycloalkyl or a 7 to 9 membered heterospirocycloalkyl, which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, C1-03-alkyl-, C1-03-alkoxy-, hydroxy-C1-03-alkyl-.
In accordance with a further embodiment, the present invention covers compounds of general formula (I), in which R4 represents ...........z.3 0 *
* *
*
_N 54\1N *

.......... C H3 I .)cl N , R10 , R13 , R11 , \\ *
( N N'N*
*A\
N¨N S¨N
µ
C H3 ' and where "*" denotes the point of attachment to the remainder of the molecule.

24 In accordance with a further embodiment, the present invention covers compounds of general formula (I), in which R3 and R4 together with the nitrogen atom form the group T r 1 ro i,i,-c H3 I N N
and where "*" denotes the point of attachment to the remainder of the molecule.
In accordance with a further embodiment, the present invention covers compounds of general formula (I), in which X and Y represent an oxygene atom.
In accordance with a further embodiment, the present invention covers compounds of general formula (I), in which R1 represents chlorine, bromine, cyano and trifluoromethyl.
In accordance with a further embodiment, the present invention covers compounds of general formula (I), in which R2 represents fluorine and R3 represents hydrogen.
In accordance with a further embodiment, the present invention covers compounds of general formula (I), in which R4 represents *
* 0 S=0 ¨0 NN

and , where "*" denotes the point of attachment to the remainder of the molecule.
In accordance with a further embodiment, the present invention covers compounds of general formula (I), in which R4 represents hydrogen, C1-06-alkyl-, which may optionally be mono- or disubstituted by identical or different substituents from the group consisting of halogen, cyano, hydroxy, C1-03-alkoxy-, -NH2, -NH-(C1-06-alkyl), -N(C1-06-alky1)2, -NH-(C1-06-alkyl)-C1-06-alkoxy, C1-06-alkyl-, C1-06-alkoxy-, -S(=0)2NH2, -C(=0)-R9, -C(=0)-NH-Rx, -NH-C(=0)-R9, -NH-S(=0)2-R9, -S(=0)2-R9, in which R9 represents methyl, -NH2 or ¨CH2-CH2-0-CH3 or rN.o,c H3 ro , where "*" denotes the point of attachment to the remainder of the molecule.
and Rx represents methyl or ¨CH2-CH2-0-CH3.

In accordance with a further embodiment, the present invention covers compounds of general formula (I), in which R4 represents C1-06-alkyl-, which may optionally be mono-or disubstituted by identical or different substituents from the group consisting of /--\ / /--( *¨N 0 *¨N K 0 *¨N 0 \ / \ __ ) * __ , , C H3 , 0 * 0 T
I /
¨T=
/T I
* ' , * C H3 ' 0 *
TNII)\---C H3 *$
OH' , _______________________________________________ N , *

0 r 0-1 0=S-1 * R12 i 1 -- 1 =
I
N N N I I Rii , * *
*
N sZ\I
N
cN_ , Rio N
, R13 ' N.NN H NS /L *( 0 =-= C H

N¨N , *
H * *
' NI) *\ _ N , \\ / (.* NV FININ
N¨N
N¨N \_.0 H
µC H3 ' H ' 3 N"N 0 R
\\ /( *\\.µ1' >ir N.NO
*r_=/
N
*/ C H3 and 5 where "*" denotes the point of attachment to the remainder of the molecule.

In accordance with a further embodiment, the present invention covers compounds of general formula (I), in which R4 represents C1-06-alkyl-, which may optionally be mono-or disubstituted by identical or different substituents from the group consisting of /--\ / 0 *¨N 0 *¨N r I
\__/ \ __ ) , , *
, 0 0 0=SI, s=0 I I
I N _________ N __ ' */ , %N
* *
*
f\jN
N
¨N¨C H 3 , N .)cl , R13 , , H
N)* *
N.NN H
\
*/ Nr , \ / HN\N
, \
___________________________________________________ C H3 and , H
ii N
*
where "*" denotes the point of attachment to the remainder of the molecule.
In accordance with a further embodiment, the present invention covers compounds of general formula (I), in which X represents an oxygene atom, Y represents a sulphur atom, R1 represents trifluoromethyl and R2 represents fluorine.
In accordance with a further embodiment, the present invention covers compounds of general formula (I), in which R5 and R6 independently of one another represent hydrogen or C1-03-alkyl-, or R5 and R6 together with the nitrogen atom form a monocyclic heterocyclyl-having 3 to 8 ring atoms which itself may optionally be substituted by C1-06-alkyl-.

In accordance with a further embodiment, the present invention covers compounds of general formula (I), in which R5 and R6 independently of one another represent hydrogen or C1-03-alkyl-, or R5 and R6 together with the nitrogen atom form a monocyclic heterocyclyl-having 4 to 6 ring atoms which itself may optionally be substituted by C1-03-alkyl-.
In accordance with a further embodiment, the present invention covers compounds of general formula (I), in which R3 represents C1-06-alkyl-.
In accordance with a further embodiment, the present invention covers compounds of general formula (I), in which R3 represents C1-03-alkyl-.
In accordance with a further embodiment, the present invention covers compounds of general formula (I), in which R9 represents C1-06-alkyl- or -NH2 In accordance with a further embodiment, the present invention covers compounds of general formula (I), in which R9 represents C1-03-alkyl- or -N H2.
In accordance with a further embodiment, the present invention covers compounds of general formula (I), in which Rx represents C1-06-alkoxy-C1-06-alkyl-.
In accordance with a further embodiment, the present invention covers compounds of general formula (I), in which Rx represents C1-03-alkoxy-C1-03-alkyl-.
Of selected interest are those compounds of formula (I), in which X represents a nitrogen, a sulphur or an oxygene atom, represents a sulphur or an oxygene atom, R1 represents hydrogen, halogen, C1-06-alkyl, halo-C1-06-alkyl and cyano, R2 represents fluorine or chlorine, R3 represents hydrogen or C1-06-alkyl, R4 represents hydrogen or represents C1-06-alkyl-, which may optionally be mono-or polysubstituted by identical or different substituents from the group consisting of halogen, cyano, hydroxy, Ci-03-alkoxy-, -N H2, -NH-(Ci-Cs-alkyl), -N(C1-06-alky1)2, -NH-(C1-06-alkyl)-C1-06-alkoxy, 01-06-alkyl-, Ci-Cs-alkoxy-, -S(=0)2NH2, -C(=0)-R9, -C(=0)-NH-Rx, -NH-C(=0)-R9, -NH-S(=0)2-R9, -S(=0)2-R9, -S(=0)(=NRY)-Rx, -S(=0)-Rx, 03-C10-cycloalkyl- which itself may optionally be mono- or polysubstituted by dentical or different substituents from the group consisting of of halogen, cyano, nitro, hydroxy, amino, oxo, carboxy, C1-06-alkyl-, Ci-Cs-alkoxy-, Ci-06-alkoxy-C1-06-alkyl-, hydroxy-Ci-Cs-alkyl-, C1-06-alkylamino-, C1-06-alkylcarbonylamino-, amino-C1-Cs-alkyl-, Ci-Cs-alkylamino-Ci-Cs-alkyl-, halo-CI-Cs-alkyl-, halo-Cs-alkoxy-, 03-C10-cycloalkyl-, phenyl-, halophenyl-, phenyl-CI-Cs-alkyl-, phenoxy-, pyridinyl-, ¨C(=0)-NR5R6, -NH-C(=0)-R8, ¨C(=0)-R7, -S(=0)2-NR5R6, ¨S(=0)-R8, -S(=0)(=NR5)-R6, -S(=0)2-R8, ¨NH-S(=0)2-R8, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, monocyclic heteroaryl- having 5 or 6 ring atoms which itself may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, cyano, nitro, carboxy, C1-06-alkyl-, Ci-Cs-alkoxy-, 01-06- alkoxy-Ci-Cs-alkyl-, hydroxy-C1-06-alkyl-, 01-06-alkylamino-, amino-C1-06-alkyl-, Ci-Cs-alkylamino-Ci-Cs-alkyl, halo-CI-Cs-alkyl-, halo-Ci-Cs-alkoxy-, 03-C10-cycloalkyl and a monocyclic heterocyclyl radical having 3 to 8 ring atoms, monocyclic heterocyclyl- having 3 to 8 ring atoms which itself may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, cyano, oxo, carboxy, C1-06-alkyl-, -carboxy-Ci-Cs-alkyl-, Ci-Cs-alkoxy-, Ci-Cs-alkoxy-Ci-Cs-alkyl-, 01-06-alkylamino-, amino-C1-06-alkyl-, Ci-Cs-alkylamino-Ci-Cs-alkyl-, hydroxy-Ci-Cs-alkyl-, halo-CI-Cs-alkyl-, halo-Ci-Cs-alkoxy-, 03-Cio-cycloalkyl- and a monocyclic heterocyclyl radical having 3 to 8 ring atoms, phenyl- which itself may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, cyano, nitro, carboxy, C1-06-alkyl-, Ci-Cs-alkoxy-, Ci-Cs-alkoxy-Ci-Cs-alkyl-, Ci-Cs-alkyl-amino-, amino-C1-06-alkyl-, C1-06-alkylaminocarbonyl-, C1-06-alkyl-aminosulphonyl-, Ci-Cs-alkylamino-Ci-Cs-alkyl-, hydroxy-Ci-Cs-alkyl-, halo-C1-06-alkyl-, halo-Ci-Cs-alkoxy-, 03-C10-cycloalkyl- and a monocyclic heterocyclyl radical having 3 to 8 ring atoms, spirocycloalkyl-, heterospirocycloalkyl-, bicycloalkyl-, heterobicycloalkyl-, bridged cycloalkyl or a bridged heterocycloalkyl, naphthyl or bicyclic heteroaryl, or partially saturated bicyclic aryl- or heteroaryl, each of which mentioned supra may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, cyano, nitro, hydroxy, amino, oxo, carboxy, C1-06-alkyl-, C1-06-alkoxy-, C1-06-alkoxy-C1-06-alkyl-, hydroxy-C1-06-alkyl-, C1-06-alkylamino-, C1-06-alkylcarbonylamino-, amino-C1-Cs-alkyl-, C1-06-alkylamino-C1-06-alkyl-, halo-C1-06-alkyl-, halo-06-alkoxy-, 03-C10-cycloalkyl-, phenyl-, halophenyl-, phenyl-CI-Cs-alkyl-, phenoxy-, pyridinyl-, -C(=0)-NR5R6, -NH-C(=0)-R8, -C(=0)-R7, -S(=0)2-NR5R6, -S(=0)-R8, -S(=0)(=NR5)-R6, -S(=0)2-R8, -NH-S(=0)2-R8, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, or R4 represents 03-C10-cycloalkyl- which may optionally be mono- or polysubstituted by dentical or different substituents from the group consisting of of of halogen, cyano, nitro, hydroxy, amino, oxo, carboxy, C1-06-alkyl-, Ci-Cs-alkoxy-, 01-06-alkoxy-C1-06-alkyl-, hydroxy-C1-06-alkyl-, C1-06-alkylamino-, 01-06-alkylcarbonylamino-, amino-C1-06-alkyl-, Ci-Cs-alkylamino-Ci-Cs-alkyl-, halo-06-alkyl-, halo-Ci-Cs-alkoxy-, 03-C10-cycloalkyl-, phenyl-, halophenyl-, phenyl-C1-06-alkyl-, phenoxy-, pyridinyl-, -C(=0)-NR5R6, -NH-C(=0)-R8, -C(=0)-R7, -S(=0)2-NR5R6, -S(=0)-R8, -S(=0)(=NR5)-R6, -S(=0)2-R8, -NH-S(=0)2-R8, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, or represents monocyclic heteroaryl- having 5 or 6 ring atoms which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of of halogen, cyano, nitro, hydroxy, amino, carboxy, C1-06-alkyl-, Ci-Cs-alkoxy-, Ci-Cs-alkoxy-Ci-Cs-alkyl-, hydroxy-C1-06-alkyl-, 01-06-alkylamino-, C1-06-alkylcarbonylamino-, amino-C1-06-alkyl-, C1-06-alkylamino-C1-06-alkyl-, halo-CI-Cs-alkyl-, halo-Ci-Cs-alkoxy-, 03-C10-cycloalkyl-, phenyl-, halophenyl-, phenyl-CI-Cs-alkyl-, phenoxy-, pyridinyl-, -C(=0)-NR5R6, -NH-C(=0)-R8, -C(=0)-R7, -S(=0)2-NR5R6, -S(=0)-R8, -S(=0)(=NR5)-R6, -S(=0)2-R8, -NH-S(=0)2-R8, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, or represents monocyclic heterocyclyl- having 3 to 8 ring atoms which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of of halogen, cyano, nitro, hydroxy, amino, oxo, carboxy, C1-06-alkyl-, C1-06-alkoxy-, C1-06-alkoxy-C1-06-alkyl-, hydroxy-C1-06-alkyl-, Ci-5 Cs-alkylamino-, Ci-Cs-alkylcarbonylamino-, amino-CI-Cs-alkyl-, 01-alkylamino-C1-06-alkyl-, halo-C1-06-alkyl-, halo-C1-06-alkoxy-, 03-C10-cycloalkyl-, phenyl-, halophenyl-, phenyl-01-06-alkyl-, phenoxy-, pyridinyl-, -C(=0)-NR5R6, -NH-C(=0)-R8, -C(=0)-R7, -S(=0)2-NR5R6, -S(=0)-R8, -S(=0)(=NR5)-R6, -S(=0)2-R8, -NH-S(=0)2-R8, or a monocyclic heterocyclyl 10 radical having 3 to 8 ring atoms, or represents phenyl- which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of of halogen, cyano, nitro, hydroxy, amino, carboxy, C1-06-alkyl-, C1-06-alkoxy-, C1-06-alkoxy-C1-15 alkyl-, hydroxy-C1-06-alkyl-, C1-06-alkylamino-, C1-06-alkylcarbonylamino-, amino-C1-06-alkyl-, C1-06-alkylamino-C1-06-alkyl-, halo-C1-06-alkyl-, halo-01-alkoxy-, 03-C10-cycloalkyl-, phenyl-, halophenyl-, phenyl-CI-Cs-alkyl-, phenoxy-, pyridinyl-, -C(=0)-NR5R6, -NH-C(=0)-R8, -C(=0)-R7, -S(=0)2-NR5R6, -S(=0)-R8, -S(=0)(=NR5)-R6, -S(=0)2-R8, -NH-S(=0)2-R8, or a monocyclic heterocyclyl 20 radical having 3 to 8 ring atoms, or represents a spirocycloalkyl radical, a heterospirocycloalkyl radical, a bicycloalkyl, a heterobicycloalkyl radical, a bridged cycloalkyl radical or a bridged heterocycloalkyl radical, a naphthyl radical or a bicyclic heteroaryl

25 radical, or a partially saturated bicyclic aryl- or heteroaryl radical, where the radicals mentioned may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of of halogen, cyano, nitro, hydroxy, amino, oxo, carboxy, C1-06-alkyl-, C1-06-alkoxy-, C1-06-alkoxy-C1-06-alkyl-, hydroxy-Ci-Cs-alkyl-, C1-06-alkylamino-, C1-06-alkylcarbonylamino-, 30 amino-C1-06-alkyl-, Ci-Cs-alkylamino-Ci-Cs-alkyl-, halo-CI-Cs-alkyl-, halo-Ci-Cs-alkoxy-, 03-C10-cycloalkyl-, phenyl-, halophenyl-, phenyl-CI-Cs-alkyl-, phenoxy-, pyridinyl-, -C(=0)-NR5R6, -NH-C(=0)-R8, -C(=0)-R7, -S(=0)2-NR5R6, -S(=0)-R8, -S(=0)(=NR5)-R6, -S(=0)2-R8, -NH-S(=0)2-R8, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, or R3 and R4 together with the nitrogen atom form a 4 to 10 membered heterocycloalkyl ring, which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of of halogen, cyano, nitro, hydroxy, amino, oxo, carboxy, C1-06-alkyl-, C1-06-alkoxy-, C1-06-alkoxy-C1-06-alkyl-, hydroxy-C1-06-alkyl-, C1-06-alkylamino-, C1-06-alkylcarbonylamino-, amino-Ci-Cs-alkyl-, Ci-Cs-alkylamino-Ci-Cs-alkyl-, halo-CI-Cs-alkyl-, halo-Ci-Cs-alkoxy-, 03-Cio-cycloalkyl-, phenyl-, halophenyl-, phenyl-CI-Cs-alkyl-, phenoxy-, pyridinyl-, -C(=0)-NR5R6, -NH-C(=0)-R3, -C(=0)-R7, -S(=0)2-NR5R6, -S(=0)-R3, -S(=0)(=NR5)-R6, -S(=0)2-R3, -NH-S(=0)2-R3, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, R5 and R6 independently of one another represent hydrogen, Ci-03-alkyl-, cyclopropyl- or di-C1-03-alkylamino-C1-03-alkyl-, R7 represents hydroxy, Ci-Cs-alkyl-, Ci-Cs-alkoxy-, halo-Ci-03-alkyl-, hydroxy-Ci-03-alkyl-, Ci-03-alkoxy-Ci-03-alkyl-, 03-08-cycloalkyl-, phenyl-, monocyclic heterocyclyl- having 3 to 8 ring atoms or monocyclic heteroaryl- having 5 or 6 ring atoms where phenyl-, heteroaryl- and heterocyclyl- may optionally be mono- or disubstituted by halogen, Ci-03-alkoxy- or Ci-03-alkyl-, R3 represents Ci-Cs-alkyl-, R9 represents Ci-Cs-alkyl-, -N H2, -NH-CI-Cs-alkyl, -N(C1-06-alky1)2, or Ci-06-alkoxy-Ci-Cs-alkyl-, or represents monocyclic heterocyclyl- having 3 to 8 ring atoms which itself may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of of halogen, cyano, nitro, hydroxy, amino, oxo, carboxy, Ci-Cs-alkyl-, Ci-Cs-alkoxy-, Ci-Cs-alkoxy-Ci-Cs-alkyl-, hydroxy-Ci-Cs-alkyl-, Ci-Cs-alkylamino-, Ci-Cs-alkylcarbonylamino-, amino-CI-Cs-alkyl-, 01-06-alkylamino-C1-06-alkyl-, halo-CI-Cs-alkyl-, halo-Ci-Cs-alkoxy-, 03-C10-cycloalkyl-, phenyl-, halophenyl-, phenyl-01-06-alkyl-, phenoxy-, pyridinyl-, -C(=0)-NR5R6, -NH-C(=0)-R3, -C(=0)-R7, -S(=0)2-NR5R6, -S(=0)-R3, -S(=0)(=NR5)-R6, -S(=0)2-R3, -NH-S(=0)2-R3, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, Rx represents C1-06-alkyl- or Ci-Cs-alkoxy-Ci-Cs-alkyl-, RY represents hydrogen, halo-CI-Cs-alkyl, C1-06-alkyl, C1-06-alkyl substituted with 03-06-cycloalkyl, and their polymorphs, enantiomers, diastereomers, racemates, tautomers, solvates, physiologically acceptable salts and solvates of these salts Of selected interest are those compounds of formula (I), in which X represents an oxygene atom, Y represents a sulphur or an oxygene atom, R1 represents hydrogen, halogen, C1-06-alkyl, halo-C1-06-alkyl and cyano, R2 represents fluorine, R3 represents hydrogen or C1-06-alkyl, R4 represents hydrogen or represents C1-06-alkyl-, which may optionally be mono-or disubstituted by identical or different substituents from the group consisting of halogen, cyano, hydroxy, C1-03-alkoxy-, -NH2, -NH-(C1-06-alkyl), -N(C1-06-alky1)2, -NH-(C1-06-alkyl)-C1-06-alkoxy, C1-06-alkyl-, C1-06-alkoxy-, -S(=0)2NH2, -C(=0)-R9, -C(=0)-NH-Rx, -NH-C(=0)-R9, -NH-S(=0)2-R9, -S(=0)2-R9, -S(=0)(=NRY)-Rx, -S(=0)-Rx, 03-C10-cycloalkyl-, monocyclic heteroaryl- having 5 or 6 ring atoms which itself may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, cyano, nitro, hydroxy, amino, carboxy, C1-06-alkyl-, C1-06-alkoxy-, C1-06-alkoxy-C1-06-alkyl-, hydroxy-C1-06-alkyl-, 01-06-alkylamino-, C1-06-alkylcarbonylamino-, amino-C1-06-alkyl-, C1-06-alkylamino-C1-06-alkyl-, halo-C1-06-alkyl-, halo-C1-06-alkoxy-, 03-C10-cycloalkyl-, phenyl-, halophenyl-, phenyl-C1-06-alkyl-, phenoxy-, pyridinyl-, -C(=0)-NR5R6, -NH-C(=0)-R3, -C(=0)-R7, -S(=0)2-NR5R6, -S(=0)-R3, -S(=0)(=NR5)-R6, -S(=0)2-R3, -NH-S(=0)2-R3, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, monocyclic heterocyclyl- having 4 to 8 ring atoms which itself may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, cyano, nitro, hydroxy, amino, oxo, carboxy, C1-06-alkyl-, C1-06-alkoxy-, C1-06-alkoxy-C1-06-alkyl-, hydroxy-C1-06-alkyl-, 01-06-alkylamino-, C1-06-alkylcarbonylamino-, amino-C1-06-alkyl-, C1-06-alkylamino-C1-06-alkyl-, halo-CI-Cs-alkyl-, halo-Ci-Cs-alkoxy-, 03-C10-cycloalkyl-, phenyl-, halophenyl-, phenyl-CI-Cs-alkyl-, phenoxy-, pyridinyl-, -C(=0)-NR5R6, -NH-C(=0)-R3, -C(=0)-R7, -S(=0)2-NR5R6, -S(=0)-R3, -S(=0)(=NR5)-R6, -S(=0)2-R3, -NH-S(=0)2-R3, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, phenyl- which itself may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, cyano, nitro, hydroxy, amino, carboxy, C1-06-alkyl-, C1-06-alkoxy-, Ci-Cs-alkoxy-Ci-Cs-alkyl-, hydroxy-Ci-Cs-alkyl-, Ci-Cs-alkylamino-, 01-06-alkylcarbonylamino-, amino-C1-06-alkyl-, Ci-Cs-alkylamino-Ci-Cs-alkyl-, halo-06-alkyl-, halo-Ci-Cs-alkoxy-, 03-C10-cycloalkyl-, phenyl-, halophenyl-, phenyl-C1-06-alkyl-, phenoxy-, pyridinyl-, ¨C(=0)-NR5R6, -NH-C(=0)-R8, ¨C(=0)-R7,-S(=0)2-NR5R6, ¨S(=0)-R8, -S(=0)(=NR5)-R6,-S(=0)2-R8, ¨NH-S(=0)2-R8, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, spirocycloalkyl-, heterospirocycloalkyl-, bicycloalkyl-, heterobicycloalkyl-, bridged cycloalkyl or a bridged heterocycloalkyl, naphthyl or bicyclic heteroaryl, or partially saturated bicyclic aryl- or heteroaryl, each of which mentioned may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, cyano, nitro, hydroxy, amino, oxo, carboxy, Ci-Cs-alkyl-, Ci-Cs-alkoxy-, Ci-Cs-alkoxy-Ci-Cs-alkyl-, hydroxy-C1-06-alkyl-, 01-alkylamino-, C1-06-alkylcarbonylamino-, amino-C1-06-alkyl-, C1-06-alkylamino-C1-06-alkyl-, halo-CI-Cs-alkyl-, halo-Ci-Cs-alkoxy-, 03-C10-cycloalkyl-, phenyl-, halophenyl-, phenyl-CI-Cs-alkyl-, phenoxy-, pyridinyl-, ¨C(=0)-NR5R6, -NH-C(=0)-R8, ¨C(=0)-R7,-S(=0)2-NR5R6, ¨S(=0)-R8, -S(=0)(=NR5)-R6,-S(=0)2-R8, ¨NH-S(=0)2-R8, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, or R4 represents monocyclic heterocyclyl- having 3 to 8 ring atoms which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, cyano, nitro, hydroxy, amino, oxo, carboxy, Ci-Cs-alkyl-, Ci-Cs-alkoxy-, Ci-Cs-alkoxy-Ci-Cs-alkyl-, hydroxy-C1-06-alkyl-, 01-alkylamino-, C1-06-alkylcarbonylamino-, amino-C1-06-alkyl-, C1-06-alkylamino-C1-06-alkyl-, halo-CI-Cs-alkyl-, halo-Ci-Cs-alkoxy-, 03-C10-cycloalkyl-, phenyl-, halophenyl-, phenyl-CI-Cs-alkyl-, phenoxy-, pyridinyl-, ¨C(=0)-NR5R6, -NH-C(=0)-R8, ¨C(=0)-R7,-S(=0)2-NR5R6, ¨S(=0)-R8, -S(=0)(=NR5)-R6,-S(=0)2-R8, ¨NH-S(=0)2-R8, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, or represents phenyl- which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, cyano, nitro, hydroxy, amino, carboxy, C1-06-alkyl-, C1-06-alkoxy-, Ci-Cs-alkoxy-Ci-Cs-alkyl-, hydroxy-Ci-Cs-alkyl-, Ci-Cs-alkylamino-, 01-06-alkylcarbonylamino-, amino-C1-06-alkyl-, Ci-Cs-alkylamino-Ci-Cs-alkyl-, halo-06-alkyl-, halo-Ci-Cs-alkoxy-, 03-C10-cycloalkyl-, phenyl-, halophenyl-, phenyl-C1-06-alkyl-, phenoxy-, pyridinyl-, -C(=0)-NR5R6, -NH-C(=0)-R3, -C(=0)-R7, -S(=0)2-NR5R6, -S(=0)-R3, -S(=0)(=NR5)-R6, -S(=0)2-R3, -NH-S(=0)2-R3, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, or R3 and R4 together with the nitrogen atom form a 4 to 10 membered heterocycloalkyl ring, which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, cyano, nitro, hydroxy, amino, oxo, carboxy, C1-06-alkyl-, Ci-Cs-alkoxy-, Ci-Cs-alkoxy-Ci-Cs-alkyl-, hydroxy-Ci-Cs-alkyl-, C1-06-alkylamino-, C1-06-alkylcarbonylamino-, amino-C1-06-alkyl-, Ci-Cs-alkylamino-Ci-Cs-alkyl-, halo-CI-Cs-alkyl-, halo-Ci-Cs-alkoxy-, 03-010-cycloalkyl-, phenyl-, halophenyl-, phenyl-CI-Cs-alkyl-, phenoxy-, pyridinyl-, -C(=0)-NR5R6, -NH-C(=0)-R3, -C(=0)-R7, -S(=0)2-NR5R6, -S(=0)-R3, -S(=0)(=NR5)-R6, -S(=0)2-R3, -NH-S(=0)2-R3, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, or together with the nitrogen atom form a heterospirocycloalkyl or heterobicycloalkyl group, each of which mentioned may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, cyano, nitro, hydroxy, amino, oxo, carboxy, C1-06-alkyl-, Ci-Cs-alkoxy-, Ci-Cs-alkoxy-Ci-Cs-alkyl-, hydroxy-Ci-Cs-alkyl-, C1-06-alkylamino-, 01-06-alkylcarbonylamino-, amino-C1-06-alkyl-, Ci-Cs-alkylamino-Ci-Cs-alkyl-, halo-06-alkyl-, halo-Ci-Cs-alkoxy-, 03-C10-cycloalkyl-, phenyl-, halophenyl-, phenyl-C1-06-alkyl-, phenoxy-, pyridinyl-, -C(=0)-NR5R6, -NH-C(=0)-R3, -C(=0)-R7, -S(=0)2-NR5R6, -S(=0)-R3, -S(=0)(=NR5)-R6, -S(=0)2-R3, -NH-S(=0)2-R3, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, R5 and R6 independently of one another represent hydrogen, C1-03-alkyl-, cyclopropyl- or di-01-03-alkylamino-01-03-alkyl-, R7 represents hydroxy, 01-06-alkyl-, 01-06-alkoxy-, halo-01-03-alkyl-, hydroxy-Ci-03-alkyl-, 01-03-alkoxy-01-03-alkyl-, 03-08-cycloalkyl-, phenyl-, monocyclic heterocyclyl- having 3 to 8 ring atoms or monocyclic heteroaryl- having 5 or 6 ring atoms where phenyl-, heteroaryl- and heterocyclyl- may optionally be mono- or disubstituted by halogen, 01-03-alkoxy- or C1-03-alkyl-, R3 represents C1-06-alkyl-, R9 represents C1-06-alkyl-, -NH2, -NH-C1-06-alkyl, -N(C1-06-alky1)2, C1-06-alkoxy-C1-06-alkyl-, or 5 represents monocyclic heterocyclyl- having 3 to 8 ring atoms which itself may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, cyano, nitro, hydroxy, amino, oxo, carboxy, Ci-Cs-alkyl-, Ci-Cs-alkoxy-, Ci-Cs-alkoxy-Ci-Cs-alkyl-, hydroxy-Ci-Cs-alkyl-, 01-alkylamino-, C1-06-alkylcarbonylamino-, amino-C1-06-alkyl-, C1-06-alkylamino-1 0 C1-06-alkyl-, halo-C1-06-alkyl-, halo-C1-06-alkoxy-, 03-C10-cycloalkyl-, phenyl-, halophenyl-, phenyl-Ci-Cs-alkyl-, phenoxy-, pyridinyl-, ¨C(=0)-NR5R6, -NH-C(=0)-R3, ¨C(=0)-R7, -S(=0)2-NR5R6, ¨S(=0)-R3, -S(=0)(=NR5)-R6, -S(=0)2-R3, ¨NH-S(=0)2-R3, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, Rx represents CI-Cs-alkyl- or C1-06-alkoxy-C1-06-alkyl-, 15 RY represents hydrogen, halo-CI-Cs-alkyl, CI-Cs-alkyl, CI-Cs-alkyl substituted with 03-06-cycloalkyl, and their polymorphs, enantiomers, diastereomers, racemates, tautomers, solvates, physiologically acceptable salts and solvates of these salts.
Of selected interest are those compounds of formula (I), in which X represents a sulphur or an oxygene atom, Y represents a sulphur or an oxygene atom, R1 represents hydrogen, halogen, CI-Cs-alkyl, halo-CI-Cs-alkyl or cyano, R2 represents fluorine, R3 represents hydrogen or CI-Cs-alkyl, R4 represents hydrogen or represents CI-Cs-alkyl-, which may optionally be mono-or polysubstituted by identical or different substituents from the group consisting of halogen, cyano, hydroxy, Ci-03-alkoxy-, -N(C1-06-alky1)2, -C(=0)-R9, -C(=0)-NH-Rx, ¨C(=0)-NR5R6, -NH-C(=0)-R9, -NH-S(=0)2-R9 or -S(=0)2-R9, or a 03-C10-cycloalkyl- which itself may optionally substituted by hydroxy, or a monocyclic heteroaryl- having 5 or 6 ring atoms which itself may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of cyano, CI-Cs-alkyl-, C1-06-alkoxy- or C1-06-alkoxy-C1-06-alkyl-, or a monocyclic heterocyclyl- having 3 to 8 ring atoms which itself may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, hydroxyl, carboxy, C1-06-alkyl- or hydroxy-C1-06-alkyl-, or a phenyl, 5 to 12 membered heterospirocycloalkyl or partially saturated bicyclic heteroaryl, each of which mentioned supra may optionally be substituted by ¨C(=0)-NR5R6, or R4 represents a 03-C10-cycloalkyl- which may optionally substituted by ¨C(=0)-NR5R6 or C1-06-alkoxy-C1-06-alkyl-or represents a monocyclic heteroaryl- having 5 or 6 ring atoms which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, C1-06-alkyl-, halo-C1-06-alkyl-, 03-Cio-cycloalkyl-,¨C(=0)-NR5R6, -S(=0)2-R3 or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, or represents a monocyclic heterocyclyl- having 3 to 8 ring atoms which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, oxo, C1-06-alkylamino-C1-06-alkyl or monocyclic heterocyclyl radical having 3 to 8 ring atoms or represents a phenyl- which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, C1-06-alkoxy- or halo-C1-06-alkyl-, or represents a 5 to 12 membered heterospirocycloalkyl radical, or a bridged heterocycloalkyl radical, or R3 and R4 together with the nitrogen atom form a 4 to 10 membered heterocycloalkyl or a 5 to 12 membered heterospirocycloalkyl, which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, C1-06-alkyl-, C1-06-alkoxy- or hydroxy-C1-06-alkyl-, R5 and R6 independently of one another represent hydrogen or C1-03-alkyl-, R5 and R6 together with the nitrogen atom form a monocyclic heterocyclyl-having 3 to 8 ring atoms which itself may optionally be substituted by CI-Cs-alkyl-, R3 represents CI-Cs-alkyl-, R9 represents CI-Cs-alkyl- or -NH2, Rx represents C1-06-alkoxy-C1-06-alkyl-, and their polymorphs, enantiomers, diastereomers, racemates, tautomers, solvates, physiologically acceptable salts and solvates of these salts.
Of selected interest are those compounds of formula (I), in which X represents a sulphur or an oxygene atom, Y represents a sulphur or an oxygene atom, R1 represents hydrogen, halogen, CI-Cs-alkyl, halo-CI-Cs-alkyl or cyano, R2 represents fluorine, R3 represents hydrogen or C1-03-alkyl, R4 represents hydrogen or represents CI-Cs-alkyl-, which may optionally be mono-or polysubstituted by identical or different substituents from the group consisting of halogen, cyano, hydroxy, C1-03-alkoxy-, -N(C1-03-alkyl)2, -C(=0)-R9, -C(=0)-NH-Rx, ¨C(=0)-NR5R6, -NH-C(=0)-R9, -NH-S(=0)2-R9, -S(=0)2-R9, or a 03-07-cycloalkyl- which itself may optionally substituted by hydroxy, or a monocyclic heteroaryl- having 5 or 6 ring atoms which itself may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of cyano, CI-Cs-alkyl-, C1-06-alkoxy- or C1-06-alkoxy-C1-06-alkyl-, or a monocyclic heterocyclyl- having 4 to 6 ring atoms which itself may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, hydroxyl, carboxy, CI-Cs-alkyl- or hydroxy-Ci-06-alkyl-, or a phenyl, 7 to 9 membered heterospirocycloalkyl or partially saturated bicyclic heteroaryl, each of which mentioned supra may optionally be substituted by ¨C(=0)-NR5R6, or R4 represents a 03-07-cycloalkyl- which may optionally substituted by ¨C(=0)-NR5R6or C1-06-alkoxy-C1-06-alkyl-or represents a monocyclic heteroaryl- having 5 or 6 ring atoms which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, C1-03-alkyl-, halo-C1-03-alkyl-, 03-07-cycloalkyl-, ¨C(=0)-NR5R6, -S(=0)2-R3 or a monocyclic heterocyclyl radical having 4 to 6 ring atoms, or represents a monocyclic heterocyclyl- having 4 to 6 ring atoms which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, oxo, C1-03-alkylamino-C1-03-alkyl or monocyclic heterocyclyl radical having 4 to 6 ring atoms or represents a phenyl- which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, C1-03-alkoxy- or halo-C1-03-alkyl-, or represents a 7 to 9 membered heterospirocycloalkyl radical, or a bridged heterocycloalkyl radical, or R3 and R4 together with the nitrogen atom form a 4 to 6 membered heterocycloalkyl or a 7 to 9 membered heterospirocycloalkyl, which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, C1-03-alkyl-, C1-03-alkoxy-, hydroxy-C1-03-alkyl-, R5 and R6 independently of one another represent hydrogen or C1-03-alkyl-, R5 and R6 together with the nitrogen atom form a monocyclic heterocyclyl-having 4 to 6 ring atoms which itself may optionally be substituted by C1-03-alkyl-, R3 represents C1-03-alkyl-, R9 represents C1-03-alkyl- or -NH2, Rx represents C1-03-alkoxy-C1-03-alkyl-, and their polymorphs, enantiomers, diastereomers, racemates, tautomers, solvates, physiologically acceptable salts and solvates of these salts.

Of special interest are those compounds of formula (I) in which X represents an oxygene atom, Y represents a sulphur or an oxygene atom, R1 represents hydrogen, chlorine, bromine, methyl-, trifluoromethyl and cyano, R2 represents fluorine, R3 represents hydrogen or methyl, R4 represents hydrogen, C1-06-alkyl-, which may optionally be mono- or disubstituted by identical or different substituents from the group consisting of halogen, cyano, hydroxy, C1-03-alkoxy-, -NH2, -NH-(C1-06-alkyl), -N(C1-06-alky1)2, -NH-(C1-06-alkyl)-C1-06-alkoxy, C1-06-alkyl-, C1-06-alkoxy-, -S(=0)2NH2, -C(=0)-R9, -C(=0)-NH-R9, -NH-C(=0)-Rx, -NH-S(=0)2-R9, -S(=0)2-R9, *_N/ *N1 ) * ______ K \O * _N
\/ _____________________ /
, , C H 3 , 0 -g =0 -0 *ZI *)- I */ I ,*/ I
0 *
)¨

* /
\
, * , 0 0 ¨1 0 =S ¨1 *

,\ ______________________________________ I\ ________________ R ii * *
* 1 N N NA _ .)LR io N , , , CH

N .NI\I H N Z
N , S /IN * 0 C H
H N Ni ---1 r 3 )=N
H *
*
1\1) N' , N /. H NN
N ¨N
gl ¨N \ __ /-C H 3 t H 3 ' H ' N ' IV
N , 0 )\/( *----\---/
C H 3' * ---.-1-N1 -0IR14 and or R4 represents :-.--0 , *
*
N y_ 54\11\1 *

cH3 Rio N . 1 1 , R13 ' R
, H *
1\1) 0 N *
1\1/ K
K N' *Ak q N' \\ ii N¨N S¨N \\¨S
, and \CI-13 ' 5 or R3 and R4 together with the nitrogen atom form the group I
Ni __________________ pc) r0 N
>, NrN( *., CH3 and , R9 represents methyl, -NH2 or ¨CH2-CH2-0-CH3 or rN,...0 H3 r0 *N.) , Rx represents methyl or ¨CH2-CH2-0-CH3, R10 represents hydrogen, methyl, methoxy and cyano R11 represents hydrogen and trifluoromethyl, R12 represents hydrogen, fluorine and methoxy, R13 represents hydrogen and methyl, R14 represents hydrogen and ¨CH2-0-CH3, where "*" denotes the point of attachment to the remainder of the molecule, and their polymorphs, enantiomers, diastereomers, racemates, tautomers, solvates, physiologically acceptable salts and solvates of these salts.
Further of selected interest are those compounds of formula (I) in which X represents an oxygene atom, Y represents an oxygene atom, R1 represents hydrogen, chlorine, bromine, methyl-, trifluoromethyl and cyano, R2 represents fluorine, R3 represents hydrogen or methyl, R4 represents hydrogen, CI-Cs-alkyl-, which may optionally be mono- or disubstituted by identical or different substituents from the group consisting of halogen, cyano, hydroxy, C1-03-alkoxy-, -NH2, -NH-(C1-06-alkyl), -N(C1-06-alky1)2, -NH-(C1-06-alkyl)-C1-06-alkoxy, CI-Cs-alkyl-, C1-06-alkoxy-, -S(=0)2NH2, -C(=0)-R9, -C(=0)-NH-Rx, -NH-C(=0)-R9, -NH-S(=0)2-R9, -S(=0)2-R9, wo 2018/228920 PCT/EP2018/065036 /--\ / / ( *¨N 0 *¨N ) * ___________________ ( 0 *¨N 0 \ / \ ( C H3 , \\
¨0 is:0 0 T=0 I
* , */
, * C H3 , 0 *
NA\---C H3 *$
) I OH , N
, _______________________________________________ N , *

I, 0 0¨I 0=S *
Ti I R12 I I I
N ______________________________________________________ 11 N ______________________________ N
*
N fZ\L
N
_1\1)_ ,)LR1 o \cl ______ N, , R13 , N.NN H N.NS )N * 0 C H3 HN X N
)-14 , N¨N , H *
N)r Nr , \\ / (.*
N7. HN
N¨N
N¨N \
_________________________________________________ C H3 µC H3 ' H ' N"N 0 Ac > R
N
)\ /( * i .NO
N *
C H3 ' and or wo 2018/228920 PCT/EP2018/065036 R4 represents S,---0 * µµ
* *
*
\I *

-N N -C H3 , N .)cl , R13 , , H * * *
e.) 1\1) ci0 N
V , V V
\\ / (m m *Aµ
\LS

C H3 ' and Or R3 and R4 together with the nitrogen atom form the group I
NI ____________________ P0 r 0 N
* ri,i,-N
* C H3 */ , and , R9 represents methyl, -NH2 or ¨CH2-CH2-0-CH3 or r0 *
, Rx represents methyl or ¨CH2-CH2-0-CH3, R19 represents hydrogen, methyl, methoxy and cyano R11 represents hydrogen and trifluoromethyl, R12 represents hydrogen, fluorine and methoxy, R13 represents hydrogen and methyl, R14 represents hydrogen and ¨CH2-0-CH3, where "*" denotes the point of attachment to the remainder of the molecule, and their polymorphs, enantiomers, diastereomers, racemates, tautomers, solvates, physiologically acceptable salts and solvates of these salts.

wo 2018/228920 PCT/EP2018/065036 Thereof of special interest are those compounds of formula (I), in which X represents an oxygene atom, Y represents an oxygene atom, R1 represents chlorine, bromine, cyano and trifluoromethyl, R2 represents fluorine, R3 represents hydrogen, R4 represents hydrogen, CI-Cs-alkyl-, which may optionally be mono- or disubstituted by identical or different substituents from the group consisting of halogen, cyano, hydroxy, C1-03-alkoxy-, -NH2, -NH-(C1-06-alkyl), -N(C1-06-alky1)2, -NH-(C1-06-alkyl)-C1-06-alkoxy, CI-Cs-alkyl-, C1-06-alkoxy-, -S(=0)2NH2, -C(=0)-R9, -C(=0)-NH-Rx, -NH-C(=0)-R9, -NH-S(=0)2-R9, or /--\ / 0 *¨N 0 *¨N r I , \/ \ __ ) , *
, 0 0 0=SI, , */ I
N __________________________________ , I
N __________________________________________________ , \
N
*/
*
*
*
_N N f4\1N
________________________ _ C H3 %'R10 __________________________________ N, , R13 , , H * *
N.NN H N, N\ ___________________________________ / , \ HN - N
, \
__________________________________________________________ C H3 and , H
N
ti N
*
or R4 represents *
* 0 =0 N H S---S --O
\\
0 */./
0 and , R9 represents methyl, -NH2 or ¨CH2-CH2-0-CH3 or rNO H 3 N) *
5 , Rx represents methyl or ¨CH2-CH2-0-CH3, R10 represents hydrogen, R13 represents hydrogen, where "*" denotes the point of attachment to the remainder of the molecule, 10 and their polymorphs, enantiomers, diastereomers, racemates, tautomers, solvates, physiologically acceptable salts and solvates of these salts.
Further of selected interest are those compounds of formula (I) in which 15 X represents an oxygene atom, Y represents a sulphur atom, R1 represents trifluoromethyl, R2 represents fluorine, R3 represents hydrogen, 20 R4 represents C1-03-alkyl-, which may optionally be mono-substituted by -N(C1-03-alky1)2, C1-06-alkoxy-, or /--\
*¨N 0 where "*" denotes the point of attachment to the remainder of the molecule, and their polymorphs, enantiomers, diastereomers, racemates, tautomers, solvates, 25 .. physiologically acceptable salts and solvates of these salts.

Compounds of most interest are those as follows:
- 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-1Apyridin-4-yl]oxylpheny1)-343-(morpholin-4-y1)propyl]urea;
- 1-(3,5-d ifl uoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-1Apyrid in-4-yl]oxylphenyI)-3-(2-methoxyethyl)urea;
- 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-1Apyridin-4-yl]oxylpheny1)-343-(methylsulfonyl)propyl]urea;
- 1-(2,2-difluoroethyl)-3-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-1Apyridin-4-yl]oxylphenyOurea;
- N3-[(3 ,5-d ifl uoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-1Apyrid in-4-yl]oxylphenyl)carbamoy1]-beta-alan inamide;
- 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-1Apyridin-4-yl]oxylpheny1)-3-(pyridin-4-ylmethypurea;
- 1-(3,5-d ifl uoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-1Apyrid in-4-yl]oxylphenyI)-3-[(1-hydroxycyclopropyl)methyl]urea;
- 4-{[(3,5-d ifl uoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-1Apyrid in-4-yl]oxylphenyl)carbamoyl]aminolbutanamide;
- 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-1Apyridin-4-yl]oxylpheny1)-3-(3-methoxypropypurea;
- 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-1Apyridin-4-yl]oxylpheny1)-342-(morpholin-4-y1)-2-oxoethyl]urea;
- 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-1Apyridin-4-yl]oxylpheny1)-3-(pyridin-3-ylmethypurea;
- 1-(3,5-d ifl uoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-1Apyrid in-4-yl]oxylphenyI)-3-(pyridin-2-ylmethyl)urea;
- 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-1Apyridin-4-yl]oxylpheny1)-342-(pyridin-4-ypethyl]urea;
- (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-1Apyridin-4-yl]oxylpheny1)-342-hydroxy-3-(morpholin-4-y1)propyl]urea;
- (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-1Apyridin-4-yl]oxylpheny1)-3-(tetrahydrofuran-2-ylmethypurea;
- 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-1Apyridin-4-yl]oxylpheny1)-3-(tetrahydro-2H-pyran-4-ylmethypurea;
- 1-(3,5-d ifl uoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-1Apyrid in-4-yl]oxylphenyI)-3-(1H-1,2,3-triazol-5-ylmethypurea;

- N2-[(3 ,5-d ifl uoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyrid in-4-yl]oxylphenyl)carbamoyl]glycinamide;
- 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-342-(morpholin-4-ypethyl]urea;
- 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-342-(piperidin-1-ypethyl]urea;
- 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-343-(piperidin-1-y1)propyl]urea;
- 1-(3,5-d ifl uoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyrid in-4-yl]oxylpheny1)-343-(dimethylamino)propyl]urea;
- 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-342-(dimethylamino)ethyl]urea;
- 1-(3,5-d ifl uoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyrid in-4-yl]oxylphenyI)-3-[(1,1-d ioxidoth ietan-3-yl)methyl]urea;
- N-(2-{[(3,5-d ifl uoro-4-{[3-(trifl uoromethyl)-1H-pyrrolo[2,3-b]pyrid in-yl]oxylphenyl)carbamoyl]am inolethypacetamide;
- (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-341-(morpholin-4-y1)propan-2-yl]urea;
- (+/-)-1-(3,5-d ifl uoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyrid in-4-yl]oxylpheny1)-342-(morpholin-4-yl)propyl]urea;
- 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-342-(methylsulfonypethyl]urea;
- 3-{[(3,5-d ifl uoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyrid in-4-yl]oxylphenyl)carbamoyl]am inolpropane-1-sulfonamide;
- 3-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-1-methyl-142-(morpholin-4-ypethyl]urea;
- N-(2-{[(3 ,5-d ifl uoro-4-{[3-(trifl uoromethyl)-1H-pyrrolo[2,3-b]pyrid in-4-yl]oxylphenyl)carbamoyl]aminolethyl)methanesu lfonamide;
- 1-(3,5-d ifl uoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyrid in-4-yl]oxylpheny1)-3-pyrid in-3-ylurea;
- 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-343-(trifluoromethyl)phenyl]urea;
- 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(1,3,4-thiadiazol-2-yOurea;

- 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-342-fluoro-5-(trifluoromethyl)phenyl]urea;
- 1-(3,5-d ifl uoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyrid in-4-yl]oxylpheny1)-3-pyridazin-3-ylurea ;
- 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(2-methoxyphenyOurea;
- 1-(2,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-343-(morpholin-4-y1)propyl]urea;
- 1-(2,5-d ifl uoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyrid in-4-yl]oxylpheny1)-342-(morpholin-4-yl)ethyl]urea;
- 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-d ifl uoropheny11-343-(piperid in-1-yl)propyl]urea;
- 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-342-(dimethylamino)ethyl]urea;
- 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-d ifl uoropheny11-342-(piperid in-1-yl)ethyl]u rea;
- 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-343-(morpholin-4-y1)propyl]urea;
- 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-d ifl uoropheny1}-3-(2-methoxyethyl)urea;
- 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-ethylurea;
- 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-342-(morpholin-4-ypethyl]urea;
- 1-benzy1-3-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyrid in-4-yl)oxy]-3,5-d ifl uorophenyllurea - 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-d ifl uoropheny1}-3-(pyrimid in-5-ylmethypurea ;
- 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(pyridin-4-ylmethypurea;
- 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-d ifl uoropheny1}-3-(2-cyanoethyl)urea;
- 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(3-methylbutypurea;
- 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(1,2-oxazol-3-yOurea;

- 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-pyridazin-3-ylurea;
- 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyllurea;
- N-{24({4-[(3-ch loro-1H-pyrrolo[2 ,3-b]pyrid in-4-yl)oxy]-3,5-d ifl uorophenyllcarbamoy1)-amino]ethyllacetamide;
- 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-342-(dimethylamino)ethyl]urea;
- 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-343-(dimethylamino)propyl]urea;
- 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-butylurea;
- 1-benzy1-3-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyrid in-4-yl)oxy]-3,5-d ifluorophenyllurea ;
- 1-(2,3-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-343-(morpholin-4-y1)propyl]urea;
- 1-(2,3-d ifl uoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyrid in-4-yl]oxylpheny1)-342-(morpholin-4-yl)ethyl]urea;
- 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-342-(dimethylamino)ethyl]thiourea;
- 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-342-(morpholin-4-ypethyl]thiourea;
- 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(2-methoxyethypthiourea;
- 1-(3,5-d ifl uoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyrid in-4-yl]oxylpheny1)-3-ethylthiourea - and - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-343-(morpholin-4-y1)propyl]thiourea, - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(oxetan-3-ylmethypurea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyOurea - 1-(3,5-d ifl uoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyrid in-4-yl]oxylpheny1)-3-methylu rea - 3-(3,5-d ifl uoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyrid in-4-yl]oxylpheny1)-1,1-dimethylurea - N-(3 ,5-d ifl uoro-4-{[3-(trifl uoromethyl)-1H-pyrrolo[2,3-b]pyrid in-4-yl]oxylphenyl)morpholine-4-carboxamide - N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-4-methylpiperazine-1-carboxamide - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-342-(4-methylpiperazin-1-y1)-2-oxoethyl]urea 5 - N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide - N2-[(3 ,5-d ifl uoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyrid in-4-yl]oxylphenyl)carbamoy1]-N-methylglycinamide - 1-(3,5-d ifl uoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyrid in-4-yl]oxylphenyI)-3-(1,2-10 thiazol-4-yl)urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(1-methyl-1H-pyrazol-4-y1)urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(6-methylpyridin-3-yOurea 15 - 1-[(1-acetylazetidin-3-yl)methyl]-3-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyOurea - N2-[(3 ,5-d ifl uoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyrid in-4-yl]oxylphenyl)carbamoy1]-N-(2-methoxyethyl)glycinamide - (+/-)-1-(3,5-d ifl uoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyrid in-4-yl]oxylphenyI)-3-20 [(1,1-dioxidothietan-2-yl)methyl]urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(2-methylpyrimidin-5-yOurea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(1H-pyrazol-4-yOurea 25 - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-342-(1-oxa-6-azaspiro[3.3]hept-6-ypethyl]urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-342-(1,1-dioxido-1-thia-6-azaspiro[3.3]hept-6-ypethyl]urea - (+/-)-1-(3,5-d ifl uoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyrid in-4-yl]oxylphenyI)-3-30 (2-oxopyrrolidin-3-yl)urea - (+/-)-1-(3,5-d ifl uoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyrid in-4-yl]oxylphenyI)-3-(1,1-d ioxidotetrahyd roth iophen-3-yOurea - (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(5-oxopyrrolidin-3-yOurea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yOurea - 1-(3,5-d ifl uoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyrid in-4-yl]oxylphenyI)-3-(1H-pyrazol-3-ylmethyl)urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(1H-imidazol-2-ylmethypurea - 1-(3,5-d ifl uoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyrid in-4-yl]oxylphenyI)-3-[(1-methy1-1H-pyrazol-3-y1)methyl]urea - 1-(3,5-d ifl uoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyrid in-4-yl]oxylphenyI)-3-(1,3-thiazol-2-ylmethyl)urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(pyrimidin-4-ylmethypurea - 1-(3,5-d ifl uoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyrid in-4-yl]oxylphenyI)-3-[(2-methylpyrid in-4-yl)methyl]urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(pyridazin-3-ylmethypurea - 1-(3,5-d ifl uoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyrid in-4-yl]oxylphenyI)-3-[(5-methy1-1H-imidazol-2-y1)methyl]urea - 1-(3,5-d ifl uoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyrid in-4-yl]oxylphenyI)-3-{[3-(methoxymethyl)-1,2,4-oxadiazol-5-yl]methyllurea - 1-(3,5-d ifl uoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyrid in-4-yl]oxylphenyI)-3-[(5-methy1-4 H-1,2,4-triazol-3-yl)methyl]urea - (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(tetrahydrofuran-3-yOurea - 1-(3,5-d ifl uoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyrid in-4-yl]oxylphenyI)-3-[(3R)-tetra hyd rofuran-3-yl]u rea - 1-(3,5-d ifl uoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyrid in-4-yl]oxylphenyI)-3-[(3S)-tetra hyd rofuran-3-yl]u rea - 1-(3,5-d ifl uoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyrid in-4-yl]oxylphenyI)-3-{3-[(2R,6R)-2,6-di methylmorpholin-4-yl]propyllurea - 1-(3,5-d ifl uoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyrid in-4-yl]oxylphenyI)-3-[(1-methy1-1H-imidazol-2-y1)methyl]urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(4-methyl-1,2,5-oxadiazol-3-y1)methyl]urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(2-methoxypyridin-4-y1)methyl]urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(1-methyl-1H-imidazol-4-y1)methyl]urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-{2-[(2RS,6RS)-2,6-dimethylmorpholin-4-yl]ethyllurea - 1-[(2-cyanopyridin-4-yl)methyl]-3-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyOurea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(pyridazin-4-ylmethyl)urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(1,2,4-oxadiazol-3-ylmethypurea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(1,3-oxazol-2-ylmethypurea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(1,3-thiazol-5-ylmethypurea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-342-(2-oxa-6-azaspiro[3.3]hept-6-ypethyl]urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(5-methyl-1,3,4-oxadiazol-2-y1)methyl]urea - N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-N'-[(3-methyloxetan-3-y1)methyl]urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(5-methylpyridazin-3-yOurea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(2R)-tetrahydrofuran-2-ylmethyl]urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(2S)-tetrahydrofuran-2-ylmethyl]urea - (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(5,5-dimethyltetrahydrofuran-2-yl)methyl]urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(tetrahydro-2H-pyran-4-yOurea - (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(tetrahydro-2H-pyran-2-ylmethypurea - (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-1Apyridin-4-yl]oxylpheny1)-3-(tetrahydro-2H-pyran-3-yOurea - (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-1Apyridin-4-yl]oxylpheny1)-3-[(2-methyltetrahydrofuran-2-y1)methyl]urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-1Apyridin-4-yl]oxylpheny1)-3-(2-methoxy-2-methylpropypurea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-1Apyridin-4-yl]oxylpheny1)-342-methyl-2-(morpholin-4-y1)propyl]urea - (+/-)-1-(3,5-d ifl uoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-1Apyrid in-4-yl]oxylphenyI)-3-(tetrahydro-2H-pyran-3-ylmethyl)urea - (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-1Apyridin-4-yl]oxylpheny1)-3-(tetrahydrofuran-3-ylmethypurea - 1-{4-[(3-chloro-1H-pyrrolo[2,3-1Apyridin-4-ypoxy]-3,5-difluorophenyll-3-pyridazin-4-ylurea - 1-{4-[(3-chloro-1H-pyrrolo[2,3-1Apyridin-4-ypoxy]-3,5-difluorophenyll-3-(6-methylpyridazin-3-yOurea - 1-{4-[(3-chloro-1H-pyrrolo[2,3-1Apyridin-4-ypoxy]-3,5-difluorophenyll-3-pyridin-3-ylurea - 1-{4-[(3-chloro-1H-pyrrolo[2,3-1Apyridin-4-ypoxy]-3,5-difluorophenyll-3-pyridin-2-ylurea - 1-[3,5-difluoro-4-(1H-pyrrolo[2,3-1Apyridin-4-yloxy)phenyl]-342-(piperidin-1-ypethyl]urea - N3-{[3,5-difluoro-4-(1H-pyrrolo[2,3-1Apyridin-4-yloxy)phenyl]carbamoyll-beta-alaninamide - 1-[3,5-difluoro-4-(1H-pyrrolo[2,3-1Apyridin-4-yloxy)phenyl]-3-(1H-1,2,3-triazol-5-ylmethyl)urea - 1-[3,5-d ifl uoro-4-(1H-pyrrolo[2,3-1Apyrid in-4-yloxy)pheny1]-343-(dimethylamino)propyl]urea - 4-({[3,5-difluoro-4-(1H-pyrrolo[2,3-1Apyridin-4-yloxy)phenyl]carbamoyllamino)butanamide - 1-[3,5-difluoro-4-(1H-pyrrolo[2,3-1Apyridin-4-yloxy)phenyl]-3-(2-methoxyethypurea - 1-[3,5-difluoro-4-(1H-pyrrolo[2,3-1Apyridin-4-yloxy)phenyl]-3-(pyridin-2-ylmethypurea - 1-[3,5-difluoro-4-(1H-pyrrolo[2,3-1Apyridin-4-yloxy)phenyl]-343-(methylsulfonyl)propyl]urea - 1-[3,5-difluoro-4-(1H-pyrrolo[2,3-1Apyridin-4-yloxy)phenyl]-342-(dimethylamino)ethyl]urea - 1-[3,5-d ifl uoro-4-(1H-pyrrolo[2,3-1Apyrid in-4-yloxy)pheny1]-3[3-(piperid in-1-yl)propyl]urea - 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(3-methoxypropypurea - 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-[(1-methyl-1H-pyrazol-3-yl)methyl]urea - 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(1,3-thiazol-2-ylmethyl)urea - 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(1H-pyrazol-3-ylmethyl)urea - N3-({4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyllcarbamoy1)-beta-alaninamide - 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-342-(piperidin-1-ypethyl]urea - N-{24({4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyllcarbamoyl)amino]ethyllmethanesulfonamide - 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-343-(morpholin-4-y1)propyl]urea - N-{24({4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyllcarbamoyl)amino]ethyllacetamide - 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-342-(morpholin-4-yI)-2-oxoethyl]urea - 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(pyridin-2-ylmethyl)urea - 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-[(1,1-dioxidothietan-3-yl)methyl]urea - 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(2-methoxyethypurea - 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(pyridin-4-ylmethyl)urea - N2-({4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyllcarbamoyl)glycinamide - 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-343-(piperidin-1-y1)propyl]urea - 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(1H-1,2,3-triazol-4-ylmethyl)urea - 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-343-(methylsulfonyl)propyl]urea - 44({4-[(3-bromo-1H-pyrrolo[2,3-b]pyrid in-4-yl)oxy]-3,5-difluorophenyllcarbamoyl)amino]butanamide 5 - 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-342-(4-methylpiperazin-1-y1)-2-oxoethyl]urea - 1-{3,5-difluoro-4-[(3-methy1-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]phenyll-342-(dimethylamino)ethyl]urea - (+/-)-1-{4-[(3-cyano-1H-pyrrolo[2,3-b]pyrid in-4-yl)oxy]-3,5-difluoropheny11-3-10 (tetrahydrofuran-3-yl)urea - 1-{4-[(3-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-342-(dimethylamino)ethyl]urea - (+/-)-1-{4-[(3-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(tetrahydrofuran-2-ylmethypurea 15 - 1-{4-[(3-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(3-methoxypropypurea - 1-{4-[(3-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-343-(morpholin-4-y1)propyl]urea - 1-{4-[(3-cyano-1H-pyrrolo[2,3-b]pyrid in-4-yl)oxy]-3,5-d ifl uoropheny11-3-[(1-methyl-1H-20 pyrazol-3-yl)methyl]urea - 1-{4-[(3-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(1,3-thiazol-2-ylmethyl)urea - 1-{4-[(3-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(pyridin-4-ylmethyl)urea 25 - 1-{4-[(3-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(2-methoxyethypurea - 1-{4-[(3-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(1H-pyrazol-3-ylmethyl)urea - (+/-)-1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyrid in-4-yl)oxy]-3,5-difluoropheny11-3-30 (tetrahydrofuran-3-yl)urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(6-methoxypyridazin-3-yOurea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(6,7-dihydro-5H-cyclopenta[c]pyridazin-3-yOurea - 1-(6-bromopyridazin-3-y1)-3-{4-[(3-chloro-1H-pyrrolo[2,3-1Apyridin-4-ypoxy]-3,5-difluorophenyllurea - (+/-)-1-{4-[(3-chloro-1H-pyrrolo[2,3-1Apyridin-4-ypoxy]-3,5-difluorophenyll-3-(tetrahydrofuran-2-ylmethypurea - 1-{4-[(3-chloro-1H-pyrrolo[2,3-1Apyriclin-4-ypoxy]-3,5-difluorophenyll-3-[(3S)-tetrahydrofuran-3-yl]urea - 1-{4-[(3-chloro-1H-pyrrolo[2,3-1Apyriclin-4-ypoxy]-3,5-difluorophenyll-3-[(1-methyl-1H-pyrazol-3-y1)methyl]urea - 1-{4-[(3-chloro-1H-pyrrolo[2,3-1Apyridin-4-ypoxy]-3,5-difluorophenyll-3-(2-oxaspiro[3.3]hept-6-yOurea - 1-{4-[(3-chloro-1H-pyrrolo[2,3-1Apyridin-4-ypoxy]-3,5-difluorophenyll-346-(difluoromethyl)pyridazin-3-yl]urea - (+/-)-1-{4-[(3-chloro-1H-pyrrolo[2,3-1Apyridin-4-ypoxy]-3,5-difluorophenyll-3-(tetrahydrofuran-3-yOurea - 1-{4-[(3-chloro-1H-pyrrolo[2,3-1Apyridin-4-ypoxy]-3,5-difluorophenyll-3-(3-methoxypropyl)urea - 1-{4-[(3-chloro-1H-pyrrolo[2,3-1Apyriclin-4-ypoxy]-3,5-difluorophenyll-3-[(3R)-tetrahydrofuran-3-yl]urea - 1-{4-[(3-chloro-1H-pyrrolo[2,3-1Apyridin-4-ypoxy]-3,5-difluorophenyll-3-(1H-pyrazol-3-ylmethyl)urea - 1-{4-[(3-chloro-1H-pyrrolo[2,3-1Apyridin-4-ypoxy]-3,5-difluorophenyll-3-(2,2,2-trifluoroethypurea - (+/-)-N-{4-[(3-chloro-1H-pyrrolo[2,3-1Apyridin-4-ypoxy]-3,5-difluorophenyll-3-[(dimethylamino)methyl]pyrrolidine-1-carboxamide - 1-{4-[(3-chloro-1H-pyrrolo[2,3-1Apyridin-4-ypoxy]-3,5-difluorophenyll-3-[(4-methyl-1,2,5-oxadiazol-3-y1)methyl]urea - 1-{4-[(3-chloro-1H-pyrrolo[2,3-1Apyridin-4-ypoxy]-3,5-difluorophenyll-3-(2-fluoroethypurea - N-{4-[(3-chloro-1H-pyrrolo[2,3-1Apyriclin-4-ypoxy]-3,5-difluorophenyll-2-oxa-7-azaspiro[3.5]nonane-7-carboxamide - 1-{4-[(3-chloro-1H-pyrrolo[2,3-1Apyridin-4-ypoxy]-3,5-difluorophenyll-3-(2,2-difluoroethypurea - 1-{4-[(3-chloro-1H-pyrrolo[2,3-1Apyriclin-4-ypoxy]-3,5-difluorophenyll-3-[(4-methyl-1H-imidazol-2-y1)methyl]urea - 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(6-methoxypyridazin-3-yOurea - 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(1,3,4-thiadiazol-2-yOurea - 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(1,3-thiazol-2-ylmethyl)urea - 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(6-iodopyridazin-3-yOurea - 1-{4-[(3-ch loro-1H-pyrrolo[2,3-b]pyriclin-4-yl)oxy]-3,5-d ifl uoropheny11-346-(morpholin-4-yl)pyridazin-3-yl]urea - 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(5-methylpyridazin-3-yOurea - 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(6-cyclopropylpyridazin-3-yOurea - (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(1-methyl-5-oxopyrrolidin-3-yOurea - N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-4,4-difluoropiperidine-1-carboxamide - 1-(3,5-d ifl uoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyrid in-4-yl]oxylpheny1)-343-(propan-2-yloxy)propyl]urea - N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-methoxyazetidine-1-carboxamide - N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-1-oxa-6-azaspiro[3.3]heptane-6-carboxamide - N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-2-oxa-6-azaspiro[3.5]nonane-6-carboxamide - N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyriclin-4-yl]oxylpheny1)-N'-{[3-(propan-2-ypoxetan-3-yl]methyllurea - 1-(3,5-d ifl uoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyrid in-4-yl]oxylpheny1)-343-methyl-3-(morpholin-4-yl)butyl]urea - 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyriclin-4-ypoxy]-3,5-difluorophenyll-3-[(4-methyl-1,2,5-oxadiazol-3-Amethyl]urea - (+1-) 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(tetrahydrofuran-2-ylmethypurea - 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-pyridazin-3-ylurea - 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(6-methylpyridazin-3-yOurea - 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(1,3,4-thiadiazol-2-yOurea - 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-[(4-methyl-1H-imidazol-2-y1)methyl]urea - 1-{4-[(3-cyano-1H-pyrrolo[2,3-b]pyrid in-4-yl)oxy]-3,5-d ifl uorophenyI}-3-(6-methylpyridazin-3-yl)urea - 1-{4-[(3-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-pyridazin-3-ylurea - 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-{1-[(4-methylpiperazin-1-y1)carbonyl]cyclopropyllurea - 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-341-(morpholin-4-ylcarbonyl)cyclopropyl]urea - 14({4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyllcarbamoyl)amino]-N,N-dimethylcyclopropanecarboxamide - 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-d ifl uoropheny11-341-(piperid in-1-ylcarbonyl)cyclopropyl]urea - (+/-)1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(1-methoxypropan-2-yOurea - 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-(methoxymethyl)cyclopropyl]urea - (+1-) 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(2,2-dimethyltetrahydrofuran-3-y1)urea - (+1-) 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(5-oxaspiro[3.4]oct-7-yOurea - (+1-) 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyrid in-4-yl)oxy]-3,5-difluoropheny11-3-[(trans)-4-(pyrrolid in-1-yl)tetrahyd rofuran-3-yl]urea - N2-({4-[(3-ch loro-1H-pyrrolo[2,3-b]pyrid in-4-yl)oxy]-3,5-difluorophenyllcarbamoyI)-N , N-dimethylalaninamide - N2-({4-[(3-ch loro-1H-pyrrolo[2,3-b]pyrid in-4-yl)oxy]-3,5-difluorophenyllcarbamoyI)-N , N-dimethylvalinamide - (+/-)1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(3-methyltetrahydrofuran-3-yOurea - (+/-)1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-347-oxabicyclo[2.2.1]hept-2-yl]urea - mixture of isomers - (+/-)-1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(1-methyl-2-oxopyrrolidin-3-yOurea - N-(3 ,5-d ifl uoro-4-{[3-(trifl uoromethyl)-1H-pyrrolo[2,3-b]pyrid in-4-yl]oxylphenyl)azetidi ne-1-carboxamide - N-(3 ,5-d ifl uoro-4-{[3-(trifl uoromethyl)-1H-pyrrolo[2,3-b]pyrid in-4-yl]oxylphenyl)pyrrolidine-1-carboxamide - N-(3 ,5-d ifl uoro-4-{[3-(trifl uoromethyl)-1H-pyrrolo[2,3-b]pyrid in-4-yl]oxylpheny1)-N'-[(3-fluorooxetan-3-yl)methyl]urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(2-hydroxy-2-methylpropypurea - (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[2-hydroxy-2-methyl-3-(morpholin-4-y1)propyl]urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(3-hydroxy-3-methylbutypurea - 64({4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyllcarbamoyl)amino]-N-methylpyridazine-3-carboxamide - 1-(6-tert-butylpyridazin-3-y1)-3-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyllurea - 64({4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyllcarbamoyl)amino]-N,N-dimethylpyridazine-3-carboxamide - 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-346-(trifluoromethyppyridazin-3-yl]urea - 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-(methylsulfonyl)pyridazin-3-yl]urea - (+I-)-N-(3 ,5-d ifl uoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyrid in-4-yl]oxylpheny1)-N'-(2-fluoro-3-methoxypropyl)urea - (+/-)-N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-N'-[(4,4-dimethyloxetan-2-y1)methyl]urea - (+/-)-N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-N'-(2-fluoro-3-methoxy-2-methylpropypurea - N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-N'-{[3-(hydroxymethypoxetan-3-yl]methyllurea - N-(3 ,5-d ifl uoro-4-{[3-(trifl uoromethyl)-1H-pyrrolo[2,3-b]pyrid in-4-yl]oxylpheny1)-N'-[(3-hyd roxyoxetan-3-yl)methyl]urea 5 - N-(2 ,5-d ifl uoro-4-{[3-(trifl uoromethyl)-1H-pyrrolo[2,3-b]pyrid in-4-yl]oxylpheny1)-N'-[(3-methyloxetan-3-yl)methyl]urea - N-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)sulfanyl]-3,5-difluorophenyll-N'42-(morpholin-4-y1)-2-oxoethyl]urea - N-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyrid in-4-yl)sulfany1]-3,5-d ifl uorophenyll-N'-(2-10 methoxyethyl)urea - N-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyrid in-4-yl)sulfany1]-3,5-d ifl uorophenyll-N'-ethylurea - N-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyrid in-4-yl)sulfany1]-3,5-d ifl uorophenyllmorpholine-4-carboxamide - N-(3 ,5-d ifl uoro-4-{[3-(propan-2-y1)-1H-pyrrolo[2,3-b]pyrid in-4-yl]oxylpheny1)-N'-[(3-15 fluorooxetan-3-yl)methyl]urea - N-(3 ,5-d ifl uoro-4-{[3-(3,3,3-trifluoropropy1)-1H-pyrrolo[2,3-b]pyrid in-4-yl]oxylpheny1)-N'-[(3-fluorooxetan-3-yl)methyl]urea - (+/-)-N43,5-difluoro-4-({341 ,1,1-trifluoropropan-2-y1]-1H-pyrrolo[2,3-b]pyrid in-4-ylloxy)pheny1]-N'-[(3-fluorooxetan-3-yl)methyl]urea 20 - N-(3,5-difluoro-4-{[3-(propan-2-y1)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-N'-(2-methoxyethypurea - N-(3,5-difluoro-4-{[3-(propan-2-y1)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)-N'-[(3-methyloxetan-3-yl)methyl]urea - N-(3 ,5-d ifl uoro-4-{[3-(propan-2-y1)-1H-pyrrolo[2,3-b]pyrid in-4-yl]oxylpheny1)-N'-{[3-25 (propan-2-yl)oxetan-3-yl]nethyllurea - N-(3,5-difluoro-4-{[3-(propan-2-y1)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)morpholine-4-carboxamide - N-(3,5-difluoro-4-{[3-(propan-2-y1)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-N'42-(morpholin-4-y1)-2-oxoethyl]urea 30 - (+/-)-N43,5-difluoro-4-({341 ,1,1-trifluoropropan-2-y1]-1H-pyrrolo[2,3-b]pyrid in-4-ylloxy)pheny1]-N'-(2-methoxyethypurea - (+/-)-N44-({3-(butan-2-y1)-1H-pyrrolo[2,3-b]pyridin-4-ylloxy)-3,5-difluoropheny1FN'-(2-methoxyethypurea - (+I-)-N-[3 ,5-d ifl uoro-4-({3-(3-methylbutan-2-y1)-1H-pyrrolo[2,3-b]pyridin-4-35 ylloxy)pheny1]-N'-(2-methoxyethypurea ¨ N-(3,5-difluoro-4-{[3-(pentan-3-y1)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-N'-(2-methoxyethypurea ¨ N-(3,5-difluoro-4-{[3-(2-methylpropy1)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-N'-(2-methoxyethypurea ¨ (+I-)-N-[3 ,5-d ifl uoro-4-({3[4,4,4-trifluorobutan-2-y1]-1H-pyrrolo[2,3-b]pyrid in-4-ylloxy)pheny1]-N'-(2-methoxyethypurea ¨ N-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-2-methylazetidine-1-carboxamide ¨ N-{4-[(3-ch loro-1H-pyrrolo[2,3-b]pyrid in-4-yl)oxy]-3,5-d ifl uorophenyllazetidine-1-carboxamide ¨ N'-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-N,N-dimethylurea ¨ (+/-)-N-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-4,4-difluoro-3-(hydroxymethyl)piperidine-1-carboxamide ¨ N-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-N'-(1 -methoxy-2-methylpropan-2-yl)urea ¨ (+/-)-N-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-W-1-oxaspiro[4.4]nonan-6-ylurea ¨ mixture of isomers ¨ (+/-)-N-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-N'41-(morpholin-4-y1)-1-oxopropan-2-yl]urea and their polymorphs, enantiomers, diastereomers, racemates, tautomers, solvates, physiologically acceptable salts and solvates of these salts.
The compounds of general formula (1) of the present invention can be converted to any salt, preferably pharmaceutically acceptable salts, as described herein, by any method which is .. known to the person skilled in the art. Similarly, any salt of a compound of general formula (1) of the present invention can be converted into the free compound, by any method which is known to the person skilled in the art.
Compounds of general formula (1) of the present invention demonstrate a valuable pharmacological spectrum of action, which could not have been predicted.
Compounds of the present invention have surprisingly been found to effectively inhibit MAP4K1 and it is possible therefore that said compounds be used for the treatment or prophylaxis of diseases, preferably cancer or conditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signaling, in humans and animals.

Disorders and conditions particularly suitable for treatment with an MAP4K1 inhibitor of the present invention are liquid and solid tumours, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases. Those disorders also include lymphomas, sarcomas, and leukaemias.
Examples of breast cancers include, but are not limited to, triple negative breast cancer, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.
Examples of cancers of the respiratory tract include, but are not limited to, small-cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.
Examples of brain cancers include, but are not limited to, brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, glioblastoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumour.
Tumours of the male reproductive organs include, but are not limited to, prostate and testicular cancer.
Tumours of the female reproductive organs include, but are not limited to, endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.
Examples of ovarian cancer include, but are not limited to serous tumour, endometrioid tumour, mucinous cystadenocarcinoma, granulosa cell tumour, Sertoli-Leydig cell tumour and arrhenoblastoma.
Examples of cervical cancer include, but are not limited to squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma, small cell carcinoma, neuroendocrine tumour, glassy cell carcinoma and villoglandular adenocarcinoma.
Tumours of the digestive tract include, but are not limited to, anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.
Examples of esophageal cancer include, but are not limited to esophageal cell carcinomas and adenocarcinomas, as well as squamous cell carcinomas, leiomyosarcoma, malignant melanoma, rhabdomyosarcoma and lymphoma.
Examples of gastric cancer include, but are not limited to intestinal type and diffuse type gastric adenocarcinoma.
Examples of pancreatic cancer include, but are not limited to ductal adenocarcinoma, adenosquamous carcinomas and pancreatic endocrine tumours.
Tumours of the urinary tract include, but are not limited to, bladder, penile, kidney, renal pelvis, ureter, urethral and human papillary renal cancers.
Examples of kidney cancer include, but are not limited to renal cell carcinoma, urothelial cell carcinoma, juxtaglomerular cell tumour (reninoma), angiomyolipoma, renal oncocytoma, Bellini duct carcinoma, clear-cell sarcoma of the kidney, mesoblastic nephroma and Wilms' tumour.

Examples of bladder cancer include, but are not limited to transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma, sarcoma and small cell carcinoma.
Eye cancers include, but are not limited to, intraocular melanoma and retinoblastoma.
Examples of liver cancers include, but are not limited to, hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.
Skin cancers include, but are not limited to, squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.
Head-and-neck cancers include, but are not limited to, squamous cell cancer of the head and neck, laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, salivary gland cancer, lip and oral cavity cancer and squamous cell.
Lymphomas include, but are not limited to, AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin's disease, and lymphoma of the central nervous system.
Sarcomas include, but are not limited to, sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.
Leukemias include, but are not limited to, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.
The term "treating" or "treatment" as stated throughout this document is used conventionally, for example the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of a disease or disorder, such as a carcinoma.
The compounds of the present invention can be used in particular in therapy and prevention, i.e. prophylaxis, of tumour growth and metastases, especially in solid tumours of all indications and stages with or without pre-treatment of the tumour growth.
Generally, the use of chemotherapeutic agents and/or anti-cancer agents in combination with a compound or pharmaceutical composition of the present invention will serve to:
1. yield better efficacy in reducing the growth of a tumour or even eliminate the tumour as compared to administration of either agent alone, 2. provide for the administration of lesser amounts of the administered chemotherapeutic agents, 3. provide for a chemotherapeutic treatment that is well tolerated in the patient with fewer deleterious pharmacological complications than observed with single agent chemotherapies and certain other combined therapies, 4. provide for treating a broader spectrum of different cancer types in mammals, especially humans, 5. provide for a higher response rate among treated patients, 6. provide for a longer survival time among treated patients compared to standard chemotherapy treatments, 7. provide a longer time for tumour progression, and/or 8. yield efficacy and tolerability results at least as good as those of the agents used alone, compared to known instances where other cancer agent combinations produce antagonistic effects.
In addition, the compounds of general formula (I) of the present invention can also be used in combination with radiotherapy and/or surgical intervention.
In a further embodiment of the present invention, the compounds of general formula (I) of the present invention may be used to sensitize a cell to radiation, i.e. treatment of a cell with a compound of the present invention prior to radiation treatment of the cell renders the cell more susceptible to DNA damage and cell death than the cell would be in the absence of any treatment with a compound of the present invention. In one aspect, the cell is treated with at least one compound of general formula (I) of the present invention.
Thus, the present invention also provides a method of killing a cell, wherein a cell is administered one or more compounds of the present invention in combination with conventional radiation therapy.
The present invention also provides a method of rendering a cell more susceptible to cell death, wherein the cell is treated with one or more compounds of general formula (I) of the present invention prior to the treatment of the cell to cause or induce cell death. In one aspect, after the cell is treated with one or more compounds of general formula (I) of the present invention, the cell is treated with at least one compound, or at least one method, or a combination thereof, in order to cause DNA damage for the purpose of inhibiting the function of the normal cell or killing the cell.
In other embodiments of the present invention, a cell is killed by treating the cell with at least one DNA damaging agent, i.e. after treating a cell with one or more compounds of general formula (I) of the present invention to sensitize the cell to cell death, the cell is treated with at least one DNA damaging agent to kill the cell. DNA damaging agents useful in the present invention include, but are not limited to, chemotherapeutic agents (e.g. cis platin), ionizing radiation (X-rays, ultraviolet radiation), carcinogenic agents, and mutagenic agents.

In other embodiments, a cell is killed by treating the cell with at least one method to cause or induce DNA damage. Such methods include, but are not limited to, activation of a cell signalling pathway that results in DNA damage when the pathway is activated, inhibiting of a cell signalling pathway that results in DNA damage when the pathway is inhibited, and 5 inducing a biochemical change in a cell, wherein the change results in DNA damage. By way of a non-limiting example, a DNA repair pathway in a cell can be inhibited, thereby preventing the repair of DNA damage and resulting in an abnormal accumulation of DNA
damage in a cell.
10 In one aspect of the invention, a compound of general formula (I) of the present invention is administered to a cell prior to the radiation or other induction of DNA damage in the cell. In another aspect of the invention, a compound of general formula (I) of the present invention is administered to a cell concomitantly with the radiation or other induction of DNA damage in the cell. In yet another aspect of the invention, a compound of general formula (I) of the present 15 invention is administered to a cell immediately after radiation or other induction of DNA
damage in the cell has begun.
In another aspect, the cell is in vitro. In another embodiment, the cell is in vivo.
20 .. The compounds of the present invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutically active ingredients where the combination causes no unacceptable adverse effects. The present invention also covers such pharmaceutical combinations. For example, the compounds of the present invention can be combined with: 131I-chTNT, abarelix, abiraterone, aclarubicin, adalimumab, ado-trastuzumab 25 .. emtansine, afatinib, aflibercept, aldesleukin, alectinib, alemtuzumab, alendronic acid, alitretinoin, altretamine, amifostine, aminoglutethimide, hexyl aminolevulinate, amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, anetumab ravtansine, angiotensin II, antithrombin III, aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase, atezolizumab, axitinib, azacitidine, basiliximab, belotecan, bendamustine, besilesomab, 30 belinostat, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, blinatumomab, bortezomib, buserelin, bosutinib, brentuximab vedotin, busulfan, cabazitaxel, cabozantinib, calcitonine, calcium folinate, calcium levofolinate, capecitabine, capromab, carbamazepine carboplatin, carboquone, carfilzomib, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, ceritinib, cetuximab, chlorambucil, chlormadinone, chlormethine, cidofovir, 35 cinacalcet, cisplatin, cladribine, clodronic acid, clofarabine, cobimetinib, copanlisib , crisantaspase, crizotinib, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daratumumab, darbepoetin alfa, dabrafenib, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, depreotide, deslorelin, dianhydrogalactitol, dexrazoxane, dibrospidium chloride, dianhydrogalactitol, diclofenac, dinutuximab, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin + estrone, dronabinol, eculizumab, edrecolomab, elliptinium acetate, elotuzumab, eltrombopag, endostatin, enocitabine, enzalutamide, epirubicin, epitiostanol, epoetin alfa, epoetin beta, epoetin zeta, eptaplatin, eribulin, erlotinib, esomeprazole, estradiol, estramustine, ethinylestradiol, etoposide, everolimus, exemestane, fadrozole, fentanyl, filgrastim, fluoxymesterone, floxuridine, fludarabine, fluorouracil, flutamide, folinic acid, formestane, fosaprepitant, fotemustine, fulvestrant, gadobutrol, gadoteridol, gadoteric acid meglu mine, gadoversetamide, gadoxetic acid, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, Glucarpidase, glutoxim, GM-CSF, goserelin, granisetron, granulocyte colony stimulating factor, histamine dihydrochloride, histrelin, hydroxycarbamide,1-125 seeds, lansoprazole, ibandronic acid, ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, indisetron, incadronic acid, ingenol mebutate, interferon alfa, interferon beta, interferon gamma, iobitridol, iobenguane (1231), iomeprol, ipilimumab, irinotecan, ltraconazole, ixabepilone, ixazomib, lanreotide, lansoprazole, lapatinib, lasocholine, lenalidomide, lenvatinib, lenograstim, lentinan, letrozole, leuprorelin, levamisole, levonorgestrel, levothyroxine sodium, lisuride, lobaplatin, lomustine, lonidamine, masoprocol, medroxyprogesterone, megestrol, melarsoprol, melphalan, mepitiostane, mercaptopurine, mesna, methadone, methotrexate, methoxsalen, methylaminolevulinate, methylprednisolone, methyltestosterone, metirosine, mifamurtide, miltefosine, miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, mogamulizumab, molgramostim, mopidamol, morphine hydrochloride, morphine sulfate, nabilone, nabiximols, nafarelin, naloxone + pentazocine, naltrexone, nartograstim, necitumumab, nedaplatin, nelarabine, neridronic acid, netupitant/palonosetron, nivolumab, pentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustine, nintedanib, nitracrine, nivolumab, obinutuzumab, octreotide, ofatumumab, olaparib, olaratumab, omacetaxine mepesuccinate, omeprazole, ondansetron, oprelvekin, orgotein, orilotimod, osimertinib, oxaliplatin, oxycodone, oxymetholone, ozogamicine, p53 gene therapy, paclitaxel, palbociclib, palifermin, palladium-103 seed, palonosetron, pamidronic acid, panitumumab, panobinostat, pantoprazole, pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin beta), pembrolizumab, pegfilgrastim, peginterferon alfa-2b, pembrolizumab, pemetrexed, pentazocine, pentostatin, peplomycin, Perflubutane, perfosfamide, Pertuzumab, picibanil, pilocarpine, pirarubicin, pixantrone, plerixafor, plicamycin, poliglusam, polyestradiol phosphate, polyvinylpyrrolidone + sodium hyaluronate, polysaccharide-K, pomalidomide, ponatinib, porfimer sodium, pralatrexate, prednimustine, prednisone, procarbazine, procodazole, .. propranolol, quinagolide, rabeprazole, racotumomab, radium-223 chloride, radotinib, raloxifene, raltitrexed, ramosetron, ramucirumab, ranimustine, rasburicase, razoxane, refametinib , regorafenib, risedronic acid, rhenium-186 etidronate, rituximab, rolapitant, romidepsin, romiplostim, romurtide, roniciclib , samarium (153Sm) lexidronam, sargramostim, satumomab, secretin, siltuximab, sipuleucel-T, sizofiran, sobuzoxane, sodium glycididazole, sonidegib, sorafenib, stanozolol, streptozocin, sunitinib, talaporfin, talimogene laherparepvec, tamibarotene, tamoxifen, tapentadol, tasonermin, teceleukin, technetium (99mTc) nofetumomab merpentan, 99mTc-HYNIC-[Tyr3]-octreotide, tegafur, tegafur +
gimeracil +
oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, thyrotropin alfa, tioguanine, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, trametinib, tramadol, trastuzumab, trastuzumab emtansine, treosulfan, tretinoin, trifluridine + tipiracil, trilostane, triptorelin, trametinib, trofosfamide, thrombopoietin, tryptophan, ubenimex, valatinib , valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vismodegib, vorinostat, vorozole, yttrium-90 glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid, zorubicin.
The compounds of the invention can further be combined with other reagents targeting the immune system, such as immune checkpoint inhibitors, e.g. aPD-1/-L1 axis antagonists.
PD-1, along with its ligands PD-L1 and PD-L2, function as negative regulators of T cell activation. MAP4K1 suppresses immune cell function. PD-L1 is overexpressed in many cancers and overexpression of PD-1 often occurs concomitantly in tumor infiltrating T cells.
Thus results in attenuation of T cell activation and evasion of immune surveillance, which contributes to impaired antitumor immune responses. (Keir M E et al. (2008) Annu. Rev.
lmmunol. 26:677).
In addition, the inventive compounds can also be used as a therapeutic in a variety of other disorders wherein MAP4K1 is involved such as, cardiovascular and lung diseases.
Accordingly, the compounds according to the invention are suitable for the treatment and/or prophylaxis in particular of cardiovascular, inflammatory and fibrotic disorders and of renal disorders, in particular of acute and chronic renal insufficiency, and also of acute and chronic renal failure.
Accordingly, the compounds according to the invention can be used in medicaments for the treatment and/or prophylaxis of cardiovascular, inflammatory and fibrotic disorders, renal disorders, in particular of acute and chronic renal insufficiency, and also of acute and chronic renal failure.
For the purpose of the present invention the term renal insufficiency comprises both acute and chronic manifestations of renal insufficiency, and also underlying or related renal disorders such as diabetic and non-diabetic nephropathies, hypertensive nephropathies, ischaemic renal disorders, renal hypoperfusion, intradialytic hypotension, obstructive uropathy, renal stenoses, glomerulopathies, glomerulonephritis (such as, for example, primary glomerulonephritides;
minimal change glomerulonephritis (lipoidnephrosis); membranous glomerulonephritis; focal segmental glomerulosclerosis (FSGS); membrane-proliferative glomerulonephritis; crescentic glomerulonephritis; mesangioproliferative glomerulonephritis (IgA nephritis, Berger's disease);
post-infectious glomerulonephritis; secondary glomerulonephritides: diabetes mellitus, lupus erythematosus, amyloidosis, Goodpasture syndrome, Wegener granulomatosis, Henoch-Schonlein purpura, microscopic polyangiitis, acute glomerulonephritis, pyelonephritis (for example as a result of: urolithiasis, benign prostate hyperplasia, diabetes, malformations, abuse of analgesics, Crohn's disease), glomerulosclerosis, arteriolonecrose of the kidney, tubulointerstitial diseases, nephropathic disorders such as primary and congenital or aquired renal disorder, Alport syndrome, nephritis, immunological kidney disorders such as kidney transplant rejection and immunocomplex-induced renal disorders, nephropathy induced by toxic substances, nephropathy induced by contrast agents, diabetic and non-diabetic nephropathy, renal cysts, nephrosclerosis, hypertensive nephrosclerosis and nephrotic syndrome which can be characterized diagnostically, for example by abnormally reduced creatinine and/or water excretion, abnormally elevated blood concentrations of urea, nitrogen, potassium and/or creatinine, altered activity of renal enzymes, for example glutamyl synthetase, altered urine osmolarity or urine volume, elevated microalbuminuria, macroalbuminuria, lesions on glomerulae and arterioles, tubular dilatation, hyperphosphataemia and/or the need for dialysis. The present invention also comprises the use of the compounds according to the invention for the treatment and/or prophylaxis of sequelae of renal insufficiency, for example pulmonary oedema, heart failure, uremia, anemia, electrolyte disturbances (for example hypercalemia, hyponatremia) and disturbances in bone and carbohydrate metabolism.
The present invention also comprises the use of the compounds according to the invention for the treatment and/or prevention of sequelae of renal insufficiency, for example pulmonary oedema, heart failure, uraemia, anaemia, electrolyte disturbances (for example hyperkalaemia, hyponatraemia) and disturbances in bone and carbohydrate metabolism.
The compounds according to the invention are further suitable for the treatment and/or prevention of polycystic kidney disease (PCKD) and of the syndrome of inappropriate ADH
secretion (SIADH).
Furthermore, the compounds according to the invention are also suitable for the treatment and/or prophylaxis of metabolic syndrome, hypertension, resistant hypertension, acute and chronic heart failure, coronary heart disease, stable and unstable angina pectoris, peripheral and cardiac vascular disorders, arrhythmias, atrial and ventricular arrhythmias and impaired conduction, for example atrioventricular blocks degrees I-Ill (AB block I-III), supraventricular tachyarrhythmia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachyarrhythmia, Torsade de pointes tachycardia, atrial and ventricular extrasystoles, AV-junctional extrasystoles, sick sinus syndrome, syncopes, AV-nodal re-entry tachycardia, Wolff-Parkinson-White syndrome, of acute coronary syndrome (ACS), autoimmune cardiac disorders (pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathies), shock such as cardiogenic shock, septic shock and anaphylactic shock, aneurysms, boxer cardiomyopathy (premature ventricular contraction (PVC)), for treatment and/or prophylaxis of thromboembolic disorders and ischaemias such as myocardial ischaemia, myocardial infarction, stroke, cardiac hypertrophy, transient and ischaemic attacks, preeclampsia, inflammatory cardiovascular disorders, spasms of the coronary arteries and peripheral arteries, oedema formation, for example pulmonary oedema, cerebral oedema, renal oedema or oedema caused by heart failure, peripheral circulatory disturbances, reperfusion damage, arterial and venous thromboses, myocardial insufficiency, endothelial dysfunction, to prevent restenoses, for example after thrombolysis therapies, percutaneous transluminal angioplasties (PTA), transluminal coronary angioplasties (PTCA), heart transplants and bypass operations, and also micro- and macrovascular damage (vasculitis), increased levels of fibrinogen and of low-density lipoprotein (LDL) and increased concentrations of plasminogen activator inhibitor 1 (PAI-1), and also for treatment and/or prophylaxis of erectile dysfunction and female sexual .. dysfunction.
In addition, the compounds according to the invention are also suitable for treatment and/or prophylaxis of asthmatic disorders, pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH) including left-heart disease, HIV, sickle cell anaemia, thromboembolisms (CTEPH), sarcoidosis, COPD or pulmonary fibrosis-associated pulmonary hypertension, chronic-obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), acute lung injury (ALI), alpha-1-antitrypsin deficiency (AATD), pulmonary fibrosis, pulmonary emphysema (for example pulmonary emphysema induced by cigarette smoke) and cystic fibrosis (CF).
The compounds described in the present invention are also active compounds for control of central nervous system disorders characterized by disturbances of the NO/cGMP
system.
They are suitable in particular for improving perception, concentration, learning or memory after cognitive impairments like those occurring in particular in association with situations/diseases/syndromes such as mild cognitive impairment, age-associated learning and memory impairments, age-associated memory losses, vascular dementia, craniocerebral trauma, stroke, dementia occurring after strokes (post stroke dementia), post-traumatic craniocerebral trauma, general concentration impairments, concentration impairments in children with learning and memory problems, Alzheimer's disease, Lewy body dementia, dementia with degeneration of the frontal lobes including Pick's syndrome, Parkinson's disease, progressive dementia with corticobasal degeneration, amyolateral sclerosis (ALS), Huntington's disease, demyelinization, multiple sclerosis, thalamic degeneration, Creutzfeld-5 Jacob dementia, HIV dementia, schizophrenia with dementia or Korsakoff's psychosis. They are also suitable for treatment and/or prophylaxis of central nervous system disorders such as states of anxiety, tension and depression, CNS-related sexual dysfunctions and sleep disturbances, and for controlling pathological disturbances of the intake of food, stimulants and addictive substances.
The compounds according to the invention are furthermore also suitable for controlling cerebral blood flow and thus represent effective agents for controlling migraines. They are also suitable for the prophylaxis and control of sequelae of cerebral infarction (cerebral apoplexy) such as stroke, cerebral ischaemia and craniocerebral trauma. The compounds according to the invention can likewise be used for controlling states of pain and tinnitus.
In addition, the compounds according to the invention have anti-inflammatory action and can therefore be used as anti-inflammatory agents for treatment and/or prophylaxis of sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory disorders of the kidney, chronic intestinal inflammations (IBD, Crohn's disease, UC), pancreatitis, peritonitis, rheumatoid disorders, inflammatory skin disorders and inflammatory eye disorders.
Furthermore, the compounds according to the invention can also be used for treatment and/or prophylaxis of autoimmune diseases.
The compounds according to the invention are also suitable for treatment and/or prophylaxis of fibrotic disorders of the internal organs, for example the lung, the heart, the kidney, the bone marrow and in particular the liver, and also dermatological fibroses and fibrotic eye disorders.
In the context of the present invention, the term fibrotic disorders includes in particular the following terms: hepatic fibrosis, cirrhosis of the liver, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage resulting from diabetes, bone marrow fibrosis and similar fibrotic disorders, scleroderma, morphea, keloids, hypertrophic scarring (also following surgical procedures), naevi, diabetic retinopathy, proliferative vitroretinopathy and disorders of the connective tissue (for example sarcoidosis).
The compounds according to the invention are also suitable for controlling postoperative scarring, for example as a result of glaucoma operations.

The compounds according to the invention can also be used cosmetically for ageing and keratinized skin.
Moreover, the compounds according to the invention are suitable for treatment and/or prophylaxis of hepatitis, neoplasms, osteoporosis, glaucoma and gastroparesis.
The present invention further provides for the use of the compounds according to the invention for treatment and/or prophylaxis of disorders, especially the disorders mentioned above.
The present invention further provides for the use of the compounds according to the invention for the treatment and/or prophylaxis of chronic renal disorders, acute and chronic renal insufficiency, diabetic, inflammatory or hypertensive nephropaties, fibrotic disorders, cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischemias, vascular disorders, thromboembolic disorders, arteriosclerosis, sickle cell anemia, erectile dysfunction, benign prostate hyperplasia, dysuria associated with benign prostate hyperplasia, Huntington, dementia, Alzheimer and Creutzfeld-Jakob.
The present invention further provides a method for treatment and/or prophylaxis of disorders, in particular the disorders mentioned above, using an effective amount of at least one of the compounds according to the invention.
The present invention further provides a method for the treatment and/or prophylaxis of chronic renal disorders, acute and chronic renal insufficiency, diabetic, inflammatory or hypertensive nephropathies, fibrotic disorders, cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischemias, vascular disorders, thromboembolic disorders, arteriosclerosis, sickle cell anemia, erectile dysfunction, benign prostate hyperplasia, dysuria associated with benign prostate hyperplasia, Huntington, dementia, Alzheimer and Creutzfeld-Jakob.
In another embodiment, the inventive compounds can also be used to treat or to prevent uterine fibroids (uterine leiomyoma or uterine myoma) in women.
Uterine fibroids are benign tumors of the myometrium, the smooth muscle layer of the uterus.
Uterine fibroids grow slowly during a women's life, and their growth is dependent on the female sexual hormones estradiol and progesterone [Kawaguchi K et al.
lmmunohistochemical analysis of oestrogen receptors, progesterone receptors and Ki-67 in leiomyoma and myometrium during the menstrual cycle and pregnancy Virchows Arch A Pathol Anat Histopathol. 1991;419(4):309-15.], therefore the highest prevalence of uterine fibroids with approx. 70% and >80% in white and afro-american women, respectively, is found from 35 years of age onwards to menopause, when they shrink due to reduced hormone levels [Baird DD et al. High cumulative incidence of uterine leiomyoma in black and white women:
Ultrasound evidence Am J Obstet Gynecol. 2003 Jan;188(1):100-7.]. Approx 30%
and 45% of white and afro-american women, respectively, do show clinically relevant symptoms due to their fibroids, which are heavy menstrual bleeding and pain, which is related to the menstrual cycle [David M et al. Myoma-associated pain frequency and intensity: a retrospective evaluation of 1548 myoma patients. Eur J Obstet Gynecol Reprod Biol. 2016 Apr;199:137-40].
Heavy menstrual bleeding in this respect is defined by a blood loss of more than 80 mL in a menstrual bleeding period [Fraser IS et al. The FIGO Recommendations on Terminologies and Definitions for Normal and Abnormal Uterine Bleeding, Semin Reprod Med 2011;
29(5): 383-390]. Submucosal position of the uterine fibroids, e.g. those located directly below the endometrium, seems to have an even more severe effect on uterine bleeding, which may result in anemia in affected women [Yang JH et al. Impact of submucous myoma on the severity of anemia. Fertil Steril. 2011 Apr;95(5):1769-72]. Furthermore, uterine fibroids, due to their symptoms, do severly affect the quality of life of affected women [Downes E et al. The burden of uterine fibroids in five European countries. Eur J Obstet Gynecol Reprod Biol. 2010 Sep;152(1):96-102].
Compounds of the present invention can be utilized to inhibit, block, reduce or decrease MAP4K1 activation by exogenous and/or endogenous ligands for the reduction of tumour growth and the modulation of dysregulated immune responses e.g. to block immunosuppression and increase immune cell activation and infiltration in the context of cancer and cancer immunotherapy; 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; which is effective to treat the disorder.
The present invention also provides methods of treating a variety of other disorders wherein MAP4K1 is involved such as, but not limited to, disorders with dysregulated immune responses, inflammation, vaccination for infection & cancer, viral infections, obesity and diet-induced obesity, adiposity, metabolic disorders, hepatic steatosis and uterine fibroids.
These disorders have been well characterized in humans, but also exist with a similar etiology in other mammals, and can be treated by administering pharmaceutical compositions of the present invention.
The term "treating" or "treatment" as used in the present text is used conventionally, e.g., the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of a disease or disorder, such as liquid and solid tumours.
In accordance with a further aspect, the present invention covers compounds of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for use in the treatment or prophylaxis of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant signaling.
The pharmaceutical activity of the compounds according to the invention can be explained by their activity as MAP4K1 inhibitors.
In accordance with a further aspect, the present invention covers the use of compounds of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for the treatment or prophylaxis of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant signaling, particularly liquid and solid tumours.
In accordance with a further aspect, the present invention covers the use of compounds of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, in a method of treatment or prophylaxis of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant signaling, particularly liquid and solid tumours.
In accordance with a further aspect, the present invention covers use of a compound of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for the preparation of a pharmaceutical composition, preferably a medicament, for the prophylaxis or treatment of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signaling, particularly liquid and solid tumours.
In accordance with a further aspect, the present invention covers a method of treatment or prophylaxis of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signaling, particularly liquid and solid tumours, using an effective amount of a compound of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same.

In accordance with a further aspect, the present invention covers pharmaceutical compositions, in particular a medicament, comprising a compound of general formula (I), as described supra, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, a salt thereof, particularly a pharmaceutically acceptable salt, or a mixture of same, and one or more excipients), in particular one or more pharmaceutically acceptable excipient(s). Conventional procedures for preparing such pharmaceutical compositions in appropriate dosage forms can be utilized.
The present invention furthermore covers pharmaceutical compositions, in particular medicaments, which comprise at least one compound according to the invention, conventionally together with one or more pharmaceutically suitable excipients, and to their use for the above mentioned purposes.
It is possible for the compounds according to the invention to have systemic and/or local activity. For this purpose, they can be administered in a suitable manner, such as, for example, via the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, otic route or as an implant or stent.
For these administration routes, it is possible for the compounds according to the invention to be administered in suitable administration forms.
For oral administration, it is possible to formulate the compounds according to the invention to dosage forms known in the art that deliver the compounds of the invention rapidly and/or in a modified manner, such as, for example, tablets (uncoated or coated tablets, for example with enteric or controlled release coatings that dissolve with a delay or are insoluble), orally-disintegrating tablets, films/wafers, films/lyophylisates, capsules (for example hard or soft gelatine capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions. It is possible to incorporate the compounds according to the invention in crystalline and/or amorphised and/or dissolved form into said dosage forms.
Parenteral administration can be effected with avoidance of an absorption step (for example intravenous, intraarterial, intracardial, intraspinal or intralumbal) or with inclusion of absorption (for example intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal).
Administration forms which are suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophylisates or sterile powders.

Examples which are suitable for other administration routes are pharmaceutical forms for inhalation [inter alia powder inhalers, nebulizers], nasal drops, nasal solutions, nasal sprays;
tablets/films/wafers/capsules for lingual, sublingual or buccal administration; suppositories; eye drops, eye ointments, eye baths, ocular inserts, ear drops, ear sprays, ear powders, ear-5 rinses, ear tampons; vaginal capsules, aqueous suspensions (lotions, mixturae agitandae), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (such as, for example, patches), milk, pastes, foams, dusting powders, implants or stents.
The compounds according to the invention can be incorporated into the stated administration 10 forms. This can be effected in a manner known per se by mixing with pharmaceutically suitable excipients. Pharmaceutically suitable excipients include, inter alia, = fillers and carriers (for example cellulose, microcrystalline cellulose (such as, for example, Avice1 ), lactose, man nitol, starch, calcium phosphate (such as, for example, Di-Cafosc))), 15 = ointment bases (for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols), = bases for suppositories (for example polyethylene glycols, cacao butter, hard fat), = solvents (for example water, ethanol, isopropanol, glycerol, propylene glycol, medium chain-length triglycerides fatty oils, liquid polyethylene glycols, paraffins), 20 = surfactants, emulsifiers, dispersants or wetters (for example sodium dodecyl sulfate), lecithin, phospholipids, fatty alcohols (such as, for example, Lanette ), sorbitan fatty acid esters (such as, for example, Span ), polyoxyethylene sorbitan fatty acid esters (such as, for example, Tweenc)), polyoxyethylene fatty acid glycerides (such as, for example, Cremophorc)), polyoxethylene fatty acid esters, polyoxyethylene fatty alcohol 25 ethers, glycerol fatty acid esters, poloxamers (such as, for example, Pluronic ), = buffers, acids and bases (for example phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine), = isotonicity agents (for example glucose, sodium chloride), 30 = adsorbents (for example highly-disperse silicas), = viscosity-increasing agents, gel formers, thickeners and/or binders (for example polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropyl-cellulose, carboxymethylcellulose-sodium, starch, carbomers, polyacrylic acids (such as, for example, Carbopolc)); alginates, gelatine), = disintegrants (for example modified starch, carboxymethylcellulose-sodium, sodium starch glycolate (such as, for example, Explotabc)), cross- linked polyvinylpyrrolidone, croscarmellose-sodium (such as, for example, AcDiSolc))), = flow regulators, lubricants, glidants and mould release agents (for example magnesium stearate, stearic acid, talc, highly-disperse silicas (such as, for example, Aerosil )), = coating materials (for example sugar, shellac) and film formers for films or diffusion membranes which dissolve rapidly or in a modified manner (for example polyvinylpyrrolidones (such as, for example, Kollidonc)), polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellu lose, hydroxypropyl-methylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates such as, for example, Eudragir)), = capsule materials (for example gelatine, hydroxypropylmethylcellulose), = synthetic polymers (for example polylactides, polyglycolides, polyacrylates, polymethacrylates (such as, for example, Eudragir), polyvinylpyrrolidones (such as, for example, Kollidonc)), polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols and their copolymers and blockcopolymers), = plasticizers (for example polyethylene glycols, propylene glycol, glycerol, triacetine, triacetyl citrate, dibutyl phthalate), = penetration enhancers, = stabilisers (for example antioxidants such as, for example, ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate), = preservatives (for example parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate), = colourants (for example inorganic pigments such as, for example, iron oxides, titanium dioxide), = flavourings, sweeteners, flavour- and/or odour-masking agents.
The present invention furthermore relates to a pharmaceutical composition which comprise at least one compound according to the invention, conventionally together with one or more pharmaceutically suitable excipient(s), and to their use according to the present invention.
In accordance with another aspect, the present invention covers pharmaceutical combinations, in particular medicaments, comprising at least one compound of general formula (I) of the present invention and at least one or more further active ingredients, in particular for the treatment and/or prophylaxis of cancer or conditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signalinggeneric name disorders, particularly liquid and solid tumours.

The term "combination" in the present invention is used as known to persons skilled in the art, it being possible for said combination to be a fixed combination, a non-fixed combination or a kit-of-parts.
A "fixed combination" in the present invention is used as known to persons skilled in the art and is defined as a combination wherein, for example, a first active ingredient, such as one or more compounds of general formula (I) of the present invention, and a further active ingredient are present together in one unit dosage or in one single entity. One example of a "fixed combination" is a pharmaceutical composition wherein a first active ingredient and a further active ingredient are present in admixture for simultaneous administration, such as in a formulation. Another example of a "fixed combination" is a pharmaceutical combination wherein a first active ingredient and a further active ingredient are present in one unit without being in admixture.
A non-fixed combination or "kit-of-parts" in the present invention is used as known to persons skilled in the art and is defined as a combination wherein a first active ingredient and a further active ingredient are present in more than one unit. One example of a non-fixed combination or kit-of-parts is a combination wherein the first active ingredient and the further active ingredient are present separately. It is possible for the components of the non-fixed combination or kit-of-parts to be administered separately, sequentially, simultaneously, concurrently or chronologically staggered.
Based upon standard laboratory techniques known to evaluate compounds useful for the treatment of cancer or conditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signaling, by standard toxicity tests and by standard pharmacological assays for the determination of treatment of the conditions identified above in mammals, and by comparison of these results with the results of known active ingredients or medicaments that are used to treat these conditions, the effective dosage of the compounds of the present invention can readily be determined for treatment of each desired indication. The amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.
The total amount of the active ingredient to be administered will generally range from about 0.001 mg/kg to about 200 mg/kg body weight per day, and preferably from about 0.01 mg/kg to about 20 mg/kg body weight per day. Clinically useful dosing schedules will range from one to three times a day dosing to once every four weeks dosing. In addition, it is possible for "drug holidays", in which a patient is not dosed with a drug for a certain period of time, to be beneficial to the overall balance between pharmacological effect and tolerability. It is possible for a unit dosage to contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day or less than once a day. The average daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily vaginal dosage regimen will preferably be .. from 0.01 to 200 mg/kg of total body weight. The average daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily.
The transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg. The average daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.
Of course the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like. The desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests.
Experimental section NMR peak forms are stated as they appear in the spectra, possible higher order effects have not been considered. The multiplicities are stated according to the signal form which appears in the spectrum, NMR-spectroscopic effects of a higher order were not taken into consideration. Multiplicity of the NMR signals: s = singlet, d = doublet, t =
triplet, q = quartet, .. quin = quintet, br = broad signal, m = multiplet. NMR signals: shift in [ppm]. Combinations of multiplicity could be e.g. dd = doublet from doublet.
In some cases not all H atoms are found as a signal in the NMR because the signal could overlays with a solvent signal or it is a very broad signal dependent on the NMR solvent used.
Chemical names were generated using the ACD/Name software from ACD/Labs. In some cases generally accepted names of commercially available reagents were used in place of ACD/Name generated names.

Table 1 lists the abbreviations used in this paragraph and in the Examples section as far as they are not explained within the text body. Other abbreviations have their meanings customary per se to the skilled person.
Table 1: Abbreviations PBMCs Peripheral blood mononuclear cells AUC Area Under Curve DMF N,N-dimethylformamide DMSO dimethyl sulphoxide EAE experimental autoimmune encephalomyelitis EDTA Ethylenediaminetetraacetic acid Expl. Example FCS fetal calf serum h hour LPS lipopolysaccharide mL milliliter min. minute(s) MW microwave PBMC peripheral blood mononuclear cells RT or rt room temperature sat. saturated SDS Sodium dodecyl sulfate TNFa tumour necrosis factor alpha pL microliter uM micromolar IFNg Interferon gamma 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.
The example testing experiments described herein serve to illustrate the present invention and the invention is not limited to the examples given.
Experimental section ¨ general part All reagents, for which the synthesis is not described in the experimental part, are either commercially available, or are known compounds or may be formed from known compounds by known methods by a person skilled in the art.
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 chromatography, particularly flash column chromatography, using for example prepacked silica gel cartridges, e.g.
Biotage SNAP
5 cartidges KP-Sil or KP-NH in combination with a Biotage autopurifier system (5P4 or lsolera Four ) and eluents such as gradients of hexane/ethyl acetate or DCM/methanol. In some cases, the compounds may be purified by preparative HPLC using for example 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 10 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 provide those compounds of the present invention which possess a sufficiently basic or acidic functionality in the form of a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a 15 trifluoroacetate or formate salt for example, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt for example. A salt of this type can either be transformed into its free base or free acid form, respectively, by various methods known to the person skilled in the art, or be used as salts in subsequent biological assays. It is to be understood that the specific form (e.g. salt, free base etc.) of a compound of the present 20 invention as isolated and as described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity.
General synthesis of compounds of general formula (I) of the present invention The following paragraphs outline a variety of synthetic approaches suitable to prepare compounds of the general formula (I), and intermediates useful for their synthesis.
In addition to the routes described below, also other routes may be used to synthesise the target compounds, in accordance with common general knowledge of a person skilled in the art of organic synthesis. The order of transformations exemplified in the following schemes is therefore not intended to be limiting, and suitable synthesis steps from various schemes can be combined to form additional synthesis sequences. In addition, interconversion of any of the substituents, in particular R1, R2, R3and R4, which are as defined in formula (I) supra, can be achieved before and/or after the exemplified transformations. These modifications can be, for example, the introduction of protective groups, cleavage of protective groups, reduction or oxidation of functional groups, halogenation, metallation, metal catalysed coupling reactions, exemplified by but not limited to e.g. Buchwald, Suzuki, Sonogashira and Ullmann coupling, ester saponifications, amide coupling reactions, and/or substitution or other reactions known to a person skilled in the art. These transformations include those which introduce a functionality allowing for further interconversion of substituents. Appropriate protective groups and their introduction and cleavage are well-known to a person skilled in the art (see for example T.W.
Greene and P.G.M. Wuts in Protective Groups in Organic Synthesis, 41h edition, Wiley 2006).
Further, it is possible that two or more successive steps may be performed without work-up being performed between said steps, e.g. a "one-pot" reaction, as it is well-known to a person skilled in the art.

F i NyN'IR4 R2 el 2 Y
/ I + R3 H N'R4 R1 X
/ I I
PG N----N
(II) (III) H (I) F NCY H
R1 X Si 2 F N 0 14111 R

/ I or NN% / I
i N---N
PG i PG
(IVa) (IVb) i YCN or \R4 el 0 NI'R4 (Va for R4 = H) Z (Vb) Scheme 1: Preparation of compounds of general formula (I) from the two amines (II) and (III) via an intermediately formed isocyanate (IVa) or (Va) with the corresponding second amine or via an intermediately formed activated carbamate (IVb) or (Vb) with the corresponding second amine.

Compounds of general formula (I) can be assembled according to Scheme 1, by reaction of amine derivatives of formula (II), in which R1, R2, and X are as defined for the compounds of general formula (I), and a second amine derivative (III), in which R3, and R4 are as defined for the compounds of general formula (I), by means of urea formation well known to the person skilled in the art. Said urea formation can be performed by reaction of compounds of the formula (II) with the intermediacy of a formed and possibly isolated isocyanate or isothiocyantate (IVa) using a suitable reagent such as 1,1-carbonylbis-1H-imidazole, di- or triphosgene for Y=0, or as thiophosgene or 1,11-thiocarbonylbis-1H-imidazole for Y=S.
Compounds of general formula (I) can be assembled according to Scheme 1, by reaction of amine derivatives of formula (II), in which R1, R2, X, and Y are as defined for the compounds of general formula (I), and a second amine derivative (III), in which R3, and R4 are as defined for the compounds of general formula (I), by means of urea formation well known to the person skilled in the art. Said urea formation can be performed by reaction of compounds of the formula (II) with the intermediacy of a formed and possibly isolated isocyanate (IVa) using a suitable reagent such as 1,11-carbonylbis-1H-imidazole, di- or triphosgene for Y=0, or as thiophosgene or 1,11-thiocarbonylbis-1H-imidazole for Y=S. Compounds of general formula (I) can also be assembled by conversion of amine derivatives of formula (II) to an intermediately formed and possibly isolated carbamate or thiocarbamate (IVb) using a suitable reagent such as phenyl chloroformate or 0-phenyl chlorothionoformate in which Z is H, NO2, or perfluoro in an appropriate solvent such as tetrahydrofuran, dichloromethane, or ethylacetate in the presence of an appropriate base such as pyridine, sodium hydrogencarbonate, or triethylamine. This intermediate IV(b) is then reacted with the second amine derivative (III) in an appropriate solvent such as pyridine, or dimethylformamide. In a similar way the compounds of general formula (I) can be assembled using the amine (III) as starting material.
.. With the former described reaction the amine (III) can react to the intermediately formed isocyanate (Va for R3 = H), if it is not commercially available, in which R4 and Y are as defined for the compounds of general formula (I) or the carbamate (Vb) using a suitable reagent such as phenyl chloroformate or 0-phenyl chlorothionoformate in which Z is H, NO2, or perfluoro and R3, R4 and Y are as defined for the compounds of general formula (I) with the second amine (II).
Depending on the choice of protecting group PG in formula (II), (IVa), and (IVb), which is preferentially trimethylsilylethyloxymethyl (SEM), but can be any other protecting group well known to the person skilled in the art, the deprotection can be performed using trifluoroacetic acid in the case of trimethylsilylethyloxymethyl, in an inert solvent such as dichloromethane, within a temperature range from 0 C to the boiling point of the used solvent.
The deprotection in the case of trimethylsilylethyloxymethyl can be also performed using tetra-butylammonium fluoride in the presence of ethylenediamine in an inert solvent such as tetrahydrofuran within a temperature range from 0 C to the boiling point of the used solvent. In the case of a toluenesulfonyl-group (Tos) the deprotection can be performed by using for example sodium hydroxide in methanol within a temperature range from 0 C to the boiling point of the used solvent.
Preferred herein is the performance of said urea formation using the amine (II) and the intermediately formed and maybe isolated carbamate (IVb) or cyanate (Vb) and the subsequent reaction with the second amine (II) in DMF or pyridine as a solvent, within a temperature range from 0 C to 100 C.
The amine intermediates of formula (II) are known to the person skilled in the art and can, if not commercially available, be prepared according to Schemes 3 and 4 shown below. The second amine derivatives of formula (III) are either commercially available in some structural variety, or they can be prepared using synthetic methods described in many textbooks such as March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition.
As illustrated in Scheme 2, the amine derivatives of formula (II) are known, commercially available, or can be prepared from the commercially available heterocyle of the formula (VI), in which Ria represents a hydrogen or a trifluoromethyl group. Said heterocycle of the formula (VI) can be reacted with nitric acid, in the case of leaving group (LG) = NO2, or in a two step sequence for LG = Cl using MCPBA to form a 7-N-oxide, which then reacts in a subsequent step with methanesulfonyl chloride to give intermediate heterocycles of formula (VII).
Compounds of the formula (VII) are converted to chlorides of formula (VIII) using a two step sequence, which begins with production of a 7-N-oxide which then reacts in a subsequent step with trichloroacetyl chloride in the presence of hexamethyldisilazane (HMDS).
Said heterocycles of formula (VII) can be transformed to the protected intermediates of the formula (IX) using an apprioate reagent such as trimetylsilylethoxymethyl chloride, thisopropylsily1 chloride, trityl chloride or tosylchloride or other reagents known to a person skilled in the art.
Preferably, trimetylsilylethoxymethyl chloride is used, in the presence of a base such as sodium hydride, triethyl amine, or ethyl diisopropyl amine in an inert solvent such as THF, DMSO or DMF.
Protected heterocycles of the formula (IX) are then reacted with a compound of the formula (X) in the presence of sodium hydride or an alkali carbonate, such as sodium carbonate, potassiumcarbonate, or cesium carbonate, in a suitable solvent such as DMSO or DMF, as well known to the person skilled in the art, to give compounds of formula (XI). For compounds of (X) with X=NH it may be necessary to protect the other amino function in an intermediate fashion.

Dechlorination is preferentially performed using a hydrogen atmosphere and palladium on carbon as catalyst in an inert solvent such as ethanol, ethyl acetate or dichloromethane at 20 ¨
50 C as described in Org. Process Res. Dev. 2010, page 168-173, to give a subset of the amines of the formula (II) named (11a) in which Ria are as defined for compounds of gerenal formula (VI).
LG LG
R1 a R1 a R1 a NN % N--"N NN-CI
H H H
(VI) (VII) (VIII) Pia = H, CF3 R1 a LG
NNCI
i PG
(IX) LG = Cl, NO2 F NH R R1 a X el 2 (IX) -v.
/ I

N' Cl i (X) PG (XI) R el 2 1 a X
R
-3,..
/ I
NN
i PG
(11a) Scheme 2: Preparation of compounds of formula (11a) from compounds of formula (VI).
All other amines of the subset (11b) from the general formula (II) can be assembled from the amine (11a) with Ria=H according to Scheme 3. Protection of the free amine in (11a) with Ria=H
using trifluoroacetic anhydride in an inert solvent such as dichloromethane in the presence of an tertiary amine such as triethyl amine or ethyl diisopropyl amine, yields the amides of the general formula (XII) in which R2, and X are as defined for the compounds of general formula (I). Said amides of formula (XII) can be converted into halogen substituted compounds of the general formula (XIII) with Rib = Cl, Br, or I using the corresponding N-halo-succinimide in an inert solvent such as dichloro methane or tetrachloro methane. In the case of compounds of the general formula (XIII) with Rib = ON, and Ci-06-alkyl, a subsequent reaction of a said halogen compound of the general formula (XII) with Rib = Br or I is used as starting material.
5 For formation of the corresponding nitrile, a reaction using cuprous cyanide in an inert solvent such as dimethyl formamide or dimethyl acetamide at elevated temperatures, for example between 90 ¨ 120 C is required. Furthermore, a palladium-catalyzed method known to the person skilled in the art, for example, with zinc cyanide or potassium ferrocyanide as described in Chem. Soc. Rev., 2011, 40, 5049-5067 can be utilized. For the preparation of compounds 10 of the general formula (XIII) with Rib = Ci-06-alkyl a Suzuki reaction known to the person skilled in the art is used as described, for example in Metal-Catalyzed Cross-Coupling Reactions, Second Edition (Editors: Armin de Meijere, Frangois Diederich, Wiley-VCH) or in Catal. Lett. (2016) page 820-840. After saponification of compounds of the general formula (XII) using lithium,sodium or potassium hydroxide, the compounds of the general formula (11b) 15 are obtained. Taken together, formulae (11a) and (11b) constitute formula (II).
N
H. Fri(F
F N H 2 F el 2 0 F

PG PG
pa with RI a = H) (XII) H.ri F(F

R1 b 0 'R2 0 F
_ 1 b 0 R
/ I / I
PG PG
(XIII) (1Ib with Rib = Cl, Br, 1, C1-C6-alykl, CN) Scheme 3: Preparation of compounds of formula (11b) from compounds of formula (11a).

A complementary approach to compounds of formula (II) is described in Scheme 4. The respective polyfluoro-nitrobenzene derivatives of formula (XIII) are reacted with 4-hydroxy-7-azaindole (XII) (e.g. U52007/238726), in a suitable solvent system, for example dimethylsulfoxide, in the presence of a base, for example potassium carbonate or cesium carbonate, in a temperature range from room temperature to the boiling point of the respective solvent. Preferable the reaction is carried out at room temperature to furnish intermediates of general formula (XIV).
lntemediates of general formula (XIV), are then protected with an appropriate protecting group, for example using an appropriate reagent such as trimetylsilylethoxymethyl chloride, triisopropylsilyl chloride or trityl chloride or other reagents known to a person skilled in the art.
Preferably, trimetylsilylethoxymethyl chloride is used, in the presence of a base such as sodium hydride, triethylamine, or ethyldiisopropylamine in an inert solvent such as tetrahydrofuran, dimethylsulfoxide or dimethylformamide to afford compounds of formula (XV).
Compounds of formula (XV) can be converted into halogen substituted compounds of the general formula (XVI) with R1 = Cl, Br, or I using the corresponding N-halo-succinimide in an inert solvent such as dichloromethane, dimethylformamide, or tetrachloromethane, in a temperature range from room temperature to the boiling point of the respective solvent.
Preferable the reaction is carried out at room temperature to furnish intermediates of general formula (XVI).
Compounds of general formula (XVI), where R1 = I, can be reacted with trifluoromethylation reagents, for example diphenyl(trifluoromethyl)sulfonium trifluoromethanesulfonate as described in Angew. Chem. Int. Ed. 2011, 50, pg. 1896-1900, or any other reagent know to one skilled in the art, to afford compounds of general formula (XVI) where R1 = CF3.
Preferably, diphenyl(trifluoromethyl)sulfonium trifluoromethanesulfonate is used, in the presence of additives, such as copper(0), in a solvent such as dimethylformamide, in a temperature range from room temperature to the boiling point of the respective solvent. Ideally, the reaction is carried out at 60 C to furnish intermediates of general formula (XVI) where R1 =
CF3.
In the case of compounds of the general formula (XVI) with R1 = CN, and C1-C6-alkyl, a subsequent reaction of a said halogen compounds of the general formula (XVI) with R1= Br or I is required. For formation of the corresponding nitrile, a reaction using cuprous cyanide in an inert solvent such as dimethyl formamide or dimethyl acetamide at elevated temperatures, for example between 90 ¨ 120 C is required. Furthermore, a palladium-catalyzed method known to the person skilled in the art, for example, with zinc cyanide or potassium ferrocyanide as described in Chem. Soc. Rev., 2011, 40, 5049-5067 can be utilized. For the preparation of compounds of the general formula (XVI) with R1= Ci-06-alkyl a Suzuki reaction known to the person skilled in the art is used as described, for example in Metal-Catalyzed Cross-Coupling Reactions, Second Edition (Editors: Armin de Meijere, Francois Diederich, Wiley-VCH) or in Catal. Lett. (2016) page 820-840.
Additionally, compounds of the general formula (XVI) with R1 = C1-C6-alkyl and halo-C1-C6-alkyl can be formed from compounds of the general formula (XVI) with R1 = Br by a light promoted, nickel catalysed reaction as described in J. Am. Chem. Soc. 2016, 138, 8084-8087 and Org. Lett. 2016, 18, 4012, and known to one skilled in the art.
Preferentially, compounds of general formula (XVI) with R1 = Br are reacted with alkylbromides or haloaklybromides in the presence of a photoredox catalyst such as Ir(41,61-dF-5-CF3-ppy)2(4,41-dtbbpy)PF6, a nickel precatalyst such as nickel 11 chloride dimethoxyethane adduct, and a ligand such as 4,4'-Di-tert-buty1-2,2'-bipyridine, with a base such as sodium carbonate, 2,6-dimethoxypyridine, or lithium carbonate, with additives such as tris(trimehylsilyl)silane, in a solvent or solvent mixture such as dimethoxyethane, N,N-dimethylacetamide/trifluorotoluene or 1,3-dimethy1-2-imidazolidinone/trifluorotoluene, irradiated with light generated by two 40W
Kessil LED
aquarium lights, at a temperature between 0 C and the boiling point of the respective solvent.
Ideally the reaction is performed between room temperature and 35 C to afford compounds of general formula (XVI) with R1 = C1-C6-alkyl and halo-C1-C6-alkyl.
Reduction of the nitro functionalitiy contained within compounds of formula (XVI) affords amines of formula (II). The reduction of a nitro functionality can be performed for example under hydrogene atmosphere and a Pd or Pt/V catalyst in an inert solvent such as dichloromethane, methanol, ethanol or ethyl acetate from room temperature to the boiling point of the respective solvent.. Preferentially, the reaction is performed with the addition of a reducing agent, for example Iron(0), with additives such as ammonium chloride, in an appropriate mixture of solvents, for example a mixture of water, tetrahydrofuran, and methanol, in a temperature range from room temperature to the boiling point of the respective solvent.
Ideally the reaction is performed at 80 C to furnish amine intermediates of general formula (II).
The reaction can be carried out using alternative reducing agents to those skilled in the art, for example tin(I1)chloride, in an appropriate solvent, such as methanol, in a temperature range from room temperature to the boiling point of the respective solvent. Ideally the reaction is performed at room temperature to furnish amine intermediates of general formula (II).

OH
VII

R
V
2 I -a N---"N F /
R
H
N----N
(XII) (XIII) H
(XIV) R

-a. - Ra.
PG PG
(XV) (XVI) R
N--""Nr i PG (II) Scheme 4: Preparation of compounds of formula (II for X=0) from compounds of formula (XII).
Method 1: (prep. HPLC) System: Labomatic, Pump: HD-5000, Fraction Collector:
LABOCOL
.. Vario-4000, UV-Detector: Knauer UVD 2.1S; Column: Chromatorex RP C18 10pm 125x30 mm; Solvent: A = water + 0.1% Vol. ammonia (99%), B = Acetonitril; Flow: 150 mL/min;
temperature: room temperature Method 2: Waters Acquity UPLCMS SingleQuad; Colum: Acquity UPLC BEH C18 1.7 .. 50x2.1mm; eluent A: water + 0.2 vol % aqueous ammonia (32%), eluent B:
acetonitrile;
gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 mL/min; temperature:
60 C; DAD
scan: 210-400 nm Method 3: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1.7 .. 50x2.1mm; eluent A: water + 0.1 vol % formic acid (99%), eluent B:
acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 mL/min; temperature: 60 C; DAD scan:

nm Method 4: (prep. HPLC) System: Waters Autopurificationsystem; column: Waters XBrigde 018 5p 100x30mm; eluent A: water + 0.1 Vol-% formic acid (99%), eluent B:
acetonitrile; gradient:
0.00-0.50 min 8% B (40->70mUmin), 0.51-5.50 min 16-36% B (70mL/min), DAD scan:

400 nm EXPERIMENTAL SECTION - INTERMEDIATES
Intermediate 1 phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsily1)ethoxy]methyl}-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}phenyl)carbamate H
N
. 0 F
0,..F
F F
I \
N...--N
0) ?
H3C¨/Si-c H3 To solution of 3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylaniline (4.00 g, 8.71 mmol, see Synthesis 2007, page 251-258, Org. Process Res. Dev. 2010, page 168-173) in pyridine (4.0 mL) and THF (60 mL) was slowly added at 0 C phenyl carbonochloridate (1.2 mL, 9.6 mmol). After stirring this mixture 5 minutes at 0 C and then 30 minutes at room temperature ethyl acetate was added. This organic phase was washed with 1N hydrochloric acid (75mL), water, concentrated aqueous sodium hydrogencarbonate, brine, dried over sodium sulfate, filtered and concentrated to dryness. The resulting residue was purified via a Biotage chromatography system (100g snap KP-Sil column, hexane /0 ¨ 100% ethyl acetate, then ethyl acetate! 0 ¨ 75%
methanol) to obtain 4.53 g (92 % purity, 83 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.10 (s, 9H), 0.79 - 0.86 (m, 2H), 3.54 -3.61 (m, 2H), 5.69 (s, 2H), 6.61 (d, 1H), 7.24 - 7.32 (m, 3H), 7.42 - 7.50 (m, 4H), 8.27 -8.33 (m, 1H), 8.35 -8.40 (m, 1H), 10.81 (s, 1H).

Intermediate 2 1 -(3,5-difluoro-44[3-(trifluoromethyl)-1 -{[2-(tri methylsi lyl)ethoxy]methyl}-1 H-pyrrolo[2,3-b]pyridin-4-yl]oxy}pheny1)-343-(morpholin-4-y1)propyl]urea OTh H H
cN\/XN N
Ir .F
F
;,..F
F F
I \
N...--N
0) ?
H3C-oSi-0 H3 To solution of phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (1.20 g, 2.07 mmol, intermediate 1) in DMF
(10 mL) was added 3-(morpholin-4-yl)propan-1-amine (300 pL, 2.1 mmol) and this mixture was stirred at 60 C for 2 hours. After cooling to room temperature ethyl acetate and water was 10 added. After separation of the organic phase the aqueous phase was extracted two times with ethyl acetate. The combined organic phases were washed 3 times with halfconcentrated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated to dryness.
The resulting residue was purified 3 times via a Biotage chromatography system (55g and 2 15 times 28g snap KP-NH column, hexane /0 ¨ 100% ethyl acetate, then ethyl acetate /0 ¨
100% methanol) to obtain 970 mg (95 % purity, 71 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.12 - -0.08 (m, 9H), 0.83 (t, 2H), 1.60 (quin, 2H), 2.27 - 2.36 (m, 6H), 3.13 (q, 2H), 3.53 - 3.62 (m, 6H), 5.68 (s, 2H), 6.42 (t, 1H), 6.57 (d, 1H), 7.34 - 7.41 (m, 2H), 8.28 (d, 1H), 8.36 (s, 1H), 8.99 (s, 1H).

Intermediate 3 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsily1)ethoxy]methyl}-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}pheny1)-3-(2-methoxyethyl)urea 1-1.,C H H
"O\NN
0 .F
F
F
F F
I \
N-----N
0) H3C-,Si-c H3 In analogy to intermediate 2), using 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(2-methoxyethypurea (150 mg, 259 pmol, intermediate 1) and 2-methoxyethanamine (19.4 mg, 259 pmol) in DMF
(1.5 mL), we obtained after one single purification using a Biotage chromatography system 99.8 mg (93 % purity, 64 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 --0.08 (m, 9H), 0.79 - 0.86 (m, 2H), 3.24 - 3.29 (m, 5H), 3.39 (t, 2H), 3.54 - 3.60 (m, 2H), 5.68 (s, 2H), 6.49 (t, 1H), 6.57 (d, 1H), 7.33 - 7.40 (m, 2H), 8.29 (d, 1H), 8.36 (s, 1H), 9.11 (s, 1H).
Intermediate 4 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsily1)ethoxy]methyl}-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}pheny1)-343-(methylsulfonyl)propyl]urea H H
0- N/xN N
O
* F
F
C:1-F
FJF
I \
N-----N
0) ?
H3C-oSi_c H3 In analogy to intermediate 2), using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) and 3-(methylsulfonyl)propan-1-amine hydrochloride (1:1) (44.9 mg, 259 pmol) together with N,N-diisopropylethylamine (45 pL, 260 pmol) in DMF (1.5 mL), we obtained after one single purification using a Biotage chromatography system 106 mg (94 %
purity, 62% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 - -0.08 (m, 9H), 0.80 - 0.86 (m, 2H), 1.83 - 1.91 (m, 2H), 2.99 (s, 3H), 3.10 - 3.16 (m, 2H), 3.22 (q, 2H), 3.55 - 3.60 (m, 2H), 5.68 (s, 2H), 6.55 -6.60 (m, 2H), 7.36 - 7.43 (m, 2H), 8.29 (d, 1H), 8.36 (s, 1H), 9.09 (s, 1H).
Intermediate 5 1-(2,2-difluoroethyl)-3-(3,5-difluoro-44[3-(trifluoromethyl)-1-{[2-(trimethylsily1)ethoxy]methyl}-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}phenyl)urea F
H H
F---cN
. F
F
::114F
F F
I \
N-----I\I
0) ?
H30-,Si-c H3 In analogy to intermediate 2), using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) and 2,2-difluoroethanamine (21.0 mg, 259 pmol) in DMF
(1.5 mL), we obtained after one single purification using a Biotage chromatography system 88.5 mg (94 %
purity, 57% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 - -0.08 (m, 9H), 0.79 - 0.87 (m, 2H), 3.48 ¨ 3.61 (m, 4H), 5.68 (s, 2H), 6.07 (tt, 1H), 6.58 (d, 1H), 6.78 (t, 1H), 7.36 - 7.44 (m, 2H), 8.29 (d, 1H), 8.36 (s, 1H), 9.24 (s, 1H).

Intermediate 6 N3-[(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsily1)ethoxy]methyl}-pyrrolo[2,3-1Apyridin-4-yl]oxy}phenyl)carbamoyl]-beta-alaninamide )r--NØ0NN
F

01 .
F
)4F
F F
I \
N-----N\
o) ?
H3C-,Si-c H3 In analogy to intermediate 2), using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) and beta-alaninamide (22.8 mg, 259 pmol) together with N,N-diisopropylethylamine (45 pL, 260 pmol) in DMF (1.5 mL), we obtained after one single purification using a Biotage chromatography system 100 mg (94% purity, 64%
yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 - -0.08 (m, 9H), 0.80 - 0.86 (m, 2H), 2.28 (t, 2H), 3.26 - 3.32 (m, 2H), 3.54 - 3.60 (m, 2H), 5.68 (s, 2H), 6.44 (t, 1H), 6.57 (d, 1H), 6.92 (br s, 1H), 7.30 - 7.44 (m, 3H), 8.28 (d, 1H), 8.36 (s, 1H), 9.15 (s, 1H).
Intermediate 7 1 -(3,5-difluoro-44[3-(trifluoromethyl)-1 -{[2-(tri methylsi lyl)ethoxy]methyl}-1 H-pyrrolo[2,3-b]pyridin-4-yl]oxy}pheny1)-3-(pyridin-4-ylmethyl)urea Nl&N N
10( *F
F
F
F )4F
I \
N----Nµ
o) ?
H3C-Si_ c H3 In analogy to intermediate 2),using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) and 1-(pyridin-4-yl)methanamine (28.0 mg, 259 pmol) in DMF (1.5 mL), we obtained after one single purification using a Biotage chromatography system 145 mg (92 % purity, 87% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 - -0.08 (m, 9H), 0.79 - 0.86 (m, 2H), 3.54 - 3.61 (m, 2H), 4.35 (d, 2H), 5.68 (s, 2H), 6.58 (d, 1H), 7.04 (t, 1H), 7.30 (d, 2H), 7.38 - 7.45 (m, 2H), 8.28 (d, 1H), 8.36 (s, 1H), 8.52 (d, 2H), 9.30 (s, 1H).
Intermediate 8 1 -(3,5-difluoro-44[3-(trifluoromethyl)-1 -{[2-(tri methylsi lyl)ethoxy]methyl}-1 H-pyrrolo[2,3-b]pyridin-4-yl]oxy}pheny1)-3-[(1-hydroxycyclopropyl)methyl]urea HH
C'"DN
N F
F F
I

H3C¨,Si-c H3 In analogy to intermediate 2), using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (200 mg, 345 pmol, intermediate 1) and 1-(aminomethyl)cyclopropanol (30.1 mg, 345 pmol) in DMF (2.0 mL,

26 mmol), we obtained after one single purification using a Biotage chromatography system 151 mg (92% purity, 70% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 - -0.08 (m, 9H), 0.48 - 0.53 (m, 2H), 0.54 - 0.60 (m, 2H), 0.79 - 0.87 (m, 2H), 3.22 (d, 2H), 3.54 - 3.61 (m, 2H), 5.42 (s, 1H), 5.68 (s, 2H), 6.47 (t, 1H), 6.58 (d, 1H), 7.33 - 7.40 (m, 2H), 8.28 (d, 1H), 8.36 (s, 1H), 9.09 (s, 1H).

Intermediate 9 4-{[(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsily1)ethoxy]methyl}-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)carbamoyl]amino}butanamide H

F
I

H30¨oSI-0 H3 5 In analogy to intermediate 2), using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (175 mg, 302 pmol, intermediate 1) and 4-aminobutanamide hydrochloride (1:1) (41.8 mg, 302 pmol) together with N,N-diisopropylethylamine (53 pL, 300 pmol) in DMF (1.8 mL), we obtained after one single purification using a Biotage chromatography system 110 mg (85 %
purity, 53 %
10 yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1H-NMR (400MHz, DMSO-d6): 6 [ppm]= -0.11 - -0.08 (m, 9H), 0.80 - 0.86 (m, 2H), 1.65 (quin, 2H), 2.08 (t, 2H), 3.09 (q, 2H), 3.55 - 3.60 (m, 2H), 5.68 (s, 2H), 6.45 (t, 1H), 6.57 (d, 1H), 6.77 (br s, 1H), 7.30 (br s, 1H), 7.36 - 7.43 (m, 2H), 8.28 (d, 1H), 8.36 (s, 1H), 9.02 (s, 1H).
Intermediate 10 1-(3,5-difluoro-44[3-(trifluoromethyl)-1-{[2-(trimethylsily1)ethoxy]methyl}-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}pheny1)-3-(3-methoxypropyl)urea rs 0 mH H
113,"
0 =F
F F
I
o) H3C¨oSL..c H3 In analogy to intermediate 2), using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) and 3-methoxypropan-1-amine (23.1 mg, 259 pmol) in DMF
(1.5 mL), we obtained after one single purification using a Biotage chromatography system 88.0 mg (94 %
purity, 56% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 - -0.08 (m, 9H), 0.80 - 0.86 (m, 2H), 1.67 (tt, 2H), 3.11 -3.18 (m, 2H), 3.24 (s, 3H), 3.34 - 3.39 (m, 2H), 3.54 - 3.60 (m, 2H), 5.68 (s, 2H), 6.42 (t, 1H), 6.57 (d, 1H), 7.35 - 7.42 (m, 2H), 8.28 (d, 1H), 8.36 (s, 1H), 9.01 (s, 1H).
Intermediate 11 1 -(3,5-difluoro-44[3-(trifluoromethyl)-1 -{[2-(tri methylsi lyl)ethoxy]methyl}-1 H-pyrrolo[2,3-b]pyridin-4-yl]oxy}pheny1)-342-(morpholin-4-y1)-2-oxoethyl]urea (NN&N

F F
I
0) H 3 C¨SL,. H3 In analogy to intermediate 2), using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) and 2-amino-1-(morpholin-4-yl)ethanone (37.3 mg, 259 pmol) in DMF
(1.5 mL), we obtained after one single purification using a Biotage chromatography system 124 mg (94 % purity, 72 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 - -0.08 (m, 9H), 0.80 - 0.86 (m, 2H), 3.39 - 3.49 (m, 4H), 3.54 - 3.62 (m, 6H), 4.01 (d, 2H), 5.68 (s, 2H), 6.54 - 6.62 (m, 2H), 7.33 - 7.40 (m, 2H), 8.28 (d, 1H), 8.36 (s, 1H), 9.46 (s, 1H).

Intermediate 12 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsily1)ethoxy]methyl}-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}pheny1)-3-(pyridin-3-ylmethyl)urea N
I H
= F
F
F )4FF
I \
N1'----Nµ
o) ?
H3C-,Si-c H3 In analogy to intermediate 2), using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) and 1-(pyridin-3-yl)methanamine (28.0 mg, 259 pmol) in DMF (1.5 mL), we obtained after one single purification using a Biotage chromatography system 99.8 mg (93 % purity, 61 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 --0.08 (m, 9H), 0.79 - 0.86 (m, 2H), 3.54 - 3.60 (m, 2H), 4.34 (d, 2H), 5.68 (s, 2H), 6.58 (d, 1H), 7.02 (t, 1H), 7.35 - 7.44 (m, 3H), 7.72 (dt, 1H), 8.28 (d, 1H), 8.36 (s, 1H), 8.47 (dd, 1H), 8.53 (d, 1H), 9.21 (s, 1H).
Intermediate 13 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsily1)ethoxy]methyl}-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}pheny1)-3-(pyridin-2-ylmethyl)urea i µ N H
N
r * F
F
F
F )4F
I \
N-----Nµ
o ) ?
H3C-,Si....c H3 In analogy to intermediate 2), suing phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) and 1-(pyridin-2-yl)methanamine (28.0 mg, 259 pmol) in DMF (1.5 mL), we obtained after one single purification using a Biotage chromatography system 90.0 mg (80 % purity, 47% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 - -0.08 (m, 9H), 0.79 - 0.86 (m, 2H), 3.53 - 3.62 (m, 2H), 4.43 (d, 2H), 5.68 (s, 2H), 6.58 (d, 1H), 7.03 (t, 1H), 7.26 - 7.32 (m, 1H), 7.34 - 7.43 (m, 3H), 7.79 (td, 1H), 8.28 (d, 1H), 8.36 (s, 1H), 8.53 (ddd, 1H), 9.36 (s, 1H).
Intermediate 14 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsily1)ethoxy]methyl}-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}pheny1)-342-(pyridin-4-y1)ethyl]urea H H

NC' /7 .F

F
F
F F
I \
N...--N
0) ?
H3C-,Si-c H3 In analogy to intermediate 2), using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) and 2-(pyridin-4-yl)ethanamine (31.6 mg, 259 pmol) in DMF (1.5 mL), we obtained after one single purification using a Biotage chromatography system 123 mg (92 %
purity, 72% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 - -0.08 (m, 9H), 0.80 - 0.86 (m, 2H), 2.80 (t, 2H), 3.40 (q, 2H), 3.54 - 3.61 (m, 2H), 5.68 (s, 2H), 6.44 (t, 1H), 6.57 (d, 1H), 7.25 - 7.30 (m, 2H), 7.34 - 7.41 (m, 2H), 8.28 (d, 1H), 8.36 (s, 1H), 8.47 - 8.51 (m, 2H), 9.03 (s, 1H).

Intermediate 15 (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsily1)ethoxy]methyl}-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}pheny1)-3-[(2S)-2-hydroxy-3-(morpholin-4-y1)propyl]urea * F
F
I

H3C-oSI-c H3 In analogy to intermediate 2), using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) and (+/-)-1-amino-3-(morpholin-4-yl)propan-2-ol ethanedioate (1:1) (64.8 mg, 259 pmol) together with N,N-diisopropylethylamine (45 pL, 260 pmol) in DMF
(1.5 mL), we obtained after one single purification using a Biotage chromatography system 75.5 mg (93 %
purity, 42% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 - -0.08 (m, 9H), 0.79 - 0.86 (m, 2H), 2.28 (d, 2H), 2.36 - 2.45 (m, 4H), 2.93 - 3.01 (m, 1H), 3.29 ¨ 3.36 (m, 1H), 3.53 - 3.62 (m, 6H), 3.64 - 3.75 (m, 1H), 4.82 (d, 1H), 5.68 (s, 2H), 6.37 (t, 1H), 6.57 (d, 1H), 7.32 - 7.40 (m, 2H), 8.29 (d, 1H), 8.36 (s, 1H), 9.13 (s, 1H).
Intermediate 16 (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsily1)ethoxy]methyl}-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}pheny1)-3-[(2R)-tetrahydrofuran-2-ylmethyl]urea Ci\H
>or * F
F )4FF
I
o H
3C¨SL = C H3 In analogy to intermediate 2),using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) and (+/-)-1-[tetrahydrofuran-2-yl]methanamine (26.2 mg, 259 pmol) in DMF (1.5 mL), we obtained after one single purification using a Biotage chromatography system 162 mg (80% purity, 85% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 - -0.08 (m, 9H), 0.80 - 0.86 (m, 2H), 1.47 - 1.56 (m, 1H), 1.78 - 1.95 (m, 3H), 3.07 - 3.15 (m, 1H), 3.21 -3.28 (m, 1H), 3.57 (t, 2H), 3.61 -3.67 (m, 1H), 3.75 - 3.82 (m, 1H), 3.84 - 3.91 (m, 1H), 5.68 (s, 2H), 6.45 (t, 1H), 6.58 (d, 1H), 7.33 -7.40 (m, 2H), 8.28 (d, 1H), 8.36 (s, 1H), 9.07 (s, 1H).
Intermediate 17 1-(3,5-difl uoro-4-{[3-(trifl uoromethyl)-1-{[2-(tri methylsi lyl)ethoxy]methyl}-1 H-pyrro lo[2,3-b]pyri di n-4-yl]oxy}phenyI)-3-(tetrahydro-2H-pyran-4-ylmethyl)urea Oc H H
N N
lir *F
F
;1-F
F F
I \
N...--N
0) ?
H3C¨Si-r H3 rs= `-' u3., 1 1 In analogy to intermediate 2), using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) and 1-(tetrahydro-2H-pyran-4-yl)methanamine (29.8 mg, 259 pmol) in DMF (1.5 mL), we obtained after one single purification using a Biotage chromatography system 205 mg (80% purity, 105% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 - -0.08 (m, 9H), 0.80 - 0.86 (m, 2H), 1.12 - 1.25 (m, 2H), 1.56 (br d, 2H), 1.61 - 1.72 (m, 1H), 3.01 (t, 2H), 3.22 - 3.31 (m, 2H), 3.55 - 3.60 (m, 2H), 3.85 (br dd, 2H), 5.68 (s, 2H), 6.53 (t, 1H), 6.57 (d, 1H), 7.35 - 7.42 (m, 2H), 8.28 (d, 1H), 8.36 (s, 1H), 8.99 (s, 1H).

Intermediate 18 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsily1)ethoxy]methyl}-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}pheny1)-3-(1H-1,2,3-triazol-5-ylmethyl)urea N., I H H
NNN N
12r F
F F
I
NN\
o H 3C -Si-r 1_4 '3 H
In analogy to intermediate 2), using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) and 1-(1 H-1,2,3-triazol-5-yl)methanamine hydrochloride (1:1) (69.6 mg, 518 pmol) together with N,N-diisopropylethylamine (90 pL, 520 pmol) in DMF
(1.5 mL), we obtained after one single purification using a Biotage chromatography system 95.6 mg (95 %
purity, 60% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 - -0.08 (m, 9H), 0.80 - 0.86 (m, 2H), 3.53 - 3.61 (m, 2H), 4.38 (d, 2H), 5.68 (s, 2H), 6.58 (d, 1H), 6.94 (t, 1H), 7.37 - 7.44 (m, 2H), 7.69 (s, 1H), 8.28 (d, 1H), 8.36 (s, 1H), 9.25 (s, 1H).
Intermediate 19 N2-[(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsily1)ethoxy]methyl}-pyrrolo[2,3-1Apyridin-4-yl]oxy}phenyl)carbamoyl]glycinamide H2N&Irly 61 =F F F
F )4F
I
NNµ
o H3C-,Si-c H3 In analogy to intermediate 2), using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) and glycinamide hydrochloride (1:1) (28.6 mg, 259 pmol) together with N,N-diisopropylethylamine (45 pL, 260 pmol) in DMF (1.5 mL), we obtained after one single purification using a Biotage chromatography system 90.7 mg (93 % purity, 58 %
yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 - -0.08 (m, 9H), 0.79 - 0.87 (m, 2H), 3.54 - 3.61 (m, 2H), 3.70 (d, 2H), 5.68 (s, 2H), 6.53 (t, 1H), 6.58 (d, 1H), 7.10 (s, 1H), 7.37 (d, 2H), 7.45 (s, 1H), 8.28 (d, 1H), 8.36 (s, 1H), 9.34 (s, 1H).
Intermediate 20 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsily1)ethoxy]methyl}-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}pheny1)-342-(morpholin-4-y1)ethyl]urea H H
N yNN

/ I
NN-/

To a solution of 3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylaniline (50.0 mg, 109 pmol, intermediate 1) in dichloromethane (10 mL) was added at 0 C N,N-diisopropylethylamine (42.2 mg, 326 pmol) and bis(trichloromethyl) carbonate (32.3 mg, 109 pmol). After stirring at 0 C for 0.5 hour a solution of 2-(morpholin-4-yl)ethanamine (21.3 mg, 163 pmol) in dichloromethane (2 mL) was added slowly. The reaction mixture was allowed to stir at 0 C for another 1 hour. A
similar experiment using 3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylaniline (100.0 mg, 218 pmol) was done. Both reaction mixture were quenched by water and extracted with dichloromethane. The combined organic phases were washed with aqueous sodium bicarbonate solution, dried over sodium sulfate and after filtration evaporated to dryness. The residue was subjected to column chromatography with methanol! dichloromethane (1:10/v:v) to afford 55 mg (41% yiled) of the desired title compound.

Intermediate 21 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsily1)ethoxy]methyl}-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}pheny1)-342-(piperidin-1-y1)ethyl]urea H H
N N
y / I
NN%

\C H3 In analogy to intermediate 20), in a single experiment using 3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylaniline (100 mg, 218 pmol, intermediate 1), 2-(piperidin-1-yl)ethanamine (41.9 mg, 326 pmol), N,N-diisopropylethylamine (84.4 mg, 653 pmol) and bis(trichloromethyl) carbonate (64.6 mg, 218 pmol) in dichloromethane (15 mL), we obtained 45 mg (34% yield) of the desired title compound.
Intermediate 22 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsily1)ethoxy]methyl}-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}pheny1)-343-(piperidin-1-y1)propyl]urea H H
F NyNN

/ I

In analogy to intermediate 20), in a single experiment using 3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylaniline (100 mg, 218 pmol, intermediate 1), 3-(piperidin-1-yl)propan-1-amine (46.4 mg, 326 pmol), N,N-diisopropylethylamine (84.4 mg, 653 pmol) and bis(trichloromethyl) carbonate (64.6 mg, 218 pmol) in dichloromethane (15 mL), we obtained 43 mg (31% yield) of the desired title compound.

Intermediate 23 1-(3,5-difluoro-44[3-(trifluoromethyl)-1-{[2-(trimethylsily1)ethoxy]methyl}-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}pheny1)-343-(dimethylamino)propyl]urea H H
F N H
leF 0 3 N

(0--N__gi-C H3 In analogy to intermediate 20), in two experiments using 3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylaniline (20 + 100 mg, 44 pmol + 218 pmol, intermediate 1), N,N-dimethylpropane-1,3-diamine (6.67 + 33.4 mg, 65.3 +
326 pmol), triethylamine (18 + 91 pL, 130 + 653 pmol) and bis(trichloromethyl) carbonate (12.9 + 64.6 mg, 43.5 + 218 pmol) in dichloromethane (3 + 15 mL), we obtained 65 mg (51% yield) of the desired title compound.
Intermediate 24 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsily1)ethoxy]methyl}-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}pheny1)-342-(dimethylamino)ethyl]urea H H

¨3 N

In analogy to intermediate 20), in a single experiment using 3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylaniline (100 mg, 218 pmol, intermediate 1), N,N-dimethylethane-1,2-diamine (28.8 mg, 326 pmol), N,N-diisopropylethylamine (28.8 mg, 326 pmol) and bis(trichloromethyl) carbonate (64.6 mg, 218 pmol) in dichloromethane (15 mL), we obtained 54 mg (43% yield) of the desired title compound.

Intermediate 25 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsily1)ethoxy]methyl}-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}pheny1)-3-[(1,1-dioxidothietan-3-y1)methyl]urea 0 s 0=1-Soi:
H
N N
F
)4F
F F
I
0) H3C¨Si¨rs 1.4 H3k:
In analogy to intermediate 2),using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (100 mg, 173 pmol), intermediate 1) and 1-(1,1-dioxidothietan-3-yl)methanamine (23.3 mg, 173 pmol) in DMF (1.0 mL, 13 mmol), we obtained after one single purification using a Biotage chromatography system 83.9 mg (91 % purity, 71 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 --0.08 (m, 9H), 0.80 - 0.86 (m, 2H), 2.68 - 2.72 (m, 1H), 3.34 -3.39 (m, 2H), 3.54 - 3.60 (m, 2H), 3.89 - 3.96 (m, 2H), 4.19 -4.27 (m, 2H), 5.68 (s, 2H), 6.58 (d, 1H), 6.77 (t, 1H), 7.36 - 7.44 (m, 2H), 8.28 (d, 1H), 8.36 (s, 1H), 9.22 (s, 1H).
Intermediate 26 N-(2-{[(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsily1)ethoxy]methyl}-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}phenyl)carbamoyl]amino}ethyl)acetamide JJ 1-4 r H H
N
r = F
F F
I
0) H3C¨oSi¨c H3 In analogy to intermediate 2), using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (100 mg, 173 pmol), intermediate 1) and N-(2-aminoethyl)acetamide (17.6 mg, 173 pmol) in DMF (1.0 mL, 13 mmol), we obtained after one single purification using a Biotage chromatography system 69.0 mg (90 % purity, 61 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.12 --0.08 (m, 9H), 0.79 - 0.87 (m, 2H), 1.82 (s, 3H), 3.11 -3.19 (m, 4H), 3.54 - 3.61 (m, 2H), 5.68 (s, 2H), 6.43 (t, 1H), 6.57 (d, 1H), 7.35 - 7.44 (m, 2H), 7.96 (br s, 1H), 8.29 (d, 1H), 8.36 (s, 1H), 9.11 (s, 1H).
.. Intermediate 27 (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsily1)ethoxy]methyl}-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}pheny1)-3-[1-(morpholin-4-y1)propan-2-yl]urea ,,,1-1 ),rN H
ON
rNNC'`' H
3 0 . F
F
0,..F
F F
I \
N...--N
0) ?
H3C¨/Si-c 1j3 In analogy to intermediate 2), using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (100 mg, 173 pmol), intermediate 1) and (+/-)-1-(morpholin-4-yl)propan-2-amine (24.9 mg, 173 pmol) in DMF
(1.0 mL, 13 mmol), we obtained after one single purification using a Biotage chromatography system 82.0 mg (100% purity, 75% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.10 --0.08 (m, 9H), 0.79 - 0.87 (m, 2H), 1.11 (d, 3H), 2.18 -2.25 (m, 1H), 2.35 -2.46 (m, 4H), 3.53 - 3.61 (m, 6H), 3.84 (spt, 1H), 5.68 (s, 2H), 6.23 (d, 1H), 6.57 (d, 1H), 7.34 - 7.41 (m, 2H), 8.29 (d, 1H), 8.36 (s, 1H), 9.00 (s, 1H), 9.32 (s, 1H).

Intermediate 28 (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsily1)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}pheny1)-342-(morpholin-4-y1)propyl]urea H H
rNN N
CIN
( . F
F
F
F
):). F
I \
N-.---N
0) H3C¨,Si-c H3 In analogy to intermediate 2), using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (100 mg, 173 pmol), intermediate 1) and (+/-)-2-(morpholin-4-yl)propan-1-amine (24.9 mg, 173 pmol) in DMF
(1.0 mL, 13 mmol), we obtained after one single purification using a Biotage chromatography system 84.8 mg (100% purity, 78% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 --0.08 (m, 9H), 0.79 - 0.87 (m, 2H), 0.93 (d, 3H), 2.36 - 2.44 (m, 2H), 2.62 (sxt, 1H), 3.04 - 3.20 (m, 2H), 3.55 - 3.65 (m, 6H), 5.68 (s, 2H), 6.28 (t, 1H), 6.58 (d, 1H), 7.34 - 7.41 (m, 2H), 8.29 (d, 1H), 8.36 (s, 1H), 9.22 (s, 1H).
Intermediate 29 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsily1)ethoxy]methyl}-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}pheny1)-342-(methylsulfonyl)ethyl]urea 0 , ,,.I-1 H
'S" N
H CI ' 0 3 ir . F
F
F
F F
I \
N...--N
0) ?
H3C¨oSi-c H3 In analogy to intermediate 2), using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (100 mg, 173 pmol), intermediate 1) and 2-(methylsulfonyl)ethanamine hydrochloride (1:1) (27.5 mg, 173 pmol) together with N,N-diisopropylethylamine (30 pL, 170 pmol) in DMF (1.0 mL, 13 mmol), we obtained after one single purification using a Biotage chromatography system 72.0 mg (100 % purity, 69% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 - -0.07 (m, 9H), 0.83 (t, 2H), 3.04 (s, 3H), 3.32 (t, 2H), 3.52 - 3.60 (m, 4H), 5.68 (s, 2H), 6.58 (d, 1H), 6.61 (t, 1H), 7.39 (d, 2H), 8.28 (d, 1H), 8.36 (s, 1H), 9.33 (s, 1H).
Intermediate 30 3-{[(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsily1)ethoxy]methyl}-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)carbamoyl]amino}propane-1-sulfonamide ;sg H H
0 \/XN N
r . F
F

F F
I \
N...--N
0) ?
H3C¨oSi-0 H3 In analogy to intermediate 2), using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (100 mg, 173 pmol), intermediate 1) and 3-aminopropane-1-sulfonamide hydrochloride (1:1) (30.1 mg, 173 pmol) together with N,N-diisopropylethylamine (30 pL, 170 pmol) in DMF (1.0 mL, 13 mmol), we obtained after one single purification using a Biotage chromatography system 66.1 mg (85 % purity, 52% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 - -0.08 (m, 9H), 0.79 - 0.86 (m, 2H), 1.86 (quin, 2H), 2.95 - 3.02 (m, 2H), 3.21 (q, 2H), 5.68 (s, 3H), 6.51 - 6.60 (m, 2H), 6.82 (s, 2H), 7.39 (d, 2H), 8.26 - 8.32 (m, 2H), 8.36 (s, 1H), 9.06 (s, 1H).

Intermediate 31 3-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsily1)ethoxy]methyl}-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}pheny1)-1-methyl-1-[2-(morpholin-4-y1)ethyl]urea H
NNNZTh FCLF F
I
(0 H3c--St-C H3 In analogy to intermediate 2), using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (100 mg, 173 pmol), intermediate 1) and N-methyl-2-(morpholin-4-yl)ethanamine (24.9 mg, 173 pmol) in DMF (1.0 mL, 13 mmol), we obtained after one single purification using a Biotage chromatography system 68.3 mg (91 % purity, 57 % yield) of the desired title compound.
.. 1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.12 --0.08 (m, 9H), 0.79 - 0.87 (m, 2H), 2.37 -2.47 (m, 6H), 2.99 (s, 3H), 3.35 - 3.49 (m, 2H), 3.52 - 3.62 (m, 6H), 5.68 (s, 2H), 6.57 (d, 1H), 7.49 -7.58 (m, 2H), 8.27 - 8.31 (m, 1H), 8.36 (s, 1H), 8.84 (s, 1H).
Intermediate 32 N-(2-{[(3,5-difluoro-44[3-(trifluoromethyl)-1-{[2-(trimethylsily1)ethoxy]methyl}-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}phenyl)carbamoyl]amino}ethyl)methanesulfonamide r. 0 H
N
* F
F F
I
0) H3C¨Si-r 1.4 =-= "3 In analogy to intermediate 2), using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (100 mg, 173 pmol), intermediate 1) and N-(2-aminoethyl)methanesulfonamide (24.8 mg, 96%
purity, 173 pmol) in DMF (1.0 mL, 13 mmol), we obtained after one single purification using a Biotage chromatography system 104 mg (93% purity, 90% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 - -0.08 (m, 9H), 0.79 - 0.86 (m, 2H), 2.92 (s, 3H), 3.01 - 3.07 (m, 2H), 3.22 (q, 2H), 3.54 - 3.60 (m, 2H), 5.68 (s, 2H), 6.54 (br t, 1H), 6.58 (d, 1H), 7.12 (br s, 1H), 7.35 - 7.43 (m, 2H), 8.28(d, 1H), 8.36(s, 1H), 9.23(s, 1H).
Intermediate 33 1-(3,5-d ifi uoro-4-{[3-(trifl uoromethyl)-1-{[2-(tri methylsi lyl)ethoxy]methyl}-1 H-pyrro lo[2,3-b]pyri di n-4-yl]oxy}phenyI)-3-pyri di n-3-ylurea ,,,H H
Ni "rN
0 . F

F
F
F F
I \
N...--N
0) ?
H3C¨,Si-c H3 In analogy to intermediate 2), using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (100 mg, 173 pmol), intermediate 1) and pyridin-3-amine (16.2 mg, 173 pmol) in DMF (1.0 mL, 13 mmol), we obtained after one single purification using a Biotage chromatography system 68.2 mg (93 %
purity, 64% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.10 --0.08 (m, 9H), 0.79 - 0.87 (m, 2H), 3.55 - 3.61 (m, 2H), 5.69 (s, 2H), 6.61 (d, 1H), 7.35 (ddd, 1H), 7.45 - 7.51 (m, 2H), 7.95 (ddd, 1H), 8.23 (dd, 1H), 8.30 (d, 1H), 8.38 (s, 1H), 8.63 (d, 1H), 9.13 (s, 1H), 9.36 (br s, 1H).

Intermediate 34 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsily1)ethoxy]methyl}-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}pheny1)-343-(trifiuoromethyl)phenyl]urea H H
= NrN
* F

F F
I
0) H3C¨,Si-c H3 In analogy to intermediate 2), using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (100 mg, 173 pmol), intermediate 1) and 3-(trifluoromethyl)aniline (27.8 mg, 173 pmol) in DMF (1.0 mL, 13 mmol), we obtained after one single purification using a Biotage chromatography system 40.0 mg (85 % purity, 30 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 --0.08 (m, 9H), 0.80 - 0.86 (m, 2H), 3.55 - 3.61 (m, 2H), 5.69 (s, 2H), 6.60 - 6.63 (m, 1H), 7.36 (d, 1H), 7.46 - 7.57 (m, 3H), 7.59 - 7.65 (m, 1H), 8.01 (s, 1H), 8.28 - 8.32 (m, 1H), 8.38 (s, 1H), 9.33 (br s, 2H).
Intermediate 35 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsily1)ethoxy]methyl}-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}pheny1)-3-(1,3,4-thiadiazol-2-yOurea F = A\ I

F F
I
(0 H3C¨Sis-C H3 To a solution of 1,3,4-thiadiazol-2-amine (66.0 mg, 653 pmol) in dichloromethane (9.0 mL) and pyridine (2.0 mL) was added di-1H-imidazol-1-ylmethanone (116 mg, 718 pmol) and the mixture was stirred at reflux for 30 minutes. Then this mixture was cooled to room tempetature and added to a solution of 3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylaniline (300 mg, 653 pmol, see Synthesis 2007, page 251-258, Org. Process Res. Dev. 2010, page 168-173) in dichloromethane (3.0 mL) and pyridine (3.0 mL) and stirred at 60 C for 16 hours. After cooling to room temperature ethyl acetate and water was added. The aqueous phase was separated and washed twice with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The resulting residue was purified via a Biotage chromatography system (28g snap KP-NH column, hexane /0 - 100%
ethyl acetate, then ethyl acetate! 0- 100% methanol) to obtain 127 mg (86 %
purity, 29 %
yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 - -0.07 (m, 9H), 0.80 - 0.87 (m, 2H), 3.54 - 3.61 (m, 2H), 5.69 (s, 2H), 6.61 (d, 1H), 7.71 -7.80 (m, 2H), 8.29 (d, 1H), 8.35 (s, 1H), 8.75 (s, 1H), 10.41 (br s, 1H), 10.74 (br s, 1H).
Intermediate 36 1-(3,5-difluoro-44[3-(trifluoromethyl)-1-{[2-(trimethylsily1)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}pheny1)-342-fluoro-5-(trifluoromethyl)phenyl]urea H H
NN
F = 0 F F
I

To a solution of 3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylaniline (100 mg, 218 pmol, see Synthesis 2007, page 251-258, Org. Process Res. Dev. 2010, page 168-173) and 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene (49.1 mg, 239 pmol) in dichloromethane (1.5 mL) and pyridine (1.5 mL) was stirred at 60 C for 3 hours. After cooling to room temperature ethyl acetate and water was added. The aqueous phase was separated and washed twice with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The resulting residue was purified via a Biotage chromatography system (11g snap KP-NH column, hexane / 0 ¨ 100% ethyl acetate, then ethyl acetate / 0 ¨
100% methanol) to obtain 240 mg (80 % purity, 133 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 - -0.08 (m, 9H), 0.77 - 0.89 (m, 2H), 3.55 - 3.61 (m, 2H), 5.69 (s, 2H), 6.61 (d, 1H), 7.41 - 7.55 (m, 2H), 8.30 (d, 1H), 8.38 (s, 1H), 8.59 (ddd, 2H), 9.09 (br s, 1H), 9.48 (d, 1H), 9.61 (s, 1H).
Intermediate 37 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsily1)ethoxy]methyl}-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}pheny1)-3-pyridazin-3-ylurea N, N, FN0 ¨U
F F
I
(0 H 3C-81¨C H3 In analogy to intermediate 36), using pyridazin-3-amine (103 mg, 1.09 mmol), di-1H-imidazol-1-ylmethanone (194 mg, 1.20 mmol) and 3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylaniline (500 mg, 1.09 mmol), we obtained after one single purification using a Biotage chromatography system 222 mg (92 %
purity, 32% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 - -0.07 (m, 9H), 0.80 - 0.86 (m, 2H), 3.53 - 3.62 (m, 2H), 5.69 (s, 2H), 6.62 (d, 1H), 7.49 - 7.56 (m, 2H), 7.68 (dd, 1H), 8.05 (dd, 1H), 8.30 (d, 1H), 8.38 (s, 1H), 8.92 (dd, 1H), 10.02 (br s, 1H), 10.16 (br s, 1H).

Intermediate 38 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsily1)ethoxy]methyl}-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}pheny1)-3-(2-methoxyphenyl)urea O'CH 3 H H
F NN
F F F
-.....
F
H3C /a, PH3 I
H C-SI N'N/
3 \----\ /
0-'1 In analogy to intermediate 36), using 1-isocyanato-2-methoxybenzene (56 pL, 420 pmol), N,N-diisopropylethylamine (110 pL, 650 pmol) and 3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylaniline (150 mg, 326 pmol, see Synthesis 2007, page 251-258, Org. Process Res. Dev. 2010, page 168-173), we obtained after one single purification using a Biotage chromatography system 175 mg (30 % purity, 88 % yield) of the desired title compound.
Intermediate 39 4-{[6-chloro-3-(trifluoromethyl)-1-{[2-(trimethylsily1)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}-2,5-difluoroaniline F F
F........)7 F
H3C, PH3 / I
-Si N
H----3C N Cl \----\ /

A solution of 6-chloro-4-nitro-3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridine (460 mg, 1.16 mmol, see Synthesis 2007, page 251-258, Org. Process Res. Dev. 2010, page 168-173), 4-amino-2,5-difluorophenol (185 mg, 1.28 mmol) and potassium carbonate (482 mg, 3.49 mmol) in DMSO (4.6 mL) was stirred at 120 C
for 3 hours.
After cooling to room temperature the reaction mixture was diluted with ethyl actate (200 mL).
This organic phase was washed twotimes with water (30 mL) and once with brine (20 mL), then dried over sodium sulfate and after filtration dried to dryness. The resulting residue was purified via a Biotage chromatography system (28g snap KP-NH column, hexane /
0 ¨ 70%
ethyl acetate) to obtain 301 mg (92 % purity, 48 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.10 --0.07 (m, 9H), 0.81 -0.89 (m, 2H), 3.53 - 3.61 (m, 2H), 5.57 - 5.65 (m, 4H), 6.48 (d, 1H), 6.76 (dd, 1H), 7.30 (dd, 1H), 8.37 (s, 1H).

Intermediate 40 2,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsily1)ethoxy]methyl}-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}aniline F F

H3C, PH3 / I
H C¨SI N----N%
3 \----\ /

To a solution of 4-{[6-chloro-3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}-2,5-difluoroaniline (298 mg, 603 pmol) and triethylamine (100 pL, 720 pmol) in ethanol (21 mL) was given 10% Pd on carbon (29.8 mg). This mixture was stirred in an hydrogen atmosphere for 7 hours at room temperature. Then the mixture was filtered through Celite and the Celite was washed with ethyl acetate. The organic phase was evaporated to dryness and the resulting residue was purified via a Biotage chromatography system (28g snap KP-NH column, hexane /10 ¨ 70% ethyl acetate) to obtain 174 mg (90 %
purity, 61 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.10 --0.07 (m, 9H), 0.80 - 0.87 (m, 2H), 3.53 - 3.60 (m, 2H), 5.54 (s, 2H), 5.67 (s, 2H), 6.50 (dd, 1H), 6.75 (dd, 1H), 7.23 (dd, 1H), 8.25 (d, 1H), 8.31 (d, 1H).
Intermediate 41 phenyl (2,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsily1)ethoxy]methyl}-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}phenyl)carbamate H
F NO
F.¨F F

H3C, PH3 / I
H 3C-"Si NN%
j In analogy to intermediate 1), using 2,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylaniline (170 mg, 370 pmol), intermediate 40) and phenyl carbonochloridate (51 pL, 407 pmol) in pyridine (170 pL, 2.1 mmol), we obtained after one single purification using a Biotage chromatography system 195 mg (95 % purity, 91 % yield) of the desired title compound.

1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.10 --0.07 (m, 9H), 0.79 - 0.87 (m, 2H), 3.54 - 3.61 (m, 2H), 5.69 (s, 2H), 6.64 (dd, 1H), 6.72 - 6.78 (m, 2H), 7.13 - 7.31 (m, 2H), 7.42 - 7.48 (m, 1H), 7.61 (dd, 1H), 7.88 (dd, 1H), 8.30 (d, 1H), 8.37 (d, 1H), 9.32 (s, 1H).
Intermediate 42 1-(2,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsily1)ethoxy]methyl}-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}pheny1)-343-(morpholin-4-y1)propyl]urea H H (C) F NyNN.) F-_______017 F
H3C, P-I3 / I
H 3C -"Si NN%
0--i In analogy to intermediate 2), phenyl (2,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (90.0 mg, 155 pmol, intermediate 41) and 3-(morpholin-4-yl)propan-1-amine (45 pL, 311 pmol) in DMF (750 pL), we obtained after one single purification using a Biotage chromatography system 93.9 mg (89% purity, 94% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 - -0.07 (m, 9H), 0.80 - 0.88 (m, 2H), 1.60 (quin, 2H), 2.27 -2.38 (m, 6H), 3.14 (q, 2H), 3.54 -3.61 (m, 6H), 5.68 (s, 2H), 6.56 (dd, 1H), 6.69 -6.78 (m, 1H), 7.51 (dd, 1H), 8.21 - 8.29 (m, 2H), 8.34 (d, 1H), 8.59 (s, 1H).
Intermediate 43 1-(2,5-difluoro-44[3-(trifluoromethyl)-1-{[2-(trimethylsily1)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}pheny1)-342-(morpholin-4-y1)ethyl]urea H H
F 6 NyNN

F..-......__0 F
H3C, PH3 / I
H3C--Si NN

In analogy to intermediate 2), using phenyl (2,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (90.0 mg, 155 pmol, intermediate 41) and 2-(morpholin-4-yl)ethanamine (41 pL, 310 pmol) in DMF (750 pL), we obtained after one single purification using a Biotage chromatography system 72.5 mg (95 % purity, 76% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.10 --0.07 (m, 9H), 0.79 - 0.88 (m, 2H), 2.36 - 2.43 (m, 6H), 3.24 (q, 2H), 3.54 - 3.63 (m, 6H), 5.68 (s, 2H), 6.54 - 6.58 (m, 1H), 6.72 - 6.78 (m, 1H), 7.51 (dd, 1H), 8.22 - 8.30 (m, 2H), 8.34 (s, 1H), 8.80 (s, 1H).
Intermediate 44 phenyl {4-[(3-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-1Apyridin-4-y1)oxy]-3,5-difluorophenyl}carbamate H 0 .N---\<
4. 0 F

N
N
LO
Si 1-1,01 'CH-, To solution of 4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluoroaniline (1.20 g, 2.82 mmol, synthesis see ChemMedChem 3, (2008), p. 1893 if., cpd 63) in ethyl acetate (20 mL) and saturated sodium bicarbonate solution (10 mL) was slowly added at RT phenyl carbonochloridate (441 mg, 2.82 mmol). After stirring this mixture 5 hours, the mixture was diluted with water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The resulting residue was purified via a Biotage chromatography system (KP-Sil snap column; hexane / ethyl acetate gradient eith up to 35% ethyl acetate) to obtain 1.37 g (89 % yield) of the desired title compound.
1H-NMR (400 MHz, CDCI3) 6 [ppm]: -0.05 (s, 9H), 0.89 - 0.95 (m, 2H), 3.52 -3.58 (m, 2H), 5.63 (s, 2H), 6.31 (d, 1H), 7.12 (bs, 1H); 7.17-7.22 (m, 2H); 7.23-7.31 (m, 4H
+ 0H013); 7.40-7.45 (m, 2H); 8.14 (d, 1H).

Intermediate 45 1-{4-[(3-ch loro-1-{[2-(tri methyls ilyl)ethoxy]methy1}-1 H-pyrro lo[2,3-b]pyri di n -4-yl)oxy]-3,5-difluoropheny1}-343-(piperidin-1-yl)propyl]urea H N,/'/
F 4. 0 N
N
LO
Si H3C'l 'CH3 To solution of phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (120 mg, 0.22 mmol, intermediate 44) in DMF (2.4 mL) was added 3-(piperidin-1-yl)propan-1-amine (31.3 mg, 0.22 mmol) and this mixture was stirred at 60 C for 3 hours. The mixture was diluted with water and extracted two times with ethyl acetate. The combined organic phases were washed 3 times with halfconcentrated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated to dryness. The resulting residue was purified via a Biotage chromatography system (KP-Sil snap column;
dichloromethane / methanol gradient with up to 10% methanol) to obtain 122 mg (88 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.12 --0.08 (m, 9H), 0.82 (t, 2H), 1.33-1.45 (m, 2H);
1.45-1.57 (m, 4H); 1.47-1.68 (m, 2H); 2.30-2.46 (m, 4H); 3.11 (q, 2H); 3.53 (dd, 2H); 5.60 (s, 2H); 6.41-6.50 (d+m, 2H); 7.36-7.41 (m, 2H); 7.84 (s, 1H); 8.17 (d, 1H); 9.08 (bs, 1H).

Intermediate 46 1-{4-[(3-ch loro-1-{[2-(tri methyls ilyl)ethoxy]methy1}-1 H-pyrro lo[2,3-b]pyri di n -4-yl)oxy]-3,5-difluoropheny1}-342-(di methylami no)ethyl]urea H N.....y'N' N-.....

Ck....õ
, N
N
LO
Si H3C' I 'CH3 According to the synthesis of intermediate 45, 175 mg (0.32 mmol) phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-y1)oxy]-3,5-difluorophenyllcarbamate (intermediate 44) and 28 mg (0.32 mmol) N,N-dimethylethane-1,2-diamine in 3.5 mL DMF
were heated at 60 C for 3 hours. After workup, the resulting residue was purified via a Biotage chromatography system (KP-Sil snap column; dichloromethane / methanol gradient with up to 3% methanol) to yield to 122 mg (67%)of the title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.12- -0.07 (m, 9H); 0.79-0.85 (m, 2H);
2.21 (s, 6H);
2.34-2.42 (m, 2H); 3.20 (q, 2H); 3.50-3.56 (m, 2H); 5.60 (s, 2H); 6.32 (t, 1H); 6.42 (d, 1H);
7.33-7.39 (m, 2H); 7.84 (s, 1H); 8.17 (d, 1H); 9.21 (s, 1H).
Intermediate 47 1-{4-[(3-ch loro-1-{[2-(tri methylsi lyl)ethoxy]methyl}-1 H-pyrro lo[2,3-b]pyri di n -4-yl)oxy]-3,5-difluoropheny1}-342-(piperidin-1-yl)ethyl]urea H
H N,ys's NO
N-.....\<
F * 0 CI
/N \
LO
Si H30--1 '0H3 According to the synthesis of intermediate 45, 85 mg (0.156 mmol) phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-y1)oxy]-3,5-difluorophenyllcarbamate (intermediate 44) and 20 mg (0.156 mmol) 2-(piperidin-1-yl)ethanamine in 1.7 mL DMF were heated at 60 C for 2 hours. After workup, the resulting residue was purified via a Biotage chromatography system (KP-Sil snap column dichloromethane / methanol gradient with up to 10% methanol) to yield to 51 mg (54%)of the title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.12- -0.07 (m, 9H); 0.79-0.85 (m, 2H);
1.33-1.76 (m, 6H); 3.50-3.56 (m, 2H); 5.60 (s, 2H); 6.42 (d, 1H); 7.35-7.43 (m, 2H); 7.84 (s, 1H); 8.17 (d, 1H);
9.38 (bs, 1H).
Intermediate 48 1-{4-[(3-ch loro-1-{[2-(tri methyls ilyl)ethoxy]methy1}-1 H-pyrro lo[2,3-b]pyri di n -4-yl)oxy]-3,5-difluoropheny1}-343-(morpholin-4-yl)propyl]urea co, H N,1 F 4. 0 Cl N
N
LO
Si H3C'l 'CH3 According to the synthesis of intermediate 45, 120 mg (0.22 mmol) phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-y1)oxy]-3,5-difluorophenyllcarbamate (intermediate 44) and 31.7 mg (0.22 mmol) 3-(morpholin-4-yl)propan-1-amine in 2.4 mL DMF
were heated at 60 C for 2 hours. After workup, the resulting residue was purified via a Biotage chromatography system (KP-Sil snap column dichloromethane / methanol gradient with up to 3% methanol) to yield to 102 mg (74%)of the title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.12- -0.06 (m, 9H); 0.79-0.85 (m, 2H);
1.55-1.64 (m, 2H); 2.25-2.38 (m, 6H); 3.12 (q, 2H); 3.50-3.61 (m, 6H); 5.60 (s, 2H); 6.41-6.48 (m, 2H); 7.36-7.41 (m, 2H); 7.84 (s, 1H); 8.17 (d, 1H); 9.02 (bs, 1H).

Intermediate 49 1-{4-[(3-ch loro-1-{[2-(tri methylsi lyl)ethoxy]methyl}-1 H-pyrro lo[2,3-b]pyri di n -4-yl)oxy]-3,5-difluorophenyI}-3-(2-methoxyethyl)urea H N....../.-0-N--i F 4. 0 Cl.....) / \ /
N
N
LO
Si H 01 'C H3 According to the synthesis of intermediate 45, 150 mg (0.275 mmol) phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-y1)oxy]-3,5-difluorophenyllcarbamate (intermediate 44) and 20.6 mg (0.275 mmol) 2-methoxyethanamine in 3 mL DMF
were heated at 60 C for 2 hours. After workup, the resulting residue was purified via a Biotage chromatography system (KP-Sil snap column dichloromethane / methanol gradient with up to 3% methanol) to yield to 138 mg (91%) of the title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.12- -0.06 (m, 9H); 0.79-0.85 (m, 2H);
3.24-3.31 (m+s, 5H); 3.39 (t, 2H); 3.50-3.56 (m, 2H); 5.60 (s, 2H); 6.43 (d, 1H); 6.50 (t, 1H); 7.35-7.40 (m, 2H); 7.84 (s, 1H); 8.17 (dõ 1H); 9.12 (s, 1H).
Intermediate 50 1-{4-[(3-ch loro-1-{[2-(tri methyls i lyl)ethoxy]methyl}-1 H-pyrro lo[2,3-b]pyri di n -4-yl)oxy]-3,5-difluorophenyI}-3-ethylurea H NH......./C H3 N-....\<
F = 0 Cl_b / \ /
N
N
LO
Si H 3C' I 'C H3 According to the synthesis of intermediate 45, 175 mg (0.32 mmol) phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-y1)oxy]-3,5-difluorophenyllcarbamate (intermediate 44) and 0.16 mL (0.32 mmol) ethanamine in 3.5 mL DMF were heated at 60 C
for 2 hours. After workup, the resulting residue was purified via a Biotage chromatography system (KP-Sil snap column dichloromethane / methanol gradient with up to 3%
methanol) to yield to 140 mg (83%) of the title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.12- -0.06 (m, 9H); 0.79-0.85 (m, 2H);
1.06 (t, 3H);
3.07-3.16 (m, 2H); 3.50-3.56 (m, 2H); 5.60 (s, 2H); 6.40-6.46 (m, 2H); 7.36-7.41 (m, 2H); 7.83 (s, 1H); 8.17 (d, 1H); 9.02 (s, 1H).
Intermediate 51 1-{4-[(3-ch loro-1-{[2-(tri methyls ilyl)ethoxy]methy1}-1 H-pyrro lo[2,3-b]pyri di n -4-yl)oxy]-3,5-difluoropheny1}-342-(morpholin-4-yl)ethyl]urea H
H N......../--N/Th N----1< L/0 . 0 F

Cl N
N
LO
Si H3C--1 'CH3 According to the synthesis of intermediate 45, 50 mg (0.092 mmol) phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-y1)oxy]-3,5-difluorophenyllcarbamate (intermediate 44) and 12 mg (0.092 mmol) 2-(morpholin-4-yl)ethanamine in 1 mL
DMF were heated at 60 C for 2 hours. After workup, the resulting residue was purified via a Biotage chromatography system (KP-Sil snap column dichloromethane / methanol gradient with up to 3% methanol) to yield to 45 mg (80%) of the title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.12- -0.06 (m, 9H); 0.79-0.85 (m, 2H);
2.34-2.45 (m, 6H); 3.22 (q, 2H); 3.50-3.56 (m, 2H); 3.59 (t, 4H); 5.60 (2, 1H); 6.32 (t, 1H); 6.43 (d, 1H); 7.34-7.40 (m, 2H); 7.84 (s, 1H); 8.17 (d, 1H); 9.19 (s, 1H).

Intermediate 52 1-benzy1-3-{4-[(3-ch loro-1-{[2-(tri methyls i lyl)ethoxy]methyl}-1 H-pyrro lo[2,3-b]pyri di n-4-yl)oxy]-3,5-difl uorophenyl}urea H H N.
N-7( F * 0 CR...) , N
N
LO
Si H,C' I 'C H, According to the synthesis of intermediate 45, 150 mg (0.275 mmol) phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-y1)oxy]-3,5-difluorophenyllcarbamate (intermediate 44) and 29 mg (0.275 mmol) 1-phenylmethanamine in 3 mL DMF were heated at 60 C for 2 hours. After workup, the resulting residue was purified via a Biotage chromatography system (KP-Sil snap column dichloromethane / methanol gradient with up to 3% methanol) to yield to 150 mg (93%) of the title compound.
1H-NMR (400 MHz, CDCI3) 6 [ppm]: -0.07- -0.03 (m, 9H); 0.88-0.94 (m, 2H); 3.51-3.57 (m, 2H);
4.44 (d, 2H); 5.57 (t, 1H); 5.62 (s, 2H); 6.29 (d, 1H); 7.14-7.19 (m, 2H);
7.24 (s, 1H); 7.27-7.37 (m, 5H); 7.44 (bs, 1H); 8.11 (d, 1H).
Intermediate 53 1-{4-[(3-chl oro-1-{[2-(tri methyls ilyl)ethoxy]methy1}-1 H-pyrro lo[2,3-b]pyri di n -4-yl)oxy]-3,5-difluorophenyI}-3-(pyri midi n-5-ylmethyl)urea N z ......1 H H Nj....N
N---_\<
F 4. 0 CI
N
N
LO
Si H3C' I 'CH3 According to the synthesis of intermediate 45, 150 mg (0.275 mmol) phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-y1)oxy]-3,5-difluorophenyllcarbamate (intermediate 44) and 30 mg (0.275 mmol) 1-(pyrimidin-5-yl)methanamine in 3 mL
DMF were heated at 60 C for 4 hours. After workup, the resulting residue was purified via a Biotage chromatography system (KP-Sil snap column dichloromethane / methanol gradient with up to 3% methanol) to yield to 125 mg (77%) of the title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.12- -0.07 (m, 9H); 0.79-0.85 (m, 2H);
3.50-3.56 (m, 2H); 4.35 (d, 2H); 5.60 (s, 2H); 6.42 (d, 1H); 7.09 (t, 1H); 7.37-7.43 (m, 2H); 7.83 (s, 1H); 8.16 (s, 1H); 8.76 (s, 2H); 9.09 (s, 1H); 9.31 (s, 1H).
Intermediate 54 1-{4-[(3-ch loro-1-{[2-(tri methylsi lyl)ethoxy]methyl}-1 H-pyrro lo[2,3-b]pyri di n -4-yl)oxy]-3,5-difluorophenyI}-3-(pyridi n-4-y1 methyl)urea HH
......-- /N
\ N
N--\
F * 0 Cl k...__) / \ /
N
N
LO
Si H 3C' I 'C H3 According to the synthesis of intermediate 45, 150 mg (0.275 mmol) phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-y1)oxy]-3,5-difluorophenyllcarbamate (intermediate 44) and 30 mg (0.275 mmol) 1-(pyridin-4-yl)methanamine in 3 mL
DMF were heated at 60 C for 6 hours. After workup, the resulting residue was purified via a Biotage chromatography system (KP-Sil snap column dichloromethane / methanol gradient with up to 3% methanol) to yield to 85 mg (50%) of the title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.12- -0.07 (m, 9H); 0.79-0.85 (m, 2H);
3.50-3.56 (m, 2H); 4.34 (d, 2H); 5.60 (s, 2H); 6.43 (d, 1H); 7.07 (t, 1H); 7.29 (d, 2H);
7.38-7.44 (m, 2H); 7.84 (s, 1H); 8.17 (d, 1H); 8.51 (d, 2H); 9.33 (s, 1H).

Intermediate 55 1-{4-[(3-ch loro-1-{[2-(tri methyls i lyl)ethoxy]methyl}-1 H-pyrro lo[2,3-b]pyri di n -4-yl)oxy]-3,5-difluorophenyI}-3-(2-cyanoethyl)u rea H
H N...õ7-4N
F . 0 Ck, , N
N
LO
Si H30'1 'CH3 According to the synthesis of intermediate 45, 150 mg (0.275 mmol) phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-y1)oxy]-3,5-difluorophenyllcarbamate (intermediate 44) and 19 mg (0.275 mmol) 3-aminopropanenitrile in 3 mL DMF
were heated at 60 C for 3 hours. After workup, the resulting residue was purified via a Biotage chromatography system (KP-Sil snap column dichloromethane / methanol gradient with up to 3% methanol) to yield to 105 mg (70%) of the title compound.
1H-N MR (400 MHz, DMSO-d6) 6 [ppm]: -0.12- -0.07 (m, 9H); 0.79-0.85 (m, 2H);
2.70 (t, 2H);
3.33-3.39 (m, signal covered by water signal); 3.50-3.56 (m, 2H); 5.60 (s, 2H); 6.44 (d, 1H);
6.80 (t, 1H); 7.39-7.44 (m, 2H); 7.84 (s, 1H); 8.17 (d, 1H); 9.29 (s, 1H).
Intermediate 56 1-{4-[(3-ch loro-1-{[2-(tri methyls i lyl)ethoxy]methyl}-1 H-pyrro lo[2,3-b]pyri di n -4-yl)oxy]-3,5-difluorophenyI}-3-(3-methylbutyl)urea H N......7.---( N-....\< C H3 F 4. 0 Cl.....) / \ /
N
N
LO
Si H 01 'C H3 According to the synthesis of intermediate 45, 150 mg (0.275 mmol) phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-y1)oxy]-3,5-difluorophenyllcarbamate (intermediate 44) and 24 mg (0.275 mmol) 3-methylbutan-1-amine in 3 mL DMF
were heated at 60 C for 2 hours. After workup, the resulting residue was purified via a Biotage chromatography system (KP-Sil snap column dichloromethane / methanol gradient with up to 3% methanol) to yield to 130 mg (83%) of the title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.12- -0.07 (m, 9H); 0.79-0.85 (m, 2H);
0.89 (d, 6H);
1.33 (q. 2H); 1.55-1.65 (m, 1H); 3.11 (q, 2H); 3.50-3.56 (m, 2H); 5.60 (s, 2H); 6.39 (t, 1H); 6.43 (d, 1H); 7.36-7.41 (m, 2H); 7.83 (s, 1H); 8.17 (d, 1H); 8.96 (s, 1H).
Intermediate 57 1-{4-[(3-ch loro-1-{[2-(tri methyls i lyl)ethoxy]methyl}-1 H-pyrro lo[2,3-b]pyri di n -4-yl)oxy]-3,5-difluoropheny1}-3-(1,2-oxazol-3-yOurea H
4. 0 F

Cl k...) / \ /
N
N
LO
Si H C'i 'CH

According to the synthesis of intermediate 45, 150 mg (0.275 mmol) phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-y1)oxy]-3,5-difluorophenyllcarbamate (intermediate 44) and 23 mg (0.275 mmol) 1,2-oxazol-3-amine in 3 mL DMF were heated at 60 C for 2 hours. The reaction was further continued for 3 hours at 80 C and 7 hours at 100 C.
After workup, the resulting residue was purified via a Biotage chromatography system (KP-Sil snap column dichloromethane / methanol gradient with up to 3% methanol) to yield to 12 mg (8%) of the title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.12- -0.07 (m, 9H); 0.79-0.85 (m, 2H);
3.50-3.56 (m, 2H); 5.60 (s, 2H); 6.46 (d, 1H); 6.86 (d, 1H); 7.46-7.53 (m, 2H); 7.85 (s, 1H); 8.18 (d, 1H); 8.78 (d, 1H); 9.31 (s, 1H); 9.92 (s, 1H).

Intermediate 58 1-{4-[(3-ch loro-1-{[2-(tri methyls ilyl)ethoxy]methy1}-1 H-pyrro lo[2,3-b]pyri di n -4-yl)oxy]-3,5-difluorophenyI}-3-pyridazi n-3-ylurea H
H N......n) N--...\<
N...
-N\I
F= 0 N
N
LO
SI
WIC."' 'CH.-4 ." C H3 -According to the synthesis of intermediate 45, 580 mg (1.06 mmol) phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-y1)oxy]-3,5-difluorophenyllcarbamate (intermediate 44) and 202 mg (1.06 mmol) pyridazin-3-amine in 10 mL DMF were heated at 60 C for 5 hours. After workup, the resulting residue was purified via a Biotage chromatography system (KP-Sil snap column dichloromethane / methanol gradient with up to 3% methanol) to yield to 450 mg (74%) of the title compound.
1H-N MR (400 MHz, DMSO-d6) 6 [ppm]: -0.12- -0.07 (m, 9H); 0.80-0.86 (m, 2H);
3.50-3.56 (m, 2H); 5.61 (d, 1H); 6.48 (d, 1H);7.50-7.55 (m, 2H); 7.68 (dd, 1H); 7.86 (s, 1H); 8.05 (dd, 1H);
8.19 (d, 1H); 8.92 (dd, 1H); 9.99 (bs, 1H); 10.12 (bs, 1H).
Intermediate 59 1-{4-[(3-ch loro-1-{[2-(tri methyls ilyl)ethoxy]methy1}-1 H-pyrro lo[2,3-b]pyri di n -4-yl)oxy]-3,5-difluorophenyl}urea N---..\<
F = 0 Cl..._.) / \ /
N
N
LO
Si H C' 1 'C H3 To solution of phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (100 mg, 0.18 mmol, intermediate 44) in DMF (2.0 mL) was added an ammonium hydroxyd solution (25% in water, 0.03 mL) and this mixture was stirred at 60 C for 2 hours. The mixture was diluted with water and extracted two times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated to dryness. The resulting residue was purified via a Biotage chromatography system (KP-Sil snap column; dichloromethane / methanol gradient with up to 10%
methanol) to obtain crude 194 mg of the desired title compound that was used without further purification in the next step.
1H-N MR (400 MHz, CDCI3) 6 [ppm]: -0.09 --0.02 (s, 9H); 0.88-0.94 (m, 2H);
4.52-3.58 (m, 2H);
5.09 (bs, 2H); 5.63 (s, 2H); 6.31 (d, 1H); 7.16-7.26 (m, 3H); 7.96 (s, 1H);
8.12 (d, 1H);
Intermediate 60 Phenyl {4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}carbamate H
F NO
0 8 .
F
/ I
NN
H
4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluoroaniline (4.00 g, 13.5 mmol, synthesis see ChemMedChem 3, (2008), p. 1893 if., cpd 63) was dissolved in ethyl acetate (160 mL) and saturated aqueous sodium bicarbonate solution (80 mL) was added. Under vigorous stirring phenyl carbonochloridate (2.0 mL, 17 mmol) was added dropwise. The mixture was stirred for 6 h at room temperature. The organic layer was separated, extracted with brine and dried over sodium sulfate. The solvent was evaporated and purified by column chromatography on silica gel (eluent ethyl acetate: petroleum ether = 2:1) to yield 2.60 g (42%) of the title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 12.15 (s, 1H), 10.79 (s, 1H), 8.12 (d, 1H), 7.63 (d, 1H), 7.50-7.42 (m, 4H), 7.33-7.24 (m, 3H), 6.36 (d, 1H) Intermediate 61 4-[(3-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-13]pyridin-4-y1)oxy]-3,5-difluoroaniline Br 0 F
/ I

H3C 0) Si rsi_i µ..., 1 13 To a solution of N-(4-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yloxy)-3,5-difluorophenyl)acetamide (6.5 g, 12.7 mmol, synthesis see ChemMedChem 3, (2008), p. 1893 if., cpd 53b) in 150 mL of ethanol and 15 mL of water. Then sodium hydroxide (2.5 g, 63.4 mmol) was added. The mixture was stirred for overnight at 60 C.
Then down to room temperature and the mixture was evaporated, and the residue was purified by column chromatography with petroleum ether/ ethyl acetate (2:3/v:v) to yield 4.8 g (80 %) of the product.
1H-NMR (300 MHz, DMSO-d6): 6 [ppm] 0.01-0.08 (s, 9H), 0.80-0.86 (t, 2H), 3.50-3.56 (t, 2H), 5.60 (s, 2H), 5.83 (s, 2H), 6.38-6.42 (m, 3H), 7.84 (s, 1H), 8.15-8.18 (d, 1H).
Intermediate 62 3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine 7-oxide F F
F
/ I
N'N-F-H I

To a solution of 3-chlorobenzenecarboperoxoic acid (46.5 g, 269 mmol) in 660 mL
dichlomethane was added portionwise at 4 C 3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine (25.1 g, 135 mmol). Stirring was continued at 0-4 C for 1h and at 25 C for 2 hours. The precipitate was collected by suction, washed with dichloro methane, and dried in airstream.
filtration. The solid was then suspended in 300 mL acetone and stirred for 3 hours. The solid was the collected by filtration to obtain 13.1 g (99% purity, 48% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 7.25 (dd, 1H), 7.67 (d, 1H), 8.16 (s, 1H), 8.31 (d, 1H), 13.43 (br s, 1H).

Intermediate 63 4-chloro-3-(trifluoromethyl)-1H-pyrrolo[2,3-1Apyridine F F
F ¨......__CI
/ I
N ---- N /
H
To a suspension of 3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine 7-oxide (13.1 g, 65.0 mmol, intermediate 62) in 66 mL DMF was added at ambient temperature methanesulfonyl chloride (13 mL, 170 mmol). After stirring for 1 hour the mixture was warmed to 75 C
for 2 hours. After cooling to 0 C 15 mL water was added dropwise and then aqueous sodium hydroxide (w=30%) waas added until pH=11. After stirring for additional 20 minutes at 0 C the solid was collected by suction and the solid was dried using an airstream to obtain 11.3 g (94 % purity, 1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 7.40 (d, 1H), 8.29 (s, 1H), 8.34 (d, 1H), 12.89 (br s, 1H).
Intermediate 64 4-chloro-3-(trifluoromethyl)-1H-pyrrolo[2,3-1Apyridine 7-oxide F F
F ¨......__CI
/ I
N ---- N -H I

To a solution of 3-chlorobenzenecarboperoxoic acid (12.0 g, 69.6 mmol) in 98 mL
dichlomethane was added portionwise at 0 C 4-chloro-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine (11.8 g, 53.5 mmol, intermediate 63). Stirring was continued at 0 C
for lh and at 25 C for 2 hours. The precipitate was collected by filtration. The solid was then suspended in 40 mL acetone and stirred for 3 hours. The solid was the collected by filtration to obtain 8.54 g (99% purity, 67% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 7.38 (d, 1H), 8.24 (s, 1H), 8.30 (d, 1H).

Intermediate 65 4,6-dichloro-3-(trifluoromethyl)-1H-pyrrolo[2,3-1Apyridine F F
F.¨

/ I
NNCI
H
To a suspension of 4-chloro-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine 7-oxide (8.54 g, 36.1 mmol, intermediate 64) 200 mL THF was added at 0 C 1,1,1-trimethyl-N-(trimethylsilyl)silanamine (7.5 mL, 36 mmol) followed by dropwise addition of trichloroacetyl chloride (14 mL, 130 mmol). The mixture was stirred for 15 minutes at 0 C and then for 2 hours at 25 C. The reaction was poured into 150 mL ice water and then was sodium bicarbonate added until pH=8. This mixture was extracted threetimes with 100 mL ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and after filtration evaporated to dryness.The residue was solved in a minimum of methanol and precipitated by the addition of water. The mixture was cooled at 0 C for 1 hour. The precipitate was collected by filtration, solved again in ethyl acetate, dried over sodium sulfate and after filtration evaporated to dryness to obtain 7.65 g (83 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 7.58 (s, 1H), 8.33 (s, 1H), 13.10 (br s, 1H).
Intermediate 66 4,6-dichloro-3-(trifluoromethyl)-1-{[2-(trimethylsily1)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine F F
F_( Cl H3C, FH3 / I
H3 C¨Si NNCI
\----\ /
0'1 To a mixture of 4,6-dichloro-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine (7.65 g, 30.0 mmol, intermediate 65) and [2-(chloromethoxy)ethyl](trimethyl)silane (5.8 mL, 33 mmol) in 77 mL
DMF was added portionwise sodium hydride (3.60 g, 60 % purity, 90.0 mmol) at 0 C. After stirring for 3.5 hours this mixture was poured carefully into 100 mL ice water. This was then extracted threetimes with 50 mL ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and after filtration evaporated to dryness.
The residue was purified using a Biotage chromatography system to obtain 175 mg (30 % purity, 88 % yield) of the desired title compound.
1H-N MR (400 MHz, DMSO-d6) 6 [ppm]: -0.12 - -0.08 (m, 9H), 0.79 - 0.87 (m, 2H), 3.51 - 3.60 (m, 2H), 5.64 (s, 2H), 7.70 (s, 1H), 8.58 (s, 1H).

Intermediate 67 44[6-chloro-3-(trifluoromethyl)-1-{[2-(trimethylsily1)ethoxy]methyl}-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}-2,3-difluoroaniline F

F F
FA i l'W
H3C, PH3 H C¨Si NNCI
3 \----\ /
0 ---.
A mixture of 4,6-dichloro-3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridine (500 mg, 1.30 mmol, intermediate 66), commercially available 4-amino-2,3-difluorophenol (207 mg, 1.43 mmol) and potasium carbonate (538 mg, 3.89 mmol) in 5.0 mL
DMSO was stirred at 120 C for 3h. After cooling to room temperature this mixture was diluted with 200 mL ethyl acetate. The resulting organic phase was then extracted twotimes with 30 mL of water, 20 mL brime, dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified using a Biotage chromatography system to obtain 170 mg (93 % purity, 25% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 - -0.07 (m, 9H), 0.81 - 0.88 (m, 2H), 3.54 - 3.61 (m, 2H), 5.62 (s, 2H), 5.65 (s, 2H), 6.51 (s, 1H), 6.65 (td, 1H), 6.99 (td, 1H), 8.38 (s, 1H).
Intermediate 68 2,3-difluoro-44[3-(trifluoromethyl)-1-{[2-(trimethylsily1)ethoxy]methyl}-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}aniline F

F F
FA i l'W
H3C, PH3 H C¨SI N-----N%
3 \----\ /
0 ---.
A suspension of 4-{[6-chloro-3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}-2,3-difluoroaniline (166 mg, 336 pmol, intermediate 67), triethylamine (56 pL, 400 pmol) and Palladium on carbon! (16.6 mg, 10 %
purity, 15.6 pmol) in 11 mL ethanol was stirred for 7 hours in an hydrogen atmosphere under normal pressure. The reaction mixture was filtered over Celite, the filter cake washed with ethyl acetate and the combine organic layers were evaporated to dryness. The residue was purified using a Biotage chromatography system to obtain 142 mg (93% purity, 92% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.12 - -0.07 (m, 9H), 0.79 - 0.88 (m, 2H), 3.54 - 3.60 (m, 2H), 5.59 (s, 2H), 5.67 (s, 2H), 6.51 (dd, 1H), 6.65 (td, 1H), 6.95 (td, 1H), 8.25 (d, 1H), 8.32 (s, 1H).
Intermediate 69 phenyl (2,3-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsily1)ethoxy]methyl}-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}phenyl)carbamate F
H
F NO
F F . 8 0 F-.. ot H3c, pH3 H C¨Si N--"N%
3 \----\ /

In analogy to intermediate 1), using 2,3-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylaniline (137 mg, 298 pmol, intermediate 68) and phenyl carbonochloridate (41 pL, 330 pmol) in pyridine (140 pL), we obtained after one single purification using a Biotage chromatography system 146 mg (96 %
purity, 81 % yield) of the desired title compound.
1H-N MR (400 MHz, DMSO-d6) 6 [ppm]: -0.12 - -0.07 (m, 9H), 0.80 - 0.88 (m, 2H), 3.54 - 3.62 (m, 2H), 5.69 (s, 2H), 6.67 (d, 1H), 6.72 - 6.78 (m, 1H), 7.11 -7.19 (m, 1H), 7.22 - 7.31 (m, 2H), 7.40 - 7.48 (m, 1H), 7.62 (br t, 1H), 8.29 - 8.35 (m, 1H), 8.38 (s, 1H), 9.32 (s, 1H), 10.34 (br s, 1H).
Intermediate 70 1-(2,3-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsily1)ethoxy]methyl}-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}pheny1)-343-(morpholin-4-y1)propyl]urea F (0 H H
F F . 0 F¨........s.01 H3C, P-I3 / I
H3C¨Si NN%
0---j In analogy to intermediate 2), using phenyl (2,3-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (70.0 mg, 121 pmol, intermediate 69) and 3-(morpholin-4-yl)propan-1-amine (18 pL, 120 pmol) in DMF (600 pL), we obtained after one single purification using a Biotage chromatography system 73.1 mg (93% purity, 89% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 - -0.06 (m, 9H), 0.80 - 0.87 (m, 2H), 1.60 (quin, 2H), 2.27 - 2.38 (m, 6H), 3.14 (q, 2H), 3.53 - 3.61 (m, 6H), 5.68 (s, 2H), 6.59 (d, 1H), 6.66 (t, 1H), 7.12 - 7.18 (m, 1H), 8.02 (br t, 1H), 8.28 (d, 1H), 8.36 (s, 1H), 8.56 (s, 1H).
Intermediate 71 1-(2,3-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsily1)ethoxy]methyl}-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}pheny1)-342-(morpholin-4-y1)ethyl]urea F
H H
F iiii NyN...........õ..-.....N.õ...-õ,1 -.. F ot w H3c,FH3 e-H 3 C-SI N-----N%

In analogy to intermediate 2), using phenyl (2,3-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (70.0 mg, 121 pmol, intermediate 69) and 2-(morpholin-4-yl)ethanamine (16 pL, 120 pmol) in DMF (600 pL), we obtained after one single purification using a Biotage chromatography system 65.7 mg (93 % purity, 82% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 - -0.07 (m, 9H), 0.79 - 0.88 (m, 2H), 2.36 - 2.43 .. (m, 6H), 3.24 (q, 2H), 3.55 - 3.64 (m, 6H), 5.68(s, 2H), 6.59(d, 1H), 6.69(t, 1H), 7.13 - 7.20 (m, 1H), 8.04 (t, 1H), 8.28 (d, 1H), 8.36 (s, 1H), 8.76 (s, 1H).

Intermediate 72 1-(3,5-difluoro-44[3-(trifluoromethyl)-1-{[2-(trimethylsily1)ethoxy]methyl}-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}pheny1)-3-[2-(dimethylamino)ethyl]thiourea N N7-N' F* b H 3 F
F.TI
F F
/ I
N----N/

To solution of 3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylaniline (100 mg, 218 pmol, see Synthesis 2007, page 251-258, Org. Process Res. Dev. 2010, page 168-173) in pyridine (1.5 mL) and dichloromethana (1.5 mL) was added 2-isothiocyanato-N,N-dimethylethanamine (31.2 mg, 239 pmol).
After stirring this mixture 2 hours at 75 C and at 60 C over night an additional amount of 2-isothiocyanato-N,N-dimethylethanamine (31.2 mg, 239 pmol) was added. After heating this mixture for 2 hours at 75 C and at 60 C over three days. After cooling ethyl acetate and water was added to the reaction mixture and stirred. After separation of the organic pahe the aqueous phase was extracted two times with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The resulting residue was purified via a Biotage chromatography system (11g snap KP-NH column, hexane /0 ¨ 100%
ethylacetate, then ethyl acetate / 0 ¨ 100% methanol) to obtain 70.0 mg (95 %
purity, 52 %
yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 - -0.08 (m, 9H), 0.80 - 0.86 (m, 2H), 2.20 (s, 6H), 2.45 (t, 2H), 3.52 - 3.62 (m, 4H), 5.69 (s, 2H), 6.60 (d, 1H), 7.58 - 7.66 (m, 2H), 8.02 (br s, 1H), 8.31 (d, 1H), 8.38 (s, 1H), 10.11 (br s, 1H).

Intermediate 73 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsily1)ethoxy]methyl}-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}pheny1)-342-(morpholin-4-y1)ethyl]thiourea H H
N, N7-N"Th F * 1 0 F
F
F F
/ I
N----N/
(0 H c..-Si¨C H 3 3 sC H3 In analogy to intermediate 72), using 3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylaniline (100 mg, 218 pmol, see Synthesis 2007, page 251-258, Org. Process Res. Dev. 2010, page 168-173) and 4-(2-isothiocyanatoethyl)morpholine (twice 41.2 mg, 239 pmol) in pyridine (1.5 mL) and dichloromethane (1.5 mL) we obtained 80.9 mg (95 % purity, 56 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.12 - -0.07 (m, 9H), 0.79 - 0.86 (m, 2H), 2.39 -2.46 (m, 4H), 2.51 - 2.54 (m, 2H), 3.54 - 3.65 (m, 8H), 5.69 (s, 2H), 6.61 (d, 1H), 7.52 - 7.60 (m, 2H), 8.09 (br s, 1H), 8.31 (d, 1H), 8.38 (s, 1H), 10.07 (s, 1H).
Intermediate 74 1-(3,5-difluoro-44[3-(trifluoromethyl)-1-{[2-(trimethylsily1)ethoxy]methyl}-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}pheny1)-3-(2-methoxyethyl)thiourea N, N(D-F * 1 F
F
F F
/ I
N----N/
(0 H c..-Si¨C H3 3 sC H3 In analogy to intermediate 72), using 3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylaniline (100 mg, 218 pmol, see Synthesis 2007, page 251-258, Org. Process Res. Dev. 2010, page 168-173) and only one portion of 2-isothiocyanatoethyl methyl ether (31.9 mg, 272 pmol) in pyridine (1.5 mL) and dichloromethane (1.5 mL) and 2 hours at 75 C and 60 C for three days reaction time we obtained 45.0 mg (92 % purity, 33 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.12 - -0.08 (m, 9H), 0.80 - 0.86 (m, 2H), 3.30 (s, 3H), 3.51 (t, 2H), 3.55 - 3.61 (m, 2H), 3.67 (br s, 2H), 5.69 (s, 2H), 6.60 (d, 1H), 7.55 - 7.64 (m, 2H), 8.19 (br s, 1H), 8.31 (d, 1H), 8.38 (s, 1H), 10.02 (br s, 1H).
Intermediate 75 1-(3,5-difluoro-44[3-(trifluoromethyl)-1-{[2-(trimethylsily1)ethoxy]methyl}-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}pheny1)-3-ethylthiourea H H
CH
F* \As F
F
F F
/ I
NI---N/
(o In analogy to intermediate 72), using 3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylaniline (100 mg, 218 pmol, see Synthesis 2007, page 251-258, Org. Process Res. Dev. 2010, page 168-173) and isothiocyanatoethane (twice 20.9 mg, 239 pmol) in pyridine (1.5 mL) and dichloromethane (1.5 mL) we obtained 58.0 mg (98 % purity, 48 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 --0.07 (m, 9H), 0.79 - 0.87 (m, 2H), 1.14 (t, 3H), 3.47 - 3.60 (m, 4H), 5.69 (s, 2H), 6.60 (d, 1H), 7.49 - 7.58 (m, 2H), 8.15 (br s, 1H), 8.31 (d, 1H), 8.38 (s, 1H), 9.88 (br s, 1H).

Intermediate 76 1-(3,5-difluoro-44[3-(trifluoromethyl)-1-{[2-(trimethylsily1)ethoxy]methyl}-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}pheny1)-343-(morpholin-4-y1)propyl]thiourea H H
F Ito ws (o H3C-Sis-C H3 In analogy to intermediate 72), using 3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylaniline (100 mg, 218 pmol, see Synthesis 2007, page 251-258, Org. Process Res. Dev. 2010, page 168-173) and 4-(3-isothiocyanatopropyl)morpholine (twice 44.6 mg, 239 pmol) in pyridine (1.5 mL) and dichloromethane (1.5 mL) and an additional stirring at 100 C for 5 hours and overnight at 60 C
we obtained 71.0 mg (92% purity, 46% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 - -0.08 (m, 9H), 0.80 - 0.86 (m, 2H), 1.73 (quin, 2H), 2.28 - 2.39 (m, 6H), 3.49 - 3.60 (m, 8H), 5.69 (s, 2H), 6.60 (d, 1H), 7.53 (m, 2H), 8.16 (br s, 1H), 8.31 (d, 1H), 8.38 (s, 1H), 9.90 (br s, 1H).
Intermediate 77 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(oxetan-3-ylmethypurea H
*F

, I
N 1\1µ
0) H3C¨,Sisc H3 In analogy to intermediate 2, using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) and 1-(oxetan-3-yl)methanamine (22.5 mg, 259 pmol) in DMF
(1.5 mL), we obtained after one single purification using a Biotage chromatography system 151 mg (94% purity, 96% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 - -0.08 (m, 9H), 0.80 - 0.86 (m, 2H), 3.09 (spt, 1H), 3.34 - 3.40 (m, 2H), 3.54 - 3.60 (m, 2H), 4.31 (t, 2H), 4.62 (dd, 2H), 5.68 (s, 2H), 6.57 (d, 1H), 6.67 (t, 1H), 7.36 - 7.42 (m, 2H), 8.28 (d, 1H), 8.36 (s, 1H), 9.08 (s, 1H).
Intermediate 78 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyOurea FF
F 110, F
H3C.-81-C H3 To a solution of phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) in DMF
(1.5 mL) was added ammonia in methanol (37 pL, 7.0 M, 260 pmol) and this mixture was stirred at 60 C for 1 hour. After cooling to room temperature ethyl acetate and water was added. After separation of the organic phase the aqueous phase was extracted two times with ethyl acetate. The combined organic phases were washed with brine, dried over sodium .. sulfate, filtered and concentrated to dryness. The resulting residue was purified via a Biotage chromatography system (11g snap KP-NH column, hexane /0 ¨ 100% ethyl acetate, then ethyl acetate / 0 ¨ 100% methanol) to obtain 114 mg (94 % purity, 82 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 --0.05 (m, 9H), 0.79 - 0.87 (m, 2H), 3.54 - 3.60 (m, 2H), 5.68 (s, 2H), 6.15 (s, 2H), 6.58 (d, 1H), 7.36 - 7.42 (m, 2H), 8.28 (d, 1H), 8.36 (s, 1H), 9.07 (s, 1H).

Intermediate 79 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-methylurea I-I.,C
H ' ' N NH
F = ----(0 F
N---"N
(o H3C-Sis-C H3 In analogy to intermediate 78, using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) and methanamine in THF (130 pL, 2.0 M, 260 pmol) together in DMF (1.5 mL), we obtained after one single purification using a Biotage chromatography system 127 mg (93% purity, 88% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 --0.05 (m, 9H), 0.80 - 0.86 (m, 2H), 2.65 (d, 3H), 3.55 - 3.60 (m, 2H), 5.68 (s, 2H), 6.33 (q, 1H), 6.57 (d, 1H), 7.35 - 7.43 (m, 2H), 8.28 (d, 1H), 8.36 (d, 1H), 9.11 (s, 1H).
Intermediate 80 3-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-1,1-dimethylurea H i N,N"--C H3 F * Al FF.,(F ? F
e---N----N/
(o H 3C_ Si H 3 In analogy to intermediate 78, using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) and N-methylmethanamine in THF (130 pL, 2.0 M, 260 pmol) in DMF (1.5 mL), we obtained after one single purification using a Biotage chromatography system 176 mg (89% purity, 114% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 - -0.05 (m, 9H), 0.80 - 0.86 (m, 2H), 2.95 (s, 6H), 3.55 - 3.60 (m, 2H), 5.68 (s, 2H), 6.57 (d, 1H), 7.51 -7.57 (m, 2H), 8.29 (d, 1H), 8.36 (d, 1H), 8.78 (s, 1H).
Intermediate 81 N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)morpholine-4-carboxamide F F
11\j FO
F F
/ I
N----N/
( H3C-8L¨C H3 In analogy to intermediate 2, using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) and morpholine (23 pL, 260 pmol) together in DMF
(1.5 mL), we obtained after one single purification using a Biotage chromatography system 171 mg (92 %
purity, 107% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 --0.05 (m, 9H), 0.80 - 0.86 (m, 2H), 3.43 - 3.49 (m, 4H), 3.54 - 3.60 (m, 2H), 3.60 - 3.65 (m, 4H), 5.68 (s, 2H), 6.57 (d, 1H), 7.48 - 7.54 (m, 2H), 8.29 (d, 1H), 8.37 (s, 1H), 9.02 (s, 1H).

Intermediate 82 N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-4-methylpiperazine-1-carboxamide ,C H3 N) F *
F F
I
(o H3C-St-CH3 In analogy to intermediate 2, phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) and 1-methylpiperazine (29 pL, 260 pmol) together in DMF (1.5 mL), we obtained after one single purification using a Biotage chromatography system 248 mg (92% purity, 150 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 --0.05 (m, 9H), 0.80 - 0.86 (m, 2H), 2.20 (s, 3H), 2.33 (t, 4H), 3.42 - 3.50 (m, 4H), 3.55 - 3.60 (m, 2H), 5.68 (s, 2H), 6.57 (d, 1H), 7.47 - 7.54 (m, 2H), 8.29 (d, 1H), 8.36 (s, 1H), 8.99 (s, 1H).
Intermediate 83 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-342-(4-methylpiperazin-1-y1)-2-oxoethyl]urea H H
N N
F F 1.10 Nn NC H3 I
( Fi3d C H3 In analogy to intermediate 2, phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) and 2-amino-1-(4-methylpiperazin-1-yl)ethanone (40.7 mg, 259 pmol) together in DMF (1.5 mL), we obtained after one single purification using a Biotage chromatography system 83.5 mg (93 % purity, 47 % yield) of the desired title compound.
1H-N MR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 --0.05 (m, 9H), 0.80 - 0.86 (m, 2H), 2.19 (s, 3H), 2.27 (br t, 2H), 2.29 - 2.34 (m, 2H), 3.37 - 3.43 (m, 2H), 3.43 - 3.50 (m, 2H), 3.54 - 3.60 (m, 2H), 3.99 (d, 2H), 5.68 (s, 2H), 6.55 - 6.61 (m, 2H), 7.34 - 7.40 (m, 2H), 8.28 (d, 1H), 8.36 (s, 1H), 9.50 (s, 1H).
Intermediate 84 N-(3 ,5-d ifl uoro-4-{[3-(trifl uoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1 H-pyrrolo[2,3-b]pyrid in-4-yl]oxylphenyI)-2-oxa-6-azaspi ro[3 .3]heptane-6-carboxamide _ FT
H
F F * N'roNIT¨

FF. 7 F
N----N/
(o H3C---SI,-C H3 To a solution of phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) in DMF
(1.3 mL) was added 2-oxa-6-azaspiro[3.3]heptane ethanedioate (2:1) (74.6 mg, 259 pmol) and N,N-diisopropylethylamine (45 pL, 260 pmol) and this mixture was stirred at 50 C for 12 hours.
After cooling to room temperature ethyl acetate and water was added. After separation of the organic phase the aqueous phase was extracted two times with ethyl acetate.
The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The resulting residue was purified via a Biotage chromatography system (10g snap KP-Sil column, hexane /0 ¨ 100% ethyl acetate, then ethyl acetate /0 ¨ 100%
methanol) to obtain 71.0 mg (93 % purity, 44 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 --0.05 (m, 9H), 0.79 - 0.86 (m, 2H), 3.54 - 3.60 (m, 2H), 4.15 (s, 4H), 4.69 (s, 4H), 5.68 (s, 2H), 6.57 (d, 1H), 7.48 - 7.54 (m, 2H), 8.28 (d, 1H), 8.36 (s, 1H), 8.97 (s, 1H).

Intermediate 85 N2-[(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamoy1]-N-methylglycinamide H N' H
F F
I\10 *
FO
F F
/ I
N---"N
(0 H3c-81¨C H3 To a solution of phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) in DMF
(1.3 mL) was added N-methylglycinamide hydrochloride (1:1) (32.2 mg, 259 pmol) and N,N-diisopropylethylamine (45 pL, 260 pmol) and this mixture was stirred at 50 C
for 12 hours.
After cooling to room temperature ethyl acetate and water was added. After separation of the organic phase the aqueous phase was extracted two times with ethyl acetate.
The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The resulting residue was purified via a Biotage chromatography system (10g snap KP-Sil column, hexane / 0 ¨ 100% ethyl acetate, then ethyl acetate / 0 ¨ 100%
methanol) to obtain 146 mg (95% purity, 93% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.10 --0.05 (m, 9H), 0.80 -0.86 (m, 2H), 2.61 (d, 3H), 3.55 - 3.60 (m, 2H), 3.71 (d, 2H), 5.68 (s, 2H), 6.56 - 6.61 (m, 2H), 7.34 -7.41 (m, 2H), 7.91 (q, 1H), 8.29 (d, 1H), 8.36 (s, 1H), 9.34 (s, 1H).

Intermediate 86 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(1,2-thiazol-4-yOurea FF0F *
0 ¨N
F F
I
(0 H3c--St¨C H3 To a solution of phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) in DMF
(1.3 mL) was added 1,2-thiazol-4-amine hydrochloride (1:1) (35.4 mg, 259 pmol) and N,N-diisopropylethylamine (45 pL, 260 pmol) and this mixture was stirred at 50 C
for 12 hours.
Then additional 1,2-thiazol-4-amine hydrochloride (1:1) (35.4 mg, 259 pmol) and N,N-diisopropylethylamine (45 pL, 260 pmol) was added and stirred at 50 C for 12 hours. After cooling to room temperature ethyl acetate and water was added. After separation of the organic phase the aqueous phase was extracted two times with ethyl acetate.
The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The resulting residue was purified via a Biotage chromatography system (10g snap KP-Sil column, hexane /0 ¨ 100% ethyl acetate, then ethyl acetate /0 ¨ 100%
methanol) to obtain 155 mg (75% purity, 77% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.10 - -0.05 (m, 9H), 0.80 - 0.87 (m, 2H), 3.54 - 3.61 (m, 2H), 5.69 (s, 2H), 6.61 (d, 1H), 7.45- 7.52 (m, 2H), 8.27 - 8.33 (m, 1H), 8.36 - 8.40 (m, 1H), 8.60 (s, 1H), 8.73 (s, 1H), 9.46 (br s, 1H), 9.57 (br s, 1H).

Intermediate 87 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(1-methyl-1H-pyrazol-4-yOurea H
F

F F
I

H3C---St-C H3 In analogy to intermediate 2, using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) and 1-methyl-1H-pyrazol-4-amine (25.1 mg, 259 pmol) in DMF
(1.3 mL), we obtained after one single purification using a Biotage chromatography system (10g snap KP-Sil column, hexane / 0 - 100% ethyl acetate, then ethyl acetate /
0 - 100%
methanol) 158 mg (85% purity, 89% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 --0.05 (m, 9H), 0.80 - 0.86 (m, 2H), 3.54- 3.61 (m, 2H), 3.79 (s, 3H), 5.69 (s, 2H), 6.60 (d, 1H), 7.39 (d, 1H), 7.41 - 7.48 (m, 2H), 7.77 (s, 1H), 8.29 (d, 1H), 8.37 (s, 1H), 8.66 (s, 1H), 9.14 (s, 1H).
.. Intermediate 88 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(6-methylpyridin-3-yOurea H H
F * C H 3 (0 In analogy to intermediate 2, using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) and 6-methylpyridin-3-amine (28.0 mg, 259 pmol) together in DMF
(1.3 mL), we obtained after one single purification using a Biotage chromatography system 146 mg (98% purity, 93% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.13 - -0.05 (m, 9H), 0.79 - 0.87 (m, 2H), 2.41 (s, 3H), 3.55 - 3.61 (m, 2H), 5.69 (s, 2H), 6.61 (d, 1H), 7.19 (d, 1H), 7.43 - 7.50 (m, 2H), 7.82 (dd, 1H), 8.30 (d, 1H), 8.37 (s, 1H), 8.50 (d, 1H), 9.00 (s, 1H), 9.30 (s, 1H).
Intermediate 89 1-[(1-acetylazetidin-3-yl)methyl]-3-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyOurea N, N
F I. Al F
FO
F F
/ I
N---N/
(0 H 3C¨S1¨C H3 In analogy to intermediate 85, using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1), 1-[3-(aminomethyl)azetidin-1-yl]ethanone hydrochloride (1:1) (42.6 mg, 259 pmol) and N,N-diisopropylethylamine (45 pL, 260 pmol) together in DMF
(1.3 mL), we obtained after one single purification using a Biotage chromatography system 118 mg (100% purity, 74% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.15 - -0.06 (m, 9H), 0.79 - 0.87 (m, 2H), 1.73 (s, 3H), 2.68 - 2.72 (m, 1H), 3.26 - 3.32 (m, 2H), 3.52 - 3.61 (m, 3H), 3.76 - 3.87 (m, 2H), 4.13 (t, 1H), 5.68 (s, 2H), 6.58 (d, 1H), 6.73 (br s, 1H), 7.40 (d, 2H), 8.28 (d, 1H), 8.36 (s, 1H), 9.15 (br s, 1H).

Intermediate 90 N2-[(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamoy1]-N-(2-methoxyethyl)glycinamide H NS
NO
F
F F
I
(0 In analogy to intermediate 85, phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1), N-(2-methoxyethyl)glycinamide hydrochloride (1:1) (43.6 mg, 259 pmol) and N,N-diisopropylethylamine (45 pL, 260 pmol) together in DMF (1.3 mL), we obtained after one single purification using a Biotage chromatography system 160 mg (100 %
purity, 100% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.12 - -0.07 (m, 9H), 0.80 - 0.86 (m, 2H), 3.23 - 3.28 (m, 5H), 3.34 - 3.37 (m, 2H), 3.54 - 3.60 (m, 2H), 3.74 (d, 2H), 5.68 (s, 2H), 6.55 - 6.61 (m, 2H), 7.34 - 7.41 (m, 2H), 8.06 (t, 1H), 8.28 (d, 1H), 8.36 (s, 1H), 9.35 (s, 1H).

Intermediate 91 (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(1,1-dioxidothietan-2-y1)methyl]urea 0-Ssi H H
F
FF. F

In analogy to intermediate 85, phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1), (+/-)-141,1-dioxidothietan-2-yl]methanamine hydrochloride (1:1) (44.4 mg, 259 pmol) and N,N-diisopropylethylamine (45 pL, 260 pmol) together in DMF
(1.3 mL), we obtained after one single purification using a Biotage chromatography system 148 mg (100% purity, 92% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.15 --0.06 (m, 9H), 0.79 -0.87 (m, 2H), 1.72 - 1.82 (m, 1H), 2.19 - 2.31 (m, 1H), 3.52 - 3.60 (m, 4H), 3.96 - 4.13 (m, 2H), 4.56 (quin, 1H), 5.68 (s, 2H), 6.58 (d, 1H), 6.71 (t, 1H), 7.39 (d, 2H), 8.28 (d, 1H), 8.36 (s, 1H), 9.23 (s, 1H).
Intermediate 92 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(2-methylpyrimidin-5-yOurea F , NN-H 3O _O 3 In analogy to intermediate 2, using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) and 2-methylpyrimidin-5-amine (28.2 mg, 259 pmol) together in DMF (1.3 mL), we obtained after one single purification using a Biotage chromatography system (10g snap KP-Sil column, hexane /0 ¨ 100% ethyl acetate, then ethyl acetate /0 ¨
100% methanol) 103 mg (97 % purity, 65 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.16 - -0.06 (m, 9H), 0.80 - 0.86 (m, 2H), 2.57 (s, 3H), 3.55 - 3.61 (m, 2H), 5.69 (s, 2H), 6.61 (d, 1H), 7.45 - 7.52 (m, 2H), 8.30 (d, 1H), 8.38 (s, 1H), 8.80 (s, 2H), 9.18 (br s, 1H), 9.52 (br s, 1H).
Intermediate 93 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(1H-pyrazol-4-y1)urea H H
N.(NCI\IFI
F *
0 ¨N
F

F F
/ I
N---N/
(0 H3C¨SL¨CH3 In analogy to intermediate 2, using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) and 1H-pyrazol-4-amine (21.5 mg, 259 pmol) together in DMF
(1.3 mL), we obtained after one single purification using a Biotage chromatography system 150 mg (92% purity, 94% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.10 - -0.05 (m, 9H), 0.80 - 0.86 (m, 2H), 3.55 - 3.60 (m, 2H), 5.69 (s, 2H), 6.60 (d, 1H), 7.42 - 7.51 (m, 3H), 7.76 (s, 1H), 8.29 (d, 1H), 8.37 (s, 1H), 8.65 (s, 1H), 9.15 (s, 1H), 12.56 (br s, 1H).

Intermediate 94 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-342-(1-oxa-6-azaspiro[3.3]hept-6-y1)ethyl]urea H H
N N
y F F
/
N
H3C-,S1 H3c CH3 In analogy to intermediate 85, phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1), 2-(1-oxa-6-azaspiro[3.3]hept-6-yl)ethanamine trifluoroacetate (1:1) (66.3 mg, 259 pmol) and N,N-diisopropylethylamine (45 pL, 260 pmol) together in DMF
(1.3 mL), we obtained after one single purification using a Biotage chromatography system (10g snap KP-Sil column, hexane / 0 ¨ 100% ethyl acetate, then ethyl acetate /
0 ¨ 100%
methanol) 119 mg (85 % purity, 62 % yield) of the desired title compound.
1H-N MR (400 MHz, DMSO-d6) 6 [ppm]: -0.12 - -0.05 (m, 9H), 0.79 - 0.86 (m, 2H), 2.44 (t, 2H), 2.73 - 2.77 (m, 2H), 3.02 - 3.09 (m, 4H), 3.50 - 3.60 (m, 4H), 4.37 (t, 2H), 5.68 (s, 2H), 6.31 (t, 1H), 6.57 (d, 1H), 7.35 (d, 2H), 8.28 (d, 1H), 8.36 (s, 1H), 9.15 (s, 1H).
Intermediate 95 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-342-(1,1-dioxido-1-thia-6-azaspiro[3.3]hept-6-y1)ethyl]urea =H H
NyN1\1\9 F F

/
( In analogy to intermediate 85, phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1), 2-(1,1-dioxido-1-thia-6-azaspiro[3.3]hept-6-yl)ethanamine trifluoroacetate (1:1) (78.7 mg, 259 pmol) and N,N-diisopropylethylamine (45 pL, 260 pmol) together in DMF (1.3 mL), we obtained after one single purification using a Biotage chromatography system (10g snap KP-Sil column, hexane / 0 ¨ 100% ethyl acetate, then ethyl acetate /0 ¨ 100% methanol) 174 mg (85% purity, 85% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.17 - -0.06 (m, 9H), 0.80 - 0.86 (m, 2H), 2.19 - 2.26 (m, 2H), 3.04 - 3.11 (m, 2H), 3.23 - 3.28 (m, 2H), 3.54 - 3.60 (m, 2H), 3.78 -3.83 (m, 2H), 3.98 -4.04 (m, 2H), 5.68 (s, 2H), 6.34 (t, 1H), 6.57 (d, 1H), 7.33 - 7.41 (m, 2H), 8.28 (d, 1H), 8.36 (s, 1H), 9.17 (s, 1H).
Intermediate 96 (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(2-oxopyrrolidin-3-yOurea H ,H
F N NUN H
F F
I

In analogy to intermediate 2, using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) and (+/-)-3-aminopyrrolidin-2-one (25.9 mg, 259 pmol) together in DMF (1.3 mL), we obtained after one single purification using a Biotage chromatography system (10g snap KP-Sil column, hexane /0 ¨ 100% ethyl acetate, then ethyl acetate /0 ¨
100% methanol) 168 mg (85% purity, 94% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.15 --0.06 (m, 9H), 0.80 - 0.86 (m, 2H), 1.80- 1.91 (m, 1H), 2.38 -2.46 (m, 1H), 3.17 -3.23 (m, 2H), 3.54 -3.61 (m, 2H), 4.14 -4.22 (m, 1H), 5.68 (s, 2H), 6.58 (d, 1H), 6.68 (d, 1H), 7.35 - 7.42 (m, 2H), 7.91 (s, 1H), 8.29 (d, 1H), 8.36 (s, 1H), 9.22(s, 1H).

Intermediate 97 (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(1,1-dioxidotetrahydrothiophen-3-yOurea H ,H
F * 1\0 0 F
F F
I

In analogy to intermediate 2, using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) and (+/-)-tetrahydrothiophen-3-amine 1,1-dioxide (35.0 mg, 259 pmol) together in DMF (1.3 mL), we obtained after one single purification using a Biotage chromatography system 160 mg (89% purity, 88% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.16 --0.06 (m, 9H), 0.79 - 0.86 (m, 2H), 2.11 (dq, 1H), 2.37 - 2.47 (m, 1H), 2.98 - 3.06 (m, 1H), 3.14 - 3.31 (m, 2H), 3.40 -3.47 (m, 1H), 3.54 -3.61 (m, 2H), 4.46 (sxt, 1H), 5.68 (s, 2H), 6.57 (d, 1H), 6.92 (d, 1H), 7.36 -7.43 (m, 2H), 8.29 (d, 1H), 8.37 (s, 1H), 9.16 (s, 1H).
Intermediate 98 (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(5-oxopyrrolidin-3-yOurea H H
N N
F * .1".Q1H

F F
I
(0 H3C-St-C H3 In analogy to intermediate 85, phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1), (+/-)-4-aminopyrrolidin-2-one hydrochloride (1:1) (35.3 mg, 259 pmol) and N,N-diisopropylethylamine (45 pL, 260 pmol) together in DMF (1.2 mL), we obtained after one single purification using a Biotage chromatography system (10g snap KP-Sil column, hexane /0 ¨ 100% ethyl acetate, then ethyl acetate /0 ¨ 100% methanol) 125 mg (97 % purity, 80 % yield) of the desired title compound.
LC-MS (method 3): Rt = 1.38 min; MS (ESIpos): m/z = 586 [M+H]
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.15 - -0.06 (m, 9H), 0.80 - 0.86 (m, 2H), 2.07 (dd, 1H), 3.07 (dd, 1H), 3.49 - 3.60 (m, 3H), 4.28 - 4.36 (m, 1H), 5.68 (s, 2H), 6.57 (d, 1H), 6.95 (d, 1H), 7.35 - 7.43 (m, 2H), 7.68 (s, 1H), 8.29 (d, 1H), 8.36 (s, 1H), 8.99 (s, 1H).
Intermediate 99 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yOurea H ,H
F iloi 1::, Csit.zo I\1---N
(o In analogy to intermediate 2, using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) and tetrahydro-2H-thiopyran-4-amine 1,1-dioxide (38.6 mg, 259 pmol) together in DMF (1.3 mL), we obtained after one single purification using a Biotage chromatography system (10g snap KP-Sil column, hexane / 0 ¨ 100% ethyl acetate, then ethyl acetate /0 ¨ 100% methanol) 152 mg (98% purity, 90% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.16 --0.06 (m, 9H), 0.79 -0.86 (m, 2H), 1.89 -2.01 (m, 2H), 2.08 - 2.18 (m, 2H), 3.02 - 3.10 (m, 2H), 3.24 - 3.32 (m, 2H), 3.54 -3.60 (m, 2H), 3.84 -3.93 (m, 1H), 5.68 (s, 2H), 6.57 (d, 1H), 6.72 (d, 1H), 7.36 -7.43 (m, 2H), 8.29 (d, 1H), 8.36 (s, 1H), 8.90 (s, 1H).

Intermediate 100 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(1H-pyrazol-3-ylmethyl)urea H NH
H
Nõ, -N
F *
F F
I
(o H3C--St-C H3 In analogy to intermediate 2, using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) and 1-(1H-pyrazol-3-yl)methanamine (25.1 mg, 259 pmol) together in DMF (1.3 mL), we obtained after one single purification using a Biotage chromatography system 148 mg (100% purity, 98% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.15 - -0.06 (m, 9H), 0.80 - 0.86 (m, 2H), 3.55 - 3.60 (m, 2H), 4.26 - 4.35 (m, 2H), 5.68 (s, 2H), 6.12 - 6.19 (m, 1H), 6.58 (d, 1H), 6.74 (t, 1H), 7.39 (br d, 2H), 7.67 (s, 1H), 8.28 (d, 1H), 8.36 (s, 1H), 9.14 (br s, 1H), 12.60 -12.72 (m, 1H).
Intermediate 101 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(1H-imidazol-2-ylmethypurea HL,LNTh F
F F
I

In analogy to intermediate 85, using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) and 1-(1 H-imidazol-2-yl)methanamine hydrochloride (1:1) (34.6 mg, 259 pmol) together in DMF (1.3 mL) and N,N-diisopropylethylamine (45 pL, 260 pmol), we obtained after one single purification using a Biotage chromatography system 117 mg (85 %
purity, 66% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.16 - -0.07 (m, 9H), 0.79 - 0.86 (m, 2H), 3.55 - 3.60 (m, 2H), 4.32 (d, 2H), 5.68 (s, 2H), 6.57 (d, 1H), 6.84 (br t, 2H), 7.04 (br s, 1H), 7.37 - 7.43 (m, 2H), 8.29 (d, 1H), 8.36 (s, 1H), 9.24 (s, 1H), 11.85 (br s, 1H).
Intermediate 102 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(1-methyl-1H-pyrazol-3-y1)methyl]urea H H ,N¨C H 3 N,zNN
F * Wo F
FO
F F
/ I
N----N/
(0 In analogy to intermediate 2, using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) and 1-(1-methyl-1H-pyrazol-3-yl)methanamine (28.8 mg, 259 pmol) together in DMF (1.3 mL, 16 mmol), we obtained after one single purification using a Biotage chromatography system 207 mg (98 % purity, 132 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.16 - -0.09 (m, 9H), 0.80 - 0.86 (m, 2H), 3.55 - 3.60 (m, 2H), 3.79 (s, 3H), 4.24 (d, 2H), 5.68 (s, 2H), 6.13 (d, 1H), 6.58 (d, 1H), 6.73 (t, 1H), 7.36 -7.42 (m, 2H), 7.61 (d, 1H), 8.28 (d, 1H), 8.36 (s, 1H), 9.11 (s, 1H).

Intermediate 103 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(1,3-thiazol-2-ylmethypurea S-**
HL) F -Wo NN-o In analogy to intermediate 2, using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1), 1-(1,3-thiazol-2-yl)methanamine (29.5 mg, 259 pmol) together in DMF (1.3 mL), we obtained after one single purification using a Biotage chromatography system 216 mg (80 % purity, 111 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.13 - -0.05 (m, 9H), 0.80 - 0.86 (m, 2H), 3.55 - 3.60 (m, 2H), 4.61 (d, 2H), 5.68 (s, 2H), 6.59 (d, 1H), 7.26 (t, 1H), 7.39 - 7.46 (m, 2H), 7.63 (d, 1H), 7.74 (d, 1H), 8.28 (d, 1H), 8.36 (s, 1H), 9.39 (s, 1H).
Intermediate 104 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(pyrimidin-4-ylmethypurea N
F* 1\0 F
(o In analogy to intermediate 2, using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) and 1-(pyrimidin-4-yl)methanamine (28.2 mg, 259 pmol) together in DMF (1.3 mL), we obtained after one single purification using a Biotage chromatography system 175 mg (99% purity, 113% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.17 - -0.06 (m, 9H), 0.79 - 0.86 (m, 2H), 3.55 - 3.60 (m, 2H), 4.42 (d, 2H), 5.68 (s, 2H), 6.58 (d, 1H), 7.12 (t, 1H), 7.38 - 7.44 (m, 2H), 7.46 (dd, 1H), 8.29 (d, 1H), 8.36 (s, 1H), 8.76 (d, 1H), 9.13 (d, 1H), 9.49 (s, 1H).
Intermediate 105 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(2-methylpyridin-4-y1)methyl]urea f\s1 ....
N,zN
F * wo Fa F...
F F
/ I
N---N/
(0 In analogy to intermediate 2, using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) and 1-(2-methylpyridin-4-yl)methanamine (31.6 mg, 259 pmol) together in DMF (1.3 mL), we obtained after one single purification using a Biotage chromatography system 178 mg (86% purity, 98% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 - -0.06 (m, 9H), 0.80 - 0.86 (m, 2H), 2.45 (s, 3H), 3.55 - 3.60 (m, 2H), 4.30 (d, 2H), 5.68 (s, 2H), 6.58 (d, 1H), 7.05 (t, 1H), 7.09 (br d, 1H), 7.15 (s, 1H), 7.38 - 7.45 (m, 2H), 8.29 (d, 1H), 8.36 - 8.39 (m, 2H), 9.31 (s, 1H).

Intermediate 106 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(pyridazin-3-ylmethypurea N
N'Th H

N N
F *F
F....) F F
/ I
N---"N
(0 H 30¨Sis¨C H3 To a solution of phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) in DMF
(1.3 mL) was added 1-(pyridazin-3-yl)methanamine (28.2 mg, 259 pmol) and this mixture was stirred at 55 C over night. Additional 1-(pyridazin-3-yl)methanamine (14.1 mg, 129 pmol) was added and stirred over night at 60 C. After cooling to room temperature ethyl acetate and water was added. After separation of the organic phase the aqueous phase was extracted two times with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The resulting residue was purified via a Biotage chromatography system (10g snap KP-Sil column, hexane /0 ¨ 100% ethyl acetate, then ethyl acetate / 0 ¨ 100% methanol) to obtain 190 mg (84 % purity, 103 %
yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 --0.06 (m, 9H), 0.79 - 0.86 (m, 2H), 3.54 - 3.61 (m, 2H), 4.62 (d, 2H), 5.68 (s, 2H), 6.58 (d, 1H), 7.23 (t, 1H), 7.37 - 7.45 (m, 2H), 7.64 (dd, 1H), 7.70 (dd, 1H), 8.28 (d, 1H), 8.36 (s, 1H), 9.15 (dd, 1H), 9.43 (s, 1H).

Intermediate 107 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(5-methyl-1H-imidazol-2-y1)methyl]urea H H n-C H3 N
FF.,( F

H3C--S1,-C H3 In analogy to intermediate 85, using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) and 1-(5-methyl-1H-imidazol-2-yl)methanamine dihydrochloride (47.6 mg, 259 pmol) together in DMF (1.3 mL) and N,N-diisopropylethylamine (90 pL, 520 pmol), we obtained after one single purification using a Biotage chromatography system 145 mg (87% purity, 82% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.16 --0.06 (m, 9H), 0.80 -0.87 (m, 2H), 2.10 (s, 3H), 3.54 - 3.61 (m, 2H), 4.25 (d, 2H), 5.68 (s, 2H), 6.54 ¨ 6.72 (m, 2H), 6.79 (t, 1H), 7.36 - 7.43 (m, 2H), 8.29 (d, 1H), 8.36 (s, 1H), 9.23 (s, 1H), 11.58 (br s, 1H).
Intermediate 108 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-{[3-(methoxymethyl)-1,2,4-oxadiazol-5-yl]methyllurea FNi li\ilto,N
F*FF
F
en p N r\J
(o H3C.-S1,-C H3 In analogy to intermediate 85, using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) and 1[3-(methoxymethyl)-1,2,4-oxadiazol-5-yl]methanamine hydrochloride (1:1) (46.5 mg, 259 pmol) together in DMF (1.3 mL) and N,N-diisopropylethylamine (45 pL, 260 pmol), we obtained after one single purification using a Biotage chromatography system 184 mg (84% purity, 95% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 - -0.06 (m, 9H), 0.79 - 0.86 (m, 2H), 3.33 (s, 3H), 3.54 - 3.60 (m, 2H), 4.53 (s, 2H), 4.62 (d, 2H), 5.68 (s, 2H), 6.59 (d, 1H), 7.20 (br t, 1H), 7.37 -7.44 (m, 2H), 8.28 (d, 1H), 8.36 (s, 1H), 9.52 (s, 1H).
Intermediate 109 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(5-methyl-4H-1,2,4-triazol-3-y1)methyl]urea NN
H Fl IC H3 N, N N
H
F$ Al F
FO
F F
/ I
N----N/
( H3C-81¨C H3 In analogy to intermediate 85, using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) and 1-(5-methyl-4H-1,2,4-triazol-3-yl)methanamine dihydrochloride (47.9 mg, 259 pmol) together in DMF (1.3 mL, 16 mmol) and N,N-diisopropylethylamine (90 pL, 520 pmol), we obtained after one single purification using a Biotage chromatography system 134 mg (100% purity, 87% yield) of the desired title compound.
LC-MS (method 3): Rt = 1.37 min; MS (ESIpos): rrilz = 598 [M+H]
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 --0.06 (m, 9H), 0.80 - 0.86 (m, 2H), 3.54 - 3.60 (m, 2H), 4.29 (br s, 2H), 5.68 (s, 2H), 6.58 (d, 1H), 6.77 (br s, 1H), 7.35 -7.43 (m, 2H), 8.28 (d, 1H), 8.36 (s, 1H), 9.24 (br s, 1H), 13.43 (br s, 1H).

Intermediate 110 (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(tetrahydrofuran-3-yOurea F * 0 F
NN-(o H3C-8is-C H3 In analogy to intermediate 2, using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) and (+/-)-tetrahydrofuran-3-amine (22.5 mg, 259 pmol) together in DMF (1.3 mL), we obtained after one single purification using a Biotage chromatography system 101 mg (85% purity, 58% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.13 --0.06 (m, 9H), 0.79 -0.87 (m, 2H), 1.71 - 1.79 (m, 1H), 2.08 -2.18 (m, 1H), 3.50 (dd, 1H), 3.54 -3.61 (m, 2H), 3.67 -3.83 (m, 3H), 4.18 - 4.25 (m, 1H), 5.68 (s, 2H), 6.57 (d, 1H), 6.71 -6.79 (m, 1H), 7.35 - 7.42 (m, 2H), 8.29 (d, 1H), 8.36 (s, 1H), 8.89 (s, 1H).
Intermediate 111 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethyIsilypethy]methyll-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(3R)-tetrahydrofuran-3-yl]urea H H
N N, F

JC) F F
I
(0 H3C-St-C H3 In analogy to intermediate 2, phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) and (3R)-tetrahydrofuran-3-amine (22.5 mg, 259 pmol) together in DMF (1.3 mL), we obtained after one single purification using a Biotage chromatography system (10g snap KP-Sil column, hexane /0 - 100% ethyl acetate, then ethyl acetate /0 -100% ethanol) 104 mg (86 % purity, 60 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.13 --0.06 (m, 9H), 0.79 -0.87 (m, 2H), 1.71 - 1.79 (m, 1H), 2.08 - 2.18 (m, 1H), 3.50 (dd, 1H), 3.54 - 3.61 (m, 2H), 3.67 - 3.83 (m, 3H), 4.18 - 4.25 (m, 1H), 5.68 (s, 2H), 6.57 (d, 1H), 6.71 -6.79 (m, 1H), 7.35 - 7.42 (m, 2H), 8.29 (d, 1H), 8.36 (s, 1H), 8.89 (s, 1H).
Intermediate 112 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(3S)-tetrahydrofuran-3-yl]urea F * Ncol\jall**{
\-0 F F
I
(0 H3c--St-C H3 OH
In analogy to intermediate 85, using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1), (3S)-tetrahydrofuran-3-amine 4-methylbenzenesulfonate (1:1) (67.1 mg, 259 pmol) and N,N-diisopropylethylamine (45 pL, 260 pmol) together in DMF
(1.3 mL) we obtained after one single purification using a Biotage chromatography system (10g snap KP-Sil column, hexane / 0 - 100% ethyl acetate, then ethyl acetate /
0 - 100%
ethanol) 159 mg (100% purity, 107% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.13 --0.06 (m, 9H), 0.79 -0.87 (m, 2H), 1.71 - 1.79 (m, 1H), 2.08 -2.18 (m, 1H), 3.50 (dd, 1H), 3.54 -3.61 (m, 2H), 3.67 -3.83 (m, 3H), 4.18 - 4.25 (m, 1H), 5.68 (s, 2H), 6.57 (d, 1H), 6.71 -6.78 (m, 1H), 7.35 - 7.42 (m, 2H), 8.29 (d, 1H), 8.36 (s, 1H), 8.89 (s, 1H).

Intermediate 113 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-{3-[(2R,6R)-2,6-dimethylmorpholin-4-yl]propyllurea H3c N Nr F
N
(0 H3C--S1,-C H3 In analogy to intermediate 2, using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) and 3-[(2R,6R)-2,6-dimethylmorpholin-4-yl]propan-1-amine (44.6 mg, 259 pmol) together in DMF (1.3 mL) we obtained after one single purification using a Biotage chromatography system (10g snap KP-Sil column, hexane / 0 ¨ 100% ethyl acetate, then ethyl acetate / 0 ¨ 100% ethanol) 139 mg (90 % purity, 73 % yield) of the desired title compound.
1H-N MR (400 MHz, DMSO-d6) 6 [ppm]: -0.15 - -0.06 (m, 9H), 0.80 - 0.86 (m, 2H), 1.04 (d, 6H), 1.50 - 1.64 (m, 4H), 2.27 (t, 2H), 2.70 - 2.75 (m, 2H), 3.12 (q, 2H), 3.51 -3.60 (m, 4H), 5.68 (s, 2H), 6.42 (br t, 1H), 6.57 (d, 1H), 7.35 - 7.42 (m, 2H), 8.29 (d, 1H), 8.36 (s, 1H), 8.99 (s, 1H).
Intermediate 114 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(1-methyl-1H-imidazol-2-y1)methyl]urea H H I
F
N 1"lz *(c) b H3 FF. F
N

In analogy to intermediate 2, using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) and 1-(1-methyl-1H-imidazol-2-yl)methanamine (28.8 mg, 259 pmol) together in DMF (1.3 mL) we obtained after one single purification using a Biotage chromatography system (10g snap KP-Sil column, hexane / 0 ¨ 100% ethyl acetate, then ethyl acetate / 0 ¨ 100% ethanol) 163 mg (100 % purity, 106 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 --0.08 (m, 9H), 0.79 - 0.87 (m, 2H), 3.54 - 3.60 (m, 2H), 3.63 (s, 3H), 4.35 (d, 2H), 5.68 (s, 2H), 6.58 (d, 1H), 6.81 (d, 1H), 6.89 (t, 1H), 7.10 (d, 1H), 7.35 - 7.42 (m, 2H), 8.28 (d, 1H), 8.36 (s, 1H), 9.25 (s, 1H).
Intermediate 115 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(4-methyl-1,2,5-oxadiazol-3-y1)methyl]urea NI' s H ,/4N
N 2\1 F . Al F
FO
F F
/ I
N----N/
(0 H3C¨Sis¨C H3 In analogy to intermediate 2, using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) and 1-(4-methyl-1,2,5-oxadiazol-3-yl)methanamine (29.3 mg, 259 pmol) together in DMF (1.3 mL, 16 mmol) we obtained after one single purification using a Biotage chromatography system (10g snap KP-Sil column, hexane / 0 ¨ 100% ethyl acetate, then ethyl acetate / 0 ¨ 100% ethanol) 144 mg (86 % purity, 80 % yield) of the desired title compound.
1H-N MR (400 MHz, DMSO-d6) 6 [ppm]: -0.14 - -0.05 (m, 9H), 0.79 - 0.87 (m, 2H), 2.39 (s, 3H), 3.54 -3.61 (m, 2H), 4.51 (d, 2H), 5.68 (s, 2H), 6.58 (d, 1H), 7.10 (t, 1H), 7.36 -7.44 (m, 2H), 8.28 (d, 1H), 8.36 (s, 1H), 9.31 (s, 1H).

Intermediate 116 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(2-methoxypyridin-4-y1)methyl]urea H \ 0 N ,C H3 H Z
N N
F F$ ......(0 ess.-N----N/
( H 3C --sis-C H3 In analogy to intermediate 2, using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) and 1-(2-methoxypyridin-4-yl)methanamine (35.8 mg, 259 pmol) together in DMF (1.3 mL) we obtained after one single purification using a Biotage chromatography system (10g snap KP-Sil column, hexane / 0 ¨ 100% ethyl acetate, then ethyl acetate / 0 ¨ 100% ethanol) 136 mg (85 % purity, 72 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 - -0.06 (m, 9H), 0.79 - 0.87 (m, 2H), 3.57 (t, 2H), 3.83 (s, 3H), 4.30 (d, 2H), 5.68 (s, 2H), 6.58 (d, 1H), 6.69 (s, 1H), 6.91 (dd, 1H), 7.01 (t, 1H), 7.37 -7.44 (m, 2H), 8.10 (d, 1H), 8.28 (d, 1H), 8.36 (s, 1H), 9.27 (s, 1H).
Intermediate 117 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(1-methyl-1H-imidazol-4-y1)methyl]urea N%\õ, , H
H........õ1.......zi-k,n3 N...,..1\1 F * \\0 F
FO
F F
/ I
1\1---N/
(0 H3C---8is-C H3 In analogy to intermediate 2, using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) and 1-(1-methyl-1H-imidazol-4-yl)methanamine (28.8 mg, 259 pmol) together in DMF (1.3 mL) we obtained after one single purification using a Biotage chromatography system (10g snap KP-Sil column, hexane / 0 ¨ 100% ethyl acetate, then ethyl acetate / 0 ¨ 100% ethanol) 172 mg (87 % purity, 96 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 --0.06 (m, 9H), 0.79 - 0.86 (m, 2H), 3.53 - 3.60 (m, 2H), 3.61 (s, 3H), 4.14 (d, 2H), 5.68 (s, 2H), 6.57 (d, 1H), 6.61 -6.65 (m, 1H), 6.98 (s, 1H), 7.34 - 7.41 (m, 2H), 7.52 (s, 1H), 8.28 (d, 1H), 8.36 (s, 1H), 9.11 (s, 1H).
Intermediate 118 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-{2-[(2RS,6RS)-2,6-dimethylmorpholin-4-yl]ethyllurea N, yNN"( F * AA() o FFO

F F
I
(0 H3C¨St-0 H3 In analogy to intermediate 2, using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) and cis/trans-2-[2,6-dimethylmorpholin-4-yl]ethanamine (41.0 mg, 259 pmol) together in DMF (1.2 mL) we obtained after one single purification using a Biotage chromatography system (10g snap KP-Sil column,hexane / 0 ¨ 100% ethyl acetate, then ethyl acetate / 0 ¨ 100% ethanol) to obtain 166 mg (90 % purity, 89 % yield) of the desired title compound.
NMR of main isomer:
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.09 (s, 9H), 0.80 - 0.87 (m, 2H), 1.05 (d, 6H), 1.62 (t, 2H), 2.20 (t, 2H), 2.77 (br d, 2H), 3.19 - 3.26 (m, 2H), 3.53 - 3.61 (m, 4H), 5.68 (s, 2H), 6.30 (br t, 1H), 6.57 (d, 1H), 7.32 - 7.41 (m, 2H), 8.29 (d, 1H), 8.36 (s, 1H), 9.17 (s, 1H).

Intermediate 119 1-[(2-cyanopyridin-4-yl)methyl]-3-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyOurea H H
N N N
FF. F

H 3O_0 H3 In analogy to intermediate 85, phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1), 4-(aminomethyl)pyridine-2-carbonitrile hydrochloride (1:1) (43.9 mg, 259 pmol) and N,N-diisopropylethylamine (45 pL, 260 pmol) together in DMF (1.3 mL), we obtained after one single purification using a Biotage chromatography system (10g snap KP-Sil column, hexane / 0 ¨ 100% ethyl acetate, then ethyl acetate / 0 ¨ 100%
methanol) 111 mg (86 % purity, 59 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.17 - -0.05 (m, 9H), 0.79 - 0.87 (m, 2H), 3.54 - 3.60 (m, 2H), 4.41 (d, 2H), 5.68 (s, 2H), 6.57 (d, 1H), 7.12 (t, 1H), 7.37 - 7.45 (m, 2H), 7.65 (dd, 1H), 7.93 ¨ 7.96 (m, 1H), 8.29 (d, 1H), 8.36 (s, 1H), 8.71 (dd, 1H), 9.40 (s, 1H).
Intermediate 120 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(pyridazin-4-ylmethypurea H(\j) H /
F$
ti N
(o In analogy to intermediate 85, phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1), 1-(pyridazin-4-yl)methanamine hydrochloride (1:1) (37.7 mg, 259 pmol) and N,N-diisopropylethylamine (45 pL, 260 pmol) together in DMF (1.3 mL), we obtained after one single purification using a Biotage chromatography system (10g snap KP-Sil column, hexane /0 ¨ 100% ethyl acetate, then ethyl acetate /0 ¨ 100% methanol) 49.8 mg (89 % purity, 29 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 --0.07 (m, 9H), 0.79 - 0.87 (m, 2H), 3.54 - 3.61 (m, 2H), 4.38 (d, 2H), 5.68 (s, 2H), 6.57 (d, 1H), 7.12 (t, 1H), 7.36 - 7.46 (m, 2H), 7.56 (dd, 1H), 8.28 (d, 1H), 8.36 (s, 1H), 9.17 (dd, 1H), 9.18 - 9.20 (m, 1H), 9.46 (s, 1H).
Intermediate 121 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(1,2,4-oxadiazol-3-ylmethypurea N%\0 H
N, 1-N1\11 F * AA0 F
FO
F F
/ I
N----N/
(0 H 3C¨Sis¨C H3 In analogy to intermediate 85, using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) and 1-(1,2,4-oxadiazol-3-yl)methanamine hydrochloride (1:1) (35.1 mg, 259 pmol) together in DMF (1.3 mL) and N,N-diisopropylethylamine (45 pL, 260 pmol), we obtained after one single purification using a Biotage chromatography system (10g snap KP-Sil column, hexane / 0 ¨ 100% ethyl acetate, then ethyl acetate /
0 ¨ 100%
ethanol) 112 mg (80 % purity, 59 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.13 - -0.05 (m, 9H), 0.80 - 0.86 (m, 2H), 3.54 - 3.61 (m, 2H), 4.50 (d, 2H), 5.68 (s, 2H), 6.58 (d, 1H), 7.06 (t, 1H), 7.37 - 7.44 (m, 2H), 8.28 (d, 1H), 8.36 (s, 1H), 9.35 (s, 1H), 9.57 (s, 1H).

Intermediate 122 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(1,3-oxazol-2-ylmethypurea = H. II /
N

( In analogy to intermediate 85, using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) and 1-(1,3-oxazol-2-yl)methanamine hydrochloride (1:1) (34.8 mg, 259 pmol) together in DMF (1.3 mL) and N,N-diisopropylethylamine (45 pL, 260 pmol), we obtained after one single purification using a Biotage chromatography system (10g snap KP-Sil column, hexane /0 ¨ 100% ethyl acetate, then ethyl acetate /0 ¨ 100% ethanol) 175 mg (70 %
purity, 81 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 --0.06 (m, 9H), 0.79 - 0.87 (m, 2H), 3.54 - 3.60 (m, 2H), 4.43 (d, 2H), 5.68 (s, 2H), 6.58 (d, 1H), 7.08 (br t, 1H), 7.17 (d, 1H), 7.36 - 7.44 (m, 2H), 8.06 (d, 1H), 8.28 (d, 1H), 8.36 (s, 1H), 9.38 (s, 1H).
Intermediate 123 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(1,3-thiazol-5-ylmethypurea = H
= N S
F$
( In analogy to intermediate 2, using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) and 1-(1,3-thiazol-5-yl)methanamine (29.5 mg, 259 pmol) together in DMF (1.3 mL), we obtained after one single purification using a Biotage chromatography system (10g snap KP-Sil column, hexane /0 ¨ 100% ethyl acetate, then ethyl acetate /0 ¨
100% ethanol) 136 mg (89 % purity, 78 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.12 - -0.06 (m, 9H), 0.80 - 0.88 (m, 2H), 3.54 ¨ 3.61 (m, 2H), 4.53 (d, 2H), 5.68 (s, 2H), 6.59 (d, 1H), 7.06 (t, 1H), 7.37 - 7.44 (m, 2H), 7.79 (s, 1H), 8.28 (d, 1H), 8.36 (s, 1H), 8.98 (s, 1H), 9.20 (s, 1H).
Intermediate 124 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-342-(2-oxa-6-azaspiro[3.3]hept-6-y1)ethyl]urea H H
N N
F F
I
(0 H 3C ¨,S1 In analogy to intermediate 2, using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) and 2-(2-oxa-6-azaspiro[3.3]hept-6-yl)ethanamine (36.8 mg, 259 pmol) together in DMF (1.3 mL), we obtained after one single purification using a Biotage chromatography system (10g snap KP-Sil column, hexane / 0 ¨ 100% ethyl acetate, then ethyl acetate / 0 ¨ 100% ethanol) 116 mg (95 % purity, 68 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.15 - -0.06 (m, 9H), 0.79 - 0.86 (m, 2H), 2.35 - 2.44 (m, 2H), 3.02 (q, 2H), 3.29 (s, 4H), 3.54 - 3.60 (m, 2H), 4.60 (s, 4H), 5.68 (s, 2H), 6.40 (br t, 1H), 6.57 (d, 1H), 7.30 - 7.41 (m, 2H), 8.28 (d, 1H), 8.36 (s, 1H), 9.22 (s, 1H).

Intermediate 125 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(5-methyl-1,3,4-oxadiazol-2-y1)methyl]urea N-N
H

N N
F Y

I
N N/

H3d CH3 In analogy to intermediate 85, using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) and 1-(5-methyl-1,3,4-oxadiazol-2-yl)methanamine hydrochloride (1:1) (38.7 mg, 259 pmol) together in DMF (1.3 mL) and N,N-diisopropylethylamine (45 pL, 260 pmol), we obtained after one single purification using a Biotage chromatography system (10g snap KP-Sil column, hexane / 0 ¨ 100% ethyl acetate, then ethyl acetate /
0 ¨ 100%
methanol) 118 mg (95% purity, 72% yield) of the desired title compound.
1H-N MR (400 MHz, DMSO-d6) 6 [ppm]: -0.16 - -0.06 (m, 9H), 0.79 - 0.87 (m, 2H), 2.48 (s, 3H), 3.54 - 3.61 (m, 2H), 4.52 (d, 2H), 5.68 (s, 2H), 6.58 (d, 1H), 7.11 (t, 1H), 7.37 - 7.44 (m, 2H), 8.28 (d, 1H), 8.36 (s, 1H), 9.40 (s, 1H).
Intermediate 126 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(3-methyloxetan-3-y1)methyl]urea H H
C F H3 * AA0 F F
I
(0 H3C¨St-C H3 In analogy to intermediate 2, 250 mg phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (250 mg, 431 pmol intermediate 1) and 1-(3-methyloxetan-3-yl)methanamine (43.6 mg, 431 pmol) in DMF (2.1 mL) were reacted to give after purification of the crude product via a Biotage chromatography system (25g snap KP-Sil column, hexane / 0 ¨ 100% ethyl acetate, then ethyl acetate / 0 ¨ 100% ethanol) 178 mg (80 % purity, 56 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.15 --0.06 (m, 9H), 0.79 - 0.87 (m, 2H), 1.23 (s, 3H), 3.25 - 3.31 (m, 2H), 3.54 - 3.62 (m, 2H), 4.20 (d, 2H), 4.39 (d, 2H), 5.68 (s, 2H), 6.58 (d, 1H), 6.93 (t, 1H), 7.36 - 7.44 (m, 2H), 8.28 (d, 1H), 8.36 (s, 1H), 9.26 (br s, 1H).
Intermediate 127 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(5-methylpyridazin-3-yOurea H H
N, N N'N
F * AA0 1 F

F F
/ I
N---N/
(0 H3C¨SL¨C H3 To a solution of 5-methylpyridazin-3-amine (71.3 mg, 653 pmol) in dichloromethane (9.0 mL, 140 mmol) and pyridine (3.0 mL, 37 mmol) was added di-1H-imidazol-1-ylmethanone (116 mg, 718 pmol) and refluxed 30 minutes. After cooling down 3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylaniline (300 mg, 653 pmol, see Synthesis 2007, page 251-258, Org. Process Res. Dev. 2010, page 168-173) in dichloromethane (3.0 mL) and pyridine (2.0 mL, 25 mmol), was given to the mixture and stirred 2 nights at 55 C. After cooling to room temperature ethyl acetate and water was added. After separation of the organic phase the aqueous phase was extracted two times with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness.The resulting residue was purified via a Biotage chromatography system (25g snap KP-Sil column, hexane / 0 ¨ 100% ethyl acetate, then ethyl acetate / 0 ¨ 100% ethanol) to obtain 39.5 mg (92 % purity, 9 % yield) of the desired title compound.

LC-MS (method 3): Rt = 1.53 min; MS (ESIpos): m/z = 593 [M+H]
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.12 - -0.04 (m, 9H), 0.79 - 0.88 (m, 2H), 2.33 (s, 3H), 3.54 - 3.62 (m, 2H), 5.69 (s, 2H), 6.62 (d, 1H), 7.48 - 7.56 (m, 2H), 7.86 (s, 1H), 8.30 (d, 1H), 8.38 (s, 1H), 8.80 (d, 1H), 9.90 (s, 1H), 10.20 (s, 1H).
Intermediate 128 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(2R)-tetrahydrofuran-2-ylmethyl]urea n H H
N....1.= ----.='s F
F....) F F
/ I
N---N/
(0 H3C¨Sis¨C H3 In analogy to intermediate 2, using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1), 1-[(2R)-tetrahydrofuran-2-yl]methanamine (26.2 mg, 259 pmol) together in DMF (1.5 mL), we obtained after one single purification using a Biotage chromatography system (10g snap KP-Sil column, hexane / 0 ¨ 100% ethyl acetate, then ethyl acetate /0 ¨ 100% ethanol) 171 mg (88 % purity, 100 % yield) of the desired title compound.
LC-MS (method 3): Rt = 1.53 min; MS (ESIpos): m/z = 587 [M+H]
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.12 --0.06 (m, 9H), 0.79 -0.86 (m, 2H), 1.47 - 1.56 (m, 1H), 1.77 - 1.95 (m, 3H), 3.05 - 3.15 (m, 1H), 3.21 -3.28 (m, 1H), 3.54 -3.68 (m, 3H), 3.75 - 3.82 (m, 1H), 3.83 - 3.91 (m, 1H), 5.68 (s, 2H), 6.44 (t, 1H), 6.58 (d, 1H), 7.33 - 7.40 (m, 2H), 8.28 (d, 1H), 8.36 (s, 1H), 9.05 (s, 1H).

Intermediate 129 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(2S)-tetrahydrofuran-2-ylmethyl]urea H H
N N 01' ,z i/L----/
F . AN
F
F....) F F
/ I
N---N/
(0 H c-Si-C H3 3 sC H3 In analogy to intermediate 2, using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1), 1-[(2S)-tetrahydrofuran-2-yl]methanamine (26.2 mg, 259 pmol) together in DMF (1.5 mL), we obtained after one single purification using a Biotage chromatography system (10g snap KP-Sil column, hexane / 0 - 100% ethyl acetate, then ethyl acetate / 0 - 100% ethanol) 136 mg (86 % purity, 77 % yield) of the desired title compound.
LC-MS (method 3): Rt = 1.53 min; MS (ESIpos): m/z = 587 [M+H]
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.12 --0.06 (m, 9H), 0.79 -0.86 (m, 2H), 1.47 - 1.57 (m, 1H), 1.77 - 1.95 (m, 3H), 3.05 - 3.15 (m, 1H), 3.21 -3.28 (m, 1H), 3.54 -3.68 (m, 3H), 3.75 -3.82 (m, 2H), 5.68 (s, 2H), 6.58 (d, 1H), 7.33 - 7.40 (m, 2H), 8.28 (d, 1H), 8.36 (s, 1H), 9.07 (s, 1H).

Intermediate 130 (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(5,5-dimethyltetrahydrofuran-2-y1)methyl]urea p H3 H H
N,zNrri"---0 F * Wo F

F F
/ I
N----N/
(0 H3C-St-C H3 In analogy to intermediate 85, phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1, (+/-)-1-(5,5-dimethyltetrahydrofuran-2-yl)methanamine hydrochloride (1:1) (42.9 mg, 259 pmol) together in DMF (1.3 mL) and N,N-diisopropylethylamine (45 pL, 260 pmol), we obtained after one single purification using a Biotage chromatography system (10g snap KP-Sil column, hexane / 0 - 100% ethyl acetate, then ethyl acetate /
0 - 100%
ethanol) 177 mg (87% purity, 97% yield) of the desired title compound.
LC-MS (method 3): Rt = 1.61 min; MS (ESIpos): m/z = 615 [M+H]
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.12 --0.07 (m, 9H), 0.80 - 0.86 (m, 2H), 1.16 (s, 3H), 1.22 (s, 3H), 1.59- 1.72 (m, 3H), 1.94 - 2.01 (m, 1H), 3.03 - 3.11 (m, 1H), 3.21 -3.28 (m, 1H), 3.55 - 3.60 (m, 2H), 3.93 - 4.00 (m, 1H), 5.68 (s, 2H), 6.41 (t, 1H), 6.58 (d, 1H), 7.33 - 7.40 (m, 2H), 8.28 (d, 1H), 8.36 (s, 1H), 9.14 (s, 1H).

Intermediate 131 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(tetrahydro-2H-pyran-4-yOurea H
F
NH.(NC0 F * 0 F
....0 F F
/ I
N---N/
(0 H3C¨Sis¨CH3 .. In analogy to intermediate 2, using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1), tetrahydro-2H-pyran-4-amine (26.2 mg, 259 pmol) together in DMF
(1.3 mL), we obtained after one single purification using a Biotage chromatography system (10g snap KP-Sil column, hexane / 0 ¨ 100% ethyl acetate, then ethyl acetate /
0 ¨ 100%
ethanol) 132 mg (100% purity, 87% yield) of the desired title compound.
LC-MS (method 3): Rt = 1.51 min; MS (ESIpos): m/z = 587 [M+H]
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.13 --0.07 (m, 9H), 0.79 -0.87 (m, 2H), 1.36 - 1.47 (m, 2H), 1.74 - 1.83 (m, 2H), 3.34 - 3.42 (m, 2H), 3.54 - 3.60 (m, 2H), 3.63 -3.74 (m, 1H), 3.83 (dt, 2H), 5.68 (s, 2H), 6.52 - 6.60 (m, 2H), 7.35 - 7.41 (m, 2H), 8.28 (d, 1H), 8.36 (s, 1H), 8.95 (s, 1H).

Intermediate 132 (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(tetrahydro-2H-pyran-2-ylmethypurea N,zN
H
F AA
F F
I
(0 H3C¨St¨C H3 In analogy to intermediate 85, using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1), (+/-)-1-(tetrahydro-2H-pyran-2-yl)methanamine hydrochloride (1:1) (39.2 mg, 259 pmol) together in DMF (1.3 mL) and N,N-diisopropylethylamine (45 pL, 260 pmol), we obtained after one single purification using a Biotage chromatography system (10g snap KP-Sil column, hexane / 0 ¨ 100% ethyl acetate, then ethyl acetate /
0 ¨ 100%
ethanol) 171 mg (88% purity, 100% yield) of the desired title compound.
LC-MS (method 3): Rt = 1.58 min; MS (ESIpos): m/z = 601 [M+H]
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.13 --0.07 (m, 9H), 0.79 -0.87 (m, 2H), 1.12 - 1.27 (m, 1H), 1.39 - 1.59 (m, 4H), 1.73 - 1.82 (m, 1H), 2.98 -3.06 (m, 1H), 3.23 (ddd, 1H), 3.28 ¨
3.39 (m, 2H), 3.54 - 3.61 (m, 2H), 3.86 - 3.93 (m, 1H), 5.68 (s, 2H), 6.50 (br t, 1H), 6.57 (d, 1H), 7.33 - 7.39 (m, 2H), 8.28 (d, 1H), 8.36 (s, 1H), 9.15 (s, 1H).

Intermediate 133 (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(tetrahydro-2H-pyran-3-yOurea H H
N,y1\1-..00 F
F....)-2 F F
/ I
N---N/
(0 H3C--S1¨CH3 In analogy to intermediate 85, phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1), (+/-)-tetrahydro-2H-pyran-3-amine hydrochloride (1:1) (35.6 mg, 259 pmol) together in DMF (1.3 mL) and N,N-diisopropylethylamine (45 pL, 260 pmol), we obtained after one single purification using a Biotage chromatography system (10g snap KP-Sil column, hexane /0 ¨ 100% ethyl acetate, then ethyl acetate /0 ¨ 100% ethanol) 148 mg (100 % purity, 97% yield) of the desired title compound.
LC-MS (method 3): Rt = 1.52 min; MS (ESIpos): m/z = 587 [M+H]
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.12 --0.07 (m, 9H), 0.80 -0.86 (m, 2H), 1.47 - 1.57 (m, 2H), 1.63 - 1.73 (m, 1H), 1.80 - 1.89 (m, 1H), 3.24 (dd, 1H), 3.43 - 3.50 (m, 1H), 3.55 - 3.66 (m, 4H), 3.72 (dd, 1H), 5.68 (s, 2H), 6.57 (d, 1H), 6.61 (br d, 1H), 7.33 -7.41 (m, 2H), 8.29 (d, 1H), 8.36 (s, 1H), 9.02 (s, 1H).

Intermediate 134 (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(2-methyltetrahydrofuran-2-y1)methyl]urea F

F F
I

In analogy to intermediate 2, phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1), (+/-)-1-(2-methyltetrahydrofuran-2-yl)methanamine (29.8 mg, 259 pmol) together in DMF (1.2 mL), we obtained after one single purification using a Biotage chromatography system (10g snap KP-Sil column, hexane / 0 - 100% ethyl acetate, then ethyl acetate / 0 - 100% ethanol) 154 mg (95 % purity, 94 % yield) of the desired title compound.
LC-MS (method 3): Rt = 1.57 min; MS (ESIpos): m/z = 601 [M+H]
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.13 - -0.07 (m, 9H), 0.79 - 0.87 (m, 2H), 1.12 (s, 3H), 1.55- 1.63 (m, 1H), 1.71 - 1.80 (m, 1H), 1.82- 1.93 (m, 2H), 3.11 -3.20 (m, 2H), 3.54 -3.61 (m, 2H), 3.71 - 3.79 (m, 2H), 5.68 (s, 2H), 6.42 (t, 1H), 6.58 (d, 1H), 7.33 -7.40 (m, 2H), 8.28 (d, 1H), 8.36 (s, 1H), 9.10 (s, 1H).
Intermediate 135 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(2-methoxy-2-methylpropypurea NN.)(o_C H3 F F
F-....11101 F
H3C,F13 / I
H 3C -Si \\OJ

In analogy to intermediate 2, phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1), 2-methoxy-2-methylpropan-1-amine (26.7 mg, 259 pmol) together in DMF (1.5 mL), we obtained after one single purification using a Biotage chromatography system (11g snap KP-NH column, hexane /50 ¨ 100% ethyl acetate, then ethyl acetate /0 ¨
40% ethanol) 141 mg (100% purity, 92% yield) of the desired title compound.
LC-MS (method 2): Rt = 1.56 min; MS (ESIpos): m/z = 589 [M+H]
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.12 --0.07 (m, 9H), 0.79 - 0.87 (m, 2H), 1.10 (s, 6H), 3.13 (s, 3H), 3.15 (d, 2H), 3.55 - 3.60 (m, 2H), 5.68 (s, 2H), 6.32 (t, 1H), 6.58 (d, 1H), 7.32 -7.39 (m, 2H), 8.28 (d, 1H), 8.36 (s, 1H), 9.09 (s, 1H).
Intermediate 136 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-342-methyl-2-(morpholin-4-y1)propyl]urea F NN.)(N
F F
F........11101 8 o F
H3CsiC I-13 / I
H3C-6i 1\1-N
\\01 In analogy to intermediate 2, phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1), 2-methyl-2-(morpholin-4-yl)propan-1-amine (41.0 mg, 259 pmol) together in DMF (1.5 mL), we obtained after one single purification using a Biotage chromatography system (11g snap KP-NH column, hexane / 50¨ 100% ethyl acetate, then ethyl acetate/ 0¨ 40% ethanol) 149 mg (100% purity, 89% yield) of the desired title compound.
LC-MS (method 2): Rt = 1.58 min; MS (ESIpos): m/z = 645 [M+H]
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.16 - -0.06 (m, 9H), 0.79 - 0.87 (m, 2H), 0.97 (s, 6H), 2.44 -2.48 (m, 4H), 3.10 (d, 2H), 3.54 -3.64 (m, 6H), 5.68 (s, 2H), 6.16 (t, 1H), 6.58 (d, 1H), 7.33 - 7.40 (m, 2H), 8.29 (d, 1H), 8.36 (s, 1H), 9.29 (s, 1H).

Intermediate 137 (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(tetrahydro-2H-pyran-3-ylmethypurea H H
F F
F-__01:101 8 F
H3C, C, H3 /
H C¨SI

In analogy to intermediate 85, phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1), (+/-)-1-(tetrahydro-2H-pyran-3-yl)methanamine hydrochloride (1:1) (39.2 mg, 259 pmol) together in DMF (1.5mL) and N,N-diisopropylethylamine (45 pL, 260 pmol), we obtained after one single purification using a Biotage chromatography system (11g snap KP-NH column, hexane /50 ¨ 100% ethyl acetate, then ethyl acetate /0 ¨ 40%
ethanol) 138 mg (100% purity, 88% yield) of the desired title compound.
LC-MS (method 2): Rt = 1.53 min; MS (ESIpos): m/z = 601 [M+H]
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.15 --0.06 (m, 9H), 0.79 -0.88 (m, 2H), 1.14 - 1.30 (m, 1H), 1.40 - 1.52 (m, 1H), 1.54 - 1.79 (m, 3H), 2.96 - 3.02 (m, 2H), 3.09 (dd, 1H), 3.30 (ddd, 1H), 3.54 - 3.61 (m, 2H), 3.68 - 3.79 (m, 2H), 5.68 (s, 2H), 6.48 (t, 1H), 6.57 (d, 1H), 7.34 -7.42 (m, 2H), 8.28 (d, 1H), 8.36 (s, 1H), 8.95 (s, 1H).
Intermediate 138 (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(tetrahydrofuran-3-ylmethypurea H
F NTN
F
H3C, F H3 H C¨SI

In analogy to intermediate 85, phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1), (+/-)-1-(tetrahydrofuran-3-yl)methanamine hydrochloride (1:1) (35.6 mg, 259 pmol) together in DMF (1.5 mL) and N,N-diisopropylethylamine (45 pL, 260 pmol) we obtained after one single purification using a Biotage chromatography system (11g snap KP-NH column, hexane /50 - 100% ethyl acetate, then ethyl acetate /0 - 40%
ethanol) 147 mg (97% purity, 94% yield) of the desired title compound.
LC-MS (method 2): Rt = 1.49 min; MS (ESIpos): m/z = 587 [M+H]
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.14 --0.07 (m, 9H), 0.80 -0.86 (m, 2H), 1.51 - 1.60 (m, 1H), 1.88 - 1.99 (m, 1H), 2.34 - 2.41 (m, 1H), 3.06 - 3.14 (m, 2H), 3.42 (dd, 1H), 3.54 - 3.77 (m, 5H), 5.68 (s, 2H), 6.54 - 6.60 (m, 2H), 7.36 - 7.42 (m, 2H), 8.28 (d, 1H), 8.36 (s, 1H), 8.99 (s, 1H).
Intermediate 139 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-pyridazin-4-ylurea H
H N.....fil N--.1< N
F

Cl....) / \ /
N
N
Lo Si 1-1C". 1 'C I-1,, ' C H3 ' A
To solution of phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (90 mg, 0.16 mmol, intermediate 44) in DMF (1 mL) was added pyridazin-4-amine (23.5 mg, 247 pmol) and this mixture was stirred at 60 C for 4 hours. The mixture was diluted with water and extracted two times with ethyl acetate. The combined organic phases were washed 3 times with halfconcentrated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated to dryness. The resulting residue was purified via a Biotage chromatography system (KP-Sil snap column;
dichloromethane / methanol gradient with up to 3% methanol) to obtain 46 mg (48 % yield) of he desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.12-0.07 (m, 9H); 0.79-0.86 (m, 2H); 3.50-3.56 (m, 2H); 5.61 (s, 2H); 6.47 (d, 1H); 7.47-7.53 (m, 2H); 7.82 (dd, 1H); 7.85 (s, 1H); 8.19 (d, 1H);
8.95-8.99 (m, 1H); 9-21-9.24 (m, 1H); 9.74 (bs, 2H).

Intermediate 140 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(6-methylpyridazin-3-yOurea H N
H NõKr 9- --V
N-----1 V..--.....--C H3 F = 0 CI
N
N
LO
Si H3C-- I 'CH3 To solution of phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (730 mg, 1.34 mmol, intermediate 44) in DMF (10 mL) was added 6-methylpyridazin-3-amine (219 mg, 2.01 mmol) and this mixture was stirred at 60 C for 4 hours. The mixture was diluted with water and extracted two times with ethyl acetate. The combined organic phases were washed 3 times with halfconcentrated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated to dryness. The resulting residue was purified via a Biotage chromatography system (KP-Sil snap column;
dichloromethane / methanol gradient with up to 2% methanol) to obtain 580 mg (70 % yield) of he desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.12 - -0.06 (m, 9H); 0.80-0.86 (m, 2H);
2.25 (s, 3H);
3.50-3.56 (m, 2H); 5.81 (s, 2H); 6.47 (d, 1H); 7.49-7.59 (m, 3H); 7.85 (s, 1H); 7.91 (d, 1H); 8.19 (d, 1H); 9.92 (bs, 1H); 10.2 (bs, 1H).

Intermediate 141 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-pyridin-3-ylurea H
H N.......01 N---µ \
F 4. 0 Cik......, , N
N
LO
Si H3C-- I 'CH3 To solution of phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (110 mg, 0.2 mmol, intermediate 44) in DMF (1.7 mL) was added pyridin-3-amine (28.4 mg, 302 pmol) and this mixture was stirred at 60 C for 4 hours. The mixture was diluted with water and extracted two times with ethyl acetate. The combined organic phases were washed 3 times with halfconcentrated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated to dryness. The resulting residue was purified via a Biotage chromatography system (KP-Sil snap column;
dichloromethane / methanol gradient with up to 3% methanol) to obtain 111 mg (96 % yield) of he desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.12 - -0.06 (m, 9H); 0.80-0.86 (m, 2H);
3.50-3.56 (m, 2H); 5.81 (s, 2H); 6.47 (d, 1H); 7.34 (ddd, 1H); 7.45-7.52 (m, 2H); 7.85 (s, 1H); 7.95 (ddd, 1H);
8.18 (d, 1H); 8.22 (dd, 1H); 8.63 d, 1H); 9.25 (bs, 1H); 9.49 (bs, 1H).

Intermediate 142 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-pyridin-2-ylurea H N
4. 0 CI
LO
Si H 'C H

To solution of phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (90 mg, 0.17 mmol, intermediate 44) in DMF (1 mL) was added pyridin-2-amine (23.3 mg, 247 pmol) and this mixture was stirred at 60 C for 4 hours. The mixture was diluted with water and extracted two times with ethyl acetate. The combined organic phases were washed 3 times with halfconcentrated aqueous sodium .. chloride solution, dried over sodium sulfate, filtered and concentrated to dryness. The resulting residue was purified via a Biotage chromatography system (KP-Sil snap column;
dichloromethane / methanol gradient with up to 3% methanol) to obtain 33 mg (35 % yield) of the desired title compound.
1H-NMR (400 MHz, CDCI3) 6 [ppm]: -0.07 - -0.02 (m, 9H); 0.89-0.95 (m, 2H);
3.52-3.58 (m, 2H); 5.84 (s, 2H); 6.35 (d, 1H); 6.81 (bd, 1H); 7.00-7.05 (m, 1H); 7.39-7.47 (m, 2H); 7.68-7.80 (m+bs, 2H); 8.14 (d, 1H); 8.28-8.31 (m, 1H); 12.25 (bs, 1H).
Intermediate 143 4-(2,6-difluoro-4-nitrophenoxy)-1H-pyrrolo[2,3-b]pyridine 11+

I

A solution of 1,2,3-trifluoro-5-nitrobenzene (CAS No. [66684-58-0]; 3.59 g, 20.3 mmol) and 1 H-py rr 010[2 ,3-1D]py ridin-4-ol (CAS No. [74420-02-3]; 1.10 eq., 2.99 g, 22.3 mmol) in DMSO
(65 mL) was treated with potassium carbonate (4.00 eq, 11.2 g, 81.1 mmol) and stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (500 mL) and washed with water (3 x 200 mL) and brine (150 mL), dried with sodium sulfate and concentrated in vacuo. The obtained material was purified by flash chromatography (SiO2-hexane/ ethyl acetate) to give the title compound (3.1 g, 52%).
LC-MS (method 2): R1= 1.13 min; MS (ESIpos): rniz = 292 [M+H].
1H-NMR (400 MHz, DMSO-d6) 6 [ppm] = 6.35 (d, 1H), 6.59 (d, 1H), 7.47 (d, 1H), 8.13 (d, 1H), 8.37 - 8.43 (m, 2H), 11.97 (br s, 1H).
Intermediate 144 4-(2,6-difluoro-4-nitrophenoxy)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridine 11+
=0 I
N N
H3C-Sisr, H3d Ln--13 An ice-cooled solution of 4-(2,6-difluoro-4-nitrophenoxy)-1H-pyrrolo[2,3-b]pyridine (intermediate 143; 3.11 g, 10.7 mmol) in acetonitrile (100 mL) was treated with N,N-diisopropyl ethylamine (1.80 eq, 3.35 mL, 19.2 mmol) and [2-(chloromethoxy)ethyl](trimethyl)silane (CAS
No. [76513-69-4]; 1.40 eq, 2.65 mL, 15.0 mmol), warmed tort and stirring continued overnight.
The reaction mixture was poured on ice water (150 mL) and the aqueous phase extracted with ethyl acetate (2 x 400 mL). The combined organic layers were washed with brine (150 mL), dried with sodium sulfate and concentrated in vacuo. The obtained material was purified by flash chromatography (KP-NI-1 -5i02-hexane/ ethyl acetate) to give the title compound (3.9 g, 85%).
LC-MS (method 2): Rt = 1.58 min; MS (ESIpos): rniz = 422 [M+H].
1H-NMR (400 MHz, DMSO-d6) 6 [ppm] = -0.11 (s, 9H), 0.79 - 0.83 (m, 2H), 3.50 -3.54 (m, 2H), 5.64 (s, 2H), 6.48 (d, 1H), 6.69 (d, 1H), 7.66 (d, 1H), 8.20 (d, 1H), 8.38 - 8.44 (m, 2H).

Intermediate 145 3,5-difluoro-4-[(1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]aniline I
Oj H3c.'-"Sisr,s H3d k,n3 A solution of 4-(2,6-difluoro-4-nitrophenoxy)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridine (intermediate 144; 1.73 g, 4.11 mmol) in ethyl acetate (32 mL) was treated with palladium on carbon (10wr/o; 0.05 eq., 218 mg, 0.205 mmol) and stirred under a hydrogen atmosphere at rt for 2 h. The reaction mixture was filtrated over Celite, washed with ethyl acetate and the filtrate concentrated in vacuo to give the title compound (1.58 g, 93%) which was not further purified.
LC-MS (method 2): Rt = 1.42 min; MS (ESIpos): rniz = 392 [M+H].
1H-NMR (400 MHz, DMSO-d6) 6 [ppm] = -0.10 (s, 9H), 0.78 ¨ 0.83 (m, 2H), 3.49 ¨
3.53 (m, 2H), 5.61 (s, 2H), 5.80 (br s, 2H), 6.35 ¨ 6.40 (m, 3H), 6.45 (d, 1H), 7.57 (d, 1H), 8.13 (d, 1H).
Intermediate 146 phenyl {3,5-difluoro-4-[(1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]phenyllcarbamate 0 110 0 1.
I
0-j H 3C¨S1 H3d CH3 An ice-cooled solution of 3,5-difluoro-4-[(1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]aniline (intermediate 145; 1.46 g, 3.73 mmol) and pyridine (5.0 eq., 1.5 mL, 19 mmol) in THF (13 mL) was treated with phenyl chloroformate (CAS No. [1885-14-9]; 1.1 eq, 0.51 mL, 4.1 mmol), the mixture warmed to rt and stirring continued for 70 minutes.
The reaction mixture was diluted with ethyl acetate and washed with 1 M
aqueous hydrochloric acid, aqueous sat. sodium hydrocarbonate solution and brine. The resulting organic layer was dried with sodium sulfate, concentrated in vacuo and the obtained material purified by flash chromatography (SiO2-hexane/ ethyl acetate) to give the title compound (1.61 g, 84 %) containing 1-{3,5-difluoro-4-[(1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyrid in-4-yl)oxy]phenyllurea.
LC-MS (method 2): Rt= 1.59 min; MS (ESIpos): rn/z = 512 [M+H].
Intermediate 147 1-{3 ,5-difluoro-4-[(1-{[2-(trimethylsilypethoxy]methy11-1 H-pyrrolo[2,3-b]pyridin-4-yl)oxy]phenyll-3-[2-(piperidin-1-yl)ethyl]urea H H
N
YO

I

To a solution of phenyl {3,5-difluoro-4-[(1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]phenyllcarbamate (100 mg, 195 pmol, intermediate 146) in DMF
(1.0 mL) was added 2-(piperidin-1-yl)ethanamine (1.00 eq., 25.1 mg, 195 pmol) and this mixture was stirred at 60 C for 75 minutes. After cooling to room temperature ethylacetate and water were added to the reaction mixture and the phases were separated. The aqueous phase was extracted two times with ethylacetate, the combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The resulting residue was purified by flash chromatography (dichloromethane/ methanol) to give the title compound (110 mg, 95%).
LC-MS (method 2): Rt= 1.51 min; MS (ESIneg): m/z = 544 [M-H]-.

Intermediate 148 N3-({3,5-difluoro-4-[(1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]phenyllcarbamoy1)-beta-alaninamide H H

I
r-I
H3C¨S1 H3d CH3 .. This intermediate was prepared in analogy to intermediate 147 by reacting phenyl {3,5-difluoro-4-[(1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]phenyllcarba-mate (100 mg, 195 pmol, intermediate 146), beta-alaninamide (1.00 eq., 17.2 mg, 195 pmol) and additionally N,N-diisopropylethylamine (2.0 eq., 68 pL, 391 pmol) in DMF
for 4 hours at 60 C to give after flash chromatography (dichloromethane/ methanol) the title compound .. (65 mg, 64%).
LC-MS (method 2): Rt= 1.25 min; MS (ESIpos): m/z = 506 [M+H].
Intermediate 149 1-{3,5-difluoro-4-[(1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]phenyll-.. 3-(1H-1,2,3-triazol-5-ylmethypurea N

I
H 3C --",S1 H3c CH3 This intermediate was prepared in analogy to intermediate 147 by reacting phenyl {3,5-d ifl uoro-4-[(1 -{[2-(trimethylsilypethoxy]methy11-1 H-pyrrolo[2,3-b]pyrid in-4-yl)oxy]phenyllcarba-mate (100 mg, 195 pmol, intermediate 146), 1-(1 H-1,2,3-triazol-5-yl)methanamine (1.00 eq., 19.2 mg, 195 pmol) and additionally N,N-diisopropylethylamine (2.0 eq., 68 pL, 391 pmol) in DMF for 4 hours at 60 C to give after flash chromatography (dichloromethane/
methanol) the title compound (48 mg, 48%).
LC-MS (method 2): R1= 1.02 min; MS (ESIpos): m/z = 516 [M+H].
Intermediate 150 1-{3,5-difluoro-4-[(1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]phenyll-343-(dimethylamino)propyl]urea H H

F NI NN'C H3 0 *
F
/ I
NN/

ri ,_, 3r "--", Si =

This intermediate was prepared in analogy to intermediate 147 by reacting phenyl {3,5-difluoro-4-[(1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]phenyllcarba-mate (100 mg, 195 pmol, intermediate 146) and N,N-dimethylpropane-1,3-diamine (1.00 eq., 20.0 mg, 195 pmol) in DMF for 2 hours at 60 C to give after flash chromatography (dichloro-methane/ methanol) the title compound (79 mg, 77%).
LC-MS (method 2): Rt = 1.44 min; MS (ESIpos): m/z = 521 [M+H].
Intermediate 151 44({3,5-difluoro-4-[(1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]phenyllcarbamoyl)amino]butanamide F illNH2 0 .
F
/ I
N N/

ri H3d CH3 This intermediate was prepared in analogy to intermediate 147 by reacting phenyl {3,5-difluoro-4-[(1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]phenyllcarba-mate (100 mg, 195 pmol, intermediate 146), 4-aminobutanamide hydrochloride (1:1) (1.00 eq.,

27.1 mg, 195 pmol) and additionally N,N-diisopropylethylamine (2.0 eq., 68 pL, 391 pmol) in DMF for 75 minutes at 60 C to give after flash chromatography (dichloromethane/ methanol) the title compound (96 mg, 91%).
LC-MS (method 2): Rt = 1.26 min; MS (ESIpos): m/z = 520 [M+H].
Intermediate 152 1-{3,5-difluoro-4-[(1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]phenyll-3-(2-methoxyethypurea =
H H

I
NN/
H3c--S1 H3d CH3 This intermediate was prepared in analogy to intermediate 147 by reacting phenyl {3,5-difluoro-4-[(1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]phenyllcarba-mate (100 mg, 195 pmol, intermediate 146) and 2-methoxyethanamine (1.00 eq., 14.7 mg, 195 pmol) in DMF for 2 hours at 60 C to give after flash chromatography (dichloromethane/
methanol) the title compound (83 mg, 86%).
LC-MS (method 2): Rt = 1.38 min; MS (ESIpos): m/z = 492 [M+H].
Intermediate 153 1-{3,5-difluoro-4-[(1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]phenyll-3-(pyridin-2-ylmethyl)urea H
N N
I
N

H3C-"St H3d CH3 This intermediate was prepared in analogy to intermediate 147 by reacting phenyl {3,5-difluoro-4-[(1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]phenyllcarba-mate (99 mg, 194 pmol, intermediate 146) and 1-(pyridin-2-yl)methanamine (1.00 eq., 20.9 mg, 194 pmol) in DMF for 2 hours at 60 C to give after flash chromatography (dichloro-methane/ methanol) the title compound (65 mg, 56%).
LC-MS (method 2): Rt= 1.38 min; MS (ESIpos): m/z = 526 [M+H].
Intermediate 154 1-{3,5-difluoro-4-[(1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]phenyll-3[3-(methylsulfonyl)propyl]urea F S' 0 *I 8 F
/ I
N F\J
0¨J
r-j H3C¨Sisr, H3d k, ri3 This intermediate was prepared in analogy to intermediate 147 by reacting phenyl {3,5-difluoro-4-[(1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]phenyllcarba-mate (100 mg, 195 pmol, intermediate 146), 3-(methylsulfonyl)propan-1-amine hydrochloride (1:1) (1.00 eq., 33.9 mg, 195 pmol) and additionally N,N-diisopropylethylamine (1.0 eq., 34 pL, 195 pmol) in DMF for 2 hours at 60 C to give after flash chromatography (dichloromethane/
methanol) the title compound (75 mg, 69%).
LC-MS (method 2): Rt= 1.31 min; MS (ESIpos): m/z = 555 [M+H].
Intermediate 155 1-{3,5-difluoro-4-[(1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]phenyll-342-(dimethylamino)ethyl]urea H H
F . NyN...................õIrC H3 F
/ I
N F\j/
0¨I
r-j H3C--S1,õ
H3d k,n3 This intermediate was prepared in analogy to intermediate 147 by reacting phenyl {3,5-difluoro-4-[(1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]phenyllcarba-mate (100 mg, 195 pmol, intermediate 146) and N,N-dimethylethane-1,2-diamine (1.00 eq., 21.5 pL, 195 pmol) in DMF for 2 hours at 60 C to give after flash chromatography (dichloro-methane/ methanol) the title compound (72 mg, 74%).
LC-MS (method 2): Rt= 1.41 min; MS (ESIneg): m/z = 504 [M-I-1]-.
Intermediate 156 1-{3,5-difluoro-4-[(1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]phenyll-343-(piperidin-1-yl)propyl]urea H H
N

I
N F\J
0¨j =,, "

This intermediate was prepared in analogy to intermediate 147 by reacting phenyl {3,5-difluoro-4-[(1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]phenyllcarba-mate (100 mg, 195 pmol, intermediate 146) and 3-(piperidin-1-yl)propan-1-amine (1.00 eq., 31.1 pL, 195 pmol) in DMF for 2 hours at 60 C to give after flash chromatography (dichloro-methane/ methanol) the title compound (65 mg, 59%).
LC-MS (method 2): Rt= 1.60 min; MS (ESIneg): m/z = 558 [M-I-1]-.
Intermediate 157 3-bromo-4-(2,6-difluoro-4-nitrophenoxy)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridine N+
Br 0 =
rIO
H3C¨"Sis Fi3d C H3 A solution of 4-(2,6-difluoro-4-nitrophenoxy)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridine (intermediate 144; 1.55 g, 3.68 mmol) in DMF (31 mL) was treated with 1-bromopyrrolidine-2,5-dione (CAS No. [128-08-5]; 1.10 eq, 720 mg, 4.05 mmol) and stirred at rt overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with aqueous sat. sodium hydrocarbonate solution and brine, filtrated over a hydrophobic phase separation filter paper and concentrated in vacuo. The obtained material was purified by flash chromatography (SiO2-hexane/ ethyl acetate) to give the title compound (1.57 g, 85%).
LC-MS (method 2): Rt = 1.61 min; MS (ESIpos): m/z = 500/502 [M+H] (Br isotope pattern).
1H-NMR (400 MHz, DMSO-d6) 6 [ppm] = -0.09 (s, 9H), 0.79 - 0.86 (m, 2H), 3.52 -3.56 (m, 2H), 5.62 (s, 2H), 6.67 (d, 1H), 7.94 (s, 1H), 8.22 (d, 1H), 8.40 - 8.45 (m, 2H).
Intermediate 158 phenyl {4-[(3-bromo-1-{[2-(trimethylsi lypethoxy]methy11-1 H-pyrrolo[2,3-b]pyrid in-4-yl)oxy]-3,5-difluorophenyllcarbamate Br I

A solution of 3-bromo-4-(2,6-difluoro-4-nitrophenoxy)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridine (intermediate 157; 3.25 g, 6.50 mmol) in methanol (130 mL) was treated with tin(II) chloride dihydrate (CAS No. [10025-69-1]; 3.00 eq, 4.40 g, 19.5 mmol) and stirred at 65 C overnight. The reaction mixture was cooled to rt and concentrated in vacuo. The residue was taken up with ethyl acetate and aqueous sat. sodium carbonate solution, filtrated over diatomite and the phases separated. The organic phase was washed with aqueous sat.
sodium carbonate solution, dried with sodium sulfate and concentrated in vacuo. The obtained material was purified by flash chromatography (5i02-hexane/ ethyl acetate) to give the title compound (2.28 g, 67%).
LC-MS (method 2): Rt = 1.53 min; MS (ESIpos): m/z = 470/472 [M+H] (Br isotope pattern).
1H-NMR (400 MHz, DMSO-d6) 6 [ppm] = -0.09 (s, 9H), 0.80 - 0.84 (m, 2H), 3.50 -3.54 (m, 2H), 5.59 (s, 2H), 5.82 (br s, 2H), 6.36 - 6.42 (m, 3H), 7.83 (s, 1H), 8.16 (d, 1H).

Intermediate 159 phenyl {4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate NO

Br :ss I
NN/
rIO
H 3C¨SI
H3d CH3 An ice-cooled solution of 4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluoroaniline (intermediate 158; 2.20 g, 4.68 mmol) and pyridine (5.0 eq., 1.9 mL, 23 mmol) in THF (25 mL) was treated with phenyl chloroformate (CAS No. [1885-14-9]; 1.3 eq, 0.76 mL, 6.1 mmol), the mixture warmed to rt and stirring continued for 4 hours.
The reaction mixture was diluted with ethyl acetate and washed with 1 M
aqueous hydrochloric acid, aqueous sat. sodium hydrocarbonate solution and brine. The resulting organic layer was dried with sodium sulfate and concentrated in vacuo to give the crude title compound (3.5 g) containing 1-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllurea which was used as is in the next steps.
LC-MS (method 2): Rt= 1.66 min; MS (ESIpos): m/z = 590/592 [M+H] (Br isotope pattern).
Intermediate 160 1-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(3-methoxypropypurea H H
Br 110 NyNo'CH3 I
rIO
H 3C ¨St H3d CH3 To a solution of phenyl {4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (225 mg, 381 pmol, intermediate 159) in DMF
(4.0 mL) was added 3-methoxypropan-1-amine (1.20 eq., 40.8 mg, 457 pmol) and this mixture was stirred at 70 C for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The organic phase was separated, dried and concentrated in vacuo. The crude product (223 mg) was used in the next step without any further purification.
LC-MS (method 2): Rt= 1.47 min; MS (ESIpos): m/z = 585/587 [M+H] (Br isotope pattern).
Intermediate 161 1-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-[(1-methyl-1H-pyrazol-3-y1)methyl]urea C Ho i J
N¨N
N IN
F . I

Brµ [ F

N N
0) rj 1_,rs Si 110%./ .
j I sC H

This intermediate was prepared in analogy to intermediate 160 by reacting phenyl {4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyrid in-4-yl)oxy]-3,5-d ifl uoro-phenyllcarbamate (225 mg, 381 pmol, intermediate 159) and 1-(1-methyl-1H-pyrazol-3-yl)methanamine (1.20 eq., 50.8 mg, 457 pmol) in DMF at 70 C for 18 hours to give after aqueous work-up the crude product (231 mg) which was used in the next step without any further purification.
LC-MS (method 2): Rt= 1.42 min; MS (ESIpos): m/z = 607/609 [M+H] (Br isotope pattern).

Intermediate 162 1-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(1,3-thiazol-2-ylmethypurea H H
NNNY
lel 8 Br I
H 3C ¨SI
H3d CH3 This intermediate was prepared in analogy to intermediate 160 by reacting phenyl {4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluoro-phenyllcarbamate (225 mg, 381 pmol, intermediate 159) and 1-(1,3-thiazol-2-yl)methanamine (1.20 eq., 52.2 mg, 457 pmol) in DMF at 70 C for 18 hours to give after aqueous work-up the crude product (233 mg) which was used in the next step without any further purification.
LC-MS (method 2): R1= 1.45 min; MS (ESIpos): m/z = 610/612 [M+H] (Br isotope pattern).
Intermediate 163 1-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(1H-pyrazol-3-ylmethyl)urea H H
NNjj---\,NH
Br I
NN/
H 3C¨Si, This intermediate was prepared in analogy to intermediate 160 by reacting phenyl {4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluoro-phenyllcarbamate (225 mg, 381 pmol, intermediate 159) and 1-(1H-pyrazol-3-yl)methanamine (1.20 eq., 44.4 mg, 457 pmol) in DMF at 70 C for 18 hours to give after aqueous work-up the crude product (226 mg) which was used in the next step without any further purification.
LC-MS (method 2): Rt= 1.38 min; MS (ESIpos): m/z = 593/595 [M+H] (Br isotope pattern).
Intermediate 164 N3-({4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamoy1)-beta-alaninamide H H
Br I

This intermediate was prepared in analogy to intermediate 160 by reacting phenyl {4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluoro-phenyllcarbamate (150 mg, 206 pmol, intermediate 159), beta-alaninamide (1.00 eq., 18.1 mg, 206 pmol) and additionally N,N-diisopropylethylamine (2.0 eq., 72 pL, 410 pmol) in DMF for 4 hours at 60 C to give after concentration of the reaction mixture in vacuo the crude product (120 mg) which was used in the next step without any further purification.
LC-MS (method 2): Rt= 1.36 min; MS (ESIpos): m/z = 584/586 [M+H] (Br isotope pattern).
Intermediate 165 1-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-342-(piperidin-1-ypethyl]urea H H
N N
y Br 0 I

This intermediate was prepared in analogy to intermediate 160 by reacting phenyl {4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluoro-phenyllcarbamate (150 mg, 206 pmol, intermediate 159) and 2-(piperidin-1-yl)ethanamine (1.00 eq., 26.4 mg, 206 pmol) in DMF for 2 hours at 60 C to give after concentration of the reaction mixture in vacuo the crude product (129 mg) which was used in the next step without any further purification.
LC-MS (method 2): Rt= 1.60 min; MS (ESIpos): m/z = 624/626 [M+H] (Br isotope pattern).
Intermediate 166 N-{24({4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamoyl)amino]ethyllmethanesulfonamide o ,C H3 Br NyNN,S0 H

I
rIO
H 3C ¨St H3d CH3 This intermediate was prepared in analogy to intermediate 160 by reacting phenyl {4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1 H-pyrrolo[2,3-b]pyrid in-4-yl)oxy]-3,5-d ifl uoro-phenyllcarbamate (150 mg, 206 pmol, intermediate 159) and N-(2-aminoethyl)methane-sulfonamide (1.00 eq., 28.4 mg, 206 pmol) in DMF for 2 hours at 60 C to give after concentration of the reaction mixture in vacuo the crude product (131 mg) which was used in the next step without any further purification.
LC-MS (method 2): Rt= 1.40 min; MS (ESIpos): m/z = 634/636 [M+H] (Br isotope pattern).

Intermediate 167 1-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-343-(morpholin-4-y1)propyl]urea H H (C) NN) Br I
r-I
H3C--"St H3d CH3 This intermediate was prepared in analogy to intermediate 160 by reacting phenyl {4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluoro-phenyllcarbamate (150 mg, 206 pmol, intermediate 159) and 3-(morpholin-4-yl)propan-1-amine (1.00 eq., 29.7 mg, 206 pmol) in DMF for 2 hours at 60 C to give after concentration of the reaction mixture in vacuo the crude product (132 mg) which was used in the next step without any further purification.
LC-MS (method 2): Rt= 1.46 min; MS (ESIpos): m/z = 640/642 [M+H] (Br isotope pattern).
Intermediate 168 N-{24({4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamoyl)amino]ethyllacetamide H H
(00/ NyNNAC H3 Br I
N'N/
r-I
H3C--"St H3d CH3 This intermediate was prepared in analogy to intermediate 160 by reacting phenyl {4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluoro-phenyllcarbamate (150 mg, 206 pmol, intermediate 159) and N-(2-aminoethyl)acetamide (1.00 eq., 21.0 mg, 206 pmol) in DMF for 2 hours at 60 C to give after concentration of the reaction mixture in vacuo the crude product (123 mg) which was used in the next step without any further purification.
LC-MS (method 2): Rt= 1.39 min; MS (ESIpos): m/z = 598/600 [M+H] (Br isotope pattern).
Intermediate 169 1-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-342-(morpholin-4-y1)-2-oxoethyl]urea F H HA
Br 1101 NN N

F
/ I
N Th/

ri H3C-SI, H3d C H3 This intermediate was prepared in analogy to intermediate 160 by reacting phenyl {4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluoro-phenyllcarbamate (150 mg, 206 pmol, intermediate 159), 2-amino-1-(morpholin-4-yl)ethanone (1.00 eq., 29.7 mg, 206 pmol) and additionally N,N-diisopropylethylamine (2.0 eq., 72 pL, 410 pmol) in DMF for 4 hours at 60 C to give after concentration of the reaction mixture in vacuo the crude product (132 mg) which was used in the next step without any further purification.
LC-MS (method 2): Rt= 1.42 min; MS (ESIpos): m/z = 640/642 [M+H] (Br isotope pattern).
Intermediate 170 1-{4-[(3-bromo-1-{[2-(trimethylsi lypethoxy]methy11-1H-pyrrolo[2,3-b]pyrid in-4-yl)oxy]-3,5-difluoropheny11-3-(pyridin-2-ylmethypurea H H
F NN' Br F
/ I
N F\j/
0¨I
ri H3C-"St H3d C H3 This intermediate was prepared in analogy to intermediate 160 by reacting phenyl {4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluoro-phenyllcarbamate (150 mg, 206 pmol, intermediate 159) and 1-(pyridin-2-yl)methanamine (1.00 eq., 22.3 mg, 206 pmol) in DMF for 2 hours at 60 C to give after concentration of the reaction mixture in vacuo the crude product (125 mg) which was used in the next step without any further purification.
LC-MS (method 2): Rt= 1.49 min; MS (ESIpos): m/z = 604/606 [M+H] (Br isotope pattern).
Intermediate 171 1-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-[(1,1-dioxidothietan-3-Amethyl]urea Ii Br I
rj This intermediate was prepared in analogy to intermediate 160 by reacting phenyl {4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1 H-pyrrolo[2,3-b]pyrid in-4-yl)oxy]-3,5-d ifl uoro-phenyllcarbamate (150 mg, 206 pmol, intermediate 159) and 1-(1,1-dioxidothietan-3-yl)methanamine (1.00 eq., 27.8 mg, 206 pmol) in DMF for 2 hours at 60 C to give after concentration of the reaction mixture in vacuo the crude product (130 mg) which was used in the next step without any further purification.
LC-MS (method 2): Rt= 1.43 min; MS (ESIpos): m/z = 631/633 [M+H] (Br isotope pattern).

Intermediate 172 1-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(2-methoxyethypurea H H

y CY

Br I

H3C¨St Fi3d CH3 This intermediate was prepared in analogy to intermediate 160 by reacting phenyl {4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluoro-phenyllcarbamate (150 mg, 206 pmol, intermediate 159) and 2-methoxyethanamine (1.00 eq., 15.5 mg, 206 pmol) in DMF for 2 hours at 60 C to give after concentration of the reaction mixture in vacuo the crude product (118 mg) which was used in the next step without any further purification.
LC-MS (method 2): Rt= 1.48 min; MS (ESIpos): m/z = 571/573 [M+H] (Br isotope pattern).
Intermediate 173 1-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-.. difluoropheny11-3-(pyridin-4-ylmethypurea 101 NH1r NH
Br I
NN/
H3C¨S1 H3d CH3 This intermediate was prepared in analogy to intermediate 160 by reacting phenyl {4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluoro-phenyllcarbamate (150 mg, 206 pmol, intermediate 159) and 1-(pyridin-4-yl)methanamine (1.00 eq., 22.3 mg, 206 pmol) in DMF for 2 hours at 60 C to give after concentration of the reaction mixture in vacuo the crude product (124 mg) which was used in the next step without any further purification.
LC-MS (method 2): Rt= 1.46 min; MS (ESIpos): m/z = 604/606 [M+H] (Br isotope pattern).
Intermediate 174 N2-({4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamoyl)glycinamide H H
/10 NyN-NH 2 Br I
H3C¨si H3d C H3 This intermediate was prepared in analogy to intermediate 160 by reacting phenyl {4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluoro-phenyllcarbamate (150 mg, 206 pmol, intermediate 159), glycinamide hydrochloride (1:1) (1.00 eq., 22.7 mg, 206 pmol) and additionally N,N-diisopropylethylamine (2.0 eq., 72 pL, 410 pmol) in DMF for 2 hours at 60 C to give after concentration of the reaction mixture in vacuo the crude product (117 mg) which was used in the next step without any further purification.
LC-MS (method 2): Rt= 1.34 min; MS (ESIpos): m/z = 570/572 [M+H] (Br isotope pattern).
Intermediate 175 1-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyrid in-4-yl)oxy]-3,5-difluoropheny11-343-(piperidin-1-Apropyl]urea H H
NyNN/
Br 0 I
N N/
oJ

H3d C H3 This intermediate was prepared in analogy to intermediate 160 by reacting phenyl {4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluoro-phenyllcarbamate (150 mg, 206 pmol, intermediate 159) and 3-(piperidin-1-yl)propan-1-amine (1.00 eq., 29.3 mg, 206 pmol) in DMF for 2 hours at 60 C to give after concentration of the .. reaction mixture in vacuo the crude product (131 mg) which was used in the next step without any further purification.
LC-MS (method 2): Rt= 1.61 min; MS (ESIpos): m/z = 638/640 [M+H] (Br isotope pattern).
Intermediate 176 1-{4-[(3-bromo-1-{[2-(trimethylsi lypethoxy]methy11-1 H-pyrrolo[2,3-b]pyrid in-4-yl)oxy]-3,5-d ifl uoropheny11-3-(1 H-1 ,2 ,3-triazol-4-ylmethypurea H H
N
NN

Br I
NN/

H3d CH3 This intermediate was prepared in analogy to intermediate 160 by reacting phenyl {4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1 H-pyrrolo[2,3-b]pyrid in-4-yl)oxy]-3,5-d ifl uoro-phenyllcarbamate (150 mg, 206 pmol, intermediate 159), 1-(1H-1,2,3-triazol-4-yl)methanamine hydrochloride (1:1) (1.00 eq., 27.7 mg, 206 pmol) and additionally N,N-diisopropylethylamine (2.0 eq., 72 pL, 410 pmol) in DMF for 2 hours at 60 C to give after concentration of the reaction mixture in vacuo the crude product (123 mg) which was used in the next step without any further purification.
LC-MS (method 2): Rt= 1.14 min; MS (ESIpos): m/z = 594/596 [M+H] (Br isotope pattern).

Intermediate 177 1-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-343-(methylsulfonyl)propyl]urea H H 0% H
µSC 3 N ).rN

Br I
NN/
H3C¨St H3d CH3 This intermediate was prepared in analogy to intermediate 160 by reacting phenyl {4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluoro-phenyllcarbamate (150 mg, 206 pmol, intermediate 159), 3-(methylsulfonyl)propan-1-amine hydrochloride (1:1) (1.00 eq., 25.7 mg, 206 pmol) and additionally N,N-diisopropylethylamine (2.0 eq., 72 pL, 410 pmol) in DMF for 2 hours at 60 C to give after concentration of the reaction mixture in vacuo the crude product (130 mg) which was used in the next step without any further purification.
LC-MS (method 2): Rt= 1.41 min; MS (ESIpos): m/z = 633/635 [M+H] (Br isotope pattern).
Intermediate 178 44({4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyllcarbamoyl)amino]butanamide =

Br I
H 3C ¨SI
H3d CH3 This intermediate was prepared in analogy to intermediate 160 by reacting phenyl {4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluoro-phenyllcarbamate (150 mg, 206 pmol, intermediate 159), 4-aminobutanamide hydrochloride (1:1) (1.00 eq., 28.5 mg, 206 pmol) and additionally N,N-diisopropylethylamine (2.0 eq., 72 pL, 410 pmol) in DMF for 2 hours at 60 C to give after concentration of the reaction mixture in vacuo the crude product (123 mg) which was used in the next step without any further purification.
LC-MS (method 2): Rt= 1.36 min; MS (ESIpos): m/z = 598/600 [M+H] (Br isotope pattern).
Intermediate 179 1-{4-[(3-bromo-1-{[2-(trimethylsi lypethoxy]methy11-1 H-pyrrolo[2,3-b]pyrid in-4-yl)oxy]-3,5-difluoropheny11-342-(4-methylpiperazin-1-y1)-2-oxoethyl]urea F N N
. 0 N
Br N 'C H3 F
/ I
NN/

r-1 This intermediate was prepared in analogy to intermediate 160 by reacting phenyl {4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-13]pyridin-4-ypoxy]-3,5-difluoro-phenyllcarbamate (150 mg, 206 pmol, intermediate 159) and 2-amino-1-(4-methylpiperazin-1-yl)ethanone (1.00 eq., 32.3 mg, 206 pmol) in DMF for 2 hours at 60 C to give after concentration of the reaction mixture in vacuo the crude product (137 mg) which was used in the next step without any further purification.
LC-MS (method 2): Rt= 1.41 min; MS (ESIpos): m/z = 653/655 [M+H] (Br isotope pattern).

Intermediate 180 4-(2,6-difluoro-4-nitrophenoxy)-3-iodo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridine 11+
(10 N

I
r-1 H3c CH3 A solution of 4-(2,6-difluoro-4-nitrophenoxy)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridine (intermediate 144; 5.00 g, 11.9 mmol) in DMF (100 mL) was treated with 1-iodopyrrolidine-2,5-dione (1.50 eq., 4.00 g, 17.8 mmol) and stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with aqueous sat. sodium hydrocarbonate solution and brine, filtrated over a hydrophobic phase separation filter paper and concentrated in vacuo. The obtained material was purified by flash chromatography (SiO2-hexane/ ethyl acetate) to give the title compound (6.27 g, 92%).
LC-MS (method 2): Rt = 1.64 min; MS (ESIpos): m/z = 548 [M+H].
1H-NMR (400 MHz, DMSO-d6) 6 [ppm] = -0.09 (s, 9H), 0.80 ¨ 0.84 (m, 2H), 3.51 ¨
3.55 (m, 2H), 5.61 (s, 2H), 6.64 (d, 1H), 7.93 (s, 1H), 8.21 (d, 1H), 8.40 ¨ 8.45 (m, 2H).
Intermediate 181 4-(2 ,6-d ifl uoro-4-n itrophenoxy)-3-methyl-1-{[2-(trimethylsi lypethoxy]methy11-1 H-pyrrolo[2,3-11+
*

I
H 3C ¨1St b]pyridine A solution of 4-(2,6-difluoro-4-nitrophenoxy)-3-iodo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridine (intermediate 180; 200 mg, 0.365 mmol) in anhydrous 1,4-dioxane (5 mL) under argon was treated with [1,1'-bis(diphenylphosphino)ferrocene]di-.. chloropalladium(II), complex with dichloromethane (CAS No. [95464-05-4];
0.05 eq., 15 mg, 18 pmol) and dropwise with dimethylzinc (CAS No. [544-97-8]; 3.00 eq, 548 pL
of a 2 M
solution in toluene) and stirred at 100 C for 30 minutes. The reaction mixture was cooled to rt and taken up with ethyl acetate and water. The phases were separated and the aqueous phase extracted with ethyl acetate. The combined organic phases were dried with sodium sulfate and concentrated in vacuo. The obtained material was purified by flash chromatography (SiO2-hexane/ ethyl acetate) to give the title compound along with starting material (20%) and dehalogenated starting material (20%, 110 mg in total).
LC-MS (method 2): Rt = 1.65 min; MS (ESIpos): rniz = 436 [M+H].
Intermediate 182 3 ,5-d ifl uoro-4-[(3-methyl-1-{[2-(trimethylsilypethoxy]methy11-1 H-pyrrolo[2,3-b]pyrid in-4-yl)oxy]aniline 0 l'W

F
/ I
NN/

rj A solution of 4-(2,6-difluoro-4-nitrophenoxy)-3-methyl-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridine (intermediate 181; 110 mg) in ethanol (10 mL) was treated with palladium(II) hydroxide on carbon (20wV/0; 0.05 eq., 14 mg, 13 pmol) and three drops of aqueous hydrochloric acid (4 M) and stirred under a hydrogen atmosphere at rt for 4 hours.
The reaction mixture was filtrated over Celite, washed with ethanol and the filtrate concentrated in vacuo to give the title compound (90 mg) which was not further purified.
LC-MS (method 2): Rt = 1.49 min; MS (ESIpos): rniz = 406 [M+H].

Intermediate 183 phenyl {3,5-difluoro-4-[(3-methyl-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]phenyllcarbamate NO
110 8 el I
N N/

H 3C -St H3d CH3 A solution of 3,5-d ifl uoro-4-[(3-methyl-1-{[2-(tri methylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyrid in-4-yl)oxy]ani line (intermediate 182; 110 mg, 0.27 mmol) in ethyl acetate (2 mL) was treated with an aqueous sat. sodium hydrocarbonate solution (2 mL) and with phenyl chloroformate (CAS No. [1885-14-9]; 3.0 eq, 0.10 mL, 0.81 mmol) and the mixture stirred at rt for 2 days. As the conversion was not complete additional amounts of phenyl chloroformate (2.0 eq, 0.07 mL, 0.54 mmol and 3.0 eq, 0.10 mL, 0.81 mmol) were sequentially added and the reaction mixture stirred for another 4 days. The reaction mixture was diluted with ethyl acetate and water, the phases separated and the aqueous phase extracted with ethyl acetate (twice).
The combined organic phases were washed with brine, dried with sodium sulfate and concentrated in vacuo. The obtained material was purified by flash chromatography (SiO2-hexane/ ethyl acetate) to give the title compound (60 mg) containing minor amounts of 1-0,5-d ifl uoro-4-[(3-methyl-1-{[2-(trimethylsi lypethoxy]methy11-1H-pyrrolo[2,3-b]pyrid in-4-yl)oxy]phenyllu rea.
LC-MS (method 2): Rt= 1.65 min; MS (ESIpos): m/z = 526 [M+H].
Intermediate 184 1-{3,5-difluoro-4-[(3-methyl-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]phenyll-342-(dimethylamino)ethyl]urea H H
NyNC H3 I
N'N/
r-1 H3c-"St H3d CH3 To a solution of phenyl {3,5-difluoro-4-[(3-methyl-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]phenyllcarbamate (intermediate 183; 60.0 mg, 114 pmol) in DMF
(2.0 mL) was added N,N-dimethylethane-1,2-diamine (1.20 eq., 12.1 mg, 137 pmol) and this mixture was stirred at 70 C for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was dried and concentrated in vacuo and the crude product (59 mg) used in the next step without any further purification.
LC-MS (method 2): R1= 1.49 min; MS (ESIneg): rrilz = 518 [M-H]-.
Intermediate 185 4-(2,6-difluoro-4-nitrophenoxy)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile N +
?

H 3C -"St H3d CH3 A solution of 4-(2,6-difluoro-4-nitrophenoxy)-3-iodo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridine (intermediate 180; 3.04 g, 5.55 mmol) in DMF (15 mL) was treated with .. copper(I) cyanide (CAS No. [544-92-3]; 1.30 eq., 647 mg, 7.22 mmol) and stirred at 120 C for hours. The reaction mixture was taken up with ethyl acetate and water, the phases separated and the aqueous phase extracted with ethyl acetate (2x). The combined organic phases were washed with water and brine, dried with sodium sulfate and concentrated in vacuo. The obtained material was purified by flash chromatography (5i02-hexane/ ethyl 20 acetate) to give the title compound (2.17 g, 87%).
LC-MS (method 2): Rt = 1.50 min; MS (ESIpos): rniz = 447 [M+H].
1H-N MR (400 MHz, DMSO-d6) 6 [ppm] = -0.10 (s, 9H), 0.82 ¨ 0.86 (m, 2H), 3.56 ¨ 3.60 (m, 2H), 5.70 (s, 2H), 6.87 (d, 1H), 8.36 (d, 1H), 8.43 ¨ 8.48 (m, 2H), 8.73 (s, 1H).

Intermediate 186 4-(4-amino-2,6-difluorophenoxy)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile ?

H 3C -"SI

A solution of 4-(2,6-difluoro-4-nitrophenoxy)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (intermediate 185; 1.05 g, 2.35 mmol) in methanol (15 mL) was treated with tin(II) chloride dihydrate (CAS No. [10025-69-1]; 3.00 eq, 1.59 g, 7.06 mmol) and stirred at 65 C overnight. The reaction mixture was cooled to rt and concentrated in vacuo.
The residue was taken up with ethyl acetate and aqueous sat. sodium carbonate solution, filtrated over diatomite and the phases separated. The organic phase was washed with aqueous sat. sodium carbonate solution, dried with sodium sulfate and concentrated in vacuo to give the title compound (630 mg, 61%) which was not further purified.
LC-MS (method 2): R1= 1.37 min; MS (ESIpos): rniz = 417 [M+H].
1H-NMR (400 MHz, DMSO-d6) 6 [ppm] = -0.09 (s, 9H), 0.81 - 0.85 (m, 2H), 3.55 -3.59 (m, 2H), 5.66 (s, 2H), 5.86 (br s, 2H), 6.38 - 6.44 (m, 2H), 6.57 (d, 1H), 8.29 (d, 1H), 8.63 (s, 1H).
Intermediate 187 phenyl {4-[(3-cyano-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyllcarbamate NO
0.
?

H3c CH3 A solution of 4-(4-amino-2,6-difluorophenoxy)-1-{[2-(trimethylsilypethoxy]methy11-1 H-pyrrolo[2,3-b]pyridine-3-carbonitrile (intermediate 186; 390 mg, 0.936 mmol) in ethyl acetate (5 mL) was treated with an aqueous sat. sodium hydrocarbonate solution (5 mL) and with phenyl chloroformate (CAS No. [1885-14-9]; 5.0 eq, 0.59 mL, 4.7 mmol) and the mixture stirred at rt for 18 hours. The reaction mixture was diluted with ethyl acetate and water, the phases separated and the aqueous phase extracted with ethyl acetate (twice). The combined organic phases were washed with brine, dried with sodium sulfate and concentrated in vacuo. The obtained material was purified by flash chromatography (SiO2-hexane/ ethyl acetate) to give the title compound (310 mg) containing 1-{4-[(3-cyano-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyllurea.
LC-MS (method 2): Rt= 1.53 min; MS (ESIpos): m/z = 537 [M+H].
Intermediate 188 4-(4-amino-2,6-difluorophenoxy)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile trifluoroacetate N
? IW 0 F
F
N--"N/ F
H
A solution of 4-(4-amino-2,6-difluorophenoxy)-1-{[2-(trimethylsilypethoxy]methy11-1 H-pyrrolo[2,3-b]pyridine-3-carbonitrile (intermediate 186; 510 mg, 1.22 mmol) in dichloromethane (5 mL) was treated with trifluoroacetic acid (40 eq., 3.8 mL, 49 mmol) and stirred at rt overnight. The reaction mixture was concentrated in vacuo and the obtained residue stirred in cyclopentyl methyl ether for 30 min. The precipitate was filtered off and the filtrate concentrated in vacuo to give the crude title compound (350 mg) which was not further purified.
LC-MS (method 2): Rt= 0.75 min; MS (ESIpos): m/z = 287 [M-CF3COO].

Intermediate 189 (+/-)-1-{4-[(3-cyano-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(tetrahydrofuran-3-yOurea H H
N N

?
0-j r-I

H3d CH3 To a solution of phenyl {4-[(3-cyano-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (intermediate 187; 333 mg, 621 pmol) in DMF
(3.0 mL) was added (+/-)-tetrahydrofuran-3-amine (1.20 eq, 64.9 mg, 745 pmol) and this mixture was stirred at 70 C for 20 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The organic phase was separated, dried and concentrated in vacuo.
The crude product (329 mg) was used in the next step without any further purification.
LC-MS (method 2): Rt= 1.33 min; MS (ESIpos): m/z = 530 [M+H].
Intermediate 190 1-{4-[(3-cyano-1-{[2-(trimethylsi lypethoxy]methy11-1 H-pyrrolo[2,3-b]pyrid in-4-yl)oxy]-3,5-difluoropheny11-3[2-(dimethylamino)ethyl]urea H H
yC H 3 ?
N'N/
r-I

H3d CH3 This intermediate was prepared in analogy to intermediate 189 by reacting phenyl {4-[(3-cyano-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophe-nyllcarbamate (155 mg, 22% purity, 63.5 pmol, intermediate 187) and N,N-dimethylethane-1,2-diamine (1.2 eq., 7.0 mg, 76 pmol) in DMF for 18 hours at 70 C to give after aqueous work-up the crude product (34 mg) which was used in the next step without any further purification.
LC-MS (method 2): Rt= 1.36 min; MS (ESIpos): m/z = 531 [M+H].

Intermediate 191 (+/-)-1-{4-[(3-cyano-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(tetrahydrofuran-2-ylmethypurea 40H NHer. L1 TN
,) H3C-"S
i, H3d CH3 This intermediate was prepared in analogy to intermediate 189 by reacting phenyl {4-[(3-cyano-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophe-nyllcarbamate (352 mg, 656 pmol, intermediate 187) and (+/-)-1-(tetrahydrofuran-2-yl)methanamine (1.20 eq., 79.6 mg, 787 pmol) in DMF for 20 hours at 70 C to give after aqueous work-up the crude product (357 mg) which was used in the next step without any further purification.
LC-MS (method 2): Rt= 1.38 min; MS (ESIpos): m/z = 544 [M+H].
Intermediate 192 1-{4-[(3-cyano-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(3-methoxypropypurea H H
0 NyN 'CH3 ?
H3C¨S
Fi3d CH3 This intermediate was prepared in analogy to intermediate 189 by reacting phenyl {4-[(3-cyano-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophe-nyllcarbamate (319 mg, 594 pmol, intermediate 187) and 3-methoxypropan-1-amine (1.20 eq., 63.6 mg, 713 pmol) in DMF for 20 hours at 70 C to give after aqueous work-up the crude product (316 mg) which was used in the next step without any further purification.
LC-MS (method 2): Rt= 1.37 min; MS (ESIpos): rrilz = 532 [M+H].
Intermediate 193 1-{4-[(3-cyano-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-343-(morpholin-4-y1)propyl]urea H H (0 N NN) N\ ? (001 Yo NN/
H3C-"Si H3d CH3 This intermediate was prepared in analogy to intermediate 189 by reacting phenyl {4-[(3-cyano-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophe-nyllcarbamate (155 mg, 22% purity, 63.5 pmol, intermediate 187) and 3-(morpholin-4-yl)propan-1-amine (1.2 eq., 11 mg, 76 pmol) in DMF for 18 hours at 70 C to give after aqueous work-up the crude product (37 mg) which was used in the next step without any further purification.
LC-MS (method 2): R1= 1.32 min; MS (ESIpos): rrilz = 587 [M+H].
Intermediate 194 1-{4-[(3-cyano-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-[(1-methyl-1H-pyrazol-3-y1)methyl]urea H H --F CN¨C H 3 ? *

r-1 H 3C-"S1 H3d CH3 This intermediate was prepared in analogy to intermediate 189 by reacting phenyl {4-[(3-cyano-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophe-nyllcarbamate (322 mg, 600 pmol, intermediate 187) and 1-(1-methyl-1H-pyrazol-yl)methanamine (1.20 eq., 80.0 mg, 720 pmol) in DMF for 20 hours at 70 C to give after aqueous work-up the crude product (332 mg) which was used in the next step without any further purification.
LC-MS (method 2): Rt= 1.32 min; MS (ESIpos): rniz = 554 [M+H].
Intermediate 195 1-{4-[(3-cyano-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(1,3-thiazol-2-ylmethypurea H HS----\\
F NN).*:..-NZ
N

F
eipn N Th/
0--i r--I

H3d C H3 This intermediate was prepared in analogy to intermediate 189 by reacting phenyl {4-[(3-cyano-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophe-nyllcarbamate (350 mg, 652 pmol, intermediate 187) and 1-(1,3-thiazol-2-yl)methanamine (1.20 eq., 89.4 mg, 783 pmol) in DMF for 20 hours at 70 C to give after aqueous work-up the crude product (363 mg) which was used in the next step without any further purification.
LC-MS (method 2): Rt= 1.35 min; MS (ESIpos): rniz = 557 [M+H].
Intermediate 196 1-{4-[(3-cyano-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(pyridin-4-ylmethypurea H HO\I
N I.F N N /
ci :, 0 F
/ I
N F\j/
0---i r--1 H3C*-S1 This intermediate was prepared in analogy to intermediate 189 by reacting phenyl {4-[(3-cyano-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophe-nyllcarbamate (140 mg, 261 pmol, intermediate 187) and 1-(pyridin-4-yl)methanamine (1.20 eq., 33.9 mg, 313 pmol) in DMF for 18 hours at 70 C to give after aqueous work-up the crude product (144 mg) which was used in the next step without any further purification.
LC-MS (method 2): Rt= 1.31 min; MS (ESIpos): rrilz = 551 [M+H].
Intermediate 197 1-{4-[(3-cyano-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluoropheny11-3-(2-methoxyethypurea H H
F
fa NyNO'C H 3 7 'w F
I-' N F\j/

ri H 3C -"SI
H3d CH3 This intermediate was prepared in analogy to intermediate 189 by reacting phenyl {4-[(3-cyano-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophe-nyllcarbamate (356 mg, 663 pmol, intermediate 187) and 2-methoxyethanamine (1.20 eq., 59.8 mg, 796 pmol) in DMF for 20 hours at 70 C to give after aqueous work-up the crude product (343 mg) which was used in the next step without any further purification.
LC-MS (method 2): R1= 1.34 min; MS (ESIpos): rrilz = 518 [M+H].
Intermediate 198 1-{4-[(3-cyano-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(1H-pyrazol-3-ylmethyl)urea H
N-N
F cill ?
F
-Dn N ,N

r--1 H3d CH3 This intermediate was prepared in analogy to intermediate 189 by reacting phenyl {4-[(3-cyano-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophe-nyllcarbamate (280 mg, 522 pmol, intermediate 187) and 1-(1H-pyrazol-3-yl)methanamine (1.20 eq., 60.8 mg, 626 pmol) in DMF for 18 hours at 70 C to give after aqueous work-up the crude product (282 mg) which was used in the next step without any further purification.
LC-MS (method 2): Rt = 1.28 min; MS (ESIpos): m/z = 540 [M+H].
Intermediate 199 4-(4-bromo-2 ,6-d ifl uorophenoxy)-1-{[2-(trimethylsi lypethoxy]methy11-1 H-pyrrolo[2,3-b]pyridine-3-carbonitrile F Br N
? l'W
F
N---"N/

ri Fi3d CH3 A solution of 4-(4-amino-2,6-difluorophenoxy)-1-{[2-(trimethylsilypethoxy]methy11-1 H-pyrrolo[2,3-b]pyridine-3-carbonitrile (intermediate 186; 1.05 g, 2.52 mmol) in tribromomethane (10 mL) was treated dropwise with a solution of 3-methylbutyl nitrite (CAS No.
[110-46-3]; 2.00 eq, 591 mg, 5.04 mmol) in tribromomethane (3 mL). The reaction mixture was heated to 100 C
for 1 hour, cooled to rt and concentrated in vacuo. The obtained material was purified by flash chromatography (5i02-hexane/ ethyl acetate) to give the title compound (800 mg, 63%).
LC-MS (method 2): Rt = 1.58 min; MS (ESIpos): m/z = 480/482 [M+H] (Br isotope pattern).
1H-NMR (400 MHz, DMSO-d6) 6 [ppm] = -0.10 (s, 9H), 0.80 ¨ 0.86 (m, 2H), 3.56 ¨
3.60 (m, 2H), 5.68 (s, 2H), 6.74 (d, 1H), 7.82 ¨ 7.86 (m, 2H), 8.31 (d, 1H), 8.69 (s, 1H).

Intermediate 200 (+/-)-1-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluoropheny11-3-(tetrahydrofuran-3-yOurea H H
N N
= T
Br I
H3C-"Si H3d CH3 To a solution of phenyl {4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (225 mg, 381 pmol, intermediate 159) in DMF
(4.0 mL) was added (+/-)-tetrahydrofuran-3-amine hydrochloride (1:1) (56.5 mg, 457 pmol) and triethylamine (1.0 eq., 53 pL, 380 pmol) and this mixture was stirred at 70 C
for 27 hours.
After cooling to room temperature ethyl acetate and water were added to the reaction mixture and the phases were separated. The organic phase was dried and concentrated in vacuo. The resulting residue was purified by flash chromatography (SiO2-hexane/ ethyl acetate) to give the title compound (109 mg, 44%).
LC-MS (method 2): Rt= 1.48 min; MS (ESIpos): m/z = 583/585 [M+H] (Br isotope pattern).
Intermediate 201 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(6-methoxypyridazin-3-yOurea H H
N N
`r I
N'N/
r-1 H3C-"Si H3d CH3 To a solution of phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) in DMF
(700 pL) was added 6-methoxypyridazin-3-amine (33.0 mg, 264 pmol, CAS No.
[7252-84-8]) and the resulting reaction mixture was stirred at 90 C overnight. After cooling to room temperature ethyl acetate and brine was added. The resulting precipitate was collected from the organic layer by filtration. The white powder was dried, to obtain 82.0 mg (70 % purity, 36 % yield) of the desired title compound.
LC-MS (method 3): Rt= 1.56 min; MS (ESIpos): rniz = 609 [M+H]
Intermediate 202 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(6,7-dihydro-5H-cyclopenta[c]pyridazin-3-yOurea I I
HY
N
NN H
F zF 1110 H3C¨S1 H3d CH3 In analogy to intermediate 201, using phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1) and 6,7-dihydro-5H-cyclopenta[c]pyridazin-3-amine (35.7 mg, 264 pmol, CAS No. [1342288-68-9]) in DMF (700 pL). The resulting precipitate was collected by filtration and dried to obtain 55.5 mg (80% purity, 30 % yield) of the desired title compound.
LC-MS (method 3): R1= 1.57 min; MS (ESIpos): rniz = 621 [M+H]

Intermediate 203 N-(6-bromopyridazin-3-y1)-N'-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllurea H H
N N
`r %Br I
r-1 H 3C ¨

To a solution of phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (150 mg, 275 pmol, intermediate 44) in DMF
(2.1 mL) was added 6-bromopyridazin-3-amine (57.4 mg, 330 pmol, CAS No. [88497-27-2]) and the resulting mixture was stirred at 90 C over night. After cooling to room temperature ethyl acetate and water was added. After separation of the organic phase the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness, to obtain the crude product 130 mg (76 % yield) which was used in the next step without further purification.
LC-MS (method 3): Rt= 1.61 min; MS (ESIpos): rrilz = 625 [M+H]
Intermediate 204 (+/-)-1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(tetrahydrofuran-2-ylmethypurea HHJN N

Cl I

H 3C ¨P.

In analogy to intermediate 2, using phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (130 mg, 238 pmol, intermediate 44) and (+/-)-1-(tetrahydrofuran-2-yl)methanamine (48.2 mg, 476 pmol, CAS No.
[4795-29-3]) in DMF (4 mL). 167 mg of the crude desired product was obtained, which was used in the next step without further purification.
LC-MS (method 3): Rt= 1.51 min; MS (ESIpos): m/z = 553 [M+H]
Intermediate 205 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluoropheny11-3-[(35)-tetrahydrofuran-3-yl]urea H H
N
T Co Cl 0 I
N'N/

H3d CH3 In analogy to intermediate 2, phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (150 mg, 275 pmol, intermediate 44), (35)-tetrahydrofuran-3-amine (47.9 mg, 549 pmol, CAS No. [104530-79-2]) together in DMF (4 mL) were reacted to obtain a crude product which was used in the next step without further purification.
LC-MS (method 2): Rt= 1.43 min; MS (ESIpos): m/z = 539 [M+H]
Intermediate 206 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(2-oxaspiro[3.3]hept-6-yOurea H H
NN
Cl I
N'N/
H3C-"St H3d CH3 To a solution of phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (150 mg, 275 pmol, intermediate 44), 2-oxaspiro[3.3]heptan-6-amine hydrochloride (1:1) (82.2 mg, 549 pmol, CAS No.
[1363381-78-5]) and triethylamine (77 pL, 550 pmol) in DMF (4 mL) was heated to 60 C for 2 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and water was added. The phases were separated and the aqueous phase was extracted two times with ethyl acetate. The combined organic layers were washed with Brine, dried over Na2SO4, filtered and evaporated to obtain the crude product which was used in the next step without further purification.
.. LC-MS (method 2): Rt= 1.43 min; MS (ESIpos): m/z = 565 [M+H]
Intermediate 207 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-[(1-methyl-1H-pyrazol-3-y1)methyl]urea H H
F N N ,N¨C H3 . 0 N
Cl 0 F
/ I
N----N/

rj H 3C¨Si, In analogy to intermediate 2, phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (130 mg, 238 pmol, intermediate 44), and 1-(1-methyl-1H-pyrazol-3-yl)methanamine (52.9 mg, 476 pmol, CAS No.
[612511-81-6]) in DMF (4 mL) were reacted to obtain a crude product which was used in the next step without further purification.
LC-MS (method 3): Rt= 1.44 min; MS (ESIpos): m/z = 563 [M+H]

Intermediate 208 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-346-(difluoromethyppyridazin-3-yl]urea H H
CI
N N
0 0 1\k F
I
NN/
r-1 H3c-"S[
H3d C H3 In analogy to intermediate 203, phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (150 mg, 275 pmol, intermediate 44), 6-(difluoromethyl)pyridazin-3-amine (47.8 mg, 330 pmol, CAS No. [1706450-11-4]) in DMF
(2.1 mL) were reacted to obtain the crude product which was used in the next step without further purification.
.. LC-MS (method 3): R1= 1.59 min; MS (ESIpos): rn/z = 597 [M+H]
Intermediate 209 (+/-)-1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(tetrahydrofuran-3-yOurea H H
N N
)C
CI
I
H3C-St 1_1 d CH3 "3 In analogy to intermediate 2, phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (130 mg, 238 pmol, intermediate 44), and (+/-)-tetrahydrofuran-3-amine (41.5 mg, 476 pmol, CAS No. [45379-55-3]) in DMF (4 mL) were reacted to obtained a crude product which was used in the next step without further purification.
LC-MS (method 3): Rt= 1.46 min; MS (ESIpos): m/z = 539 [M+H]

Intermediate 210 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(3-methoxypropypurea H H
(10 Ny 0No'CH3 I
H

In analogy to intermediate 2, phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (130 mg, 238 pmol, intermediate 44), and 3-methoxypropan-1-amine (49 pL, 480 pmol, CAS No. [109-85-3]), in DMF
(4 mL) were reacted to obtained the crude product which was used in the next step without further purification.
LC-MS (method 3): Rt = 1.49 min; MS (ESIpos): rrilz = 541 [M+H]
Intermediate 211 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluoropheny11-3-[(3R)-tetrahydrofuran-3-yl]urea H H
NN

I
H

In analogy to intermediate 2, phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (150 mg, 275 pmol, intermediate 45), and (3R)-tetrahydrofuran-3-amine (47.9 mg, 549 pmol, CAS No. [111769-26-7]) in DMF (4 mL) were reacted to obtained the crude product which was used in the next step without further purification.
LC-MS (method 2): Rt = 1.43 min; MS (ESIpos): m/z = 539 [M+H]
Intermediate 212 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(1H-pyrazol-3-ylmethyl)urea N¨N
11\11{11\11 ci 0 I
NN/
r-1 H 3C -St H3d CH3 In analogy to intermediate 2, phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyllcarbamate (150 mg, 275 pmol, intermediate 44), and 1-(1H-pyrazol-3-yl)methanamine (53.4 mg, 549 pmol, CAS No. [37599-58-9]), in DMF
(4 mL) were reacted to obtain the crude product which was used in the next step without further purification.
LC-MS (method 2): Rt = 1.40 min; MS (ESIpos): rniz = 549 [M+H]
Intermediate 213 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(2,2,2-trifluoroethyl)urea H H.)<F
NN

CI
I

Fi3d CH3 In analogy to intermediate 2, phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (150 mg, 275 pmol, intermediate 44), and 2,2,2-trifluoroethanamine (44 pL, 550 pmol, CAS No. [753-90-2]), in DMF (4 mL) were reacted to obtain the crude product which was used in the next step without further purification.
LC-MS (method 2): Rt= 1.55 min; MS (ESIpos): m/z = 551 [M+H]
Intermediate 214 (+/-)-N-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-[(dimethylamino)methyl]pyrrolidine-1-carboxamide H
F
¨C H3 F
/ I
N Th/

r-I
H3c-1 0 st In analogy to intermediate 2, phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (150 mg, 275 pmol, intermediate 44), and (+/-)-N,N-dimethy1-14-pyrrolidin-3-yl]methanamine (74.2 mg, 549 pmol, CAS No.
[99724-17-1]), in DMF (4 mL) were reacted to obtain a crude product which was used in the next step without further purification.
LC-MS (method 2): Rt= 1.55 min; MS (ESIpos): m/z = 580 [M+H]
Intermediate 215 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluoropheny11-3-[(4-methyl-1,2,5-oxadiazol-3-y1)methyl]urea H H
F õI Niir, NI-1(CH3 CI 0 sO"
F
/ I
N N/

r-i H3d CH3 In analogy to intermediate 2, phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (150 mg, 275 pmol, intermediate 44), and 1-(4-methyl-1,2,5-oxadiazol-3-yl)methanamine (62.1 mg, 549 pmol, CAS
No.
[321392-83-0]), in DMF (4.0 mL) were reacted to obtain a crude product which was used in the next step without further purification.
LC-MS (method 2): Rt= 1.53 min; MS (ESIpos): rrilz = 565 [M+H]
Intermediate 216 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluoropheny11-3-(2-fluoroethypurea H H
F *
I N N I y F

C
F
/ I
N F\j/

ri H3C-"Si, H3d C H3 In analogy to intermediate 206, phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (150 mg, 275 pmol, intermediate 44), 2-fluoroethanamine hydrochloride (60.8 mg, 549 pmol, CAS No. [460-08-2]), and triethylamine (77 pL, 550 pmol) in DMF (4.0 mL) were reacted to obtain a crude product which was used in the next step without further purification.
LC-MS (method 2): Rt= 1.47 min; MS (ESIpos): rrilz = 515 [M+H]
Intermediate 217 N-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-2-oxa-7-azaspiro[3.5]nonane-7-carboxamide H r=Ci0 F N
*I 1r CI N
F
/ I
N N/

ri H3d CH3 In analogy to intermediate 206, phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (150 mg, 275 pmol, intermediate 44), 2-oxa-7-azaspiro[3.5]nonane ethanedioate (2:1) (94.6 mg, 275 pmol, CAS
No. [1429056-

28-9]), and triethylamine (77 pL, 550 pmol) in DMF (4.0 mL) were reacted to obtain a crude product which was used in the next step without further purification.
LC-MS (method 2): Rt= 1.50 min; MS (ESIpos): rrilz = 579 [M+H]
Intermediate 218 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-y1)oxy]-3,5-difluorophenyI}-3-(2,2-difluoroethyl)urea H HL
Cl NN
I. 8 I
r-I
H 3C -St H3d CH3 In analogy to intermediate 2, phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (150 mg, 275 pmol, intermediate 44), and 2,2-difluoroethanamine (44.5 mg, 549 pmol, CAS No. [430-67-1]), in DMF (4.0 mL) were reacted to obtain a crude product which was used in the next step without further purification.
LC-MS (method 2): Rt= 1.50 min; MS (ESIpos): rrilz = 533 [M+H]
Intermediate 219 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-[(4-methyl-1H-imidazol-2-y1)methyl]urea H N

N
CI
I
N N/
oJ

H3d CH3 In analogy to intermediate 206, phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (150 mg, 275 pmol, intermediate 44), 1-(4-methyl-1H-imidazol-2-yl)methanamine dihydrochloride (106 mg, 549 pmol, CAS No.
[855250-27-0]), and triethylamine (77 pL, 550 pmol) in DMF (4.0 mL) were reacted to obtain a crude product which was used in the next step without further purification.
LC-MS (method 2): Rt= 1.42 min; MS (ESIpos): rrilz = 563 [M+H]
Intermediate 220 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-y1)oxy]-3,5-difluoropheny11-3-(6-methoxypyridazin-3-yOurea H H
N N

I
H 3C ¨SI
H3d CH3 In analogy to intermediate 203, phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (150 mg, 275 pmol, intermediate 44), and 6-methoxypyridazin-3-amine (41.2 mg, 330 pmol, CAS No. [7252-84-8]), in DMF
(2.1 mL) were reacted to obtain a crude product which was used in the next step without further purification.
LC-MS (method 3): Rt= 1.54 min; MS (ESIpos): rrilz = 578 [M+H]

Intermediate 221 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(1,3,4-thiadiazol-2-yOurea H H
N TrõN, -r CI
I
r-I

H3d CH3 In analogy to intermediate 203, phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (150 mg, 275 pmol, intermediate 44), and 1,3,4-thiadiazol-2-amine (55.6 mg, 549 pmol, CAS No. [4005-51-0]), in DMF (4.0 mL) were reacted to obtain a crude product which was used in the next step without further purification.
LC-MS (method 2): R1= 1.01 min; MS (ESIpos): rniz = 553 [M+H]
Intermediate 222 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(1,3-thiazol-2-ylmethypurea N\
CI

I
NN/
H3C¨S1 H3d CH3 In analogy to intermediate 2, phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (150 mg, 275 pmol, intermediate 44), and 1-(1,3-thiazol-2-yl)methanamine (62.7 mg, 549 pmol, CAS No. [55661-33-1]), in DMF
(4.0 mL) were reacted to obtain a crude product which was used in the next step without further purification.
LC-MS (method 2): Rt= 1.47 min; MS (ESIpos): rniz = 566 [M+H]

Intermediate 223 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(6-iodopyridazin-3-yOurea H H
N N
0 N...

I
NN/
H3C-"St H3d CH3 In analogy to intermediate 203, phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (150 mg, 275 pmol, intermediate 44), and 6-iodopyridazin-3-amine (72.9 mg, 330 pmol, CAS No. [187973-60-0]), in DMF
(2.1 mL) were reacted to obtain a crude product which was used in the next step without further purification.
LC-MS (method 3): R1= 1.62 min; MS (ESIpos): rrilz = 673 [M+H]
Intermediate 224 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-346-(morpholin-4-y1)pyridazin-3-yl]urea H H
N N
1101 1\1 CI
Lo NN/
r-1 H3c-s[
cH3 "3 In analogy to intermediate 203, phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (150 mg, 275 pmol, intermediate 44), and 6-(morpholin-4-yl)pyridazin-3-amine (59.4 mg, 330 pmol, CAS No.
[66346-91-6]), in DMF (2.1 mL) were reacted to obtain a crude product which was used in the next step without further purification.
LC-MS (method 3): Rt= 1.50 min; MS (ESIpos): rrilz = 632 [M+H]

Intermediate 225 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(5-methylpyridazin-3-yOurea H H
N N N
y (001 0 cl 0 I
NN/

H3d CH3 In analogy to intermediate 203, phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (150 mg, 275 pmol, intermediate 44), and 5-methylpyridazin-3-amine (36.0 mg, 330 pmol, CAS No. [144294-43-9]), in DMF
(2.1 mL) were reacted to obtain the crude product which was used in the next step without further purification.
LC-MS (method 3): R1= 1.54 min; MS (ESIpos): rrilz = 561 [M+H]
Intermediate 226 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(6-cyclopropylpyridazin-3-yOurea H H
NN
`N

I
NN/
r-1 H3C-"Si, H3d CH3 In analogy to intermediate 203, phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (150 mg, 275 pmol, intermediate 44), and 6-cyclopropylpyridazin-3-amine (44.6 mg, 330 pmol, CAS No. [1159814-07-9]), in DMF (2.1 mL) were reacted to obtain a crude product which was used in the next step without further purification.
LC-MS (method 3): Rt= 1.58 min; MS (ESIneg): rrilz = 587 [M+H]

Intermediate 227 (+/-)1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(1-methyl-5-oxopyrrolidin-3-yOurea H H
N N

F
H3C, C H3 /
H

In analogy to intermediate 85, phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1), (+/-)-4-amino-1-methylpyrrolidin-2-one hydrochloride (1:1) (44.8 mg, 298 pmol) together in DMF (0.7mL) and N,N-diisopropylethylamine (52 pL, 300 pmol), we obtained after one single purification using a Biotage chromatography system (11g snap KP-NH column, hexane / 50 ¨ 100% ethyl acetate, then ethyl acetate / 0 ¨ 50%
ethanol) 110 mg (100% purity, 71 % yield) of the desired title compound.
LC-MS (method 2): Rt = 1.48 min; MS (ESIneg): m/z = 598 [M-H]-1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.12 - -0.07 (m, 9H), 0.80 - 0.86 (m, 2H), 2.17 (dd, 1H), 2.61 (dd, 1H), 2.73 (s, 3H), 3.19 (dd, 1H), 3.54 - 3.60 (m, 2H), 3.64 (dd, 1H), 4.23 - 4.31 (m, 1H), 5.68 (s, 2H), 6.57 (d, 1H), 6.97 (d, 1H), 7.36 - 7.43 (m, 2H), 8.29 (d, 1H), 8.36 (s, 1H), 9.02 (s, 1H).
Intermediate 228 N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyI)-4,4-difluoropiperidine-1-carboxamide HF
F F
H3C, CH3 / I
H NN/

0"--1 In analogy to intermediate 85, phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1), 4,4-difluoropiperidine (36.1 mg, 298 pmol) together in DMF (0.7mL) and N,N-diisopropylethylamine (52 pL, 300 pmol), we obtained after one single purification using a Biotage chromatography system (11g snap KP-NH column, hexane / 50 ¨
100% ethyl acetate, then ethyl acetate / 0 ¨ 50% ethanol) 158 mg (100 % purity, 101 %
yield) of the desired title compound.
LC-MS (method 2): Rt = 1.59 min; MS (ESIpos): m/z = 607 [M+H]
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 --0.07 (m, 9H), 0.80 - 0.86 (m, 2H), 1.96 - 2.08 (m, 4H), 3.54 - 3.63 (m, 6H), 5.68 (s, 2H), 6.57 (d, 1H), 7.50 (d, 2H), 8.29 (d, 1H), 8.37 (s, 1H), 9.16 (s, 1H).
Intermediate 229 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-343-(propan-2-yloxy)propyl]urea H H
F F NyNO yC H3 F F . 0 C H3 ¨.... __.) F
H3C, P-I3 / I
H C¨SI N---N/
3 \----\ /
CD'i In analogy to intermediate 2, phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-.. (trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1), 3-(propan-2-yloxy)propan-1-amine (41 pL, 300 pmol) together in DMF (0.7 mL) we obtained the crude product, which was purified via a Biotage chromatography system (11g snap KP-NH column, hexane/ethylacetate /50 ¨ 100%
ethylacetate and ethylacetate/ethanol / 0 ¨ 50% ethanol) to obtain 140 mg (78 % purity, 70 %
yield) of the desired title compound.
LC-MS (method 2): Rt = 1.59 min; MS (ESIpos): m/z = 603 [M+H]
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 - -0.08 (m, 9H), 0.80 - 0.86 (m, 2H), 1.09 (d, 6H), 1.60 - 1.68 (m, 2H), 3.12 -3.18 (m, 2H), 3.37 - 3.41 (m, 2H), 3.48 -3.55 (m, 1H), 3.55 - 3.61 (m, 2H), 5.68 (s, 2H), 6.42 (t, 1H), 6.57 (d, 1H), 7.35 - 7.42 (m, 2H), 8.28 (d, 1H), 8.36 (s, 1H), 9.02 (s, 1H).

Intermediate 230 N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-methoxyazetidine-1-carboxamide N/yo'C H3 F
F F
F¨C),110 F
H3C, C I-13 / I
H C¨Sli N----N
3 \----\ /
0"1 In analogy to intermediate 2, phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1), 3-methoxyazetidine (25.9 mg, 298 pmol) together in DMF (0.7 mL) we obtained the crude product, which was purified via a Biotage chromatography system (11g snap KP-NH column, hexane/ethylacetate /50 ¨ 100% ethylacetate and ethylacetate/ethanol /
0¨ 50% ethanol) to obtain 151 mg (100% purity, 101 % yield) of the desired title compound.
LC-MS (method 2): Rt = 1.51 min; MS (ESIneg): m/z = 571 [M-H]-1H-N MR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 - -0.08 (m, 9H), 0.79 - 0.87 (m, 2H), 3.23 (s, 3H), 3.54 -3.60 (m, 2H), 3.79 (dd, 2H), 4.15 - 4.24 (m, 3H), 5.68 (s, 2H), 6.58 (d, 1H), 7.48 - 7.54 (m, 2H), 8.29 (d, 1H), 8.36 (s, 1H), 8.98 (s, 1H).
Intermediate 231 N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-1-oxa-6-azaspiro[3.3]heptane-6-carboxamide H

F F
FOlel 8 F
H3C, CH3 / I
H C¨i NN
3 \----\ /
0"1 In analogy to intermediate 2, phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1), 1-oxa-6-azaspiro[3.3]heptane (29.5 mg, 298 pmol) together in DMF
(0.7 mL) we obtained the crude product, which was purified via a Biotage chromatography system (11g snap KP-NH column, hexane/ethylacetate / 50 ¨ 100% ethylacetate and ethylacetate/ethanol / 0 ¨ 50% ethanol) to obtain 67.2 mg (96 % purity, 43 %
yield) of the desired title compound.
LC-MS (method 2): Rt = 1.49 min; MS (ESIpos): m/z = 585 [M+H]
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.12 - -0.08 (m, 9H), 0.77 - 0.90 (m, 2H), 2.84 (t, 2H), 3.54 - 3.60 (m, 2H), 4.07 (dd, 2H), 4.23 (dd, 2H), 4.42 (t, 2H), 5.68 (s, 2H), 6.57 (d, 1H), 7.46 -7.53 (m, 2H), 8.28 (d, 1H), 8.36 (s, 1H), 9.02 (s, 1H).
Intermediate 232 N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyI)-2-oxa-6-azaspiro[3.5]nonane-6-carboxamide H
F NN
F F 1101 8 C `0 F....._ F
H3C, P-I3 / I
H C-SI N--"N/
3 \----\ /
0 ---' In analogy to intermediate 2, phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1), 2-oxa-6-azaspiro[3.5]nonane (37.9 mg, 298 pmol) together in DMF
(0.7 mL) we obtained the crude product, which was purified via a Biotage chromatography system (11g snap KP-NH column, hexane/ethylacetate / 50 ¨ 100% ethylacetate and ethylacetate/ethanol / 0 ¨ 50% ethanol) to obtain 159 mg (100 % purity, 100 %
yield) of the desired title compound.
LC-MS (method 2): R1= 1.53 min; MS (ESIpos): m/z = 613 [M+H]
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 --0.07 (m, 9H), 0.80 - 0.87 (m, 2H), 1.43- 1.51 (m, 2H), 1.80 - 1.85 (m, 2H), 3.36 - 3.41 (m, 2H), 3.55 - 3.60 (m, 2H), 3.69 (s, 2H), 4.25 - 4.31 (m, 4H), 5.68 (s, 2H), 6.58 (d, 1H), 7.49 - 7.56 (m, 2H), 8.29 (d, 1H), 8.37 (s, 1H), 9.04 (s, 1H).

Intermediate 233 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-{[3-(propan-2-ypoxetan-3-yl]methyllurea H
NN
*
cH3 F F 0 H3c F
H3Cs_PH3 /
H 30-"Si \\OJ
In analogy to intermediate 2, phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1), 1-[3-(propan-2-yl)oxetan-3-yl]methanamine (38.5 mg, 298 pmol) together in DMF (0.7 mL) we obtained the crude product, which was purified via a Biotage chromatography system (11g snap KP-NH column, hexane/ethylacetate / 50 ¨ 100%
ethylacetate and ethylacetate/ethanol /0 ¨ 50% ethanol) to obtain 131 mg (100 % purity, 82 %
yield) of the desired title compound.
LC-MS (method 2): Rt = 1.57 min; MS (ESIpos): m/z = 615 [M+H]
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 - -0.08 (m, 9H), 0.80 - 0.86 (m, 2H), 0.91 (d, 6H), 2.01 (spt, 1H), 3.32 (d, 2H), 3.54 - 3.61 (m, 2H), 4.28 - 4.34 (m, 4H), 5.68 (s, 2H), 6.59 (d, 1H), 6.71 -6.78 (m, 1H), 7.37 - 7.44 (m, 2H), 8.28 (d, 1H), 8.36 (s, 1H), 9.12 (s, 1H).
Intermediate 234 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-343-methyl-3-(morpholin-4-y1)butyl]urea H H (0 N N
Y NJ
F F

F
H3C, CH3 / I
H 3 _ In analogy to intermediate 2, phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1), 3-methyl-3-(morpholin-4-yl)butan-1-amine dihydrochloride (73.0 mg, 298 pmol) together in DMF (0.7 mL) we obtained the crude product, which was purified via a .. Biotage chromatography system (11g snap KP-NH column, hexane/ethylacetate /50 ¨ 100%

ethylacetate and ethylacetate/ethanol / 0¨ 50% ethanol) to obtain 150 mg (92 %
purity, 81 %
yield) of the desired title compound.
LC-MS (method 2): Rt = 1.57 min; MS (ESIpos): m/z = 658 [M+H]
1H-N MR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 - -0.08 (m, 9H), 0.79 - 0.87 (m, 2H), 0.98 (s, 6H), 1.52 - 1.59 (m, 2H), 2.43 - 2.48 (m, 4H), 3.13 (dt, 2H), 3.53 - 3.61 (m, 6H), 5.68 (s, 2H), 6.35 (t, 1H), 6.57 (d, 1H), 7.34 - 7.41 (m, 2H), 8.29 (d, 1H), 8.36 (s, 1H), 9.02 (s, 1H).
Intermediate 235 1-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluoropheny11-3-[(4-methyl-1,2,5-oxadiazol-3-y1)methyl]urea N-0- .
F
Br H h1.1...../(N

........b F

N N

rj H 3C -Si I sC H

This intermediate was prepared in analogy to intermediate 160 by reacting phenyl {4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluoro-phenyllcarbamate (225 mg, 381 pmol, intermediate 159) and 1-(4-methyl-1,2,5-oxadiazol-3-yl)methanamine (1.20 eq., 51.7 mg, 457 pmol) in DMF at 70 C for 18 hours to give after aqueous work-up the crude product (232 mg) which was used in the next step without any further purification.
LC-MS (method 2): Rt = 1.49 min; MS (ESIpos): m/z = 609/611 [M+H] (Br isotope pattern).

Intermediate 236 (+1-) 1-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(tetrahydrofuran-2-ylmethypurea HHJN N

Br I
N N/

H3d CH3 This intermediate was prepared in analogy to intermediate 160 by reacting phenyl {4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluoro-phenyllcarbamate (225 mg, 381 pmol, intermediate 159) and (+/-) 1-(tetrahydrofuran-2-yl)methanamine (1.20 eq., 46.2 mg, 457 pmol) in DMF at 70 C for 18 hours to give after aqueous work-up the crude product (228 mg) which was used in the next step without any further purification.
LC-MS (method 2): Rt= 1.48 min; MS (ESIpos): m/z = 597/599 [M+H] (Br isotope pattern).
Intermediate 237 1-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyI}-3-pyridazin-3-ylurea H H
N N
`r Br 0 I
H 3C ---,St H3c CH3 This intermediate was prepared in analogy to intermediate 160 by reacting phenyl {4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluoro-phenyllcarbamate (225 mg, 381 pmol, intermediate 159), pyridazin-3-amine (1.20 eq., 43.5 mg, 457 pmol) and additionally triethylamine (0.50 eq., 27 pL, 190 pmol) in DMF at 70 C

for 27 hours to give after aqueous work-up the crude product (225 mg) which was used in the next step without any further purification.
LC-MS (method 2): Rt= 1.54 min; MS (ESIpos): m/z = 591/593 [M+H] (Br isotope pattern).
Intermediate 238 1-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(6-methylpyridazin-3-yOurea H H
N N
`r Br I

r-1 H3c CH3 This intermediate was prepared in analogy to intermediate 160 by reacting phenyl {4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluoro-phenyllcarbamate (225 mg, 381 pmol, intermediate 159), 6-methylpyridazin-3-amine (1.20 eq., 49.9 mg, 457 pmol) and additionally triethylamine (0.50 eq., 27 pL, 190 pmol) in DMF at 70 C
for 27 hours to give after aqueous work-up the crude product (230 mg) which was used in the next step without any further purification.
LC-MS (method 2): Rt= 1.47 min; MS (ESIpos): m/z = 605/607 [M+H] (Br isotope pattern).
Intermediate 239 1-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(1,3,4-thiadiazol-2-yOurea H H
N,N,N
r Br I
H 3C¨,St This intermediate was prepared in analogy to intermediate 160 by reacting phenyl {4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluoro-phenyllcarbamate (225 mg, 381 pmol, intermediate 159), 1,3,4-thiadiazol-2-amine (1.20 eq., 46.2 mg, 457 pmol) and additionally triethylamine (0.50 eq., 27 pL, 190 pmol) in DMF at 70 C
for 27 hours to give after aqueous work-up the crude product (227 mg) which was used in the next step without any further purification.
LC-MS (method 2): Rt= 1.03 min; MS (ESIpos): m/z = 597/599 [M+H] (Br isotope pattern).
Intermediate 240 1-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-[(4-methyl-1H-imidazol-2-yl)methyl]urea 1.NII
'N
F . I H

Brµ t F

N N
0) rj Si H C-1 =

This intermediate was prepared in analogy to intermediate 160 by reacting phenyl {4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1 H-pyrrolo[2,3-b]pyrid in-4-yl)oxy]-3,5-d ifl uoro-phenyllcarbamate (225 mg, 381 pmol, intermediate 159), 1-(4-methyl-1H-imidazol-yl)methanamine (1.20 eq., 50.8 mg, 457 pmol) and additionally triethylamine (0.50 eq., 27 pL, 190 pmol) in DMF at 70 C for 27 hours to give after aqueous work-up the crude product. This was purified by flash chromatography (5i02-hexane/ ethyl acetate) to give the title compound (43 mg, 19%).
LC-MS (method 2): Rt= 1.41 min; MS (ESIpos): m/z = 607/609 [M+H] (Br isotope pattern).

Intermediate 241 1-{4-[(3-cyano-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(6-methylpyridazin-3-yOurea H H
N N
N
? `N¨C H3 NN/

H3 C¨Si i H3C `-'"3 This intermediate was prepared in analogy to intermediate 189 by reacting phenyl {4-[(3-cyano-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophe-nyllcarbamate (347 mg, 647 pmol, intermediate 187) and 6-methylpyridazin-3-amine (1.20 eq., 84.7 mg, 776 pmol) in DMF for 20 hours at 70 C. The reaction mixture was filtrated and the filtrate subjected to preparative HPLC (method 4) to give the title compound (53 mg, 15%).
LC-MS (method 2): R1= 1.38 min; MS (ESIpos): rrilz = 552 [M+H].
Intermediate 242 1-{4-[(3-cyano-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-pyridazin-3-ylurea H H
N N
Y `r 1101 0 Ni ? 1\1"
NN/
r-1 H3C¨S1 H3d CH3 This intermediate was prepared in analogy to intermediate 189 by reacting phenyl {4-[(3-cyano-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophe-nyllcarbamate (389 mg, 725 pmol, intermediate 187) and pyridazin-3-amine (1.20 eq., 82.7 mg, 870 pmol) in DMF for 2.5 hours at 70 C. The reaction mixture was filtrated and the filtrate subjected to preparative HPLC (method 4) to give the title compound (30 mg, 7%).
LC-MS (method 2): Rt= 1.35 min; MS (ESIpos): rrilz = 538 [M+H].

Intermediate 243 methyl 14({4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-13]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamoyl)amino]cyclopropanecarboxylate H H
NN*-,cC H3 Cl 0 I

A solution of phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-13]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (1.00 g, 1.83 mmol, intermediate 44) and methyl 1-aminocyclopropanecarboxylate (253 mg, 2.20 mmol, CAS No. [72784-43-1]) in DMF
(4.9 mL) was heated to 90 C overnight. The reaction mixture was cooled, diluted with ethyl acetate and water was added. The layers were separated and the aqueous phase extracted twice with ethyl acetate. The combined organic layers were washed with Brine, dried over sodium sulfate, and evaporated in vacuo to afford the crude product. The crude product was purified by flash column chromatography (50g Si-snap colum, hexane/ethylacetate / 10% ¨> 60%
ethylacetate) to obtain 650 mg (56 % yield) of the title compound.
LC-MS (method 2): Rt = 1.49 min; MS (ESIpos): m/z = 567 [M+H]
1H NMR (400 MHz, DMSO-d6) 6 ppm -0.10 (s, 9 H), 0.79 - 0.85 (m, 2 H), 1.10-1.15 (m, 2 H), 1.39- 1.44 (m, 2 H), 3.50 - 3.57 (m, 2 H), 3.62 (s, 3 H), 5.60 (s, 2 H), 6.44 (d, 1 H), 7.19 (s, 1 H), 7.42 (br d, 2 H), 7.83 (s, 1 H), 8.17 (d, 1 H), 9.10 (br s, 1 H) Intermediate 244 14({4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamoyl)amino]cyclopropanecarboxylic acid H H) NN

CI
I
NN/
H 3C ¨St H3d CH3 To a solution of methyl 14({4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamoyl)amino]cyclopropanecarboxylate (600 mg, 1.06 mmol, intermediate 243) in methanol (1.5 mL) was added lithium hydroxide (5.3 mL, 1.0 M
solution in water, 5.3 mmol) and stirred overnight. Water was added, the mixture was cooled to 0 C and 1N hydrochloric acid was added dropwise until pH < 2. The formed precipitate was filtered and was washed with water followed by diethyl ether. The precipitate was dried to yield 500 mg (85% yield) of the desired title compound.
LC-MS (method 2): Rt = 0.91 min; MS (ESIpos): rrilz = 553 [M+H]
1H NMR (400 MHz, DMSO-d6) 6 ppm -0.09 (s, 9 H), 0.79 - 0.85 (m, 2 H), 1.04-1.09 (m, 2 H), 1.34 - 1.39 (m, 2 H), 3.50 - 3.56 (m, 2 H), 5.60 (s, 2 H), 6.44 (d, 1 H), 7.07 (s, 1 H), 7.42 (br d, 2 H), 7.84 (s, 1 H), 8.17 (d, 1 H), 9.05 (br s, 1 H), 12.43 (br s, 1 H) Intermediate 245 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-{1-[(4-methylpiperazin-1-y1)carbonyl]cyclopropyllurea H H
N N
1.1 Cl H3 I

H3d CH3 To a solution of 14({4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyllcarbamoyl)amino]cyclopropanecarboxylic acid (100 mg, 181 pmol, intermediate 244) in DMF (0.7 mL) was added 1-methylpiperazine (19.9 mg, 199 pmol), N,N-diisopropylethylamine (63 pL, 360 pmol, CAS No. [109-01-3]), 1-(3-DimethylaminopropyI)-3-ethylcarbodiimidhydrochloride (38.1 mg, 199 pmol) and 1-hydroxy-1H-benzotriazol hydrate (30.5 mg, 199 pmol). The resulting reaction mixture was stirred overnight at room temperature at which time ethyl acetate and water were added. The layers were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were dried with sodium sulfate and evaporated in vacuo to yield the crude product which was used in the next step without further purification.
LC-MS (method 2): Rt= 1.44 min; MS (ESIneg): rrilz = 635 [M+H]
Intermediate 246 1-{4-[(3-chloro-1-{[2-(trimethylsi lypethoxy]methy11-1 H-pyrrolo[2,3-b]pyrid in-4-yl)oxy]-3,5-difluoropheny11-341-(morpholin-4-ylcarbonyl)cyclopropyl]urea H H II
F N N
1.1 1r '<''N

CI
F
/ I
N----N/

r-1 H

In analogy to intermediate 245, 14({4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyllcarbamoyl)amino]cyclopropanecarboxylic acid (80.0 mg, 145 pmol, intermediate 244), morpholine (14 pL, 160 pmol, CAS
No. [110-91-8]), N,N-diisopropylethylamine (50 pL, 289 pmol), 1-(3-DimethylaminopropyI)-3-ethylcarbodiimide hydrochloride (30.5 mg, 159 pmol), 1-hydroxy-1H-benzotriazol hydrate (24.4 mg, 159 pmol) were reacted in DMF (1.2 mL) to afford a crude product which was used in the subsequent step without further purification.
LC-MS (method 2): Rt= 1.45 min; MS (ESIpos): rrilz = 622 [M+H]

Intermediate 247 14({4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyl}-1H-pyrrolo[2,3-13]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamoyl)amino]-N,N-dimethylcyclopropanecarboxamide H H

NN*-,1\1,C H3 _______________________________________________________ H 3C
I

In analogy to intermediate 245, 14({4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-13]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamoyl)amino]cyclopropanecarboxylic acid (80.0 mg, 145 pmol, intermediate 244), N,N-diisopropylethylamine (50 pL, 290 pmol), dimethylamine (87 pL, 2.0 M in THF, 170 pmol, CAS No. [124-40-3]), 1-(3-Dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (30.5 mg, 159 pmol), and 1-hydroxy-1H-benzotriazol hydrate (24.4 mg, 159 pmol) were reacted in DMF (1.2 mL) to afford a crude product which was used in the subsequent step without further purification.
LC-MS (method 2): Rt= 1.46 min; MS (ESIpos): rniz = 581 [M+H]
Intermediate 248 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-13]pyridin-4-ypoxy]-3,5-difluorophenyll-341-(piperidin-1-ylcarbonyl)cyclopropyl]urea H
NN
110 8 _________________________________________________ Cl I
NN/
H
H3d CH3 In analogy to intermediate 245, 14({4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-13]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamoyl)amino]cyclopropanecarboxylic acid (80.0 mg, 145 pmol, intermediate 244), N,N-diisopropylethylamine (50 pL, 290 pmol), piperidine (14 mg, 159 pmol, CAS No. [110-89-4]), 1-(3-DimethylaminopropyI)-3-ethylcarbodiimide hydrochloride (31 mg, 159 pmol), and 1-hydroxy-1H-benzotriazol hydrate (24 mg, 159 pmol) were reacted in DMF (1.2 mL) to afford a crude product which was used in the subsequent step without further purification.
LC-MS (method 2): Rt= 1.55 min; MS (ESIpos): m/z = 620 [M+H]
Intermediate 249 (+1-) 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluoropheny11-3-(1-methoxypropan-2-yOurea H H
NyNyo,C H 3 I

H3C¨S1 H3d CH3 In analogy to intermediate 2, phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (150 mg, 275 pmol, intermediate 44), and (+/-)-1-methoxypropan-2-amine (58 pL, 550 pmol, CAS No. [37143-54-7]) in DMF
(4.0 mL) were reacted to obtain a crude product which was used in the next step without further purification.
LC-MS (method 2): Rt= 1.53 min; MS (ESIpos): m/z = 541 [M+H]

Intermediate 250 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-341-(methoxymethyl)cyclopropyl]urea H H
NN,c0,CH3 ci 0 I
H3C¨S1 H3d CH3 .. In analogy to intermediate 206, phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (150 mg, 275 pmol intermediate 44), 1-(methoxymethyl)cyclopropanamine hydrochloride (1:1) (75.6 mg, 549 pmol, CAS No.
[1029716-05-9]), and triethylamine (77 pL, 550 pmol) in DMF (4.0 mL) were reacted to obtain a crude product which was used in the next step without further purification.
LC-MS (method 2): R1= 1.53 min; MS (ESIpos): m/z = 553 [M+H]
Intermediate 251 (+1-) 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(2,2-dimethyltetrahydrofuran-3-y1)urea H H
N N
0 p, Cl 0 H3 C
Li rs n3 I
H3C--"P.

In analogy to intermediate 206, phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (150 mg, 275 pmol, intermediate 44), (+/-)-2,2-dimethyltetrahydrofuran-3-amine hydrochloride (1:1) (83.3 mg, 549 pmol, CAS
No. [1350473-50-5]), triethylamine (77 pL, 550 pmol) in DMF (4.0 mL) were reacted to obtain a crude product which was used in the next step without further purification.

LC-MS (method 2): Rt= 1.54 min; MS (ESIpos): rrilz = 567 [M+H]
Intermediate 252 (+1-) 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluoropheny11-3-(5-oxaspiro[3.4]oct-7-yOurea H H
NN
Cl 0 11 I 1.1%C6 I
r-1 H3C¨S1 H3d CH3 In analogy to intermediate 206, phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (150 mg, 275 pmol, intermediate 44), (+/-)-5-oxaspiro[3.4]octan-7-amine hydrochloride (1:1) (89.9 mg, 549 pmol, CAS No.
[1955557-50-2]), and triethylamine (77 pL, 550 pmol) in DMF (4.0 mL) were reacted to obtain a crude product which was used in the next step without further purification.
LC-MS (method 2): Rt= 1.57 min; MS (ESIpos): rrilz = 579 [M+H]
Intermediate 253 (+/-)1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-[(trans)-4-(pyrrolidin-1-Atetrahydrofuran-3-yl]urea H H
F
IW L_ CI
I
r-1 H 3C ¨St H3d CH3 In analogy to intermediate 2, phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (150 mg, 275 pmol, intermediate 44), and (+/-)-4-(trans)-(pyrrolidin-1-yl)tetrahydrofuran-3-amine (85.8 mg, 549 pmol, CAS No.
[1212157-31-7]), in DMF (4.0 mL) were reacted to obtain a crude product which was used in the next step without further purification.
LC-MS (method 2): Rt= 1.50 min; MS (ESIpos): m/z = 608 [M+H]
Intermediate 254 N2-({4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-y1)oxy]-3,5-difluorophenyllcarbamoyI)-N,N-dimethylalaninamide C H
1.1 0 CH3 H3 I
H3C¨S1 H3d CH3 In analogy to intermediate 206, phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (150 mg, 275 pmol, intermediate 44), N,N-dimethylalaninamide hydrochloride (1:1) (50.3 mg, 330 pmol, CAS No.
[124491-96-9]), and triethylamine (77 pL, 550 pmol) in DMF (4.0 mL) were reacted to obtain a crude product which was used in the next step without further purification.
LC-MS (method 2): Rt= 1.47 min; MS (ESIpos): m/z = 569 [M+H]

Intermediate 255 N2-({4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamoy1)-N,N-dimethylvalinamide H
NN
N' -lel 0 CI o H3C CHH33 I

r-1 H3C¨St H3d CH3 In analogy to intermediate 2, phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (150 mg, 275 pmol, intermediate 44), and N,N-dimethylvalinamide (47.5 mg, 330 pmol, CAS No. [230643-41-1]), in DMF
(4.0 mL) were reacted to obtain a crude product which was used in the next step without further purification.
LC-MS (method 2): R1= 1.55 min; MS (ESIpos): m/z = 596 [M+H]
Intermediate 256 (+1-) 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(3-methyltetrahydrofuran-3-yOurea (10yN\
1 0 \--0/

I
H 3C ¨SI
H3d CH3 In analogy to intermediate 206, phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (150 mg, 275 pmol, intermediate 44), (+/-)-3-methyltetrahydrofuran-3-amine hydrochloride (1:1) (75.6 mg, 549 pmol, CAS No.

[1423034-45-0]), and triethylamine (77 pL, 550 pmol) in DMF (4.0 mL) were reacted to obtain a crude product which was used in the next step without further purification.
LC-MS (method 2): Rt= 1.53 min; MS (ESIpos): rrilz = 553 [M+H]
Intermediate 257 (+/-)1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-347-oxabicyclo[2.2.1]hept-2-yl]urea ¨ mixture of isomers H H
NN

a 0 I
H 3C¨Si, H3d CH3 In analogy to intermediate 2, phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyllcarbamate (150 mg, 275 pmol, intermediate 44), and (+/-)-7-oxabicyclo[2.2.1]heptan-2-amine (62.2 mg, 549 pmol, CAS No.
[1314954-35-2]) in DMF (4.0 mL) were reacted to obtain a crude product which was used in the next step without further purification.
LC-MS (method 2): Rt= 1.50 min; MS (ESIpos): rrilz = 565 [M+H]
Intermediate 258 (+/-)-1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(1-methyl-2-oxopyrrolidin-3-yOurea H H
NN

ci 0 0 µr, riO
H 3C ¨

In analogy to intermediate 2, phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (150 mg, 275 pmol, intermediate 44), and 3-amino-1-methylpyrrolidin-2-one (37.6 mg, 330 pmol, CAS No. [119329-48-5]), in DMF (4.0 mL) were reacted to obtain a crude product which was used in the next step without further purification.
LC-MS (method 2): Rt = 1.41 min; MS (ESIpos): m/z = 567 [M+H]
Intermediate 259 N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)azetidine-1-carboxamide H
F NI\p ¨.... jy F
H3C, P-I3 / I
H C¨SI NN/
3 \----\ /

In analogy to intermediate 2, phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1), azetidine (17 pL, 260 pmol) together in DMF (1.3 mL) we obtained the crude product, which was purified via a Biotage chromatography system (11g snap KP-NH
column, hexane/ethylacetate /50 ¨ 100% ethylacetate and ethylacetate/ethanol /0 ¨ 40%
ethanol) to obtain 136 mg (100 % purity, 97 % yield) of the desired title compound.
LC-MS (method 2): Rt = 1.52 min; MS (ESIneg): m/z = 541 [M-H]-1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.13 - -0.07 (m, 9H), 0.80 - 0.86 (m, 2H), 2.21 (quin, 2H), 3.55 - 3.60 (m, 2H), 3.99 (t, 4H), 5.68 (s, 2H), 6.57 (d, 1H), 7.49 -7.56 (m, 2H), 8.28 (d, 1H), 8.36 (s, 1H), 8.86 (s, 1H).

Intermediate 260 N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)pyrrolidine-1-carboxamide H
F NNI-D

F..........$) F
H3C /, F H3 I
H C¨SI N----N/
3 \----\ /
0'1 In analogy to intermediate 2, phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1), pyrrolidine (22 pL, 260 pmol) together in DMF (1.3 mL) we obtained the crude product, which was purified via a Biotage chromatography system (11g snap KP-NH
column, hexane/ethylacetate /50 ¨ 100% ethylacetate and ethylacetate/ethanol /0 ¨ 40%
ethanol) to obtain 134 mg (100 % purity, 93 % yield) of the desired title compound.
LC-MS (method 2): Rt = 1.55 min; MS (ESIneg): m/z = 555 [M-H]-1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.14 --0.06 (m, 9H), 0.79 -0.86 (m, 2H), 1.83 - 1.91 (m, 4H), 3.35 - 3.42 (m, 4H), 3.54 - 3.61 (m, 2H), 5.68 (s, 2H), 6.57 (d, 1H), 7.55 - 7.63 (m, 2H), 8.29 (d, 1H), 8.36 (s, 1H), 8.62 (s, 1H).
Intermediate 261 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(3-fluorooxetan-3-y1)methyl]urea H H5\) F NN
F F
F-........01401 8 F
F
H3C, PH3 / I
H 0¨Si N----N/
3 \----\ /
0"1 In analogy to intermediate 85, phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1), 1-(3-fluorooxetan-3-yl)methanamine (27.2 mg, 259 pmol) together in DMF (1.5 mL) and N,N-diisopropylethylamine (45 pL, 260 pmol) we obtained the crude product, which was purified via a Biotage chromatography system (11g snap KP-NH column, hexane/ethylacetate / 50 ¨ 100% ethylacetate and ethylacetate/ethanol / 0 ¨
40% ethanol) to obtain 133 mg (100% purity, 87% yield) of the desired title compound.
LC-MS (method 2): Rt = 1.49 min; MS (ESIpos): m/z = 591 [M+H]
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.12 - -0.06 (m, 9H), 0.79 - 0.86 (m, 2H), 3.55 - 3.60 (m, 2H), 3.66 (dd, 2H), 4.56 - 4.66 (m, 4H), 5.68 (s, 2H), 6.58 (d, 1H), 6.81 (t, 1H), 7.37 - 7.43 (m, 2H), 8.28 (d, 1H), 8.36 (s, 1H), 9.13 (s, 1H).
Intermediate 262 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(2-hydroxy-2-methylpropypurea H H

F 1:101 8 F F ¨.....) F
H3C, PH3 / I
HC¨Si N-'3 \----\ /

In analogy to intermediate 2, phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1), 1-amino-2-methylpropan-2-ol (24 pL, 260 pmol) together in DMF
(1.5 mL) we obtained the crude product, which was purified via a Biotage chromatography system (11g snap KP-NH column, hexane/ethylacetate / 50 ¨ 100% ethylacetate and ethylacetate/ethanol / 0 ¨ 40% ethanol) to obtain 134 mg (100 % purity, 90 %
yield) of the desired title compound.
LC-MS (method 2): Rt = 1.47 min; MS (ESIneg): m/z = 573 [M-H]-1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.14 --0.07 (m, 9H), 0.79 - 0.86 (m, 2H), 1.10 (s, 6H), 3.05 (d, 2H), 3.54 -3.60 (m, 2H), 4.58 (s, 1H), 5.68 (s, 2H), 6.34 (t, 1H), 6.58 (d, 1H), 7.31 -7.39 (m, 2H), 8.28 (d, 1H), 8.36 (s, 1H), 9.14 (s, 1H).

Intermediate 263 (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-342-hydroxy-2-methyl-3-(morpholin-4-y1)propyl]urea H H HO CH3(0 F.....F F .
NN.)c.N.) F
H3C, CH3 / I
H3C--Sli N's'N
\\01 In analogy to intermediate 2, phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1), (+/-)-1-amino-2-methyl-3-(morpholin-4-yl)propan-2-ol (51.9 mg, 298 pmol) together in DMF (0.7 mL) we obtained the crude product, which was purified via a Biotage chromatography system (11g snap KP-NH column, hexane/ethylacetate /50 ¨ 100%
ethylacetate and ethylacetate/ethanol / 0¨ 50% ethanol) to obtain 165 mg (100 % purity, 97 %
yield) of the desired title compound.
LC-MS (method 2): Rt = 1.49 min; MS (ESIpos): m/z = 660 [M+H]
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 - -0.08 (m, 9H), 0.80 - 0.86 (m, 2H), 1.07 (s, 3H), 2.20 - 2.29 (m, 2H), 2.45 - 2.48 (m, 2H), 3.07 - 3.20 (m, 2H), 3.54 - 3.60 (m, 6H), 4.55 (s, 1H), 5.68 (s, 2H), 6.28 (t, 1H), 6.58 (d, 1H), 7.32 - 7.38 (m, 2H), 8.28 (d, 1H), 8.36 (s, 1H), 9.18 (s, 1H).
Intermediate 264 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(3-hydroxy-3-methylbutypurea H H OH
F NyNIL

F-___ 1 F
H3C, H3 H 3C -Si 1\1----N
\\OJ
In analogy to intermediate 2, phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1), 4-amino-2-methylbutan-2-ol (30.7 mg, 298 pmol) together in DMF
(1.5 mL) we obtained the crude product, which was purified via a Biotage chromatography system (11g snap KP-NH column, hexane/ethylacetate /50 ¨ 100% ethylacetate and ethylacetate/ethanol / 0 ¨ 50% ethanol) to obtain 110 mg (100 % purity, 72 %
yield) of the desired title compound.
LC-MS (method 2): Rt = 1.48 min; MS (ESIpos): m/z = 589 [M+H]
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.13 --0.06 (m, 9H), 0.80 - 0.86 (m, 2H), 1.13 (s, 6H), 1.53 - 1.58 (m, 2H), 3.16 - 3.22 (m, 2H), 3.55 - 3.60 (m, 2H), 4.39 (s, 1H), 5.68 (s, 2H), 6.37 (t, 1H), 6.57 (d, 1H), 7.35 - 7.41 (m, 2H), 8.28 (d, 1H), 8.36 (s, 1H), 9.09 (s, 1H).
Intermediate 265 64({4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyllcarbamoyl)amino]-N-methylpyridazine-3-carboxamide H H
N N N
1.1 y Cl o 0 H N
I
rj H 3C --,S[
H3c CH3 In analogy to intermediate 203, phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (150 mg, 275 pmol, intermediate 44), and 6-amino-N-methylpyridazine-3-carboxamide (50.2 mg, 330 pmol, CAS No.
[1248423-87-1]) in DMF (1.1 mL) were reacted to obtain a crude product which was used in the next step without further purification.
LC-MS (method 3): Rt = 1.49 min; MS (ESIpos): m/z = 604 [M+H]

Intermediate 266 1-(6-tert-butylpyridazin-3-y1)-3-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyllurea H H
N y N N 1\1 I* 0 H3 CI
C

I
H
H3d CH3 In analogy to intermediate 203, phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (150 mg, 275 pmol, intermediate 44), and 6-tert-butylpyridazin-3-amine (49.8 mg, 330 pmol, CAS No. [82560-18-7]), in DMF
(4 mL) were reacted to obtain a crude product which was used in the next step without further purification.
LC-MS (method 3): R1= 1.68 min; MS (ESIpos): rrilz = 604 [M+H]
Intermediate 267 64({4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamoyl)amino]-N,N-dimethylpyridazine-3-carboxamide H H
N N N
y 1\1 CI
I H3C"Ns-CH3 H 3C ¨SI

In analogy to intermediate 203, phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (150 mg, 275 pmol, intermediate 44), and 6-amino-N,N-dimethylpyridazine-3-carboxamide (54.8 mg, 330 pmol, CAS
No.
[1250216-83-1]), in DMF (4.0 mL) were reacted to obtain a crude product which was used in the next step without further purification.

LC-MS (method 3): R1= 1.47 min; MS (ESIneg): rrilz = 619 [M+H]
Intermediate 268 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-y1)oxy]-3,5-difluoropheny11-346-(trifluoromethyppyridazin-3-yl]urea H H
N N N, 1\1 1:101 0 CI
I
H 3C ¨1St In analogy to intermediate 203, phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (150 mg, 275 pmol, intermediate 44), and 6-(trifluoromethyl)pyridazin-3-amine (53.8 mg, 330 pmol, CAS No.
[935777-24-5]), in DMF (1.1 mL) were reacted to obtain the crude product which was used in the next step without further purification.
LC-MS (method 3): Rt= 1.67 min; MS (ESIpos): rrilz = 615 [M+H]
Intermediate 269 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-346-(methylsulfonyl)pyridazin-3-yl]urea H H
N N N
II 1\1 )Lsi ' C H3 I
H
H3c CH3 In analogy to intermediate 203, phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (150 mg, 275 pmol, intermediate 44), and 6-(methylsulfonyl)pyridazin-3-amine (57.1 mg, 330 pmol, CAS No.
[61071-25-8]), in DMF (4.0 mL) were reacted to obtain a crude product which was used in the next step without further purification.
LC-MS (method 3): Rt = 1.51 min; MS (ESIpos): m/z = 625 [M+H]
Intermediate 270 (+/-)-N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-N'-(2-fluoro-3-methoxypropypurea F

F F
F-........ 01101 8 --cH3 F
H30,JC H3 / I
H 3C -Si N----N
\\OJ
In analogy to intermediate 85, phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-.. (trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1), (+/-)-2-fluoro-3-methoxypropan-1-amine hydrogen chloride salt (42.7 mg, 298 pmol) together in DMF (700 pL) and N,N-diisopropylethylamine (52 pL, 300 pmol) we obtained the crude product, which was purified via a Biotage chromatography system (11g snap KP-NH column, hexane/ethylacetate / 50 ¨ 100% ethylacetate and ethylacetate/ethanol / 0 ¨ 50% ethanol) to obtain 107 mg (94 % purity, 65 %
yield) of the desired title compound.
LC-MS (method 2): Rt = 1.51 min; MS (ESIpos): m/z = 593 [M+H]
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.12 - -0.06 (m, 9H), 0.79 - 0.87 (m, 2H), 3.30 (s, 3H), 3.29 - 3.60 (m, 5H), 4.61 - 4.66 (m, 1H), 4.73 - 4.79 (m, 1H), 5.68 (s, 2H), 6.58 (d, 1H), 6.69 (t, 1H), 7.35 - 7.43 (m, 2H), 8.29 (d, 1H), 8.36 (s, 1H), 9.18 (s, 1H).

Intermediate 271 (+/-)-N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-N'-[(4,4-dimethyloxetan-2-y1)methyl]urea F NN
F F

F
H3c,....pH3 / I
H 3C-6i N-'\\01 In analogy to intermediate 2, phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1), (+/-)-1-(4,4-dimethyloxetan-2-yl)methanamine (34.3 mg, 298 pmol) together in DMF (700 pL) we obtained the crude product, which was purified via a Biotage chromatography system (11g snap KP-NH column, hexane/ethylacetate /50 ¨ 100%
ethylacetate and ethylacetate/ethanol / 0 ¨ 50% ethanol) to obtain 112 mg (80 % purity, 58 %
yield) of the desired title compound.
LC-MS (method 2): Rt = 1.52 min; MS (ESIpos): m/z = 601 [M+H]
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 - -0.07 (m, 9H), 0.79 - 0.86 (m, 2H), 1.33 (s, 3H), 1.38 (s, 3H), 2.14 (dd, 1H), 2.31 (dd, 1H), 3.27 - 3.32 (m, 2H), 3.54 - 3.60 (m, 2H), 4.50 - 4.57 (m, 1H), 5.68 (s, 2H), 6.52 (t, 1H), 6.58 (d, 1H), 7.34 - 7.41 (m, 2H), 8.28 (d, 1H), 8.36 (s, 1H), 9.10 (s, 1H).
Intermediate 272 (+/-)-N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyI)-N'-(2-fluoro-3-methoxy-2-methylpropyl)urea F NN.)0, F F
F-........01101 8 0H3 F
H3C,,,,C H3 / I
H 3C-6i 1\1-N
\\OJ
In analogy to intermediate 85, phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1), (+/-)-2-fluoro-3-methoxy-2-methylpropan-1-amine hydrogen chloride salt(1/1) (46.9 mg, 298 pmol) together in DMF (700 pL) and N,N-diisopropylethylamine (52 pL, 300 pmol) we obtained the crude product, which was purified via a Biotage chromatography system (11g snap KP-NH column, hexane/ethylacetate / 50 ¨ 100% ethylacetate and ethylacetate/ethanol / 0 ¨ 50% ethanol) to obtain 107 mg (100 % purity, 68 %
yield) of the desired title compound.
LC-MS (method 2): Rt = 1.55 min; MS (ESIpos): m/z = 607 [M+H]
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 - -0.08 (m, 9H), 0.80 - 0.86 (m, 2H), 1.26 (d, 3H), 3.32 (s, 3H), 3.34 - 3.46 (m, 4H), 3.54 - 3.61 (m, 2H), 5.68 (s, 2H), 6.58 (d, 1H), 6.61 (t, 1H), 7.34 - 7.42 (m, 2H), 8.28 (d, 1H), 8.36 (s, 1H), 9.10 (s, 1H).
Intermediate 273 N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-N'-{[3-(hydroxymethypoxetan-3-yl]methyllurea OH
H F? H
F NN* 0 ¨...,,,0 F

H N--"N/
3C-6\---\i /
0-'1 In analogy to intermediate 2, phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1), [3-(aminomethyl)oxetan-3-yl]methanol (34.9 mg, 298 pmol) together in DMF (700 pL) we obtained the crude product, which was purified via a Biotage chromatography system (11g snap KP-NH column, hexane/ethylacetate /50 ¨ 100%
ethylacetate and ethylacetate/ethanol / 0 ¨ 50% ethanol) to obtain 66 mg (94 %
purity, 39 %
yield) of the desired title compound.
LC-MS (method 2): Rt = 1.40 min; MS (ESIpos): m/z = 603 [M+H]
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.12 - -0.07 (m, 9H), 0.80 - 0.86 (m, 2H), 3.39 (d, 2H), 3.54 - 3.62 (m, 4H), 4.30 (q, 4H), 4.98 (t, 1H), 5.68 (s, 2H), 6.58 (d, 1H), 6.67 (t, 1H), 7.35 -.. 7.42 (m, 2H), 8.28 (d, 1H), 8.36 (s, 1H), 9.14 (s, 1H).

Intermediate 274 N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-N'-[(3-hydroxyoxetan-3-y1)methyl]urea H H5\) F NN
F F
F-.........011101 8 0 H
F
H3Csy H3 / I
H 3C¨ i I\V"N
\\OJ
In analogy to intermediate 2, phenyl (3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (150 mg, 259 pmol, intermediate 1), 3-(aminomethyl)oxetan-3-ol (30.7 mg, 298 pmol) together in DMF
(700 pL) we obtained the crude product, which was purified via a Biotage chromatography system (11g snap KP-NH column, hexane/ethylacetate / 50 ¨ 100% ethylacetate and ethylacetate/ethanol / 0 ¨ 50% ethanol) to obtain 51 mg (89 % purity, 30 %
yield) of the desired title compound.
LC-MS (method 2): Rt = 1.40 min; MS (ESIpos): m/z = 589 [M+H]
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.15 - -0.06 (m, 9H), 0.77 - 0.87 (m, 2H), 3.35 - 3.48 (m, 2H), 3.53 - 3.61 (m, 2H), 4.34 -4.44 (m, 4H), 5.68 (s, 2H), 6.00 (s, 1H), 6.50 - 6.63 (m, 2H), 7.37 (d, 2H), 8.28 (d, 1H), 8.36 (s, 1H), 9.19 (s, 1H).
Intermediate 275 N-(2,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-N'-[(3-methyloxetan-3-y1)methyl]urea F NN
F F
F-01110 8 ,) F
H3C, C, 1-13 / I
H C¨Si N---N/
3 \----\ /
"1 In analogy to intermediate 36, in two experiments using 2,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylaniline (50 + 250 mg, 110 pmol + 544 pmol, intermediate 1), 3-(isocyanatomethyl)-3-methyloxetane (140 pL, 1.1 mmol) (27 + 140 pL, 0.21 + 1.1 mmol), in a mixture of dichloromethane (0.92 + 4.6 mL) and pyridine (0.97 + 4.8 mL), we obtained 244 mg (63% yield) of the desired title compound.
LC-MS (method 3): Rt = 1.48 min; MS (ESIpos): rrilz = 587 [M+H]
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.12 - -0.05 (m, 9H), 0.79 - 0.87 (m, 2H), 1.24 (s, 3H), 3.33 (d, 2H) 3.53 - 3.61 (m, 2H), 4.23 (d, 2H), 4.36 (d, 2H), 5.68 (s, 2H), 6.57 (d, 1H), 6.99 (t, 1H), 7.53 (dd, 1H), 8.23 - 8.30 (m, 2H), 8.35 (s, 1H), 8.67 (s, 1H).
Intermediate 276 4-[(2,6-d ifl uoro-4-n itrophenyl)su Ifany1]-1-{[2-(trimethylsi lypethoxy]methy11-1H-pyrrolo[2,3-b]pyridine +
F NO_ F
H3C, P-13 / I
H 3C ¨Si N''N/

A mixture of 4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (12 g, commercially available or prepared according to J. Med. Chem. 2017, 4636) and 2,6-difluoro-4-nitrobenzenethiol (8.11 g,commercially available) in DMF (150 mL) was stirred at room temperature under nitrogene atmosphere for 16 hours. To the reaction mixture was added 700 mL of water and the resultant mixture was extracted with threetimes with ethyl acetate.
The combined organic phase was washed with water, then brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silicagel, petrolether : ethyl acetate = 4:1 to 1:1) to afford 14.5 g ) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.12 (s, 9H), 0.80 (t, 2H),. 3.50 (t, 2H), 5.62 (s, 2H), 6.42 (d, 1H), 6.84 (d, 1H), 7.71 (d, 1H), 8.15 (d, 1H), 8.26 (d, 2H).

Intermediate 277 3-bromo-4-[(2,6-difluoro-4-nitrophenyl)sulfanyl]-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridine II+
F, Br S
F
H3C, PH3 / I
H 3C--Si 1\1-N/

A mixture of 4-((2,6-difluoro-4-nitrophenyl)thio)-1-((2-(trimethylsilypethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (14.5 g, 33 mmol, intermediate 276) and 1-bromopyrrolidine-2,5-dione (CAS No. [128-08-5], 5.82 g, 33 mmol) in dichloromethane (150 mL) was stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added aqueous saturated sodium thiosulfate (40 mL) and aqueous saturated sodium bicarbonate (40 mL). The resultant mixture was extracted with threetimes with ethyl acetate. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford (16.6 g, crude) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.09 (s, 9H), 0.82 (t, 2H), 3.53 (t, 2H), 5.61 (s, 2H), 6.55 (d, 1H), 7.99 (s, 1H), 8.10 (d, 1H), 8.30 (d, 2H).
Intermediate 278 4-[(3-bromo-1-{[2-(trimethylsi lypethoxy]methy11-1 H-pyrrolo[2,3-b]pyridin-4-yl)su Ifany1]-3 ,5-difluoroaniline F, N H 2 Br S
F
H3C, PH3 / I
H 3C--Si N--"N

To a mixture of 3-bromo-4-((2,6-difluoro-4-nitrophenyl)thio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (16.6 g, crude, intermediate 277), FeCl3 (1.05 g, 6.47 mmol), activated carbon (2.1 g) in methanol (200 mL) was added hydrazine hydrate (6.5 g, 130 mmol) drop-wise at 50 C. The reaction mixture was then stirred at reflux for 18 h.
The reaction mixture was filtered and the filtrate was concentrated under reduced pressure.
The residue was stirred in ethanol (80 mL) for 2 hours and then the mixture was filtered.
The filter cake was dried under reduced pressure to afford crude product as a white solid (5.5 g), which was combined with another batch of crude product (10.6 g, from a second experiment). This combined crude product (16.1 g) was stirred in methyl t-butyl ether (15 mL) for 2 h and the resultant mixture was filtered. The filter cake was dried in vacuum, then purified by column chromatography (silicagel petrolether : ethyl acetate = 5:1 to 1:1) to afford 8.06 g of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.09 (s, 9H), 0.81 (t, 2H), 3.50 (t, 2H), 5.57 (s, 2H), 6.31 (d, 1H), 6.42 (d, 4H), 7.89 (s, 1H), 8.06 (d, 1H).
Intermediate 279 phenyl {4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl)sulfanyl]-3,5-difluorophenyllcarbamate NO

Br H3C, CH3 / I
H NN/

0 -"-1 In analogy to intermediate 1, 4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl)sulfanyl]-3,5-difluoroaniline (600 mg, 1.23 mmol, intermediate 278), phenyl carbonochloridate (170 pL, 1.4 mmol) together in THF (10 mL) and pyridine (510 pL) we obtained a reaction mixture which was directly used for the next step Intermediate 280 N-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl)sulfanyl]-3,5-difluorophenyll-N'42-(morpholin-4-y1)-2-oxoethyl]urea N y0 o s H
NJ
Br H3C, CH3 / I
H C

To solution of phenyl {4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl)sulfanyI]-3,5-difluorophenyllcarbamate (180 mg, 297 pmol, intermediate 279) in DMF

(2.0 mL) plus trimethylamine (120 pL, 890 pmol) was added 2-amino-1-(morpholin-4-yl)ethan-1-one (64.2 mg, 445 pmol) and this mixture was stirred at 60 C for 3 hours.
After cooling to room temperature the reaction mixture was diluted with ethyl acetate. This organic phase was washed with 1N hydrochloric acid, aqueous saturated sodium bicarbonate solution, brine and , dried via a hydrophobic filter and evaporated to dryness in vacuum.
The resulting residue was purified via a Biotage chromatography system (28 g snap KP-NH
column, hexane /0 ¨ 100% ethyl acetate, then ethyl acetate /0 ¨ 70% ethanol) to obtain 189 mg (100% purity, 97% yield) of the desired title compound.
LC-MS (method 2): Rt = 1.47 min; MS (ESIpos): m/z = 656 [M+H]
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 --0.08 (m, 9H), 0.78 - 0.85 (m, 2H), 3.40 - 3.62 (m, 10H), 4.03 (d, 2H), 5.58 (s, 2H), 6.31 (d, 1H), 6.70 (t, 1H), 7.37 - 7.43 (m, 2H), 7.93 (s, 1H), 8.06 (d, 1H), 9.75 (s, 1H).
Intermediate 281 N-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl)sulfanyl]-3,5-difluorophenyll-W-(2-methoxyethypurea Br F
H3C, CH3 / I
H

In analogy to intermediate 280, phenyl {4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl)sulfanyI]-3,5-difluorophenyllcarbamate (180 mg, 297 pmol, intermediate 279), 2-methoxyethan-1-amine (33.4 mg, 445 pmol), trimethylamine (62 pL, 450 pmol) together in DMF (2.0 mL) was reacted to obtain 171 mg (100 % purity, 98 % yield) of the desired title compound.
LC-MS (method 2): Rt = 1.53 min; MS (ESIpos): m/z = 587 [M+H]
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 --0.08 (m, 9H), 0.78 - 0.85 (m, 2H), 3.26 - 3.31 (m, 5H), 3.37 - 3.42 (m, 2H), 3.47 - 3.54 (m, 2H), 5.58 (s, 2H), 6.30 (d, 1H), 6.61 (t, 1H), 7.37 -7.43 (m, 2H), 7.93 (s, 1H), 8.06 (d, 1H), 9.38 (s, 1H).

Intermediate 282 N-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl)sulfanyl]-3,5-difluorophenyll-W-ethylurea H

Br S
F

,_,C
H / I
N----N/
3C -3 \----\i /

In analogy to intermediate 280, phenyl {4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl)sulfanyl]-3,5-difluorophenyllcarbamate (180 mg, 297 pmol, intermediate 279), ethanamine (220 pL, 2.0 M in methanol, 450 pmol), trimethylamine (62 pL, 450 pmol) together in DMF (2.0 mL) was reacted to obtain 163 mg (100 % purity, 99 % yield) of the desired title compound.
LC-MS (method 2): R1= 1.56 min; MS (ESIpos): rrilz = 557 [M+H]
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 --0.08 (m, 9H), 0.78 - 0.85 (m, 2H), 1.07 (t, 3H), 3.13 (dt, 2H), 3.47 - 3.54 (m, 2H), 5.58 (s, 2H), 6.30 (d, 1H), 6.54 (t, 1H), 7.39 - 7.44 (m, 2H), 7.93 (s, 1H), 8.06 (d, 1H), 9.28 (s, 1H).
Intermediate 283 N-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl)sulfanyl]-3,5-difluorophenyllmorpholine-4-carboxamide H

Brh) F r o H3c,_,H3 , - 1 H3 C ¨si NN/
\\01 In analogy to intermediate 280, phenyl {4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl)sulfanyI]-3,5-difluorophenyllcarbamate (180 mg, 297 pmol, intermediate 279), morpholine (38.8 mg, 445 pmol), trimethylamine (62 pL, 450 pmol) together in DMF (2.0 mL) was reacted to obtain 195 mg (crude) of the desired title compound.
LC-MS (method 2): Rt = 1.54 min; MS (ESIpos): rrilz = 599 [M+H]
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: -0.11 --0.08 (m, 9H), 0.78 - 0.85 (m, 2H), 3.44 - 3.54 (m, 6H), 3.60 - 3.66 (m, 4H), 5.58 (s, 2H), 6.30 (d, 1H), 7.50 - 7.56 (m, 2H), 7.94 (s, 1H), 8.07 (d, 1H), 9.25 (s, 1H).

Intermediate 284 3-bromo-4-(2,6-difluoro-4-nitrophenoxy)-1-(4-methylbenzene-1-sulfony1)-1H-pyrrolo[2,3-b]pyridine 11+
F

Br 0 F
/ I
N--"N/

Step 1 To a stirred solution of 4-(2,6-difluoro-4-nitrophenoxy)-1H-pyrrolo[2,3-b]pyridine (5.70 g, 19.6 mmol, intermediate 143) in DMF (100 mL) was added N-bromosuccinimide (3.83 g, 21.5 mmol). The resulting mixture was stirred at room temperature for 2 hours at which time the reaction was cooled to 0 C and water was slowly added. The resulting precipitate was filtered and dried to afford 3-bromo-4-(2,6-difluoro-4-nitrophenoxy)-1H-pyrrolo[2,3-b]pyridine (7.20 g, 99 % yield) LC-MS (method 2): R1= 1.18 min; MS (ESIpos): rrilz = 370 [M+H]
1H NMR (400 MHz, DMSO-d6) 6 ppm 6.55 (d, 1 H), 7.72 (d, 1 H), 8.14 (d, 1 H), 8.41 (d, 2 H), 12.34 (br s, 1 H) Step 2 To a cooled (0 C) solution of 3-bromo-4-(2,6-difluoro-4-nitrophenoxy)-1H-pyrrolo[2,3-b]pyridine (13.0 g, 35.1 mmol) from step 1 in DMF (200 mL) was added sodium hydride (1.83 g, 60%
suspension in oil, 45.7 mmol) portionwise. The resulting mixture was stirred for 15 minutes at 0 C at which time p-Toluenesulfonylchloride (7.37 g, 38.6 mmol) was added and the reaction was allowed to warm slowly to room temperature overnight. The mixture was slowly poured into ice-water, and the resulting precipitate was filtered and dried to afford 15 g (81% yield) of the desired product.
LC-MS (method 2): Rt = 1.51 min; MS (ESIpos): rrilz = 526 [M+H]
1H NMR (400 MHz, DMSO-d6) 6 ppm 2.37 (s, 3 H), 6.87 (d, 1 H), 7.46 (d, 2 H), 8.04 (d, 2 H), 8.22 (s, 1 H), 8.31 (d, 1 H), 8.42 (d, 2 H) Intermediate 285 4-{[3-bromo-1-(4-methylbenzene-1-sulfonyI)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}-3,5-difluoroaniline F Br N H 2 n ir -F
/ I
N---N/
0 si......0 To a solution of 3-bromo-4-(2,6-difluoro-4-nitrophenoxy)-1-(4-methylbenzene-1-sulfony1)-1H-pyrrolo[2,3-b]pyridine (5.20 g, 9.92 mmol, intermediate 284) in a mixture of THF: water:
methanol (1:2:1, 200 mL), was added ammonium chloride (2.65 g, 49.6 mmol) and iron powder (2.77 g, 49.6 mmol). The resulting mixture was stirred at 80 C for 2 hours at which time the mixture was cooled and filtered over celite. The filtrate was extracted twice with ethyl acetate and the combined organic layers washed with brine, dried over sodium sulfate, and evaporated to give the crude product 4.90 g (100% yield) which was sufficiently pure for the next step without further purification.
LC-MS (method 2): Rt = 1.39 min; MS (ESIpos): rrilz = 494 [M+H]
1H NMR (400 MHz, DMSO-c16) 6 ppm 2.35 (s, 3 H), 5.85 (s, 2 H), 6.37 (d, 2 H), 6.57 (d, 1 H), 7.44 (d, 2 H), 8.02 (d, 2 H), 8.10 (s, 1 H), 8.24 (d, 1 H) Intermediate 286 di-tert-butyl (4-{[3-bromo-1-(4-methylbenzene-1-sulfonyI)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}-3,5-difluoropheny1)-2-imidodicarbonate C Hr3 H 3C, ,k, H3 r F . NO teC H 3 ill) CHC3H 3 Br 0 F
/ I
N----N/
OS '::O
S1.O

To a solution of 4-{[3-bromo-1-(4-methylbenzene-1-sulfonyI)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}-3,5-difluoroaniline (4.30 g, 8.70 mmol, intermediate 285) in THF (30 mL) was added di-tert-butyl dicarbonate (4.7 mL, 22 mmol) and dimethylaminopyridine (106 mg, 870 pmol). The resulting mixture was stirred at 75 C for 3 hours, at which time ethyl acetate and water were added and the layers were separated. The aqueous phase was extracted twice with ethyl acetate and the combind organic layers were washed with brine, dried over sodium sulfate, and evaporated to afford the crude product. The crude product was purified by flash column chromatography followed by crystallization from a mixture of dichloromethane and methanol to afford the title compound (1.68g, 28% yield).
LC-MS (method 2): R1= 1.70 min; MS (ESIpos): rniz = 696 [M+H]
1H NMR (400 MHz, DMSO-c16) 6 ppm 1.41 (s, 18 H), 2.36 (s, 3 H), 6.46 (d, 1 H), 7.45 (d, 2 H), 7.53 (d, 2 H), 8.04 (d, 2 H), 8.19 (s, 1 H), 8.31 (d, 1 H) Intermediate 287 N-(4-{[3-bromo-1-(4-methylbenzene-1-sulfony1)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}-3,5-difluoropheny1)-N'-(2-methoxyethypurea H H
F
Br 0 0 Y
N 0 NICI'C H 3 F
/ I
N N,"

To a solution of 4-{[3-bromo-1-(4-methylbenzene-1-sulfonyI)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}-3,5-difluoroaniline (4.32 g, 8.78 mmol, intermediate 285) in a 1:1 mixture of dichloromethane and pyridine (80 mL) is added 1-isocyanato-2-methoxyethane (4.44g, 43.9 mmol, CAS No.
[42170-95-6]). The reaction mixture is stirred at 60 C overnight upon which time the mixture is cooled to room temperature. Water and ethyl acetate were added and the phases were separated. The aqueous phase was extracted twice with ethyl acetate and the combined organic phases washed with brine, dried over sodium sulfate, filtered and evaporated to give the crude material. The crude material was purified by flash column chromatography to give the title compound (4.07g 78% yield).
LC-MS (method 2): Rt = 1.36 min; MS (ESIpos): rniz = 595 [M+H]
1H NMR (400 MHz, DMSO-c16) 6 ppm 2.35 (s, 3 H), 3.23 - 3.28 (m, 5 H), 3.36 -3.40 (m, 2 H), 6.46 (t, 1 H), 6.62 (d, 1 H), 7.36 (d, 2 H), 7.44 (d, 2 H), 8.03 (d, 2 H), 8.14 (s, 1 H), 8.25 (d, 1 H), 9.09 (s, 1 H) Intermediate 288 di-tert-butyl (3,5-difluoro-4-{[1-(4-methylbenzene-1-sulfony1)-3-(propan-2-y1)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)-2-imidodicarbonate 1(30 Ny0 0 _¨s1_,0 di-tert-butyl (4-{[3-bromo-1-(4-methylbenzene-1-sulfony1)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}-3,5-difluoropheny1)-2-imidodicarbonate (500 mg, 720 pmol, intermediate 286), tris(trimethylsilyl)silane (220pL, 720pmo1, CAS No. [1873-77-4]), 2-bromopropane (300 pL, 3.2 mmol, CAS No. [75-26-3]), 2,6-dimethoxypyridine (570 pL, 4.3mm01) and Ir(41,61-dF-5-CF3-ppy)2(4,41-dtbbpy)PF6 (16 mg, 14 pmol, CAS No. [870987-63-6]) were dissolved in the reaction vial in trifluorotoluene (11 mL). In a separate vial, the Ni-catalyst was prepared by dissolving Nickel (II) chloride dimethoxyethane adduct (8 mg, 36 pmol, CAS No. [29046-78-4]) and 4,4'-Di-tert-buty1-2,2'-bipyridine (10 mg, 36 pmol, CAS No. [72914-19-3]) in N,N-dimethylacetamide (4.0 mL) followed by stirring for 5 min. The catalyst solution was syringed to the sealed reaction vial and degassed by sparging with argon for 10 minutes. The MW-vial was placed in a heatblock and tempered to 40 C. The reaction mixture was pumped through the flow tubing using a peristaltic pump (Flow Setup: Loop Volume: 2mL, Tube: inner diameter:
0,2 mm wall thickness 0,2mm, 30% Peristalticpump speed ¨35seconds irradiated residence time, 9h circleflow) for 9 hours at which time water and ethyl acetate were added and the layers were separated. The aqueous phase was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulfate, and evaporated to give the crude material. The crude material was purified by flash column chromatography to afford an inseperable mixture of the desired product di-tert-butyl (3,5-difluoro-4-{[1-(4-methylbenzene-1-sulfony1)-3-(propan-2-y1)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)-2-imidodicarbonate and the de-brominated starting material di-tert-butyl [3,5-difluoro-4-({1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-4-ylloxy)phenyI]-2-imidodicarbonate (1.69 g, 59%
combined yield) LC-MS (method 2): Rt= 1.74 min; MS (ESIpos): rrilz = 659 [M+H]

Intermediate 289 3,5-difluoro-4-{[1-(4-methylbenzene-1-sulfony1)-3-(propan-2-y1)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylaniline¨hydrogen chloride (1/1) CH õ laill CI H
H 3C).____) F
NN/
0¨ 1 ¨S--0 di-tert-butyl (3,5-difluoro-4-{[1-(4-methylbenzene-1-sulfony1)-3-(propan-2-y1)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)-2-imidodicarbonate (1.69 g, 66 % purity, 1.70 mmol, intermediate 288) was dissolved in a 4 M solution of hydrochloric acid in dioxane (30 mL) and stirred at room temperature overnight. The solvent was subsequently evaporated to give the crude product which was used in the subsequent step without further purification.
LC-MS (method 2): Rt= 1.45 min; MS (ESIpos): m/z = 458 [M+H]
Intermediate 290 phenyl (3,5-difluoro-4-{[1 -(4-methylbenzene-1-sulfony1)-3-(propan-2-y1)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate H

H 3C¨._0 F
N''N/
Os'--o 44k To a stirred solution of 3,5-difluoro-4-{[1-(4-methylbenzene-1-sulfony1)-3-(propan-2-y1)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylaniline¨hydrogen chloride (1/1) (1.40 g, 66 %
purity, 1.87 mmol, intermediate 289) in THF (15 mL) and pyridine was added (2.0 mL, 25 mmol). The reaction mixture was cooled to 0 C and phenyl carbonochloridate (360 pL, 2.9 mmol, CAS
No. [1885-14-9]) was added. The resulting mixture was stirred for 30 min at 0 C, at which time it was diluted with ethyl acetate and a 2M aqueous solution of hydrochlorid acid was added slowly.
The layers were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with a saturated solution of sodium bicarbonate, followed by brine, dried over sodium sulfate, and evaporated to afford the crude product. The crude product was used without further purification.
LC-MS (method 3): Rt= 1.62 min; MS (ESIpos): m/z = 579 [M+H]
Intermediate 291 N-(3 ,5-d ifl uoro-4-{[1-(4-methylbenzene-1-su Ifony1)-3-(propan-2-y1)-1 H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-N'-[(3-fluorooxetan-3-yl)methyl]urea F NN

H 3CC H 3 . 0 F
NN
0-c' ¨0 44Ik In analogy to intermediate 2, phenyl (3,5-difluoro-4-{[1-(4-methylbenzene-1-sulfonyI)-3-(propan-2-yI)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (400 mg, 66%
purity, 457 pmol, intermediate 290), and 1-(3-fluorooxetan-3-yl)methanamine (120 mg, 1.14 mmol, CAS
No. [883311-82-8]), in DMF (3.0 mL) were reacted to obtain a crude product which was used in the next step without further purification.
LC-MS (method 2): Rt= 1.40 min; MS (ESIpos): m/z = 589 [M+H]

Intermediate 292 di-tert-butyl (3,5-difluoro-4-{[1-(4-methylbenzene-1-sulfony1)-3-(3,3,3-trifluoropropy1)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-2-imidodicarbonate z 0 di-tert-butyl (4-{[3-bromo-1-(4-methylbenzene-1-sulfony1)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}-3,5-difluoropheny1)-2-imidodicarbonate (200 mg, 288 pmol, intermediate 286), Ir(41,61-dF-5-CF3-ppy)2(4,41-dtbbpy)PF6 (6.5 mg, 5.8 pmol, CAS No. [870987-63-6]), tris(trimethylsilyl)silane (89 pL, 290 pmol, CAS No. [1873-77-4]) and lithiumcarbonate (128 mg, 1.73 mmol) were dissolved in trifluorotoluene (4.0 mL) in a MW-vial. In a separate vial, the Ni-catalyst was prepared by dissolving Nickel (II) chloride dimethoxyethane adduct (32 mg, 140 pmol, CAS No.
[29046-78-4]) and 4,4'-Di-tert-butyl-2,2'-bipyridine (39 mg, 140 pmol, CAS No.
[72914-19-3]) in N,N-dimethyl acetamide (10 mL) followed by stirring for 5 min. 0.1 mL of this catalyst solution was syringed to the sealed reaction vial and argon was bubbled through the solution for another 5 min. 3-bromo-1,1,1-trifluoropropane (180 pL, 1.7 mmol, CAS No. [460-32-2]) was added. The MW-vial was subsequently irradiated by two 40W Kessil LED Aquarium lights (40W each, 4 cm distance) placed in a water bath to keep the temperature below 35 C for 12 hours, at which time water and ethyl acetate were added and the layers were separated. The aqueous phase was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulfate, and evaporated to give the crude material, which was used without further purification.
LC-MS (method 2): Rt= 1.68 min; MS (ESIpos): rrilz = 712 [M+H]

Intermediate 293 3 ,5-d ifl uoro-4-{0 -(4-methylbenzene-1-sulfonyI)-3-(3,3,3-trifluoropropy1)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylaniline F F oF I* N H2 F
F
/ I
NN/
0_¨s1,...0 di-tert-butyl (3,5-difluoro-4-{[1-(4-methylbenzene-1-sulfonyI)-3-(3 ,3,3-trifluoropropyI)-1 H-pyrrolo[2,3-b]pyrid in-4-yl]oxylphenyI)-2-imidodicarbonate (450 mg, 632 pmol, intermediate 292) was dissolved in a 4 M solution of hydrochloric acid in dioxane (9.0 mL) and stirred at room temperature overnight. The solvent was subsequently evaporated to give the crude product which was purified by preparative HPLC to afford the title compound (190 mg, 59%
yield).
LC-MS (method 2): Rt = 1.41 min; MS (ESIpos): rniz = 512 [M+H]
1H NMR (400 MHz, DMSO-d6) 6 ppm 2.35 (s, 3 H), 2.63 - 2.73 (m, 2 H), 3.01 -3.06 (m, 2 H), 5.85 (s, 2 H), 6.38 (d, 2 H), 6.51 (d, 1 H), 7.42 (d, 2 H), 7.79 (s, 1 H), 7.97 (d, 2 H), 8.19 (d, 1 H) Intermediate 294 phenyl (3,5-d ifl uoro-4-{0 -(4-methylbenzene-1-sulfonyI)-3-(3,3,3-trifluoropropy1)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate H
............s.)FF I. N1r o, F

F
/ I
N''N/
0_¨ 1, In analogy to intermediate 290, 3,5-difluoro-4-{[1-(4-methylbenzene-1-sulfonyI)-3-(3,3,3-trifluoropropy1)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylaniline (190 mg, 371 pmol, intermediate 293) was reacted with phenyl carbonochloridate (51 pL, 410 pmol, CAS No. [1885-14-9]) and pyridine (170 pL, 2.1 mmol) in THF (3.0 mL) to afford the crude product which was used without further purification.
LC-MS (method 3): Rt= 1.56 min; MS (ESIneg): rrilz = 630 [M-H]
Intermediate 295 N-(3 ,5-d ifl uoro-4-{[1-(4-methylbenzene-1-su Ifony1)-3-(3 ,3,3-trifluoropropyI)-1 H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-N'-[(3-fluorooxetan-3-yl)methyl]urea H H.5\) F F F NN
F F
z 0 111 1 8 F
N----N
0-c' ¨0 4,Ik In analogy to intermediate 2, phenyl (3,5-difluoro-4-{[1-(4-methylbenzene-1-sulfonyI)-3-(3,3,3-trifluoropropy1)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (230 mg, 364 pmol, intermediate 294), and 1-(3-fluorooxetan-3-yl)methanamine (57.4 mg, 546 pmol, CAS No.
[883311-82-8]), in DMF (5.0 mL) were reacted to obtain a crude product which was used in the next step without further purification.
LC-MS (method 2): Rt= 1.38 min; MS (ESIpos): rrilz = 643 [M+H]

Intermediate 296 N-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-N'-[(3-fluorooxetan-3-y1)methyl]urea NN
I. 8 Br I
NN/
r-1 H3d CH3 In analogy to intermediate 2, phenyl {4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (22.0 g, 37.2 mmol, intermediate 159), and 1-(3-fluorooxetan-3-yl)methanamine (6.9 mL, 74 mmol, CAS No. [883311-82-8]), in DMF (200 mL) were reacted to obtain a crude product which was purified by flash column chromatography ((dichloromethane 100% to dichloromethane 85% / methanol 15`)/0)(Snap Ultra 375g)) to obtain the title compound (15 g, 66% yield).
LC-MS (method 2): Rt = 1.47 min; MS (ESIpos): m/z = 601 [M+H]
1H NMR (400 MHz, DMSO-d6) 6 ppm -0.09 (s, 9 H), 0.79 - 0.86 (m, 2 H), 3.50 -3.56 (m, 2 H), 3.66 (dd, 2 H), 4.61 (ddd, 4 H), 5.60 (s, 2 H), 6.44 (d, 1 H), 6.80 (t, 1 H), 7.40 (d, 2 H), 7.86 (s, 1 H), 8.17 (d, 1 H), 9.12 (s, 1 H) Intermediate 297 N-(3,5-difluoro-4-{[3-(3,3,3-trifluoroprop-1-en-2-y1)-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-N'-[(3-fluorooxetan-3-y1)methyl]urea H H.5\) NN
F.....)111.-120 0 I
H
H3d CH3 To a stirred solution of N-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-N'-[(3-fluorooxetan-3-Amethyl]urea (1.17 g, 1.95 mmol, intermediate 296) in degassed THF (30 mL) and water (15 mL) were added (1,1-Bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (142 mg, 195 pmol, CAS
No. [95464-05-4]), (3,3,3-trifluoroprop-1-en-2-yl)boronic acid (340 mg, 2.43 mmol, CAS
No. [357274-85-2]) and potassium carbonate (806 mg, 5.84 mmol) The resulting mixture was stirred at 75 C for 5h, at which time the THF was removed evaporated, and ethyl acetate was added.
The layers were separated and the aqueous phase was extracted twice with ethyl acetate.
The cominbed organic layers were washed with brine, dried over sodium sulfate, and evaporated to afford the crude product. The crude material was purified by flash column chromatography to affod an inseperable mixture of the title compound and debrominated starting material 1-{3,5-difluoro-4-[(1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]phenyll-3-[(3-fluorooxetan-3-yl)methyl]urea (500 mg, 21 `)/0 combined yield) LC-MS (method 2): R1= 1.52 min; MS (ESIpos): rrilz = 618 [M+H]
Intermediate 298 (+/-)-N-{3,5-difluoro-4-[(341,1,1-trifluoropropan-2-y1]-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]phenyll-N'-[(3-fluorooxetan-3-yl)methyl]urea H H5\) NN

To a stirred solution of N-(3 ,5-d ifl uoro-4-{[3-(3,3,3-trifluoroprop-1-en-2-yI)-1-{[2-(tri methylsilypethoxy]methy11-1 H-pyrrolo[2,3-b]pyrid in-4-yl]oxylphenyI)-N'-[(3-fluorooxetan-3-yl)methyl]urea (1.16 g, 50 % purity, 941 pmol, intermediate 297) in ethanol (50 mL), was added triethylamine (200 pL, 1.4 mmol) followed by palladium (10% on activated carbon, 100mg, 94.1 pmol). The flask was flushed with hydrogen and stirred under 1 atm of hydrogen for 4 hours, at which time he mixture was filtered over celite and rinsed with ethyl acetate. The filtrate was evaporated to afford the crude product which was used without further purification.
LC-MS (method 2): R1= 1.51 min; MS (ESIpos): rrilz = 619 [M+H]

Intermediate 299 N-(3 ,5-d ifl uoro-4-{[1-(4-methylbenzene-1-su Ifony1)-3-(propan-2-y1)-1 H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-N'-(2-methoxyethypurea H H
NyNO'C
C H3? 0 =

N-(4-{[3-bromo-1-(4-methylbenzene-1-sulfonyI)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}-3 ,5-d ifl uorophenyI)-N'-(2-methoxyethyl)u rea (10.0 mg, 16.8 pmol, intermediate 287), Ir(41,61-dF-5-0F3-ppy)2(4 ,41-dtbbpy)P F6 (380 pg, 0.34 pmol, CAS
No. [870987-63-6]), tris(trimethylsilyl)silane (5.2 pL, 17 pmol, CAS No. [1873-77-4]) and sodium carbonate (10.7 mg, 101 pmol) were dissolved in trifluorotoluene (300 pL) in a MW-vial.
In a separate vial, the Ni-catalyst was prepared by dissolving Nickel (II) chloride dimethoxyethane adduct (18 mg, 84 pmol, CAS No. [29046-78-4]) and 4,4'-Di-tert-butyl-2,2'-bipyridine (23 mg, 84 pmol, CAS No. [72914-19-3]) in dimethyl acetamide (10 mL) followed by stirring for 5 min. 0.1 mL of this catalyst solution was syringed to the sealed reaction vial and argon was bubbled through the solution for another 5 min. 2-bromopropane (7.1 pL, 76 pmol, CAS No. [75-26-3]) was added. The MW-vial was subsequently irradiated by two 40W Kessil LED Aquarium lights (40W each, 4 cm distance) placed in a water bath to keep the temperature below 35 C for 12 hours, at which time water and ethyl acetate were added and the layers were separated. The aqueous phase was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulfate, and evaporated to give the crude material, which was used without further purification.
LC-MS (method 2): Rt= 1.42 min; MS (ESIpos): rrilz = 559 [M+H]

Intermediate 300 N-(3,5-difluoro-4-{[1-(4-methylbenzene-1-sulfony1)-3-(propan-2-y1)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-N'-[(3-methyloxetan-3-yl)methyl]urea H H
F .5\) N N

F
/N j 0...-gõ.0 I.

In analogy to intermediate 2, phenyl (3,5-difluoro-4-{[1-(4-methylbenzene-1-sulfony1)-3-(propan-2-y1)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (250 mg, 66 %
purity, 286 pmol, intermediate 290), and 1-(3-methyloxetan-3-yl)methanamine (72.2 mg, 714 pmol, CAS No. [153209-97-3]), in DMF (2.0 mL) were reacted to obtain a crude product which was used in the next step without further purification.
LC-MS (method 2): Rt= 1.40 min; MS (ESIpos): rrilz = 585 [M+H]
Intermediate 301 N-(3,5-difluoro-4-{[1-(4-methylbenzene-1-sulfony1)-3-(propan-2-y1)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-N'-{[3-(propan-2-yl)oxetan-3-yl]methyllurea H H.$
OH
F*I NN
.{- C H3 H 3C 0 n il H 3C
F
/ I
N N/
0 - ' - -In analogy to intermediate 2, phenyl (3,5-difluoro-4-{[1-(4-methylbenzene-1-sulfony1)-3-(propan-2-y1)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (250 mg, 66 %
purity, 286 pmol, intermediate 290), and 1[3-(propan-2-yl)oxetan-3-ylynethanamine (92.3 mg, 714 pmol, CAS No. [1539197-30-2]) in DMF (2.0 mL) were reacted to obtain a crude product which was used in the next step without further purification.
LC-MS (method 2): Rt= 1.49 min; MS (ESIpos): rrilz = 614 [M+H]

Intermediate 302 N-(3,5-difluoro-4-{[1-(4-methylbenzene-1-sulfony1)-3-(propan-2-y1)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)morpholine-4-carboxamide H (C) F NN.) H3C-_( ?
F
e-.--N'N/

In analogy to intermediate 2, phenyl (3,5-difluoro-4-{[1-(4-methylbenzene-1-sulfony1)-3-(propan-2-y1)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (200 mg, 66 %
purity, 229 pmol, intermediate 290), and morpholine (50 pL, 570 pmol, CAS No. [110-91-8]), in DMF
(2.0 mL) were reacted to obtain a crude product which was used in the next step without further purification.
LC-MS (method 2): R1= 1.42 min; MS (ESIpos): rrilz = 571 [M+H]
Intermediate 303 N-(3,5-difluoro-4-{[1-(4-methylbenzene-1-sulfony1)-3-(propan-2-y1)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-N'42-(morpholin-4-y1)-2-oxoethyl]urea F H H.A
NN
N

z :1 F
N''N/
0...-si_.so 44k HC
In analogy to intermediate 2, phenyl (3,5-difluoro-4-{[1-(4-methylbenzene-1-sulfony1)-3-(propan-2-y1)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamate (200 mg, 66 %
purity, 229 pmol, intermediate 290), and 2-amino-1-(morpholin-4-yl)ethan-1-one (82.4 mg, 571 pmol, CAS No. [56414-96-1]) in DMF (2.0 mL) were reacted to obtain a crude product which was used in the next step without further purification.
LC-MS (method 2): Rt= 1.36 min; MS (ESIpos): rrilz = 629 [M+H]
Intermediate 304 N43,5-difluoro-4-({1-(4-methylbenzene-1-sulfony1)-3-(1,1,1-trifluoropropan-2-y1)-1H-pyrrolo[2,3-b]pyridin-4-ylloxy)pheny1]-N'-(2-methoxyethypurea H H
F C FL
fa NyNO' '' F3C-...( ?
F
N----N/
0-c' --¨

N-(4-{[3-bromo-1-(4-methylbenzene-1-sulfonyI)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}-3 ,5-difluoropheny1)-N'-(2-methoxyethypurea (390 mg, 655 pmol, intermediate 287), Ir(41,61-dF-5-CF3-ppy)2(4,41-dtbbpy)PF6 (14.7 mg, 13.1 pmol, CAS No. [870987-63-6]), tris(trimethylsilyl)silane (200 pL, 650 pmol, CAS No. [1873-77-4]) and sodium carbonate (278 mg, 2.62 mmol) were dissolved in 1,2-dimethoxyethane (14 mL) in a MW-vial. In a separate vial, the Ni-catalyst was prepared by dissolving Nickel (II) chloride dimethoxyethane adduct (7.20 mg, 32.7 pmol, CAS No. [29046-78-4]) and 4,4'-Di-tert-butyl-2,2'-bipyridine (8.79 mg, 32.7 pmol, CAS No. [72914-19-3]) in N,N-dimethyl acetamide (10 mL) followed by stirring for 5 min. The catalyst solution was syringed to the sealed reaction vial and argon was bubbled through the solution for another 5 min. 2-bromo-1,1,1-trifluoropropane (490 pL, 2.6 mmol, CAS No. [421-46-5]) was added. The MW-vial was subsequently irradiated by two 40W Kessil LED Aquarium lights (40W each, 4 cm distance) placed in a water bath to keep the temperature below 35 C for 12 hours, at which time water and ethyl acetate were added and the layers were separated. The aqueous phase was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulfate, and evaporated to give the crude material, which was used without further purification.
LC-MS (method 2): R1= 1.39 min; MS (ESIpos): rrilz = 613 [M+H]

Intermediate 305 N44-({3-(butan-2-y1)-1-(4-methylbenzene-1-sulfony1)-1H-pyrrolo[2,3-b]pyridin-4-ylloxy)-3,5-difluoropheny1]-N'-(2-methoxyethypurea H H
F C FL
fa NyN0- '' H 3C /--, j7 N----N
0_¨ 1_ 44Ik N-(4-{[3-bromo-1-(4-methylbenzene-1-sulfony1)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}-3,5-difluorophenylyN'-(2-methoxyethypurea (380 mg, 638 pmol, intermediate 287), Ir(41,61-dF-5-CF3-ppy)2(4,41-dtbbpy)PF6 (14.3 mg, 12.8 pmol, CAS No. [870987-63-6]), tris(trimethylsilyl)silane (200 pL, 640 pmol, CAS No. [1873-77-4]) and lithium carbonate (283 mg, 3.83 mmol) were dissolved in trifluorotoluene (11 mL) in a MW-vial.
In a separate vial, the Ni-catalyst was prepared by dissolving Nickel (II) chloride dimethoxyethane adduct (700 pg, 3.2 pmol, CAS No. [29046-78-4]) and 4,4'-Di-tert-butyl-2,2'-bipyridine (860 pg, 3.2 pmol, CAS No. [72914-19-3]) in N,N-dimethylacetamide (3.8 mL) followed by stirring for 5 min. The catalyst catalyst solution was syringed to the sealed reaction vial and argon was bubbled through the solution for another 5 min. 2-bromobutane (310 pL, 2.9 mmol, CAS No.
[78-76-2]) was added. The MW-vial was subsequently irradiated by two 40W
Kessil LED
Aquarium lights (40W each, 4 cm distance) placed in a water bath to keep the temperature below 35 C for 12 hours, at which time water and ethyl acetate were added and the layers were separated. The aqueous phase was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulfate, and evaporated to give the crude material, which was used without further purification.
LC-MS (method 2): Rt= 1.45 min; MS (ESIpos): rniz = 573 [M+H]

Intermediate 306 N43 ,5-difluoro-4-({1-(4-methylbenzene-1-su Ifony1)-3-(3-methylbutan-2-y1)-1 H-pyrrolo[2,3-b]pyrid in-4-ylloxy)pheny1]-N'-(2-methoxyethypurea H H
H 3C F 40 NyNo,C H3 ).......(C H39 0 (n.
N----N/
0_¨ 1_ O

N-(4-{[3-bromo-1-(4-methylbenzene-1-sulfony1)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}-3,5-difluoropheny1)-N'-(2-methoxyethypurea (360 mg, 605 pmol, intermediate 287), Ir(41,61-dF-5-CF3-ppy)2(4,41-dtbbpy)PF6 (13.6 mg, 12.1 pmol, CAS No. [870987-63-6]), tris(trimethylsilyl)silane (190 pL, 600 pmol, CAS No. [1873-77-4]) and lithium carbonate (268 mg, 3.63 mmol) were dissolved in trifluorotoluene (11 mL) in a MW-vial.
In a separate vial, the Ni-catalyst was prepared by dissolving Nickel (II) chloride dimethoxyethane adduct (6.64 mg, 30.2 pmol, CAS No. [29046-78-4]) and 4,4'-Di-tert-butyl-2,2'-bipyridine (8.11 mg, 30.2 pmol, CAS No. [72914-19-3]) in 1,3-Dimethy1-2-imidazolidinone (3.6 mL) followed by stirring for 5 min. The catalyst catalyst solution was syringed to the sealed reaction vial and argon was bubbled through the solution for another 5 min. 2-bromo-3-methylbutane (340 pL, 2.7 mmol CAS No. [18295-25-5]) was added. The MW-vial was subsequently irradiated by two 40W Kessil LED Aquarium lights (40W each, 4 cm distance) placed in a water bath to keep the temperature below 35 C for 12 hours, at which time water and ethyl acetate were added and the layers were separated. The aqueous phase was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulfate, and evaporated to give the crude material, which was used without further purification.
LC-MS (method 2): Rt= 1.48 min; MS (ESIpos): rrilz = 587 [M+H]

Intermediate 307 N-(3 ,5-d ifl uoro-4-{[1-(4-methylbenzene-1-su Ifony1)-3-(pentan-3-y1)-1 H-pyrrolo[2,3-b]pyrid in-4-yl]oxylpheny1)-N'-(2-methoxyethypurea H H
C FL
H3 F C fa NyN0- '' H 3C z 17 N----N
0_¨slo 44Ik N-(4-{[3-bromo-1-(4-methylbenzene-1-sulfony1)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}-3,5-difluoropheny1)-N'-(2-methoxyethypurea (420 mg, 705 pmol, intermediate 287), Ir(41,61-dF-5-CF3-ppy)2(4,41-dtbbpy)PF6 (15.8 mg, 14.1 pmol, CAS No. [870987-63-6]), tris(trimethylsilyl)silane (220 pL, 710 pmol, CAS No. [1873-77-4]) and lithium carbonate (313 mg, 4.23 mmol) were dissolved in trifluorotoluene (13 mL) in a MW-vial.
In a separate vial, the Ni-catalyst was prepared by dissolving Nickel (II) chloride dimethoxyethane adduct (770 pg, 3.5 pmol, CAS No. [29046-78-4]) and 4,4'-Di-tert-butyl-2,2'-bipyridine (950 pg, 3.5 pmol, CAS No. [72914-19-3]) in N,N-dimethylacetamide (4.2 mL) followed by stirring for 5 min. The catalyst catalyst solution was syringed to the sealed reaction vial and argon was bubbled through the solution for another 5 min. 3-bromopentane (390 pL, 3.2 mmol, CAS No.
[1809-10-5]) was added. The MW-vial was subsequently irradiated by two 40W
Kessil LED
Aquarium lights (40W each, 4 cm distance) placed in a water bath to keep the temperature below 35 C for 12 hours, at which time water and ethyl acetate were added and the layers were separated. The aqueous phase was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulfate, and evaporated to give the .. crude material, which was used without further purification.
LC-MS (method 2): Rt= 1.48 min; MS (ESIpos): rrilz = 587 [M+H]

Intermediate 308 N-(3 ,5-d ifl uoro-4-{[1-(4-methylbenzene-1-su Ifony1)-3-(2-methyl propyI)-1 H-pyrrolo[2,3-b]pyrid in-4-yl]oxylpheny1)-N'-(2-methoxyethypurea H H

fa NyN0- C FL'' H3C z 0 1 N--"N/
0_¨slo O

N-(4-{[3-bromo-1-(4-methylbenzene-1-sulfonyI)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}-3 ,5-d ifl uorophenyI)-N'-(2-methoxyethyl)u rea (360 mg, 605 pmol, intermediate 287), Ir(41,61-dF-5-CF3-ppy)2(4,41-dtbbpy)PF6 (13.6 mg, 12.1 pmol, CAS No. [870987-63-6]), tris(trimethylsilyl)silane (190 pL, 600 pmol, CAS No. [1873-77-4]) and lithium carbonate (268 mg, 3.63 mmol) were dissolved in trifluorotoluene (11 mL) in a MW-vial.
In a separate vial, the Ni-catalyst was prepared by dissolving Nickel (II) chloride dimethoxyethane adduct (6.64 mg, 30.2 pmol, CAS No. [29046-78-4]) and 4,4'-Di-tert-butyl-2,2'-bipyridine (8.11 mg, 30.2 pmol, CAS No. [72914-19-3]) in 1,3-Dimethy1-2-imidazolidinon (3.6 mL, 33 mmol) followed by stirring for 5 min. The catalyst catalyst solution was syringed to the sealed reaction vial and argon was bubbled through the solution for another 5 min. 1-bromo-2-methylpropane (300 pL, 2.7 mmol, CAS No. [78-77-3]) was added. The MW-vial was subsequently irradiated by two 40W Kessil LED Aquarium lights (40W each, 4 cm distance) placed in a water bath to keep the temperature below 35 C for 12 hours, at which time water and ethyl acetate were added and the layers were separated. The aqueous phase was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulfate, and evaporated to .. give the crude material, which was used without further purification.
LC-MS (method 2): Rt= 1.45 min; MS (ESIpos): m/z = 573 [M+H]

Intermediate 309 N43 ,5-difluoro-4-({1-(4-methylbenzene-1-su Ifony1)-3-(4 ,4,4-trifluorobutan-2-yI)-1 H-pyrrolo[2,3-b]pyrid in-4-ylloxy)pheny1]-N'-(2-methoxyethypurea H H
F N N C H
a Y 3 CH, 0 F3C/--, jcic7 N----N/
05' O

N-(4-{[3-bromo-1-(4-methylbenzene-1-sulfony1)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}-3,5-difluoropheny1)-N'-(2-methoxyethypurea (300 mg, 504 pmol, intermediate 287), Ir(41,61-dF-5-0F3-ppy)2(4,41-dtbbpy)PF6 (11.3 mg, 10.1 pmol, CAS No. [870987-63-6]), tris(trimethylsilyl)silane (160 pL, 500 pmol, CAS No. [1873-77-4]) and lithium carbonate (223 mg, 3.02 mmol) were dissolved in trifluorotoluene (9.0 mL) in a MW-vial.
In a separate vial, the Ni-catalyst was prepared by dissolving Nickel (II) chloride dimethoxyethane adduct (5.54 mg, 25.2 pmol, CAS No. [29046-78-4]) and 4,4'-Di-tert-butyl-2,2'-bipyridine (6.76 mg, 25.2 pmol, CAS No. [72914-19-3]) in N,N-dimethylacetamide (3.0 mL) followed by stirring for 5 min. The catalyst catalyst solution was syringed to the sealed reaction vial and argon was bubbled through the solution for another 5 min. 3-bromo-1,1,1-trifluorobutane (310 pL, 2.3 mmol, CAS No. [406-47-3]) was added. The MW-vial was subsequently irradiated by two 40W Kessil LED Aquarium lights (40W each, 4 cm distance) placed in a water bath to keep the temperature below 35 C for 12 hours, at which time water and ethyl acetate were added and the layers were separated. The aqueous phase was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulfate, and evaporated to give the crude material, which was used without further purification.
LC-MS (method 2): Rt= 1.42 min; MS (ESIpos): m/z = 628 [M+H]

Intermediate 310 N-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-2-methylazetidine-1-carboxamide NI\P

Br 0 I
r-I
H 3C ¨St H3d CH3 In analogy to intermediate 206, phenyl {4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (150 mg, 229 pmol, intermediate 159), 2-methylazetidine¨hydrogen chloride (1I1)(49.2 mg, 457 pmol, CAS No.
[1152113-37-5]), and triethylamine (64 pL, 460 pmol) in DMF (2 mL) were reacted to obtain a crude product which was used in the next step without further purification.
LC-MS (method 2): R1= 1.54 min; MS (ESIpos): m/z = 567 [M+H]
Intermediate 311 N-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllazetidine-1-carboxamide ci 0 I
r-I
H3c-St H3d CH3 In analogy to intermediate 206, phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (500 mg, 85 %
purity, 778 pmol, intermediate 44), azetidine-hydrochloride (76.5 mg, 817 pmol, CAS No. [503-29-7]) and triethylamine (120 pL, 860 pmol) in DMF (6.6 mL) were reacted to obtain a crude product which was purified by flash column chromatography to give the title compound (160 mg, 40%
yield).
LC-MS (method 2): Rt = 1.49 min; MS (ESIpos): rrilz = 509 [M+H]
1H NMR (400 MHz, DMSO-c16) 6 ppm -0.09 (s, 9 H), 0.79 - 0.86 (m, 2 H), 2.16 -2.26 (m, 2 H), 3.50 - 3.57 (m, 2 H), 3.99 (t, 4 H), 5.60 (s, 2 H), 6.43 (d, 1 H), 7.53 (d, 2 H), 7.84 (s, 1 H), 8.17 (d, 1 H), 8.86 (s, 1 H) Intermediate 312 N-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyI}-6-oxa-2-azaspiro[3.4]octane-2-carboxamide H
H 3C i F N N

Cl 0 F
H3C, PH3 / I
H 3C ---Si N---N/
0---i In analogy to intermediate 2, phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (190 mg, 348 pmol, intermediate 44), and dimethylamine (0.17 mL, 348 pmol, 2M solution in THF, CAS - 124-40-3) in DMF
(3 mL) were reacted to obtain a crude product which was used in the next step without further purification.
LC-MS (method 2): R1= 1.49 min; MS (ESIpos): rniz = 498 [M+H]
Intermediate 313 (+/-)-N-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-4,4-difluoro-3-(hydroxymethyl)piperidine-1-carboxamide F
H
F
. NT, NCtO H
CI
F
H3C, PH3 / I
H3C¨Si N''-"

In analogy to intermediate 2, phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (190 mg, 348 pmol, intermediate 44), and (+/-)-(4,4-difluoropiperidin-3-yl)methanol (105 mg, 696 pmol, CAS No.
[1331823-62-1]), in DMF (3 mL) were reacted to obtain a crude product which was used in the next step without further purification.
LC-MS (method 2): Rt= 1.61 min; MS (ESIpos): rrilz = 603 [M+H]
Intermediate 314 N-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-W-(1-methoxy-2-methylpropan-2-yOurea NH NH

y cH3 0 ,o I

H 3C¨S1 H3d C H3 In analogy to intermediate 2, phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (150 mg, 275 pmol, intermediate 44) and 1-methoxy-2-methylpropan-2-amine (56.7 mg, 549 pmol, CAS No. [20719-68-0]), in DMF (740 pL) were reacted to obtain a crude product which was used in the next step without further purification.
LC-MS (method 2): Rt= 1.59 min; MS (ESIpos): rrilz = 555 [M+H]
Intermediate 315 (+/-)-N-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-W-1-oxaspiro[4.4]nonan-6-ylurea ¨ mixture of isomers H H
CI
NN
0 1.1 I
H3C¨S1 H3d CH3 In analogy to intermediate 206, phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (150 mg, 275 pmol, intermediate 44), 1-oxaspiro[4.4]nonan-6-amine¨hydrogen chloride (1/1) (97.6 mg, 549 pmol, CAS No.
[951164-20-8], mixture of isomers) and N,N-diisopropylethylamine (140 pL, 820 pmol) in DMF
(740 pL) were reacted to obtain a crude product which was used in the next step without further purification.
LC-MS (method 2): Rt= 1.62 min; MS (ESIpos): rrilz = 594 [M+H]
Intermediate 316 N-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-N'41-(morpholin-4-y1)-1-oxopropan-2-yl]urea H H
N N
y CI
I
H 3C¨S[
H3d CH3 In analogy to intermediate 2, phenyl {4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamate (200 mg, 366 pmol, intermediate 44), and 2-amino-1-(morpholin-4-yl)propan-1-one (69.5 mg, 440 pmol, CAS No.
[124491-97-0]), in DMF (990 pL) were reacted to obtain a crude product which was used without further purification.
LC-MS (method 2): Rt= 1.47 min; MS (ESIpos): rrilz = 611 [M+H]

EXPERIMENTAL SECTION ¨ EXAMPLES
The following examples describe the embodyment of the instant invention, not restricting the invention to these examples only.
Example 1 1-(3,5-difl uoro-4-{[3-(trifl uoromethyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl]oxy}pheny1)-3-[3-(morpholin-4-y1)propyl]urea cN H H
N/N..õ..N N
F
)4F
F F
I \
N -----N
H
To a solution of 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-343-(morpholin-4-y1)propyl]urea (970 mg, 1.54 mmol, intermediate 2) in dichloromethane (21 mL) was added trifluoroacidic acid (10 mL, 140 mmol) and this mixture was stirred for 3 hours at room temperature. The reaction mixture was carefully poured into an aqueous solution of sodium hydrogenecarbonate. This aqueous phase was extracted two times with ethyl actetate. Then the combined organic phases were washed with brine, dried over sodium sulfate and then after filtration evaporated to dryness in vacuum.
The obtained crude product was purified via a Biotage chromatography system (25 g snap KP-NH column, hexane /0 ¨ 100% ethylacetate, then ethyl acetate! 0 ¨ 100%
methanol) to obtain 547 mg (97% purity, 69% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.60 (quin, 2H), 2.27 -2.37 (m, 6H), 3.12 (q, 2H), 3.58 (t, 4H), 6.42 (t, 1H), 6.46 (d, 1H), 7.34 - 7.40 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 8.98 (s, 1H), 12.63 (s, 1H).

Example 2 1-(3,5-difl uoro-4-{[3-(trifl uoromethyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyI)-3-(2-methoxyethyl)urea 2( *F
F
F
F F
I \
N----N
H
In analogy to example 1), 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(2-methoxyethypurea (99.8 mg, 178 pmol, intermediate 3) was stirred with trifluoroacidic acid (1.2 mL, 16 mmol) in dichloromethane (2.4 mL). The Biotage purified product was stirred in dichlormethane (5 mL).
Then the solid was isolated by filtration and dried in vacuum to yield 39 mg (97 % purity, 49 %
yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 3.24 - 3.30 (m, 5H), 3.39 (t, 2H), 6.44 -6.51 (m, 2H), 7.33 -7.39 (m, 2H), 8.10 (s, 1H), 8.20 (d, 1H), 9.11 (s, 1H), 12.63 (br s, 1H).
Example 3 1-(3,5-difl uoro-4-{[3-(trifl uoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}pheny1)-3-[3-(methylsulfonyl)propyl]urea os CH3 ;d H H
0 -- \N N
r . F
F
F
F F
I \
N----N
H
In analogy to example 2), 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-343-(methylsulfonyl)propyl]urea (106 mg, 171 pmol, intermediate 4) was stirred with trifluoroacidic acid (1.2 mL, 15 mmol) in dichloromethane (2.3 mL) to obtain 32.6 mg (97 %
purity, 38 %
yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.83 - 1.92 (m, 2H), 2.99 (s, 3H), 3.09 -3.17 (m, 2H), 3.22 (q, 2H), 6.46 (d, 1H), 6.54 (t, 1H), 7.36 - 7.42 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 9.06 (s, 1H), 12.62 (br s, 1H).

Example 4 1-(2,2-difluoroethyl)-3-(3,5-difluoro-44[3-(trifluoromethyl)-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}phenyl)urea F
H
F----c F

F F
I \
N...-N
H
In analogy to example 2), 1-(2,2-difluoroethyl)-3-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyOurea (88.5 mg, 156 pmol, intermediate 5) was stirred with trifluoroacidic acid (1.1 mL, 14 mmol) in dichloromethane (2.1 mL) to obtain 37.6 mg (97 % purity, 54 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 3.54 (tdd, 2H), 6.07 (tt, 1H), 6.47 (d, 1H), 6.77 (t, 1H), 7.36 - 7.42 (m, 2H), 8.10 - 8.13 (m, 1H), 8.21 (d, 1H), 9.23 (s, 1H), 12.63 (br s, 1H).
Example 5 N3-[(3,5-difluoro-44[3-(trifluoromethyl)-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}phenyl)carbamoy1]-beta-alaninamide HN H H
2yXNrN
. F

F

F F
I \
N...--N
H
In analogy to example 2), N3-[(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamoy1]-beta-alaninamide (100 mg, 174 pmol, intermediate 6) was stirred with trifluoroacidic acid (1.3 mL, 16 mmol) in dichloromethane (2.5 mL) to obtain 37.3 mg (93 % purity, 45 %
yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 2.28 (t, 2H), 3.29 (q, 2H), 6.41 - 6.49 (m, 2H), 6.92 (br s, 1H), 7.31 -7.38 (m, 2H), 7.40 (br s, 1H), 8.11 (s, 1H), 8.21 (d, 1H), 9.14 (s, 1H), 12.62 (br s, 1H).

Example 6 1-(3,5-difl uoro-4-{[3-(trifl uoromethyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyI)-3-(pyridin-4-ylmethyl)urea I&
H
Ø0. H
N N
2r *F
F
F )4FF
I \
N-----N
H
In analogy to example 2), 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(pyridin-4-ylmethypurea (145 mg, 244 pmol, intermediate 7) was stirred with trifluoroacidic acid (1.8 mL, 23 mmol) in dichloromethane (3.5 mL) to obtain 61.7 mg (95 % purity, 52 %
yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 4.35(d, 2H), 6.47 (d, 1H), 7.04 (t, 1H), 7.27 -7.32 (m, 2H), 7.37 - 7.45 (m, 2H), 8.09 - 8.12 (m, 1H), 8.21 (d, 1H), 8.49 - 8.54 (m, 2H), 9.29 (s, 1H), 12.63 (br s, 1H).
Example 7 1-(3,5-difl uoro-4-{[3-(trifl uoromethyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl]oxy}pheny1)-3-[(1 -hydroxycyclopropyl)methyl]urea H H
I-IN N
2( .F
F
F F
I \
N-..---N
H
In analogy to example 2), 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(1-hydroxycyclopropyl)methyl]urea (151 mg, 264 pmol, intermediate 8) was stirred with trifluoroacidic acid (1.9 mL, 25 mmol) in dichloromethane (3.8 mL) to obtain 103 mg (95 %
purity, 83% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 0.98 - 1.05 (m, 4H), 2.08 (s, 1H), 2.39 (qd, 2H), 6.29 -6.33 (m, 1H), 6.54 (d, 1H), 7.47 - 7.53 (m, 2H), 8.15 (s, 1H), 8.26 (d, 1H), 10.16 (s, 1H), 12.70 (br s, 1H).

Example 8 4-{[(3,5-difluoro-44[3-(trifluoromethyl)-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}pheny1)-carbamoyl]amino}butanamide H 2 N jc H/x N NH
* F
F
F
F F
I \
N N
H
In analogy to example 2), 4-{[(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamoyl]aminolbutanamide (110 mg, 187 pmol, intermediate 9) was stirred with trifluoroacidic acid (1.3 mL, 17 mmol) in dichloromethane (2.7 mL) to obtain 45.6 mg (95 % purity, 51 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.65 (quin, 2H), 2.08 (t, 3H), 3.09 (q, 2H), 6.41 -6.50 (m, 2H), 6.77 (br s, 1H), 7.30 (br s, 1H), 7.35 - 7.41 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 9.00 (s, 1H), 12.62 (br s, 1H).
Example 9 1-(3,5-difluoro-44[3-(trifluoromethyl)-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}pheny1)-3-(3-methoxypropyl)urea H H
H 3C"oN...----Nõ...N N
2( .F
F
F
F F
I \
N ----- N
H
In analogy to example 2), 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(3-methoxypropyl)urea (88.0 mg, 153 pmol, intermediate 10) was stirred with trifluoroacidic acid (1.1 mL, 14 mmol) in dichloromethane (2.2 mL) to obtain 38.6 mg (95 % purity, 54 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.67 (quin, 2H), 3.15 (q, 2H), 3.24 (s, 3H), 3.36 (t, 2H), 6.42 (t, 1H), 6.46 (d, 1H), 7.34 - 7.41 (m, 2H), 8.09 - 8.12 (m, 1H), 8.21 (d, 1H), 9.01 (s, 1H), 12.63 (br s, 1H).

Example 10 1-(3,5-difl uoro-4-{[3-(trifl uoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}pheny1)-3-[2-(morpholi n-4-yI)-2-oxoethyl]urea H
r--NN-jcõ..NN

0 = F
F
)4F
F F
I \
N-----N
H
In analogy to example 2), 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-342-(morpholin-4-y1)-2-oxoethyl]urea (124 mg, 197 pmol, intermediate 11) was stirred with trifluoroacidic acid (1.4 mL, 18 mmol) in dichloromethane (2.8 mL) to obtain 41.5 mg (97% purity, 41 %
yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 3.39 -3.49 (m, 4H), 3.58 (dt, 4H), 4.01 (d, 2H), 6.47 (d, 1H), 6.56 (t, 1H), 7.33 - 7.39 (m, 2H), 8.10 - 8.12 (m, 1H), 8.21 (d, 1H), 9.46 (s, 1H), 12.63 (br s, 1H).
Example 11 1-(3,5-difl uoro-4-{[3-(trifl uoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}pheny1)-3-(pyridi n-3-y1 methyl)urea N
(H H
N
01 *F
F
):)...F
F F
I \
N-..---N
H
In analogy to example 2), 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(pyridin-3-ylmethyl)urea (99.8 mg, 168 pmol, intermediate 12) was stirred with trifluoroacidic acid (1.2 mL, 16 mmol) in dichloromethane (2.4 mL) to obtain 86.7 mg (97% purity, 108%
yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 4.34 (d, 2H), 6.47 (d, 1H), 7.07 (t, 1H), 7.35 - 7.43 (m, 3H), 7.72 (dt, 1H), 8.11 (s, 1H), 8.21 (d, 1H), 8.46 (dd, 1H), 8.53 (d, 1H), 9.25 (s, 1H), 12.62 (br s, 1H).

Example 12 1-(3,5-difl uoro-4-{[3-(trifl uoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}pheny1)-3-(pyridi n-2-y1 methyl)urea I N
H H
N N
F
F
F F
I \
NN
H
In analogy to example 2), 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(pyridin-2-ylmethypurea (90.0 mg, 152 pmol, intermediate 13) was stirred with trifluoroacidic acid (1.1 mL, 14 mmol) in dichloromethane (2.2 mL) to obtain 30.3 mg (93% purity, 40%
yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 4.43 (d, 2H), 6.47 (d, 1H), 7.05 (t, 1H), 7.29 (ddd, 1H), 7.33 - 7.44 (m, 3H), 7.79 (td, 1H), 8.11 (s, 1H), 8.21 (d, 1H), 8.51 - 8.56 (m, 1H), 9.38 (s, 1H), 12.63 (br s, 1H).
Example 13 1-(3,5-difl uoro-4-{[3-(trifl uoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}pheny1)-3-[2-(pyridi n-4-yl)ethyl]urea H H
N ==
Nµ I yN 40 F

F

C) F
F F
N-----N
H
In analogy to example 2), 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-342-(pyridin-4-yl)ethyl]urea (123 mg, 202 pmol, intermediate 14) was stirred with trifluoroacidic acid (1.4 mL, 18 mmol) in dichloromethane (2.7 mL) to obtain 42.3 mg (95 % purity, 42 %
yield) of the desired title compound.
1H-NMR (500 MHz, DMSO-d6) 6 [ppm]: 2.80 (t, 2H), 3.36 - 3.43 (m, 2H), 6.45 (d, 1H), 6.50 (t, 1H), 7.26 - 7.30 (m, 2H), 7.34 - 7.39 (m, 2H), 8.10 (s, 1H), 8.20 (d, 1H), 8.47 - 8.50 (m, 2H), 9.07 (s, 1H), 12.63 (br s, 1H).

Example 14 (+/-)-1-(3,5-difl uoro-4-{[3-(trifl uoromethyl)-1H-pyrrolo[2,3-b]pyridi n-4-yl]oxy}pheny1)-342-hydroxy-3-(morpholin-4-yl)propyl]urea 0Th OH
N
NcH
N H
N
r . F
F
).........-F
F F
I \
N-N
H
In analogy to example 2), (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-342-hydroxy-3-(morpholin-4-y1)propyl]urea (75.5 mg, 117 pmol, intermediate 15) was stirred with trifluoroacidic acid (790 pL, 10 mmol) in dichloromethane (1.6 mL) to obtain 22.6 mg (97 %
purity, 36% yield) of the desired title compound.
1H-NMR (500 MHz, DMSO-d6) 6 [ppm]: 2.28 (d, 2H), 2.37 -2.44 (m, 4H), 2.94 -2.99 (m, 1H), 3.29 - 3.32 (m, 1H), 3.57 (t, 4H), 3.66 - 3.74 (m, 1H), 4.82 (d, 1H), 6.37 (t, 1H), 6.46 (d, 1H), 7.32 -7.38 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 9.13 (s, 1H), 12.62 (br s, 1H).
Example 15 (+/-)-1-(3,5-difl uoro-4-{[3-(trifl uoromethyl)-1H-pyrrolo[2,3-b]pyridi n-4-yl]oxy}pheny1)-3-(tetrahydrofuran-2-ylmethyl)urea CI,LH H
N
CirN * F
F
F F
I \
N-----N
H
In analogy to example 2), (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(tetrahydrofuran-2-ylmethyl)urea (162 mg, 276 pmol), intermediate 16) was stirred with trifluoroacidic acid (1.9 mL, 24 mmol) in dichloromethane (3.7 mL) to obtain 54.1 mg (97% purity, 42%
yield) of the desired title compound.
1H-NMR (500 MHz, DMSO-d6) 6 [ppm]: 1.48 - 1.56 (m, 1H), 1.77 - 1.94 (m, 3H), 3.11 (ddd, 1H), 3.24 (ddd, 1H), 3.61 - 3.67 (m, 1H), 3.78 (dt, 1H), 3.87 (qd, 1H), 6.43 -6.48 (m, 2H), 7.33 -7.38 (m, 2H), 8.10 (s, 1H), 8.21 (d, 1H), 9.07 (s, 1H), 12.62 (br s, 1H).

Example 16 1-(3,5-difl uoro-4-{[3-(trifl uoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}pheny1)-3-(tetrahydro-2H-pyran-4-ylmethyl)urea Oc H H
N N
7/ * F
F
0,..F
F F
I \
N-----N
H
In analogy to example 2), 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(tetrahydro-2H-pyran-4-ylmethypurea (205 mg, 341 pmol), intermediate 17) was stirred with trifluoroacidic acid (2.3 mL, 30 mmol) in dichloromethane (4.6 mL) to obtain 74.7 mg (95 % purity, 44 %
yield) of the desired title compound.
1H-NMR (500 MHz, DMSO-d6) 6 [ppm]: 1.18 (ddd, 2H), 1.56 (dd, 2H), 1.62 - 1.71 (m, 1H), 3.01 (t, 2H), 3.27 (dt, 2H), 3.85 (ddd, 2H), 6.46 (d, 1H), 6.50 (t, 1H), 7.35 -7.40 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 8.96 (s, 1H), 12.62 (br s, 1H).
Example 17 1-(3,5-difl uoro-4-{[3-(trifl uoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}pheny1)-3-(1H-1,2,3-triazol-5-ylmethyl)urea N
N,,L
H H
N N
, F
N
H
F F
8 101).,......-F
F
I \

H
In analogy to example 2), 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(1H-1,2,3-triazol-5-ylmethyl)urea (95.6 mg, 164 pmol), intermediate 18) was stirred with trifluoroacidic acid (1.1 mL, 14 mmol) in dichloromethane (2.2 mL) to obtain 26.5 mg (97% purity, 35%
yield) of the desired title compound.
1H-NMR (500 MHz, DMSO-d6) 6 [ppm]: 4.37 (d, 2H), 6.46 (d, 1H), 7.05 (t, 1H), 7.38 - 7.44 (m, 2H), 7.61 (s, 1H), 8.10 (s, 1H), 8.20 (d, 1H), 9.47 (br s, 1H).

Example 18 N2-[(3,5-difluoro-44[3-(trifluoromethyl)-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}pheny1)-carbamoyl]glycinamide H 2 N&II\11 H
rN . F
F
F
F F
I \
N-.---N
H
In analogy to example 2), N2-[(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamoyl]glycinamide (90.7 mg, 162 pmol), intermediate xx) was stirred with trifluoroacidic acid (1.1 mL, 14 mmol) in dichloromethane (2.2 mL) to obtain 47 mg of the title compound which was further purified via preparative HPLC according to method 1 to obtain 20.1 mg (97% purity, 28%
yield) of the desired title compound after drying.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 3.70 (d, 2H), 6.47 (d, 1H), 6.53 (t, 1H), 7.10 (s, 1H), 7.33 -7.40 (m, 2H), 7.46 (s, 1H), 8.11 (s, 1H), 8.21 (d, 1H), 9.34 (s, 1H), 12.34 (br s, 1H).
Example 19 1-(3,5-difluoro-44[3-(trifluoromethyl)-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}pheny1)-3-[2-(morpholin-4-y1)ethyl]urea H H
F N N
F y N
F........F70140: 0 Lo / I
NN%
H
To a solution of 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-342-(morpholin-4-ypethyl]urea (55.0 mg, 89.3 pmol, intermediate 20) in dichloromethane (4 mL) was added trifluoroacidic acid (200 pL, 2.6 mmol) and this mixture was stirred over night at room temperature. Then the reaction mixture was evaporated to dryness. After dilution of the residue with 4 mL of tetrahydrofuran, lithium hydroxide (6.42 mg, 268 pmol) in 1 mL of water was added. The reaction mixture was stirred at room temperature for 1 hour. Then the reaction mixture was evaporated to dryness and the residue was purified by preparative HPLC to obtain 11 mg (98 % purity, 25 %
yield) of the desired title compound.
1H-NMR (300 MHz, DMSO-d6) 6 [ppm]: 2.35 - 2.46 (m, 6H), 3.19 - 3.29 (m, 2H), 3.57 - 3.66 (m, 4H), 6.32 (br t, 1H), 6.48 (d, 1H), 7.32 - 7.44 (m, 2H), 8.12 (s, 1H), 8.22 (d, 1H), 9.18 (s, 1H), 12.63 (br s, 1H).
Example 20 1-(3,5-difluoro-44[3-(trifluoromethyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyI)-3-[2-(pi peridi n-1 -yl)ethyl]urea H H
y F F N N N
0 o F------..F; F
/ I
N'N
H
To a solution of 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-342-(piperidin-1-ypethyl]urea (45.0 mg, 73.3 pmol, intermediate 21) in 1,4-dioxane (4 mL) was added 12M hydrochloric acid (100 pL, 12 M, 1.2 mmol) and this mixture was stirred over night at 100 C. Then the reaction mixture was evaporated to dryness. After dilution of the residue with water, to this mixture was added an aqueous solution of sodium bicarbonate up to pH 8-9. The mixture was extracted with ethyl acetate.and the organic phase was dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified via column chromatography with methanol /
dichloromethane (3:7 / v:v) to obtain 13.7 mg (95 % purity, 37 % yield) of the desired title compound.
1H-NMR (300 MHz, DMSO-d6) 6 [ppm]: 1.37 - 1.46 (m, 2H), 1.48 - 1.59 (m, 4H), 2.38 (br t, 6H), 3.22 (q, 3H), 6.29 (br t, 1H), 6.48 (d, 1H), 7.32 - 7.45 (m, 2H), 8.11 (s, 1H), 8.22 (d, 1H), 9.20 (s, 1H), 12.63 (br s, 1H).

Example 21 1-(3,5-difl uoro-4-{[3-(trifl uoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}pheny1)-3-[3-(piperidin-1-yl)propyl]urea H H
F F 0 NyNN

F
F
F
/ I
N'N
H
In analogy to example 20), 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-343-(piperidin-1-y1)propyl]urea (43.0 mg, 68.5 pmol intermediate 22) was stirred with 12M
hydrochloric acid (100 pL) in 1,4-dioxane (4.0 mL) to obtain 12.7 mg (93% purity, 35% yield) of the desired title compound.
1H-NMR (300 MHz, DMSO-d6) 6 [ppm]: 1.34 - 1.44 (m, 2H), 1.45 - 1.67 (m, 6H), 2.23 - 2.36 (m, 6H), 3.12 (q, 2H), 6.46 (d, 1H), 6.51 (br t, 1H), 7.33 - 7.44 (m, 2H), 8.10 (s, 1H), 8.21 (d, 1H), 9.10 (s, 1H), 12.60 (br s, 1H).
Example 22 1-(3,5-difl uoro-4-{[3-(trifl uoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}pheny1)-3-[3-(di methylamino)propyl]urea H H

F..... F 9 F

N N-H
In analogy to example 20), 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-343-(dimethylamino)propyl]urea (65.0 mg, 111 pmol intermediate 23) was stirred with 12M
hydrochloric acid (100 pL) in 1,4-dioxane (4.0 mL) to obtain 25.9 mg (97%
purity, 50% yield) of the desired title compound.
1H-NMR (300 MHz, DMSO-d6) 6 [ppm]: 1.60 - 1.75 (m, 2H), 2.41 (s, 6H), 2.55 -2.72 (m, 2H), 3.05- 3.17 (m, 2H), 6.42 (br d, 1H), 6.67 (br s, 1H), 7.27 - 7.42 (m, 2H), 8.06 (s, 1H), 8.17 (d, 1H), 9.48 (br s, 1H), 12.60 (br s, 1H).

Example 23 1-(3,5-difl uoro-4-{[3-(trifl uoromethyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyI)-3-[2-(di methylamino)ethyl]urea H H
F
F N N,. C H 3 F.......9 0 cr) rr,_, F --3 F
P
N N
H
In analogy to example 20), 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-342-(dimethylamino)ethyl]urea (54.0 mg, 94.1 pmol intermediate 24) was stirred with 12M
hydrochloric acid (100 pL) in 1,4-dioxane (4.0 mL) to obtain 19.3 mg (96%
purity, 44% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 2.69 -2.90 (m, 2H), 3.36 - 3.39 (m, 2H), 6.47 (d, 1H), 6.63 (br s, 1H), 7.36 - 7.45 (m, 2H), 8.12 (br s, 1H), 8.22 (d, 1H), 9.57 (br s, 1H), 9.99 (br s, 1H), 12.65 (br s, 1H).
Example 24 1-(3,5-difl uoro-4-{[3-(trifl uoromethyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl]oxy}pheny1)-3-[(1 ,1 -dioxidothietan-3-yl)methyl]urea OS
011- 1.3N H H
NN
F
0 *
F
F
F F
I \
N...-N
H
In analogy to example 2), 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(1,1-dioxidothietan-3-yl)methyl]urea (83.9 mg, 135 pmol, intermediate 25) was stirred with trifluoroacidic acid (920 pL, 12 mmol) in dichloromethane (1.8 mL) to obtain 25.8 mg (97% purity, 38%
yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 2.64 - 2.75 (m, 1H), 3.36 (t, 2H), 3.89 -3.97 (m, 2H), 4.19 -4.27 (m, 2H), 6.47 (d, 1H), 6.73 - 6.79 (m, 1H), 7.36 - 7.43 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 9.19 (s, 1H), 12.63 (br s, 1H).

Example 25 N-(2-{[(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}phenyl)carbamoyl]amino}ethyl)acetamide H
r N.."".NØ01N .. N
* F
F F
I
In analogy to example 2),N-(2-{[(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamoyl]aminolethypacetamide (69.0 mg, 117 pmol, intermediate 26) was stirred with trifluoroacidic acid (800 pL, 10 mmol) in dichloromethane (1.6 mL) to obtain 32.8 mg (95 % purity, 58 % yield) of the desired title compound.
.. 1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.82 (s, 3H), 3.10 -3.19 (m, 4H), 6.41 -6.49 (m, 2H), 7.35 - 7.42 (m, 2H), 7.96 (br s, 1H), 8.10 (s, 1H), 8.20 (d, 1H), 9.12 (s, 1H), 12.63 (br s, 1H).
Example 26 (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}pheny1)-341 -(morpholin-4-yl)propan-2-yl]urea F F
I
In analogy to example 2), (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-341-(morpholin-4-y1)propan-2-yl]urea (82.0 mg, 130 pmol, intermediate 27) was stirred with trifluoroacidic acid (880 pL, 11 mmol) in dichloromethane (1.8 mL) to obtain 23.1 mg (97 % purity, 34 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.11 (d, 3H), 2.21 (dd, 1H), 2.31 - 2.45 (m, 5H), 3.57 (t, 4H), 3.78 - 3.89 (m, 1H), 6.23 (d, 1H), 6.46 (d, 1H), 7.33 - 7.40 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 8.99 (s, 1H), 12.63 (s, 1H).

Example 27 (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}pheny1)-342-(morpholin-4-y1)propyl]urea r N Fr \ii FN1 ON . F
F
F
F F
I \
N-----I\I
H
In analogy to example 2),(+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-342-(morpholin-4-y1)propyl]urea (84.8 mg, 135 pmol, intermediate 28) was stirred with trifluoroacidic acid (910 pL, 12 mmol) in dichloromethane (1.8 mL) to obtain 37.9 mg (97% purity, 55%
yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 0.93 (d, 3H), 2.36 -2.43 (m, 2H), 2.52 -2.65 (m, 3H), 3.04 - 3.20 (m, 2H), 3.54 - 3.65 (m, 4H), 6.28 (t, 1H), 6.46 (d, 1H), 7.31 -7.41 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 9.21 (s, 1H), 12.63 (br s, 1H).
Example 28 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}pheny1)-342-(methylsulfonyl)ethyl]urea o H H N
H 3 CI s 0 * F
F
1(31-F
F F
I \
N...-N
H
In analogy to example 2), 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsily1)-ethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-342-(methylsulfonypethyl]urea (72.0 mg, 118 pmol, intermediate 29) was stirred with trifluoroacidic acid (800 pL, 10 mmol) in dichloromethane (1.6 mL) to obtain 29.7 mg (95 % purity, 50 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 3.04 (s, 3H), 3.32 (t, 2H), 3.51 - 3.60 (m, 2H), 6.46 (d, 1H), 6.59 (t, 1H), 7.35 - 7.42 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 9.31 (s, 1H), 12.63 (br s, 1H).

Example 29 3-{[(3,5-difluoro-44[3-(trifluoromethyl)-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}pheny1)-carbamoyl]amino}propane-1-sulfonamide ;s H H
0- N..--NN N
F
F F

N----N
H
In analogy to example 2), 3-{[(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsily1)-ethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamoyl]aminolpropane-1-sulfonamide (66.1 mg, 106 pmol, intermediate 30) was stirred with trifluoroacidic acid (720 pL, 9.3 mmol) in dichloromethane (1.4 mL) to obtain 8.00 mg (90% purity, 14%
yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.81 -1.92 (m, 2H), 2.95 - 3.03 (m, 2H), 3.21 (q, 2H), 6.41 - 6.47 (m, 1H), 6.62 (br t, 1H), 6.82 (br s, 2H), 7.34 - 7.44 (m, 2H), 8.09 (s, 1H), 8.16 -8.23 (m, 1H), 9.13 (br s, 1H), 12.59 (br s, 1H).
Example 30 3-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}pheny1)-1-methyl-142-(morpholin-4-y1)ethyl]urea H ' N,NNZTh F * 1 0 F
F F
/ I
N''N/
H
In analogy to example 2), 3-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyrid in-4-yl]oxylpheny1)-1-methyl-142-(morpholin-4-yl)ethyl]urea (68.3 mg, 108 pmol, intermediate 31) was stirred with trifluoroacidic acid (730 pL, 9.5 mmol) in dichloromethane (1.5 mL) to obtain 10.0 mg (85 %
purity, 16 %
yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 2.40 - 2.47 (m, 6H), 2.98 (s, 3H), 3.45 (t, 2H), 3.55 (t, 4H), 6.46 (d, 1H), 7.48 - 7.56 (m, 2H), 8.09 - 8.13 (m, 1H), 8.22 (d, 1H), 8.83 (s, 1H), 12.56 (br s, 1H).

Example 31 N-(2-{[(3,5-difluoro-44[3-(trifluoromethyl)-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}pheny1)-carbamoyl]amino}ethyl)methanesulfonamide 0 r 1_4 %% ..., . . 3 H H s', N NN"(--) F * 0 H
F
FO
F F
/ I
N----N/
H
In analogy to example 2), N-(2-{[(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamoyl]aminolethyl)methanesulfonamide (104 mg, 167 pmol, intermediate 32) was stirred with trifluoroacidic acid (1.1 mL, 15 mmol) in dichloromethane (2.3 mL) to obtain 41.6 mg (97 % purity, 49 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 2.92 (s, 3H), 3.04 (q, 2H), 3.22 (q, 1H), 6.44 - 6.52 (m, 2H), 7.12 (t, 1H), 7.35 - 7.41 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 9.18 (s, 1H), 12.63 (br s, 1H).
Example 32 1-(3,5-difluoro-44[3-(trifluoromethyl)-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}pheny1)-3-pyridin-3-ylurea H H
N. NyN
0 . F

F
C)I-F
F F
I \
N...-N
H
In analogy to example 2), 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-pyridin-3-ylurea (68.2 mg, 118 pmol, intermediate 33) was stirred with trifluoroacidic acid (800 pL, 10 mmol) in dichloromethane (1.6 mL) to obtain 35.8 mg (97 % purity, 66 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 6.50 (d, 1H), 7.34 (dd, 1H), 7.44 - 7.50 (m, 2H), 7.95 (ddd, 1H), 8.12 (s, 1H), 8.21 -8.25 (m, 2H), 8.63 (d, 1H), 9.16 (br s, 1H), 9.38 (br s, 1H), 12.64 (br s, 1H).

Example 33 1-(3,5-difluoro-44[3-(trifluoromethyl)-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}pheny1)-3-[3-(trifluoromethyl)phenyl]urea F
F H
F H
jel N)r N
* F

F

F F
I \
N...--N
H
In analogy to example 2), 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-343-(trifluoromethyl)phenyl]urea (40.0 mg, 61.9 pmol, intermediate 34) was stirred with trifluoroacidic acid (420 pL, 5.4 mmol) in dichloromethane (1.5 mL) to obtain 20.1 mg (97 %
purity, 61 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 6.49 - 6.52 (m, 1H), 7.36 (d, 1H), 7.45 -7.57 (m, 3H), 7.60 -7.64 (m, 1H), 8.01 (s, 1H), 8.12 (s, 1H), 8.23 (d, 1H), 9.33 (br d, 2H), 12.64 (br s, 1H).
Example 34 1-(3,5-difluoro-44[3-(trifluoromethyl)-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}pheny1)-3-(1,3,4-thiadiazol-2-yOurea H 1-õI, N
"0 Nr" 'NI
F * 1S-2 F

F F
/ I
N---N/
H
In analogy to example 2), 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(1,3,4-thiadiazol-2-yOurea (127 mg, 217 pmol), intermediate 35) was stirred with trifluoroacidic acid (1.5 mL, 19 mmol) in dichloromethane (2.9 mL) to obtain 10.8 mg (90% purity, 10% yield) of the desired title compound after a final HPLC purification step.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 6.50 (d, 1H), 7.53 - 7.63 (m, 3H), 8.12 (br s, 1H), 8.22 (d, 1H), 9.04 (br s, 1H), 9.81 (br s, 1H), 12.65 (br s, 1H).

Example 35 1-(3,5-difluoro-44[3-(trifluoromethyl)-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}pheny1)-342-fluoro-5-(trifluoromethyl)phenyl]urea F
H H
N N #
F * 'fo F F
F

/ I
N----N/
H
In analogy to example 2), 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-342-fluoro-5-(trifluoromethyl)phenyl]urea (240 mg, 361 pmol), intermediate 36) was stirred with trifluoroacidic acid (2.4 mL, 32 mmol) in dichloromethane (4.9 mL) to obtain 80.4 mg (97 %
purity, 40 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 6.50 (d, 1H), 7.42 - 7.57 (m, 4H), 8.13 (s, 1H), 8.23 (d, 1H), 8.56 (dd, 1H), 9.11 (br s, 1H), 9.63 (br s, 1H), 12.65 (br s, 1H).
Example 36 1-(3,5-difl uoro-4-{[3-(trifl uoromethyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyI)-3-pyridazin-3-ylurea H H N
N N)\1 F = I
i z FO
F F
/ I
N---N/
H
In analogy to example 2), 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-pyridazin-3-ylurea (222 mg, 382 pmol, intermediate 37) was stirred with trifluoroacidic acid (3.0 mL, 39 mmol) in dichloromethane (6.0 mL) to obtain 43.9 mg (92 % purity, 23 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 6.50 (d, 1H), 7.49 - 7.57 (m, 2H), 7.67 (dd, 1H), 8.06 (dd, 1H), 8.12 (d, 1H), 8.22 (d, 1H), 8.91 (dd, 1H), 10.20 (br s, 1H).

Example 37 1-(3,5-difluoro-44[3-(trifluoromethyl)-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}pheny1)-3-(2-methoxyphenyl)urea O'C H 3 H H
F NN
F F
F-..
F
( I
N----N/
H
In analogy to example 2), 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(2-methoxyphenyOurea (170 mg, 279 pmol, intermediate 38) was stirred with trifluoroacidic acid (1.9 mL, 25 mmol) in dichloromethane (3.8 mL) to obtain 17.6 mg (90 % purity, 12 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 3.89 (s, 3H), 6.50 (d, 1H), 6.91 (ddd, 1H), 6.99 (td, 1H), 7.05 (dd, 1H), 7.41 (d, 2H), 8.07 - 8.14 (m, 2H), 8.22 (d, 1H), 8.37 (s, 1H), 9.79 (s, 1H), 12.64 (br s, 1H).
Example 38 1-(2,5-difluoro-44[3-(trifluoromethyl)-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}pheny1)-3-[3-(morpholin-4-y1)propyl]urea H H (C) * 8 F--..F F.....s.) F
/ I
N---"N
H
In analogy to example 1), 1-(2,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-343-(morpholin-4-yl)propyl]urea (90.0 mg, 143 pmol, intermediate 42) was stirred with trifluoroacidic acid (2.2 mL, 28.6 mmol) in dichloromethane (4.4 mL) to obtain 72 mg (90 % purity, 91 %
yield) of the desired title compound.
1H-NMR (400MHz, DMSO-d6) 6 [ppm]: 1.60 (quin, 2H), 2.27 - 2.38 (m, 6H), 3.10 -3.18 (m, 2H), 3.58 (t, 4H), 6.46 (d, 1H), 6.72 (t, 1H), 7.48 (dd, 1H), 8.09 (s, 1H), 8.20 (d, 1H), 8.24 (dd, 1H), 8.58 (s, 1H), 12.59 (br s, 1H).

Example 39 1-(2,5-difluoro-44[3-(trifluoromethyl)-1H-pyrrolo[2,3-1Apyridin-4-yl]oxy}pheny1)-3-[2-(morpholin-4-y1)ethyl]urea H H
F
F 6 NyNN

/ I
N----N
H
In analogy to example 1), 1-(2,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-342-(morpholin-4-ypethyl]urea (72.5 mg, 118 pmol, intermediate 43) was stirred with trifluoroacidic acid (1.6 mL, 21 mmol) in dichloromethane (3.2 mL) to obtain 47.6 mg (92 % purity, 77 %
yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 2.35 - 2.44 (m, 6H), 3.24 (q, 2H), 3.60 (t, 4H), 6.46 (d, 1H), 6.75 (t, 1H), 7.48 (dd, 1H), 8.09 (s, 1H), 8.20 (d, 1H), 8.26 (dd, 1H), 8.78 (s, 1H), 12.59 (br s, 1H).
Example 40 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluoropheny1}-3-[3-(piperidin-1-yl)propyl]urea H NO
H N/
N--i<
ClF 4. 0 ..) / \ d N
H
To a solution of 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-343-(piperidin-1-yl)propyl]urea (115 mg, 0.194 mmol, intermediate 45) in dichloromethane (2.3 mL) was added trifluoroacidic acid (1.1 mL, 15 mmol) and this mixture was stirred for 14 hours at room temperature. The reaction mixture was carefully poured into an aqueous solution of sodium bicarbonate. This aqueous phase was extracted two times with ethyl actetate. Then the combined organic phases were washed with brine, dried over sodium sulfate and then after filtration evaporated to dryness in vacuum. The obtained crude product was purified by HPLC (method 1) to obtain 51 mg (54 %) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.32-1.42 (m, 2H); 1.44-1.53 (m, 4H); 1.53-1.63 (m, 2H); 2.22-2.35 (m, 6H); 3.10 (q, 2H); 6.31 (d, 1H); 6.43 (t, 1H); 7.35-7.41 (m, 2H); 7.61 (s, 1H);
8.09 (d, 1H); 9.00 (s, 1H); 12.12 (s, 1H).
Example 41 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluoropheny1}-3-[2-(dimethylamino)-ethyl]urea H ,C H3 H N........"--N' N¨...\< b H3 4. 0 F

Clk...._õ)....
/ \ /
N
N
H
According to the synthesis of example 40, 115 mg (0.213 mmol) 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-y1)oxy]-3,5-difluorophenyll-342-(dimethylamino)ethyl]urea (intermediate 46) in 2.5 mL dichloromethane and 1.2 mL
trifluoreacetic acid were stirred for 14 hours. After workup, the resulting residue was purified via a Biotage chromatography system (KP-Sil snap column; dichloromethane /
methanol gradient with up to 3% methanol) to yield to 39 mg (42%) of the title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 2.17 (s, 6H); 2.33 (t, 2H); 3.19 (q, 2H);
6.28-6.33 (m, 2H); 7.32-7.38 (m, 2H); 7.61 (s, 1H); 8.09 (d, 1H); 9.19 (bs, 1H); 12.12 (bs, 1H).

Example 42 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluoropheny1}-3-[2-(piperidin-1-yl)ethyl]urea H
4. 0 F

Cl.....) / \ /
N
N
H
According to the synthesis of example 40, 48mg (0.083 mmol) 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-y1)oxy]-3,5-difluorophenyll-342-(piperidin-1-ypethyl]urea (intermediate 47) in 0.96 mL dichloromethane and 0.48 mL
trifluoreacetic acid were stirred for 14 hours. After workup, the resulting residue was purified by HPLC (method 1) to yield to 20 mg (51%) of the title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.34-1.44 (m, 2H); 1.47-1.55 (m, 4H); 2.29-2.40 (m, 6H); 3.20 (q, 2H); 6.29 (t, 1H); 6.31 (d, 1H); 7.33-7.40 (m, 2H); 7.61 (s, 1H); 8.09 (d, 1H); 9.20 (s, 1H); 12.12 (s, 1H).
Example 43 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluoropheny1}-3-[3-(morpholin-4-yl)propyl]urea r0 H Nj H N-__,-----/
F
N¨i 4. 0 Cl k____)....
/ \ /
N
N
H
According to the synthesis of example 40, 100mg (0.168 mmol) 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-y1)oxy]-3,5-difluorophenyll-343-(morpholin-4-yl)propyl]urea (intermediate 48) in 2.0 mL dichloromethane and 0.98 mL

trifluoreacetic acid were stirred for 4 hours. After workup, the resulting residue was purified by HPLC (method 1) to yield to 38 mg (46%) of the title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.56-1.64 (m, 2H); 2.29-2.40 (m, 6H); 3.12 (q, 1H);
3.57 (t, 3H); 6.31 (d, 1H); 6.43 (t, 1H); 7.34-7.41 (m, 2H); 7.61 (s, 1H);
8.09 (d, 1H); 8.99 (s, 1H); 12.12 (s, 1H).
Example 44 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluoropheny1}-3-(2-methoxy-ethyl)urea ,C H 3 õ ?
n N H
N....ic F 4. 0 Cl N
N
H
According to the synthesis of example 40, 130mg (0.234 mmol) 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-y1)oxy]-3,5-difluorophenyll-3-(2-methoxyethypurea (intermediate 49) in 2.9 mL dichloromethane and 1.3 mL
trifluoreacetic acid were stirred for 6 hours. After workup, the resulting residue was purified by HPLC (method 1) to yield to 52 mg (53%) of the title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 3.22-3.30 (m, 5H); 3.39 (t, 2H); 6.32 (d, 1H); 6.46 (t, 1H); 7.34-7.39 (m, 2H); 7.61 (s, 1H); 8.09 (d, 1H); 9.07 (s, 1H); 12.12 (s, 1H).

Example 45 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluoropheny1}-3-ethylurea H
H
N--\<
= 0 /
According to the synthesis of example 40, 130mg (0.262 mmol) 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-y1)oxy]-3,5-difluorophenyll-3-ethylurea (intermediate 50) in 3.0 mL dichloromethane and 1.5 mL trifluoreacetic acid were stirred for 14 hours. After workup, the resulting residue was purified by HPLC (method 1) to yield to 44 mg (44 %) of the title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.06 (t, 3H); 3.08-3.16 (m, 2H); 6.31 (d, 1H); 6.39 (t, 1H); 7.35-7.41 (m, 2H); 7.61 (s, 1H); 8.09 (d, 1H); 8.98 (s, 1H); 12.12 (s, 1H) Example 46 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluoropheny1}-3-[2-(morpholin-4-yl)ethyl]urea H

According to the synthesis of example 40, 42mg (0.071 mmol) 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-y1)oxy]-3,5-difluorophenyll-342-(morpholin-4-ypethyl]urea (intermediate 51) in 0.84 mL dichloromethane and 0.42 mL
trifluoreacetic acid were stirred for 4 hours. After workup, the resulting residue was purified by HPLC (method 1) to yield to 13 mg (38%) of the title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 2.35-2.44 (m, 6H); 3.22 (q, 2H); 3.57-3.61 (m, 4H);
6.31 (d, 1H); 6.35-6.42 (m, 1H); 7.34-7.41 (m, 2H); 7.61 (s, 1H); 8.09 (d, 1H); 9.24 (s, 1H);
12.12 (s, 1H).

Example 47 1-benzy1-3-{4-[(3-chloro-1H-pyrrolo[2,3-13]pyridin-4-y1)oxy]-3,5-difluorophenyl}urea H NH

F 4. 0 N
N
H
According to the synthesis of example 40, 145 mg (0.246 mmol) 1-benzy1-3-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-y1)oxy]-3,5-difluorophenyllurea (intermediate 52) in 3.0 mL dichloromethane and 1.4 mL trifluoreacetic acid were stirred for 5 hours. After workup, the resulting residue was purified by HPLC (method 1) to yield to 40 mg (36 %) of the title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 4.31 (d, 2H); 6.32 (d, 1H); 6.96 (t, 1H);
7.22-7.28 (m, 1H); 7.29-7.37 (m, 4H); 7.37-7.44 (m, 2H); 7.61 (s, 1H); 8.09 (d, 1H); 9.17 (s, 1H); 12.12 (s, 1H).
Example 48 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluoropheny1}-3-(pyrimidin-5-ylmethyl)urea N
HKN
H N
N---..µ
F . 0 Cl N
N
H
According to the synthesis of example 40, 115 mg (0.195 mmol) 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-y1)oxy]-3,5-difluorophenyll-3-(pyrimidin-5-ylmethypurea (intermediate 53) in 2.4 mL dichloromethane and 1.1 mL

trifluoreacetic acid were stirred for 6 hours. After workup, the resulting residue was purified by HPLC (method 1) to yield to 24 mg (27 %) of the title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 4.35 (d, 2H); 6.31 (d, 1H); 7.07 (t, 1H);
7.37-7.42 (m, 2H); 7.61 (s, 1H); 8.09 (d, 1H); 8.78 (s, 2H); 9.09 (s, 1H); 9.28 (s, 1H);
12.12 (s, 1H).
Example 49 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(pyridin-4-ylmethypurea ........)--1\1 H \ /
H N
N--\<
4. 0 F

Cl k___ _)....
/ \ /
N
N
H
According to the synthesis of example 40, 80 mg (0.136 mmol) 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-y1)oxy]-3,5-difluorophenyll-3-(pyridin-4-ylmethypurea (intermediate 54) in 1.7 mL dichloromethane and 0.77 mL
trifluoreacetic acid were stirred for 14 hours. After workup, the resulting residue was purified by HPLC (method 1) to yield to 30 mg (49 %) of the title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 4.34 (d, 2H); 6.31 (d, 1H); 7.17 (t, 1H);
7.29 (d, 2H);
7.38-7.45 (m, 2H); 7.60 (s, 1H); 8.09 (d, 1H); 8.49-8.54 (m, 2H); 9.42 (bs, 1H); 12.12 (bs, 1H).
Example 50 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(2-cyanoethypurea H , N
H N........./-'4 N--....µ
4. 0 F

CI.,_.....)....
/ \ /
N
N
H

According to the synthesis of example 40, 100 mg (0.182 mmol) 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-y1)oxy]-3,5-difluorophenyll-3-(2-cyanoethypurea (intermediate 55) in 2.2 mL dichloromethane and 1.0 mL
trifluoreacetic acid were stirred for 4 hours. After workup, the resulting residue was purified by HPLC (method 1) to yield to 25 mg (33 %) of the title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 2.70 (t, 2H); 3.33-3.39 (m, 2H); 6.32 (d, 1H); 6.79 (t, 1H); 7.38-7.43 (m, 2H); 7.61 (s, 1H); 8.09 (d, 1H); 9.27 (s, 1H); 12.12 (s, 1H).
Example 51 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(3-methylbutypurea H NZ( N¨...\< C H3 4. 0 F

Clk...._õ)....
/ \ /
N
N
H
According to the synthesis of example 40, 130 mg (0.229 mmol) 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-y1)oxy]-3,5-difluorophenyll-3-(3-methylbutypurea (intermediate 56) in 2.8 mL dichloromethane and 1.3 mL
trifluoreacetic acid were stirred for 6 hours. After workup, the resulting residue was purified by HPLC (method 1) to yield to 58 mg (59 %) of the title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 0.89 (d, 6H); 1.30-1.37 (m, 2H); 1.55-1.65 (m, 1H);
3.08-3.15 (m, 2H); 6.31 (d, 1H); 6.38 (t, 1H); 7.35-7.40 (m, 2H); 7.61 (s, 1H); 8.09 (d, 1H); 8.95 (s, 1H); 12.12 (s, 1H).

Example 52 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(1,2-oxazol-3-yOurea H
H N....,e,c, F = 0 N
N
H
According to the synthesis of example 40, 50 mg (0.089 mmol) 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-y1)oxy]-3,5-difluorophenyll-3-(1,2-oxazol-3-yOurea (intermediate 57) in 1.1 mL dichloromethane and 0.5 mL
trifluoreacetic acid were stirred for 6 hours. After workup, the resulting residue was purified by HPLC (method 1) to yield to 11 mg (29 %) of the title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 6.35 (d, 1H); 6.86 (d, 1H); 7.46-7.51 (m, 2H); 7.62 (s, 1H); 8.11 (d, 1H); 8.78 (d, 1H); 9.32 (bs, 1H); 9.93 (bs, 1H); 12.14 (bs, 1H).
Example 53 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-pyridazin-3-ylurea H
LµN
F .....n N:-..-N

N
N
H
According to the synthesis of example 40, 450 mg (0.78 mmol) 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-y1)oxy]-3,5-difluorophenyll-3-pyridazin-3-ylurea (intermediate 58) in 10 mL dichloromethane and 4.4 mL trifluoreacetic acid were stirred for 3 hours. During extractive workup, a white solid generated which was filtered off and collected. This yielded to 210 mg (63%) of the title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 6.36 (d, 1H); 7.49-7.54 (m, 2H); 7.62 (d, 1H); 7.68 (dd, 1H); 8.05 (dd, 1H); 8.11 (d, 1H); 8.92 (dd, 1H); 9.97 (bs, 1H); 10.09 (bs, 1H); 12.15 (bs, 1H).

Example 54 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyllurea N--...\<
0 F .

CI / \ /_-_ N N
H
According to the synthesis of example 40, 50 mg (0.11 mmol) 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-y1)oxy]-3,5-difluorophenyllurea (intermediate 59) in 1.2 mL dichloromethane and 0.6 mL trifluoreacetic acid were stirred for 2 hours. After workup, the resulting residue was purified by HPLC (method 1) to yield to 16 mg (42 %) of the title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 6.16 (s, 2H); 6.32 (d, 1H); 7.36-7.41 (m, 2H); 7.61 (s, 1H); 8.09 (d, 1H); 9.10 (s, 1H); 12.12 (s, 1H).
Example 55 N-{24({4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyllcarbamoyl)amino]ethyllacetamide H H
F NN.........., N H
0 8 LC) Cl F
/ I
N----N
H
Phenyl {4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyllcarbamate (200 mg, 90 % purity, 432 pmol, intermediate 60) was dissolved THF (2.0 mL) and N-(2-aminoethyl)acetamide (88.3 mg, 865 pmol) was added. The mixture was heated for lh to 60 C. After cooling to room temperature dichloromethane was added and the precipitate was collected by suction filtration to yield 142 mg (93% purity, 72% yield) of the title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 9.12 (s, 1H), 8.10 (d, 1H), 7.95 (br s, 1H), 7.61 (s, 1H), 7.39 (br d, 2H), 6.45 (br s, 1H), 6.32 (d, 1H), 3.15 (br s, 4H), 1.82 (s, 3H).

Example 56 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-342-(dimethylamino)ethyl]urea H H
F 00 Br NyNirC H3 F
/ I
N--"N
H
To a solution of 4-(3-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3- b]pyridin-4-yloxy)-3,5-difluorobenzenamine (100 mg, 0.175 mmol, intermediate 61) in 15 mL
dichloromethane stirring under ice-water bath, Then bis(trichloromethyl) carbonate, 62 mg (0.21 mmol) and triethylamine, 53 mg (0.5 mmol) were added at 0 C. The reaction mixture was stirred at 0 C for 10 minutes. Then N1,N1-dimethylethane-1,2-diamine, 39 mg (0.44 mmol), dissolved in dichloromethane was added slowly. The reaction mixture was stirred at 0 C for 30 minutes. Then the reaction was quenched by water and extracted with dichloromethane. The organic phase was washed by a solution of sodium bicarbonate, dried over sodium sulfate, filtered and evaporated to dryness. Then the residue was dissolved in 8 mL 1,4-dioxane and 2 mL hydrochloric acid and stirring at 10000 for 1.5 h. The mixture was evaporated to dryness and was purified by prep HPLC to afford 9.6 mg (12%) of the product.
1H-NMR (300 MHz, DMSO-d6): 6 [ppm] 2.18 (s, 6H), 2.31-2.36 (m, 2H), 3.18-3.21 (m, 2H), 6.30-6.33 (m, 2H), 7.33-7.37 (d, 2H), 7.63-7.64 (m, 1H), 8.08-8.10 (d, 1H), 9.19 (s, 1H), 12.20 (s, 1H).
Example 57 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-343-(dimethylamino)propyl]urea H

i 0yNNC H3 Br F NH
n 401 ,-, F
/ I
N- N"
H
According to the synthesis of example 56, 100 mg (0.213 mmol) 4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluoroaniline (intermediate 61), bis(trichloromethyl) carbonate (75.7 mg, 255 pmol) and N,N-dimethylpropane-1,3-diamine (54.3 mg, 531 pmol) were reacted to yield 19.3 mg (19 %) of the title compound.
1H-NMR (300 MHz, DMSO-d6): 6 [ppm] 1.55-1.58 (m, 2H), 2.15 (s, 6H), 2.22-2.27 (m, 2H), 3.09-3.16 (m, 2H), 6.31-6.34 (d, 1H), 6.49 (m, 1H), 7.37-7.41 (d, 2H), 7.65-7.66 (m, 1H), 8.09-8.11 (d, 1H), 9.06 (s, 1H), 12.22 (s, 1H).
Example 58 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-butylurea H
C H-0yN s F NH
n 0 Br ,-, F
/ I
N''N
H
According to the synthesis of example 56, 100 mg (0.213 mmol) 4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluoroaniline (intermediate 61), bis(trichloromethyl) carbonate (75.7 mg, 255 pmol) and butan-1-amine (38.9 mg, 531 pmol) were reacted to yield 6.9 mg (7%) of the title compound.
1H-NMR (300 MHz, DMSO-d6): 6 [ppm] 0.88-0.93 (t, 3H), 1.28-1.46 (m, 4H), 3.07-3.14 (m, 2H), 6.32-6.42 (m, 2H), 7.36-7.40 (d, 2H), 7.64-7.66 (m, 1H), 8.09-8.11 (d, 1H), 8.95 (s, 1H), 12.22 (s, 1H).
Example 59 1-benzy1-3-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-y1)oxy]-3,5-difluorophenyllurea 0Y NH .
F NH
n 0 Br ,-, F
/ I
N''N
H
According to the synthesis of example 56, 100 mg (0.213 mmol) 4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluoroaniline (intermediate 61), bis(trichloromethyl) carbonate (75.7 mg, 255 pmol) and benzylamine (0.058 mL, 530 pmol) were reacted to yield 6.8 mg (7%) of the title compound.
1H-NMR (300 MHz, DMSO-d6): 6 [ppm] 4.31-4.34 (d, 2H), 6.32-6.34 (d, 1H), 6.91-6.95 (m, 1H), 7.26-7.43 (m, 7H), 7.64-7.66 (m, 1H), 8.09-8.11 (d, 1H), 9.14 (s, 1H), 12.21 (s, 1H).
Example 60 1-(2,3-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-343-(morpholin-4-y1)propyl]urea F r0 H H
F N yo NN.) F F (10 F--...01 / I
N---"N
H
In analogy to example 1), 1-(2,3-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-343-(morpholin-4-y1)propyl]urea (69.0 mg, 110 pmol, intermediate 70) was stirred with trifluoroacidic acid (750 pL, 9.7 mmol) in dichloromethane (1.5 mL). After purification using a Biotage chromatography system we obtained 47 mg (92 % purity, 79 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.60 (quin, 2H), 2.26 -2.39 (m, 6H), 3.14 (q, 2H), 3.58 (t, 4H), 6.49 (d, 1H), 6.66 (t, 1H), 7.12 - 7.18 (m, 1H), 8.01 (t, 1H), 8.10 (s, 1H), 8.21 (d, 1H), 8.55 (d, 1H), 12.61 (s, 1H).
Example 61 1-(2,3-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-342-(morpholin-4-ypethyl]urea F
H H
F N N
F F
F-........110 T1 CO

/ I
N---"N
H
In analogy to example 1), 1-(2,3-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-342-(morpholin-4-yl)ethyl]urea (62.0 mg, 101 pmol, intermediate 71) was stirred with trifluoroacidic acid (700 pL, 9.1 mmol) in dichloromethane (1.4 mL). After purification using a Biotage chromatography system we obtained 35 mg (95 % purity, 68 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 2.40 (br t, 6H), 3.24 (q, 2H), 3.60 (t, 4H), 6.49 (d, 1H), 6.68 (t, 1H), 7.15 (t, 1H), 8.02 (t, 1H), 8.11 (s, 1H), 8.21 (d, 1H), 8.75 (d, 1H), 12.61 (s, 1H).
Example 62 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-342-(dimethylamino)ethyl]thiourea NN' -F$ N'cs e H3 F
F...,j F F
/ I
N----N/
H
In analogy to example 1), 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-342-(dimethylamino)ethyl]thiourea (70.0 mg, 119 pmol, intermediate 72) was stirred with trifluoroacidic acid (800 pL, 10.4 mmol) in dichloromethane (1.6 mL). After purification using a Biotage chromatography system we obtained 10.2 mg (95% purity, 18% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 2.20 (s, 6H), 2.45 (t, 2H), 3.51 - 3.64 (m, 2H), 6.49 (d, 1H), 7.57 - 7.65 (m, 2H), 8.01 (br s, 1H), 8.13 (s, 1H), 8.23 (d, 1H), 10.09 (br s, 1H), 12.65 (br s, 1H).
Example 63 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-342-(morpholin-4-ypethyl]thiourea H H
N NN/Th F * 0 S
F
F..?, F F
/ I
N---N/
H

In analogy to example 1), 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-342-(morpholin-4-ypethyl]thiourea (80.9 mg, 128 pmol, intermediate 73) was stirred with trifluoroacidic acid (870 pL, 11 mmol) in dichloromethane (1.7 mL). After purification using a Biotage chromatography system we obtained 26.7 mg (92% purity, 38% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 2.36 - 2.46 (m, 4H), 2.52 - 2.55 (m, 2H), 3.52 - 3.68 (m, 6H), 6.50 (d, 1H), 7.50 - 7.61 (m, 2H), 8.06 - 8.18 (m, 2H), 8.23 (d, 1H), 10.11 (br s, 1H), 12.65 (br s, 1H).
Example 64 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(2-methoxyethypthiourea H F m 0-"
F . N"(s F F
/ I
N---N/
H
In analogy to example 1), 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(2-methoxyethypthiourea (45.0 mg, 78.0 pmol, intermediate 74) was stirred with trifluoroacidic acid (530 pL, 6.9 mmol) in dichloromethane (1.1 mL). After purification using a Biotage chromatography system we obtained 10.3 mg (97% purity, 29% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 3.30 (s, 3H), 3.51 (t, 2H), 3.67 (q, 2H), 6.50 (d, 1H), 7.53 -7.61 (m, 2H), 8.13 (s, 1H), 8.17 (br s, 1H), 8.24 (d, 1H), 9.99 (br s, 1H), 12.66 (br s, 1H).
Example 65 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-ethylthiourea H H
N
N --.../CH3 F *
S
F
F..:LF F
(1 N----N/
H

In analogy to example 1), 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-ethylthiourea (58.0 mg, 106 pmol, intermediate 75) was stirred with trifluoroacidic acid (720 pL, 9.3 mmol) in dichloromethane (1.4 mL). After purification using a Biotage chromatography system we obtained 19.0 mg (95% purity, 41 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.14 (t, 3H), 3.45 - 3.56 (m, 2H), 6.50 (d, 1H), 7.52 (br d, 2H), 8.07 - 8.18 (m, 2H), 8.24 (d, 1H), 9.85 (br s, 1H), 12.66 (br s, 1H).
Example 66 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-343-(morpholin-4-y1)propyl]thiourea H H r'0 N) N Nr F F
F..,.0 F F
/ I
NN/
H
In analogy to example 1), 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-343-(morpholin-4-yl)propyl]thiourea (71.0 mg, 110 pmol, intermediate 76) was stirred with trifluoroacidic acid (740 pL, 9.7 mmol) in dichloromethane (1.5 mL). After purification using a Biotage chromatography system we obtained 19.1 mg (95% purity, 32% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.72 (quin, 2H), 2.29 - 2.38 (m, 6H), 3.49 -3.60 (m, 6H), 6.49 (d, 1H), 7.48 - 7.56 (m, 2H), 8.13(d, 1H), 8.15 - 8.20 (m, 1H), 8.24(d, 1H), 9.91 (br s, 1H), 12.65 (br s, 1H).

Example 67 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(oxetan-3-ylmethyl)urea ODNH H
N N
0 * F
F
F
F F
I \
NN
H
To a solution of 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(oxetan-3-ylmethypurea (119 mg, 207 pmol, intermediate 77) and ethylenediamine (57 pL, 850pM) in DMF (2.4 mL) and was added 1N
tetrabutylammonium fluoride solution in THF (830 pM, 830pL) and this mixture was stirred at 45 C overnight. The reaction mixture was cooled to room temperature and then diluted with ethylactetat. Then this organic phase were washed with water twice, brine, dried over sodium sulfate and then after filtration evaporated to dryness in vacuum. The obtained crude product was purified via a Biotage chromatography system (11 g snap KP-NH column, ethyl acetate / 0 ¨ 80% ethanol) and subsequent via HPLC to obtain 68 mg again not very pure compound. The obtained compound was solved in ethyl acetate and again extracted with water twice, brine, dried over sodium sulfate and then after filtration evaporated to dryness in vacuum. The resulting residue was purified by preparative thin layer chromatography using dichloromethane / methanol 8:2 to 0btain50mg (92 % purity, 50 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 3.08 (dt, 1H), 3.37 (t, 2H), 4.31 (t, 2H), 4.62 (dd, 2H), 6.46 (d, 1H), 6.86 (t, 1H), 7.35 - 7.43 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 9.29 (s, 1H), 12.63 (br s, 1H).
Example 68 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyOurea H

F * "(c) F.
F F
/ I
N---N/
H

In analogy to example 1, 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyOurea (114 mg, 228 pmol intermediate 78) was stirred with trifluoroacetic acid (1.0 mL, 13 mmol) in dichloromethane (2.0 mL). After purification using a Biotage chromatography system we obtained 51.7 mg (97 % purity, 59 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 6.15 (s, 2H), 6.46 (d, 1H), 7.34 - 7.42 (m, 2H), 8.09 -8.12 (m, 1H), 8.21 (d, 1H), 9.07 (s, 1H), 12.62 (br s, 1H).
Example 69 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-methylurea N N H
F . 0 F
FO
F F
/ I
N---N
H
In analogy to example 1, 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-methylurea (127 mg, 246 pmol, intermediate 79) was stirred with trifluoroacetic acid (1.7 mL, 22 mmol) in dichloromethane (3.3 mL). After purification using a Biotage chromatography system we obtained 27.8 mg (100% purity, 29% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 2.65 (d, 3H), 6.29 (q, 1H), 6.46 (d, 1H), 7.35 - 7.42 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 9.07 (s, 1H), 12.62 (br s, 1H).
Example 70 3-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-1,1-dimethylurea H ,1/4,1 N.("1---C H3 F .

F
F F
/ I
N---N/
H
In analogy to example 1, 3-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-1,1-dimethylurea (176 mg, 332 pmol, intermediate 80) was stirred with trifluoroacetic acid (2.2 mL, 29 mmol) in dichloromethane (4.5 mL). After purification using a Biotage chromatography system we obtained 49.7 mg (100% purity, 37% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 2.95 (s, 6H), 6.46 (d, 1H), 7.49 - 7.57 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 8.76 (s, 1H), 12.63 (br s, 1H).
Example 71 N-(3,5-difluoro-4-{[3-(trifluoromethyI)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)morpholine-4-carboxamide /'0 1,-,1, L) *F F
F....) F F
/ I
N---N/
H
In analogy to example 1, N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)morpholine-4-carboxamide (171 mg, 299 pmol, intermediate 81) was stirred with trifluoroacetic acid (2.0 mL, 26 mmol) in dichloromethane (4.0 mL). After purification using a Biotage chromatography system we obtained 45.5 mg (97% purity, 33% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 3.42 - 3.49 (m, 4H), 3.59 - 3.66 (m, 4H), 6.46 (d, 1H), 7.46 -7.54 (m, 2H), 8.11 (s, 1H), 8.22 (d, 1H), 9.00 (s, 1H), 12.64 (br s, 1H).
Example 72 N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-4-methylpiperazine-1-carboxamide (1\1' ii\ii Nj F
F *
F...,0 F F
/ I
N---N/
H

In analogy to example 1, N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-4-methylpiperazine-1-carboxamide (248 mg, 423 pmol, intermediate 82) was stirred with trifluoroacetic acid (2.9 mL, 37 mmol) in dichloromethane (5.7 mL). After purification using a Biotage chromatography system we obtained 55.1 mg (97% purity, 28% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 2.20 (s, 3H), 2.29 - 2.36 (m, 4H), 3.41 -3.51 (m, 4H), 6.46 (d, 1H), 7.47 - 7.53 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 8.98 (s, 1H), 12.63 (br s, 1H).
Example 73 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-342-(4-methylpiperazin-1-y1)-2-oxoethyl]urea H H
F NN
F F N
F¨k ? . 8 N

F
NN/
H
In analogy to example 1, 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-342-(4-methylpiperazin-1-yI)-2-oxoethyl]urea (83.5 mg, 130 pmol, intermediate 83) was stirred with trifluoroacetic acid (880 pL, 11 mmol) in dichloromethane (1.8 mL). After purification using a Biotage chromatography system we obtained 16.8 mg (97% purity, 25% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 2.19 (s, 3H), 2.24 - 2.34 (m, 4H), 3.37 -3.43 (m, 2H), 3.43 -3.50 (m, 2H), 4.00 (d, 2H), 6.47 (d, 1H), 6.54 (t, 1H), 7.32 - 7.40 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 9.45 (s, 1H), 12.62 (br s, 1H).

Example 74 N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide riCj) H
N N
F
F.C1:1 F F
/ I
N---N/
H
In analogy to example 1, N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-2-oxa-azaspiro[3.3]heptane-6-carboxamide (71.0 mg, 121 pmol, intermediate 84) was stirred with trifluoroacetic acid (820 pL, 11 mmol) in dichloromethane (1.6 mL). After purification using a Biotage chromatography system we obtained 24.6 mg (97 % purity, 43 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 4.15 (s, 4H), 4.69 (s, 4H), 6.46 (d, 1H), 7.50 (d, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 8.96 (s, 1H), 12.63 (br s, 1H).
Example 75 N2-[(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamoy1]-N-methylglycinamide H N' H Hy N
F *

F
F-.01 F F
/ I
N.'"N/
H
In analogy to example 1, N2-[(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamoy1]-N-methylglycinamide (140 mg, 244 pmol, intermediate 85) was stirred with trifluoroacetic acid (1.7 mL, 21 mmol) in dichloromethane (3.3 mL). After purification using a Biotage chromatography system we obtained 67.1 mg (95% purity, 59% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 2.61 (d, 3H), 3.71 (d, 2H), 6.46 (d, 1H), 6.58 (t, 1H), 7.34 -7.41 (m, 2H), 7.91 (q, 1H), 8.09 -8.13 (m, 1H), 8.21 (d, 1H), 9.33 (s, 1H), 12.63 (br s, 1H).
Example 76 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(1,2-thiazol-4-yl)urea H H
N N
tNP
F F *
0 ¨N
FO
F F
/ I
N---N/
H
In analogy to example 1, 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(1,2-thiazol-4-yOurea (155 mg, 265 pmol, intermediate 86) was stirred with trifluoroacetic acid (1.8 mL, 23 mmol) in dichloromethane (3.6 mL). After purification using a Biotage chromatography system we obtained 36.5 mg (95 % purity, 29 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 6.50 (d, 1H), 7.45 - 7.52 (m, 2H), 8.12 (s, 1H), 8.22 (d, 1H), 8.60 (s, 1H), 8.73 (s, 1H), 9.38 (s, 1H), 9.49 (s, 1H), 12.64 (br s, 1H).
Example 77 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(1-methyl-1H-pyrazol-4-yOurea H H
N ,...
..õ,is, --..CN.....0 H3 F F N *
0 ¨N
FO
F F
/ I
N----N/
H
To a solution of 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(1-methyl-1H-pyrazol-4-y1)urea (158 mg, 271 pmol, intermediate 87) in dichloromethane (3.7 mL) was added trifluoroacetic acid (1.8 mL, 24 mmol) and this mixture was stirred 3h at room temperature. The reaction mixture was carefully poured into an aqueous solution of sodium hydrogencarbonate. This aqueous phase was extracted two times with ethyl actetate. Then the combined organic phases were washed with brine, dried over sodium sulfate and then after filtration evaporated to dryness in vacuum. The obtained crude product was purified via a Biotage chromatography system (11 g snap KP-NH
column, hexane / 0 ¨ 100% ethylacetate, then ethyl acetate / 0 ¨ 100%
methanol) and the resulting compound was purified again by preparative HPLC (according to method 1) to obtain 19.9 mg (97% purity, 16% yield) of the desired title compound.
.. 1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 3.79 (s, 3H), 6.49 (d, 1H), 7.39 (d, 1H), 7.41 -7.48 (m, 2H), 7.77 (s, 1H), 8.12 (s, 1H), 8.22 (d, 1H), 8.65 (s, 1H), 9.13 (s, 1H), 12.63 (br s, 1H).
Example 78 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(6-methylpyridin-3-yl)urea H H
N,_ N

1 1\
Is AN
li_ 0 ====== --C H3 F
F, F F
/ I
N----N/
H
In analogy to example 1, 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(6-methylpyridin-3-yOurea (146 mg, 246 pmol, intermediate 88) was stirred with trifluoroacetic acid (1.7 mL, 22 mmol) in dichloromethane (3.3 mL). After purification using a Biotage chromatography system we obtained 61.4 mg (97% purity, 52% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 2.41 (s, 3H), 6.50 (d, 1H), 7.19 (d, 1H), 7.42 - 7.50 (m, 2H), 7.82 (dd, 1H), 8.12 (s, 1H), 8.22 (d, 1H), 8.49 (d, 1H), 8.99 (s, 1H), 9.28 (s, 1H), 12.64 (br s, 1H).

Example 79 1-[(1-acetylazetidin-3-yOmethy1]-3-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyOurea H H c_;, --- C H 3 , N N
F *F
F
F F
/ I
N---*N
H
In analogy to example 1, 1-[(1-acetylazetidin-3-yl)methyl]-3-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyOurea (118 mg, 192 pmol, intermediate 89) was stirred with trifluoroacetic acid (1.3 mL, 17 mmol) in dichloromethane (2.6 mL). After purification using a Biotage chromatography system we obtained 40.0 mg (90 % purity, 39 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.73 (s, 3H), 2.68 - 2.75 (m, 1H), 3.28 -3.32 (m, 2H), 3.54 (dd, 1H), 3.80 (dd, 1H), 3.84 (t, 1H), 4.13 (t, 1H), 6.47 (d, 1H), 6.64 (t, 1H), 7.34 - 7.44 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 9.05 (s, 1H), 12.63 (br s, 1H).
Example 80 N2-[(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamoy1]-N-(2-methoxyethyl)glycinamide H NS
N, 2"
F* Alo F
F.al F F
/ I
N----N/
H
In analogy to example 1, N2-[(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)carbamoy1]-N-(2-methoxyethyl)glycinamide (160 mg, 259 pmol, intermediate 90) was stirred with trifluoroacetic acid (1.8 mL, 23 mmol) in dichloromethane (3.5 mL). After purification using a Biotage chromatography system we obtained 67.6 mg (97 % purity, 52 % yield) of the desired title compound.
11-I-NMR (400 MHz, DMSO-d6) 6 [ppm]: 3.22 - 3.28 (m, 5H), 3.32 - 3.37 (m, 2H), 3.74 (d, 2H), 6.47 (d, 1H), 6.56 (t, 1H), 7.33 - 7.40 (m, 2H), 8.06 (t, 1H), 8.11 (s, 1H), 8.21 (d, 1H), 9.33 (s, 1H), 12.63 (br s, 1H).
Example 81 (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(1,1-dioxidothietan-2-y1)methyl]urea 0--_s H H......õ",0 N
N
F * ----(0 F
FD
F F
(I
N------N
H
In analogy to example 1, (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(1,1-dioxidothietan-2-y1)methyl]urea (148 mg, 239 pmol, intermediate 91) was stirred with trifluoroacetic acid (1.6 mL, 21 mmol) in dichloromethane (3.2 mL). After purification using a Biotage chromatography system we obtained 40.0 mg (95 % purity, 32 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.72 - 1.82 (m, 1H), 2.24 (dtd, 1H), 3.51 -3.62 (m, 2H), 3.96 - 4.14 (m, 2H), 4.56 (quin, 1H), 6.47 (d, 1H), 6.68 (t, 1H), 7.34 -7.42 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 9.20 (s, 1H), 12.63 (br s, 1H).
Example 82 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(2-methylpyrimidin-5-yOurea H H
N,...1.(NN
C F * I?) H 3 F
FO
F F
/ I
N----N/
H

In analogy to example 1, 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(2-methylpyrimidin-5-yOurea (103 mg, 174 pmol, intermediate 92) was stirred with trifluoroacetic acid (1.2 mL, 15 mmol) in dichloromethane (2.4 mL). After purification using a Biotage chromatography system we obtained 36.2 mg (90 % purity, 40 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 2.57 (s, 3H), 6.50 (d, 1H), 7.44 - 7.51 (m, 2H), 8.12 (s, 1H), 8.22 (d, 1H), 8.80 (s, 2H), 9.17 (br s, 1H), 9.49 (br s, 1H), 12.65 (br s, 1H).
Example 83 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(1H-pyrazol-4-y1)urea H H
N.Ne\NH
F F *0 17"--Nli FO
F F
/ I
N----N/
H
In analogy to example 1, 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(1H-pyrazol-4-yOurea (150 mg, 263 pmol, intermediate 93) was stirred with trifluoroacetic acid (1.8 mL, 23 mmol) in dichloromethane (3.6 mL). After purification using a Biotage chromatography system we obtained 18.7 mg (97% purity, 16% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 6.48 (d, 1H), 7.41 - 7.52 (m, 3H), 7.76 (br s, 1H), 8.11 (s, 1H), 8.22 (d, 1H), 8.68 (s, 1H), 9.18 (s, 1H), 12.56 (br s, 1H), 12.63 (br s, 1H).
Example 84 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-342-(1-oxa-6-azaspiro[3.3]hept-6-ypethyl]urea H H
F
laF F
F-..
F

i N----N/
H

In analogy to example 77, 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-342-(1-oxa-6-azaspiro[3.3]hept-6-ypethyl]urea (119 mg, 189 pmol, intermediate 94) was stirred with trifluoroacetic acid (1.3 mL, 17 mmol) in dichloromethane (2.6 mL). After purification using a Biotage chromatography system and a subsequent preparative HPLC (according to method 1) we obtained 21.2 mg (93% purity, 21 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 2.44 (t, 2H), 2.74 (t, 2H), 3.02 - 3.09 (m, 4H), 3.50 -3.55 (m, 2H), 4.37 (t, 2H), 6.29 (t, 1H), 6.46 (d, 1H), 7.31 -7.38 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 9.12 (s, 1H), 12.63 (br s, 1H).
Example 85 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-342-(1,1-dioxido-1-thia-6-azaspiro[3.3]hept-6-y1)ethyl]urea H H
F
6 Ny N NI\CLi% P
F F S

F.--F

N---N/
H
In analogy to example 1, 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-342-(1,1-dioxido-1-thia-6-azaspiro[3.3]hept-6-ypethyl]urea (174 mg, 257 pmol, intermediate 95) was stirred with trifluoroacetic acid (1.7 mL, 23 mmol) in dichloromethane (3.5 mL). After purification using a Biotage chromatography system we obtained 29.9 mg (95 % purity, 20 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 2.20 - 2.26 (m, 2H), 3.08 (q, 2H), 3.23 -3.28 (m, 2H), 3.78 - 3.83 (m, 2H), 3.98 - 4.04 (m, 2H), 6.32 (t, 1H), 6.46 (d, 1H), 7.32 -7.39 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 9.14 (s, 1H), 12.63 (br s, 1H).

Example 86 (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(2-oxopyrrolidin-3-yOurea H H
N
F * ' m Th. ''''-aN H

F
FO
F F
/ I
N----N/
H
In analogy to example 1, (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(2-oxopyrrolidin-3-yOurea (168 mg, 287 pmol, intermediate 96) was stirred with trifluoroacetic acid (1.9 mL, 25 mmol) in dichloromethane (3.9 mL). After purification using a Biotage chromatography system we obtained 105 mg (90% purity, 72% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.80 - 1.91 (m, 1H), 2.38 -2.44 (m, 1H), 3.20 (dd, 2H), 4.14 - 4.22 (m, 1H), 6.47 (d, 1H), 6.71 - 6.79 (m, 1H), 7.34 - 7.42 (m, 2H), 7.90 (s, 1H), 8.11 (s, 1H), 8.19 -8.24 (m, 1H), 9.25 - 9.30 (m, 1H), 12.64 (br s, 1H).
Example 87 (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(1,1-dioxidotetrahydrothiophen-3-yOurea H mH
N.....¨.1,00 F 40 W0 . 0 F
F.0 F F
/. I
N----N/
H
In analogy to example 1, (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(1,1-dioxidotetrahydrothiophen-3-yl)urea (160 mg, 258 pmol, intermediate 97) was stirred with trifluoroacetic acid (1.7 mL, 23 mmol) in dichloromethane (3.5 mL). After purification using a Biotage chromatography system we obtained 40.7 mg (93 % purity, 30 % yield) of the desired title compound.

11-I-NMR (400 MHz, DMSO-d6) 6 [ppm]: 2.11 (dq, 1H), 2.37 - 2.47 (m, 1H), 3.03 (dd, 1H), 3.14 - 3.31 (m, 2H), 3.44 (dd, 1H), 4.40 -4.51 (m, 1H), 6.46 (d, 1H), 6.90 (d, 1H), 7.35- 7.43 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 9.14 (s, 1H), 12.63 (br s, 1H).
Example 88 (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(5-oxopyrrolidin-3-yOurea H H
N
F 40N ---\.( Ql H

F
F F
/ I
N----N/
H
In analogy to example 1, (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(5-oxopyrrolidin-3-yOurea (125 mg, 213 pmol, intermediate 98) was stirred with trifluoroacetic acid (1.4 mL, 19 mmol) in dichloromethane (2.9 mL). After purification using a Biotage chromatography system we obtained 35.1 mg (97% purity, 35% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 2.07 (dd, 1H), 3.07 (dd, 1H), 3.53 (dd, 1H), 4.27 - 4.38 (m, 1H), 6.46 (d, 1H), 6.91 (d, 1H), 7.34 - 7.42 (m, 2H), 7.68 (s, 1H), 8.11 (s, 1H), 8.21 (d, 1H), 8.92 (s, 1H), 12.63 (br s, 1H).
Example 89 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)urea H H
N N
Cs...(1 µf--.....

F...aF F
/ I
N----N/
H
In analogy to example 1, 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yOurea (152 mg, 239 pmol, intermediate 99) was stirred with trifluoroacetic acid (1.6 mL, 21 mmol) in dichloromethane (3.2 mL). After purification using a Biotage chromatography system we obtained 56.1 mg (97 % purity, 45 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.90 - 2.01 (m, 2H), 2.13 (br dd, 2H), 3.06 (br d, 2H), 3.24 - 3.32 (m, 2H), 3.82 - 3.94 (m, 1H), 6.46 (d, 1H), 6.70 (d, 1H), 7.35 -7.42 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 8.87 (s, 1H), 12.63 (br s, 1H).
Example 90 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(1H-pyrazol-3-ylmethyl)urea \
H H NH
N.....NNi F * Wo F
FO
F F
/ I
N----N/
H
In analogy to example 1, 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(1H-pyrazol-3-ylmethyl)urea (147 mg, 252 pmol, intermediate 100) was stirred with trifluoroacetic acid (1.7 mL, 22 mmol) in dichloromethane (3.4 mL). After purification using a Biotage chromatography system we obtained 26.1 mg (90% purity, 21 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 4.25 - 4.37 (m, 2H), 6.11 - 6.20 (m, 1H), 6.47 (d, 1H), 6.73 (br s, 1H), 7.39 (br d, 2H), 7.67 (br s, 1H), 8.11 (s, 1H), 8.21 (d, 1H), 9.10 (s, 1H), 12.56 -12.72 (m, 2H).
Example 91 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(1H-imidazol-2-ylmethyl)urea N' H 1,71.11...N?
N, "
F * Al H
F
FO
F F
/ I
N---"N/
H

In analogy to example 1, 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(1H-imidazol-2-ylmethypurea (117 mg, 201 pmol, intermediate 101) was stirred with trifluoroacetic acid (1.4 mL, 18 mmol) in dichloromethane (2.7 mL). After purification using a Biotage chromatography system we obtained 41.3 mg (95% purity, 43% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 4.32 (d, 2H), 6.46 (d, 1H), 6.83 (t, 2H), 7.04 (br s, 1H), 7.35 - 7.44 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 9.23 (s, 1H), 11.85 (br s, 1H), 12.63 (br s, 1H).
Example 92 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(1-methyl-1H-pyrazol-3-y1)methyl]urea H H , p-c H 3 N NN
F *

F
F.., F F
/ I
N----N/
H
In analogy to example 1, 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(1-methyl-1H-pyrazol-3-y1)methyl]urea (207 mg, 347 pmol, intermediate 102) was stirred with trifluoroacetic acid (2.3 mL, 30 mmol) in dichloromethane (4.7 mL). After purification using a Biotage chromatography system we obtained 62.7 mg (97 % purity, 38 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 3.33 (s, 3H), 4.24 (d, 2H), 6.13 (d, 1H), 6.47 (d, 1H), 6.72 (t, 1H), 7.34 - 7.42 (m, 2H), 7.61 (d, 1H), 8.11 (s, 1H), 8.21 (d, 1H), 9.09 (s, 1H), 12.63 (br s, 1H).

Example 93 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(1,3-thiazol-2-ylmethyl)urea H H
N Ni"-----=N
F
F-5) F F
/ I
N---N/
H
In analogy to example 1, 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(1,3-thiazol-2-ylmethypurea (216 mg, 359 pmol, intermediate 103) was stirred with trifluoroacetic acid (2.4 mL, 32 mmol) in dichloromethane (4.9 mL). After purification using a Biotage chromatography system we obtained 62.5 mg (97 % purity, 36 % yield) of the desired title compound.
1H-N MR (400 MHz, DMSO-d6) 6 [ppm]: 4.61 (d, 2H), 6.49 (d, 1H), 7.25 (t, 1H), 7.38 - 7.46 (m, 2H), 7.63 (d, 1H), 7.74 (d, 1H), 8.11 (s, 1H), 8.21 (d, 1H), 9.37 (s, 1H), 12.63 (s, 1H).
Example 94 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(pyrimidin-4-ylmethyl)urea NN
N

F
F... 7 F F
/ I
N N/
H
In analogy to example 1, 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(pyrimidin-4-ylmethyl)urea (175 mg, 294 pmol, intermediate 104) was stirred with trifluoroacetic acid (2.0 mL, 26 mmol) in dichloromethane (4.0 mL). After purification using a Biotage chromatography system we obtained 35.8 mg (97 % purity, 25 % yield) of the desired title compound.
11-I-NMR (400 MHz, DMSO-d6) 6 [ppm]: 4.43 (d, 2H), 6.47 (d, 1H), 7.07 (t, 1H), 7.36 - 7.43 (m, 2H), 7.46 (dd, 1H), 8.11 (s, 1H), 8.21 (d, 1H), 8.76 (d, 1H), 9.13 (d, 1H), 9.43 (s, 1H), 12.63 (br s, 1H).
Example 95 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(2-methylpyridin-4-y1)methyl]urea f)\..1 ....
H H \

F *F
F-5) F F
/ I
N----N/
H
In analogy to example 1, 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(2-methylpyridin-4-y1)methyl]urea (178 mg, 293 pmol, intermediate 105) was stirred with trifluoroacetic acid (2.0 mL, 26 mmol) in dichloromethane (4.0 mL). After purification using a Biotage chromatography system we obtained 73.0 mg (95% purity, 50% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 2.45 (s, 3H), 4.30 (d, 2H), 6.47 (d, 1H), 7.00 (t, 1H), 7.09 (br d, 1H), 7.15 (s, 1H), 7.36 - 7.45 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 8.37 (d, 1H), 9.25 (s, 1H), 12.63 (br s, 1H).

Example 96 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(pyridazin-3-ylmethyl)urea N
, H H....)01 /
N N
F * --1 F
F..0 F F
/. I
N----N/
H
In analogy to example 1, 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(pyridazin-3-ylmethypurea (190 mg, 320 pmol, intermediate 106) was stirred with trifluoroacetic acid (2.2 mL, 28 mmol) in dichloromethane (4.3 mL). After purification using a Biotage chromatography system we obtained 50.2 mg (97 % purity, 33 % yield) of the desired title compound.
1H-N MR (400 MHz, DMSO-d6) 6 [ppm]: 4.62 (d, 2H), 6.47 (d, 1H), 7.21 (t, 1H), 7.36 - 7.44 (m, 2H), 7.62 -7.72 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 9.15 (dd, 1H), 9.40 (s, 1H), 12.63 (br s, 1H).
Example 97 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(5-methyl-1H-imidazol-2-y1)methyl]urea N---._, H Fi..........õ2_ .,1-13 F
N.....N N
H 40 wo F
F., F F
/ I
N----N/
H
In analogy to example 1, 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(5-methyl-1H-imidazol-2-y1)methyl]urea (145 mg, 243 pmol, intermediate 107) was stirred with trifluoroacetic acid (1.6 mL, 21 mmol) in dichloromethane (3.3 mL). After purification using a Biotage chromatography system we obtained 70.1 mg (90% purity, 56% yield) of the desired title compound.

1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 2.10 (s, 3H), 4.25 (d, 2H), 6.46 (d, 1H), 6.67 (br s, 1H), 6.78 (t, 1H), 7.35 - 7.42 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 9.21 (s, 1H), 11.55 (br s, 1H), 12.63 (br s, 1H).
Example 98 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-{[3-(methoxymethyl)-1,2,4-oxadiazol-5-yl]methyllurea d Niõ, I-1 1-I j... P
N1"1 I a F * "(0 F N I
F
F F
/ I
N---N/
H
In analogy to example 1, 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-{[3-(methoxymethyl)-1,2,4-oxadiazol-5-yl]methyllurea (184 mg, 293 pmol, intermediate 108) was stirred with trifluoroacetic acid (2.0 mL, 26 mmol) in dichloromethane (4.0 mL). After purification using a Biotage chromatography system we obtained 47.0 mg (90 % purity, 29 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 3.34 (s, 3H), 4.53 (s, 2H), 4.62 (d, 2H), 6.48 (d, 1H), 7.17 (t, 1H), 7.36 -7.44 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 9.49 (s, 1H), 12.63 (br s, 1H).
Example 99 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(5-methyl-4H-1,2,4-triazol-3-yl)methyl]urea NI-N
H Fi.õ..}.. \)¨C H3 N N N
H
F 40 'fo F
F
F F
/ I
N----N/
H

In analogy to example 1, 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(5-methyl-4 H-1,2,4-triazol-3-yl)methyl]urea (134 mg, 224 pmol, intermediate 109) was stirred with trifluoroacetic acid (1.5 mL, 20 mmol) in dichloromethane (3.0 mL). After purification using a Biotage chromatography system we obtained 29.9 mg (90 % purity, 26 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 2.30 (s, 3H), 4.30 (br d, 2H), 6.47 (d, 1H), 6.80 (br s, 1H), 7.34 - 7.42 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 9.21 (s, 1H), 12.63 (br s, 1H), 13.43 (br s, 1H).
Example 100 (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(tetrahydrofuran-3-yOurea H H
F N
F *
FO
F F
/ I
N----N/
H
In analogy to example 1, (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(tetrahydrofuran-3-yOurea (101 mg, 176 pmol, intermediate 110) was stirred with trifluoroacetic acid (1.2 mL, 16 mmol) in dichloromethane (2.4 mL). After purification using a Biotage chromatography system we obtained 49.1 mg (85% purity, 53% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.68 - 1.82 (m, 1H), 2.07- 2.19 (m, 1H), 3.50 (dd, 1H), 3.66 - 3.85 (m, 3H), 4.16 -4.26 (m, 1H), 6.46 (d, 1H), 6.72 (br d, 1H), 7.33 -7.43 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 8.86 (s, 1H), 12.63 (br s, 1H).

Example 101 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(3R)-tetrahydrofuran-3-yl]urea H H
N.(N,,..\
F illo o \---O
F
FO
F F
/ I
N---N/
H
In analogy to example 77, 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(3R)-tetrahydrofuran-3-yl]urea (104 mg, 182 pmol, intermediate 111) was stirred with trifluoroacetic acid (1.2 mL, 16 mmol) in dichloromethane (2.5 mL). After purification using a Biotage chromatography system and a subsequent preparative HPLC (according to method 1) we obtained 25.4 mg (95 % purity, 30% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.70- 1.79 (m, 1H), 2.13 (dq, 1H), 3.50 (dd, 1H), 3.67 -3.84 (m, 3H), 4.18 - 4.25 (m, 1H), 6.46 (d, 1H), 6.74 (br d, 1H), 7.34 - 7.41 (m, 2H), 8.11 (d, 1H), 8.21 (d, 1H), 8.88 (br s, 1H), 11.57 - 12.46 (m, 1H).
Example 102 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(3S)-tetrahydrofuran-3-yl]urea H H
F F = N'(Na66*.K
0 \---0 F..,0 F F
/ I
N---N/
H
In analogy to example 1, 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(3S)-tetrahydrofuran-3-yl]urea (159 mg, 278 pmol, intermediate 112) was stirred with trifluoroacetic acid (1.9 mL, 24 mmol) in dichloromethane (3.8 mL). After purification using a Biotage chromatography system we obtained 49.4 mg (95% purity, 38% yield) of the desired title compound.

11-I-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.70 - 1.79 (m, 1H), 2.08 -2.18 (m, 1H), 2.13 (dq, 1H), 3.50 (dd, 1H), 3.67 - 3.84 (m, 3H), 4.18 -4.25 (m, 1H), 6.46 (d, 1H), 6.72 (br d, 1H), 7.34 - 7.41 (m, 2H), 8.11 (d, 1H), 8.21 (d, 1H), 8.85 (s, 1H), 12.63 (br s, 1H).
Example 103 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-{3-[(2R,6R)-2,6-dimethylmorpholin-4-yl]propyllurea H H N..,/"CH3 N Nr F
F...):) F F
/ I
N--"N/
H
In analogy to example 1, 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-{3-[(2R,6R)-2,6-dimethylmorpholin-4-yl]propyllurea (139 mg, 212 pmol, intermediate 113) was stirred with trifluoroacetic acid (1.4 mL, 19 mmol) in dichloromethane (2.9 mL). After purification using a Biotage chromatography system we obtained 54.8 mg (95 % purity, 47 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.04 (d, 6H), 1.51 - 1.64 (m, 4H), 2.27 (t, 2H), 2.73 (br d, 2H), 3.12 (q, 2H), 3.50 - 3.59 (m, 2H), 6.41 (t, 1H), 6.46 (d, 1H), 7.34 -7.42 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 8.98 (s, 1H), 12.63 (br s, 1H).
Example 104 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(1-methyl-1H-imidazol-2-y1)methyl]urea N' H H 1_1 s N N-N
F *
b H3 F
F F
N---N/
H

In analogy to example 1, 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(1-methyl-1H-imidazol-2-y1)methyl]urea (163 mg, 273 pmol, intermediate 114) was stirred with trifluoroacetic acid (1.8 mL, 24 mmol) in dichloromethane (3.7 mL). After purification using a Biotage chromatography system we obtained 53.4 mg (90 % purity, 38 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 3.63 (s, 3H), 4.35 (d, 2H), 6.47 (d, 1H), 6.81 (d, 1H), 6.87 (t, 1H), 7.10 (d, 1H), 7.34 - 7.42 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 9.21 (s, 1H), 12.63 (br s, 1H).
Example 105 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(4-methyl-1,2,5-oxadiazol-3-y1)methyl]urea N' =
H m1-1,4N
F$ Noll C H 3 F
F...,0 F F
/ I
N.--"N
H
In analogy to example 1, 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(4-methyl-1,2,5-oxadiazol-3-y1)methyl]urea (144 mg, 241 pmol, intermediate 115) was stirred with trifluoroacetic acid (1.6 mL, 21 mmol) in dichloromethane (3.3 mL). After purification using a Biotage chromatography system (11g snap KP-NH column, hexane / 0 ¨ 100% ethyl acetate, then ethyl acetate / 0 ¨ 100% ethanol), we obtained 69.3 mg (93 % purity, 57 %
yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 2.39 (s, 3H), 4.52 (d, 2H), 6.47 (d, 1H), 7.08 (t, 1H), 7.35 - 7.43 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 9.29 (s, 1H), 12.63 (br s, 1H).

Example 106 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(2-methoxypyridin-4-y1)methyl]urea 1 ...
L, 1 =C H3 H " N 7 0 N

F F
FO
F F
/ I
N----N/
H
In analogy to example 1, 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(2-methoxypyridin-4-y1)methyl]urea (139 mg, 222 pmol, intermediate 116) was stirred with trifluoroacetic acid (1.5 mL, 20 mmol) in dichloromethane (3.0 mL). After purification using a Biotage chromatography system (11g snap KP-NH column, hexane /0 ¨ 100% ethyl acetate, then ethyl acetate / 0 ¨ 100% ethanol), we obtained 73.4 mg (90 % purity, 60 %
yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 3.83 (s, 3H), 4.30 (d, 2H), 6.47 (d, 1H), 6.69 (s, 1H), 6.91 (dd, 1H), 6.99 (t, 1H), 7.37 - 7.43 (m, 2H), 8.08 - 8.13 (m, 2H), 8.21 (d, 1H), 9.25 (s, 1H), 12.63 (s, 1H).
Example 107 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(1-methyl-1H-imidazol-4-y1)methyl]urea N%\
H Flyizz....ssi¨CH3 F * NN

F
FO
F F
/ I
N----N
H
In analogy to example 1, 1 -(3,5-difluoro-4-{[3-(trifluoromethyl)-1 -{[2-(trimethylsilypethoxy]methy11-1 H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyI)-3-[(1-methyl-1H-imidazol-4-yl)methyl]urea (172 mg, 288 pmol, intermediate 117) was stirred with trifluoroacetic acid (2.0 mL, 25 mmol) in dichloromethane (3.9 mL). After purification using a Biotage chromatography system (11g snap KP-NH column, hexane /0 ¨ 100% ethyl acetate, then ethyl acetate! 0¨ 100% ethanol), we obtained 46.6 mg (90% purity, 31 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 3.61 (s, 3H), 4.14 (d, 2H), 6.47 (d, 1H), 6.61 (t, 1H), 6.98 (s, 1H), 7.33 -7.40 (m, 2H), 7.52 (s, 1H), 8.11 (s, 1H), 8.21 (d, 1H), 9.08 (s, 1H), 12.63 (br s, 1H).
Example 108 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-{2-[(2RS,6RS)-2,6-dimethylmorpholin-4-yl]ethyllurea H
N NN"( FO*
F F
/ I
N----N/
H
In analogy to example 1, 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-{2-[(2RS,6RS)-2,6-dimethylmorpholin-4-yl]ethyllurea (166 mg, 258 pmol, intermediate 118) was stirred with trifluoroacetic acid (1.7 mL, 23 mmol) in dichloromethane (3.5 mL). After purification using a Biotage chromatography system (11g snap KP-NH column, hexane! 0 ¨ 100% ethyl acetate, then ethyl acetate! 0 ¨ 100% ethanol), we obtained 26.2 mg (90 % purity, 18 %
yield) of the desired title compound.
NMR of main isomer:
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.05 (d, 6H), 2.28 - 2.45 (m, 4H), 2.77 (br d, 2H), 3.19 -3.26 (m, 2H), 3.52 - 3.61 (m, 2H), 6.30 (t, 1H), 6.46 (d, 1H), 7.32 - 7.41 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 9.16 (s, 1H), 12.63 (br s, 1H).

Example 109 1-[(2-cyanopyridin-4-yl)methyl]-3-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyOurea \......1 ........
H

N NJN
F * 0 F
F..,0 F F
/ I
N----N/
H
In analogy to example 77, 1-[(2-cyanopyridin-4-yl)methyl]-3-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyOurea (111 mg, 179 pmol, intermediate 119) was stirred with trifluoroacetic acid (1.2 mL, 16 mmol) in dichloromethane (2.4 mL). After purification using a Biotage chromatography system and a subsequent preparative HPLC (according to method 1) we obtained 35.6 mg (97 %
purity, 39% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 4.41 (d, 2H), 6.46 (d, 1H), 7.10 (t, 1H), 7.36 - 7.43 (m, 2H), 7.65 (dd, 1H), 7.95 (d, 1H), 8.11 (s, 1H), 8.21 (d, 1H), 8.71 (d, 1H), 9.38 (s, 1H), 12.59 (br s, 1H).
Example 110 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(pyridazin-4-ylmethyl)urea N, H Hj:)1 /
F$ NN

F
FO
F F
/ I
N----N
H
In analogy to example 77, 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(pyridazin-4-ylmethypurea (49.8 mg, 83.8 pmol, intermediate 120) was stirred with trifluoroacetic acid (570 pL, 7.4 mmol) in dichloromethane (1.1 mL). After purification using a Biotage chromatography system and a subsequent preparative HPLC (according to method 1) we obtained 8.10 mg (97% purity, 20% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 4.38 (d, 2H), 6.46 (d, 1H), 7.11 (t, 1H), 7.35 - 7.44 (m, 2H), 7.56 (dd, 1H), 8.11 (s, 1H), 8.21 (d, 1H), 9.15 - 9.20 (m, 2H), 9.40 (s, 1H), 12.33 (br s, 1H).
Example 111 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(1,2,4-oxadiazol-3-ylmethypurea N%\ 0 H H
F AA
F F
I
In analogy to example 1, 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(1,2,4-oxadiazol-3-ylmethypurea (112 mg, 192 pmol, intermediate 121) was stirred with trifluoroacetic acid (1.3 mL, 17 mmol) in dichloromethane (2.6 mL). After purification using a Biotage chromatography system (11g snap KP-NH column, hexane / 0 ¨ 100% ethyl acetate, then ethyl acetate / 0 ¨ 100% ethanol), we obtained 29.7 mg (97 % purity, 33 %
yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 4.50 (d, 2H), 6.47 (d, 1H), 7.06 (t, 1H), 7.35 - 7.44 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 9.34 (s, 1H), 9.57 (s, 1H), 12.06 (br s, 1H).

Example 112 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(1,3-oxazol-2-ylmethyl)urea N----H
N, 2`1,11--C-) F * AA0 F
FO
F F
/ I
N----N
H
In analogy to example 77, 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(1,3-oxazol-2-ylmethypurea (175 mg, 300 pmol), intermediate 122) was stirred with trifluoroacetic acid (2.0 mL, 26 mmol) in dichloromethane (4.1 mL). After purification using a Biotage chromatography system and a subsequent preparative HPLC (according to method 1) we obtained 36.7 mg (97% purity, 26% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 4.43 (d, 2H), 6.47 (d, 1H), 7.03 (t, 1H), 7.17 (s, 1H), 7.36 -7.43 (m, 2H), 8.06 (s, 1H), 8.11 (s, 1H), 8.21 (d, 1H), 9.32 (s, 1H), 12.60 (br s, 1H).
Example 113 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(1,3-thiazol-5-ylmethyl)urea N
H H I
N,zNLY
S
F * wo F
F...aF F
/ I
N--"N/
H
In analogy to example 77, 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(1,3-thiazol-5-ylmethyl)urea (136 mg, 227 pmol, intermediate 123) was stirred with trifluoroacetic acid (1.5 mL, 20 mmol) in dichloromethane (3.1 mL). After purification using a Biotage chromatography system and a subsequent preparative HPLC (according to method 1) we obtained 18.9 mg (97% purity, 17% yield) of the desired title compound.

1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 4.53 (d, 2H), 6.48 (d, 1H), 7.05 (t, 1H), 7.37 - 7.43 (m, 2H), 7.79 (s, 1H), 8.11 (s, 1H), 8.21 (d, 1H), 8.98 (d, 1H), 9.19 (s, 1H), 12.63 (br s, 1H).
Example 114 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-342-(2-oxa-6-azaspiro[3.3]hept-6-y1)ethyl]urea H H
F N N
F F
F-01(101 YO N\...A

F
/ I
N-----N/
H
To a solution of 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-342-(2-oxa-6-azaspiro[3.3]hept-6-ypethyl]urea (116 mg, 185 pmol, intermediate 124) in dichloromethane (2.5 mL) was added trifluoroacetic acid (1.3 mL, 16 mmol) and this mixture was stirred 3h at room temperature. The reaction mixture was carefully poured into an aqueous solution of sodium hydrogencarbonate.
This aqueous phase was extracted two times with ethyl actetate. Then the combined organic phases were washed with brine, dried over sodium sulfate and then after filtration evaporated to dryness in vacuum. The obtained crude product was purified by preparative HPLC (according to method 1) to obtain 29.8 mg (97 % purity, 31 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 2.39 - 2.46 (m, 2H), 3.04 (q, 2H), 3.29 -3.33 (m, 4H), 4.60 (s, 4H), 6.29 (br t, 1H), 6.46 (d, 1H), 7.31 - 7.38 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 9.11 (s, 1H), 12.63 (br s, 1H).
Example 115 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(5-methyl-1,3,4-oxadiazol-2-y1)methyl]urea N¨N
H H( F I
F \\ ¨C H 3 NN 0 y F --...FI.I 8 F
/ I
N----N/
H
In analogy to example 114, 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]urea (118 mg, 197 pmol, intermediate 125) was stirred with trifluoroacetic acid (1.3 mL, 17 mmol) in dichloromethane (2.7 mL). After purification using a preparative HPLC (according to method 1) we obtained 9.80 mg (97 % purity, 10 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 2.48 (s, 3H), 4.51 (d, 2H), 6.47 (d, 1H), 7.10 (t, 1H), 7.37 - 7.43 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 9.38 (s, 1H).
Example 116 N-(3 ,5-d ifl uoro-4-{[3-(trifl uoromethyl)-1H-pyrrolo[2,3-b]pyrid in-4-yl]oxylphenyI)-N'-[(3-methyloxetan-3-yl)methyl]urea H H) F NN.5\
F F
F-__\... j'1/4(. 8 C H3 F
/ I
N--"N/
H
In analogy to example 67, N-(3,5-d ifl uoro-4-{[3-(trifluoromethyl)-1-{[2-(tri methylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyrid in-4-yl]oxylphenyI)-N'-[(3-methyloxetan-3-yl)methyl]urea (124 mg, 212 pmol, intermediate 126) were reacted with 1N tetra-N-butylammoniumfluoride in tetrahydrofurane (850 pL, 1.0 M, 850 pmol) and ethylenediamine (58 pL, 870pM) in DMF (2.5 mL) to give after purification via a Biotage chromatography system, a subsequent HPLC chromatography followed by a preparative thin layer chromatography using dichloromethane / methanol (8:2) 34.3 mg (95 % purity, 34 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.23 (s, 3H), 3.28 - 3.32 (m, 2H), 4.21 (d, 2H), 4.38 (d, 2H), 6.47 (d, 1H), 6.79 (t, 1H), 7.36 - 7.44 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 9.12 (s, 1H), 12.64 (br s, 1H).

Example 117 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(5-methylpyridazin-3-yOurea f F

F F
/ I
N----N
H
In analogy to example 1, 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(5-methylpyridazin-3-yOurea (39.5 mg, 66.4 pmol, intermediate 127) was stirred with trifluoroacetic acid (450 pL, 5.8 mmol) in dichloromethane (900 pL). After purification using a Biotage chromatography system (11g snap KP-NH column, hexane / 0 ¨ 100% ethyl acetate, then ethyl acetate / 0 ¨
100% ethanol), we obtained 13.2 mg (92% purity, 39% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 2.33 (s, 3H), 6.51 (d, 1H), 7.51 (d, 2H), 7.86 (s, 1H), 8.13 (s, 1H), 8.23 (d, 1H), 8.80 (d, 1H), 9.91 (br s, 1H), 10.21 (br s, 1H), 12.65 (br s, 1H).
Example 118 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(2R)-tetrahydrofuran-2-ylmethyl]urea OLDH H
N,)\i---..1.
iso Alo F F
F..aF F
/ I
N----N/
H
In analogy to example 114, 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(2R)-tetrahydrofuran-2-ylmethyl]urea (171 mg, 291 pmol, intermediate 128) was stirred with trifluoroacetic acid (2.0 mL, 26 mmol) in dichloromethane (3.9 mL). After purification using a preparative HPLC
(according to method 1) we obtained 24.5 mg (97 % purity, 18 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.47 - 1.57 (m, 1H), 1.77 - 1.95 (m, 3H), 3.06 - 3.16 (m, 1H), 3.20 - 3.29 (m, 1H), 3.61 - 3.67 (m, 1H), 3.75 - 3.82 (m, 1H), 3.83 -3.91 (m, 1H), 6.40 - 6.49 (m, 2H), 7.32 - 7.40 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 9.04 (s, 1H), 12.59 (br s, 1H).

Example 119 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(2S)-tetrahydrofuran-2-ylmethyl]urea F * N'foN
F F
I
In analogy to example 114, 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(2S)-tetrahydrofuran-2-ylmethyl]urea (136 mg, 232 pmol, intermediate 129) was stirred with trifluoroacetic acid (1.6 mL, 20 mmol) in dichloromethane (3.1 mL). After purification using a preparative HPLC
(according to method 1) we obtained 42.6 mg (97 % purity, 39 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.47 - 1.57 (m, 1H), 1.77 - 1.95 (m, 3H), 3.06 - 3.16 (m, 1H), 3.20 - 3.29 (m, 1H), 3.61 - 3.67 (m, 1H), 3.75 - 3.82 (m, 1H), 3.83 -3.91 (m, 1H), 6.40 - 6.49 (m, 2H), 7.32 - 7.40 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 9.04 (s, 1H), 12.37 (br s, 1H).
Example 120 (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(5,5-dimethyltetrahydrofuran-2-y1)methyl]urea y-c H 3 H H
N Nzefs-s F *0 F
F F
I
In analogy to example 114, (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(5,5-dimethyltetrahydrofuran-2-y1)methyl]urea (177 mg, 288 pmol), intermediate 130) was stirred with trifluoroacetic acid (1.9 mL, 25 mmol) in dichloromethane (3.9 mL). After purification using a preparative HPLC (according to method 1) we obtained 49.8 mg (92 % purity, 33 % yield) of the desired title compound.

11-I-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.16 (s, 3H), 1.22 (s, 3H), 1.59- 1.74 (m, 3H), 1.93 -2.03 (m, 1H), 3.03 - 3.11 (m, 1H), 3.21 - 3.29 (m, 1H), 3.92 - 4.00 (m, 1H), 6.39 (br t, 1H), 6.47 (d, 1H), 7.32 - 7.39 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 9.12 (s, 1H), 12.62 (br s, 1H).
Example 121 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(tetrahydro-2H-pyran-4-yOurea H H
N
F . N'(c) Cc) F
F..,0 F F
/ I
N---N/
H
In analogy to example 1, 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(tetrahydro-2H-pyran-4-yOurea (132 mg, 225 pmol, intermediate 131) was stirred with trifluoroacetic acid (1.5 mL, mmol) in dichloromethane (3.0 mL). After purification using a Biotage chromatography system (11g snap KP-NH column, hexane / 0 ¨ 100% ethyl acetate, then ethyl acetate / 0 ¨
100% ethanol), we obtained 44.2 mg (97 % purity, 42 % yield) of the desired title compound.
15 1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.36 - 1.47 (m, 2H), 1.75- 1.83 (m, 2H), 3.38 (dt, 2H), 3.64 - 3.74 (m, 1H), 3.83 (dt, 2H), 6.46 (d, 1H), 6.50 (d, 1H), 7.34 - 7.41 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 8.88 (s, 1H), 12.63 (br s, 1H).
Example 122 20 (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(tetrahydro-2H-pyran-2-ylmethypurea N N
I.

F F
FO
F F
/ I
N---N/
H
In analogy to example 1, (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(tetrahydro-2H-pyran-2-ylmethyl)urea (128 mg, 213 pmol, intermediate 132) was stirred with trifluoroacetic acid (1.4 mL, 19 mmol) in dichloromethane (2.9 mL). After purification using a Biotage chromatography system (11g snap KP-NH column, hexane /0 ¨ 100% ethyl acetate, then ethyl acetate / 0 ¨ 100% ethanol) we obtained 32.0 mg (92 % purity, 29 %
yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.13 - 1.30 (m, 1H), 1.40 - 1.51 (m, 3H), 1.55 (br d, 1H), 1.77 (br s, 1H), 2.98 - 3.06 (m, 1H), 3.23 (ddd, 1H), 3.28 - 3.40 (m, 2H), 3.86 - 3.93 (m, 1H), 6.41 -6.49 (m, 2H), 7.32 - 7.38 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 9.08 (s, 1H), 12.63 (br s, 1H).
Example 123 (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(tetrahydro-2H-pyran-3-yOurea H H
F N N
F F

F ?
F
N----N/
H
In analogy to example 1, (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(tetrahydro-2H-pyran-3-yOurea (145 mg, 247 pmol, intermediate 133) was stirred with trifluoroacetic acid (1.7 mL, 22 mmol) in dichloromethane (3.4 mL). After purification using a Biotage chromatography system (11g snap KP-NH column, ethyl acetate / 0 ¨ 50% ethanol) we obtained 76.4 mg (97 %
purity, 66% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.46 - 1.58 (m, 2H), 1.62 - 1.74 (m, 1H), 1.79 - 1.90 (m, 1H), 3.25 (dd, 1H), 3.42 - 3.51 (m, 1H), 3.57 - 3.67 (m, 2H), 3.72 (dd, 1H), 6.46 (d, 1H), 6.54 (d, 1H), 7.32 - 7.39 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 8.93 (s, 1H), 12.63 (s, 1H).

Example 124 (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(2-methyltetrahydrofuran-2-y1)methyl]urea F F... N.{N j.ren F . 8 . F F
/ I
N----N/
H
In analogy to example 1, (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-[(2-methyltetrahydrofuran-2-y1)methyl]urea (150 mg, 250 pmol, intermediate 134) was stirred with trifluoroacetic acid (1.7 mL, 22 mmol) in dichloromethane (3.4 mL). After purification using a Biotage chromatography system (11g snap KP-NH column, ethyl acetate / 0 ¨ 50%
ethanol) we obtained 86.4 mg (97% purity, 71 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.12 (s, 3H), 1.52- 1.66 (m, 1H), 1.72-1.93 (m, 3H), 3.15 (ddd, 2H), 3.75 (td, 2H), 6.38 (t, 1H), 6.47 (d, 1H), 7.32 - 7.39 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 9.05 (s, 1H), 12.63 (s, 1H).
Example 125 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(2-methoxy-2-methylpropypurea F NN.)(cl-0 H3 F F . 8 F-,.....s.01 F
/ I
N-----N/
H
In analogy to example 1, 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(2-methoxy-2-methylpropypurea (136 mg, 231 pmol, intermediate 135) was stirred with trifluoroacetic acid (1.6 mL, 21 mmol) in dichloromethane (3.2 mL). After purification using a Biotage chromatography system (11g snap KP-NH column, ethyl acetate! 0¨ 50% ethanol) we obtained 84.9 mg (97 % purity, 78 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.10 (s, 6H), 3.13 (s, 3H), 3.15 (d, 2H), 6.31 (t, 1H), 6.47 (d, 1H), 7.31 -7.38 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 9.08 (s, 1H), 12.63 (s, 1H).

Example 126 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-342-methyl-2-(morpholin-4-y1)propyl]urea F NN.)(N

F-__ 40 8 F
N----N/
H
In analogy to example 1, 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-342-methyl-2-(morpholin-4-y1)propyl]urea (144 mg, 224 pmol, intermediate 136) was stirred with trifluoroacetic acid (1.6 mL, 20 mmol) in dichloromethane (3.1 mL). After purification using a Biotage chromatography system (11g snap KP-NH column, ethyl acetate / 0 - 50%
ethanol) we obtained 89.2 mg (95% purity, 74% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 0.97 (s, 6H), 2.44 - 2.48 (m, 4H), 3.10 (d, 2H), 3.57 -3.65 (m, 4H), 6.16 (t, 1H), 6.47 (d, 1H), 7.33 - 7.39 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 9.27 (s, 1H), 12.63 (s, 1H).
Example 127 (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(tetrahydro-2H-pyran-3-ylmethypurea H H
F NyN.,..rrro F F

F/
F
/ I
N''N/
H
In analogy to example 1, (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(tetrahydro-2H-pyran-3-ylmethypurea (134 mg, 223 pmol, intermediate 137) was stirred with trifluoroacetic acid (1.6 mL, 20 mmol) in dichloromethane (3.1 mL). After purification using a Biotage chromatography system (11g snap KP-NH column, ethyl acetate! 0- 50% ethanol) we obtained 86.4 mg (95 % purity, 78 % yield) of the desired title compound.

11-I-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.16 - 1.31 (m, 1H), 1.40 - 1.52 (m, 1H), 1.54 - 1.80 (m, 3H), 2.94 - 3.03 (m, 2H), 3.09 (dd, 1H), 3.26 - 3.32 (m, 1H), 3.68 - 3.79 (m, 2H), 6.44 - 6.50 (m, 2H), 7.34 - 7.41 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 8.93 (s, 1H), 12.63 (s, 1H).
.. Example 128 (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(tetrahydrofuran-3-ylmethypurea F NH NH
.,,,,Co F F

F
/ I
N''N/
H
In analogy to example 1, (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(tetrahydrofuran-3-ylmethypurea (143 mg, 244 pmol, intermediate 138) was stirred with trifluoroacetic acid (1.7 mL, 22 mmol) in dichloromethane (3.4 mL). After purification using a Biotage chromatography system (11g snap KP-NH column, ethyl acetate! 0¨ 50% ethanol) we obtained 84.4 mg (95 A purity, 72 A yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.55 (td, 1H), 1.87- 1.98 (m, 1H), 2.34 -2.46 (m, 1H), 3.05 - 3.15 (m, 2H), 3.42 (dd, 1H), 3.62 (q, 1H), 3.66 - 3.77 (m, 2H), 6.47 (d, 1H), 6.56 (t, 1H), 7.33 - 7.43 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 8.97 (s, 1H), 12.63 (br s, 1H).
Example 129 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-pyridazin-4-ylurea H
H

N N-___CA
--\( 'N
. 1\i' F

Cl.....) / \ /
N
N
H
To 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-pyridazin-4-ylurea (43.0 mg, 100 A purity, 78.6 pmol, intermediate 139) in dichloromethane (900 pL) was added trifluoroacetic acid (420 pL, 5.5 mmol) and this mixture was stirred over night at room temperature. The reaction mixture was carefully poured into an aqueous solution of sodium hydrogencarbonate. This aqueous phase was extracted two times with ethyl actetate. Then the combined organic phases were washed with brine and then evaporated to dryness in vacuum. The obtained crude product was purified by preparative HPLC (according to method 2) to obtain 6.00 mg (95% purity, 17% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 6.36 (d, 1H), 7.47 - 7.53 (m, 2H), 7.63 (s, 1H), 7.82 (dd, 1H), 8.11 (d, 1H), 8.96 (d, 1H), 9.23 (d, 1H), 9.92 (br s, 2H), 12.14 (br s, 1H).
Example 130 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(6-methylpyridazin-3-yOurea H N . ) H N.,_(:=1..-IN ....
N¨i " I
--, C H3 = 0 F

Clk,......)....
/ \ /
N
N
H
To 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-y1)oxy]-3,5-difluoropheny11-3-(6-methylpyridazin-3-yOurea (580 mg, 1.03 mmol, intermediate 140) in dichloromethane (40 mL) was added trifluoroacetic acid (5.6 mL, 72 mmol) and this mixture was stirred over night at room temperature. The reaction mixture was carefully poured into an aqueous solution of sodium hydrogencarbonate. This aqueous phase was extracted two times with ethyl actetate. Then the combined organic phases were washed with brine and then evaporated to dryness in vacuum. The obtained crude product was purified via a Biotage chromatography system (KP-NH snap column; dichloromethane I methanol gradient with up to 100% methanol) to obtain 90 mg (19 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 2.55 (s, 3H); 6.36 (d, 1H); 7.48-7.58 (m, 3H); 7.63 (d, 1H); 7.92 (d, 1H); 8.11 (d, 1H); 9.93 (bs, 1H); 10.2 (bs, 1H); 12.15 (bs, 1H).

Example 131 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-pyridin-3-ylurea H
H N.......01 N--µ, \
F 4. 0 Cl......) / \ /
N
N
H
To 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-y1)oxy]-3,5-difluorophenyI}-3-pyridin-3-ylurea (105 mg, 192 pmol, intermediate 141) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL, 13 mmol) and this mixture was stirred over night at room temperature. The reaction mixture was carefully poured into an aqueous solution of sodium hydrogencarbonate. This aqueous phase was extracted two times with ethyl actetate.
Then the combined organic phases were washed with brine and then evaporated to dryness in vacuum. The obtained crude product was purified by preparative HPLC (according to method 2) to obtain 23 mg (27 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 6.35 (d, 1H); 7.34 (ddd, 1H); 7.45-7.50 (m, 2H); 7.62 (d, 1H); 7.93-7.98 (m, 1H); 8.11 (d, 1H); 8.22 (dd, 1H); 8.63 (d, 1H); 9.19 (bs, 1H); 9.42 (bs, 1H); 12.14 (bs, 1H).
Example 132 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-pyridin-2-ylurea H N

N---µ
--,.
F$ 0 Clk..õ) / \ /
N
N
H
To 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyI}-3-pyridin-2-ylurea (30.0 mg, 54.9 pmol, intermediate 142) in dichloromethane (0.6 mL) was added trifluoroacetic acid (0.3 mL, 3.8 mmol) and this mixture was stirred over night at room temperature. The reaction mixture was carefully poured into an aqueous solution of sodium hydrogencarbonate. This aqueous phase was extracted two times with ethyl actetate. Then the combined organic phases were washed with brine and then evaporated to dryness in vacuum. The obtained crude product was purified by preparative HPLC
(according to method 3) to obtain 4 mg (17% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 6.36 (d, 1H); 7.03-7.08 (m, 1H); 7.47 (d, 1H); 7.58-7.64 (m, 3H); 7.75-7.82 (m, 1H); 8.11 (d, 1H); 8.30-8.34 (m, 1H); 9.77 (bs, 1H); 11.18 (bs, 1H);
12.14 (bs, 1H).
.. Example 133 1-[3,5-d ifl uoro-4-(1H-pyrrolo[2,3-b]pyrid in-4-yloxy)pheny1]-3[2-(piperid in-1-yl)ethyl]urea H H
F N NN
F
/ I
N----N/
H
To a 1-{3,5-difluoro-4-[(1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]phenyll-342-(piperidin-1-ypethyl]urea (110 mg, 202 pmol, intermediate 147) in dichloromethane (300 pL) was added trifluoroacetic acid (20.0 eq., 310 pL) and this mixture was stirred overnight at room temperature. The reaction mixture was evaporated to dryness in vacuo to give a mixture of the title compound and 1-(3,5-difluoro-4-{[1-(hydroxymethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-342-(piperidin-1-ypethyl]urea. To this crude material THF
(500 pL) and aqueous sodium hydroxide (400 pL, 2.0 M, 790 pmol) were added and the mixture stirred at 50 C overnight. The reaction mixture was evaporated to dryness in vacuo and the residue subjected to preparative HPLC (method 4) to give the title compound (10 mg, 9%).
LC-MS (method 2): R1= 1.09 min; MS (ESIpos): m/z = 416 [M+H].
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.39¨ 1.42 (m, 2H), 1.49¨ 1.54 (m, 4H), 2.32 ¨ 2.37 (m, 6H), 3.20 (q, 2H), 6.28¨ 6.30 (m, 2H), 6.40 (d, 1H), 7.32 ¨7.38 (m, 2H), 7.40 (dd, 1H), 8.08 (d, 1H), 9.21 (bs, 1H), 11.82 (bs, 1H).

Example 134 N3-{[3,5-difluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]carbamoyll-beta-alaninamide H H
F NN.,rN H2 . 8 0 F
/ I
N---N/
H
In analogy to example 133 N3-({3,5-difluoro-4-[(1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]phenyllcarbamoyI)-beta-alaninamide (65.0 mg, 129 pmol, intermediate 148) was treated with trifluoroacetic acid (198 pL) in dichloromethane and subsequently with aqueous sodium hydroxide (260 pL, 2.0 M, 520 pmol) in THF to give after preparative HPLC (method 4) the title compound (1.7 mg, 2%).
LC-MS (method 2): Rt = 0.77 min; MS (ESIpos): rrilz = 376 [M+H].
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 2.28 (t, 2H), 3.29 (q, 2H), 6.17 - 6.45 (m, 3H), 6.92 (bs, 1H), 7.31 -7.41 (m, 4H), 7.97 - 8.08 (m, 1H), 9.11 -9.13 (m, 1H), 11.47-11.82 (m, 1H).
Example 135 1-[3,5-difluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)pheny1]-3-(1H-1,2,3-triazol-5-ylmethyl)urea N
No F
H
401 N1rN

F
/ I
NN/
H
In analogy to example 133 1-{3,5-difluoro-4-[(1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]phenyll-3-(1H-1,2,3-triazol-5-ylmethyl)urea (48.0 mg, 93 pmol, intermediate 149) was treated with trifluoroacetic acid (143 pL) in dichloromethane and subsequently with aqueous sodium hydroxide (190 pL, 2.0 M, 370 pmol) in THF to give after preparative HPLC (method 4) the title compound (6.5 mg, 12%).
LC-MS (method 2): Rt = 0.59 min; MS (ESIpos): rrilz = 386 [M+H].
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 4.38 - 4.44 (m, 3H), 6.17 - 6.40 (m, 1H), 6.86 - 6.90 (m, 1H), 7.06 - 7.41 (m, 3H), 7.72 (bs, 1H), 7.97 - 8.08 (m, 1H), 9.11 -9.13 (m, 1H), 11.48 -11.83 (m, 1H), 14.85 (bs, 1H).

Example 136 1-[3,5-difluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)pheny1]-343-(dimethylamino)propyl]urea F
/ I
NN/
H
In analogy to example 133 1-{3,5-difluoro-4-[(1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]pheny11-343-(dimethylamino)propyl]urea (51.0 mg, 131 pmol, intermediate 150) was treated with trifluoroacetic acid (1 mL) in dichloromethane and subsequently with aqueous sodium hydroxide (200 pL, 2.0 M, 390 pmol) in THF to give after preparative HPLC (method 4) the title compound (15 mg, 29%).
LC-MS (method 2): Rt = 0.96 min; MS (ESIpos): rrilz = 390 [M+H].
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.56 (quint, 2H), 2.13 (s, 6H), 2.23 (t, 2H), 3.12 (q, 2H), 6.29 (d, 1H), 6.39 (d, 1H), 6.60 (t, 1H), 7.34 ¨ 7.40 (m, 3H), 8.07 (d, 1H), 9.17 (bs, 1H), 11.82 (bs, 1H).
Example 137 4-({[3,5-difluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]carbamoyllamino)butanamide F . ill {111N H 2 F
/ I
NN/
H
In analogy to example 133 44({3,5-difluoro-4-[(1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]phenyllcarbamoyl)amino]butanamide (96.0 mg, 185 pmol, intermediate 151) was treated with trifluoroacetic acid (285 pL) in dichloromethane and subsequently with aqueous sodium hydroxide (370 pL, 2.0 M, 740 pmol) in THF to give after preparative HPLC (method 4) the title compound (1.2 mg, 1%).
LC-MS (method 2): Rt = 0.79 min; MS (ESIpos): rrilz = 390 [M+H].
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.65 (quint, 2H), 2.08 (t, 2H), 3.09 (q, 2H), 4.44 (s, 1H), 6.17 ¨ 6.28 (m, 1H), 6.39 ¨ 6.46 (m, 1H), 6.77 (bs, 1H), 7.07.(d, 1H), 7.31 ¨7.41 (m, 3H), 7.97 ¨ 8.08 (m, 1H), 8.98 ¨ 9.00 (m, 1H), 11.48 ¨ 11.82 (m, 1H).

Example 138 1-[3,5-difluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)pheny1]-3-(2-methoxyethypurea H H
F . NyNo,CH3 F
/ I
N----N/
H
In analogy to example 133 1-{3,5-difluoro-4-[(1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]pheny11-3-(2-methoxyethypurea (68.0 mg, 138 pmol, intermediate 152) was treated with trifluoroacetic acid (213 pL) in dichloromethane and subsequently with aqueous sodium hydroxide (280 pL, 2.0 M, 560 pmol) in THF to give after preparative HPLC
(method 4) the title compound (1.7 mg, 2%).
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 3.24 ¨ 3.31 (m, 7H), 6.28 ¨ 6.29 (m, 1H), 6.40 (d, 1H), 6.51 (t, 1H), 7.32 ¨ 7.40 (m, 3H), 8.07 (d, 1H), 9.13 (bs, 1H), 11.82 (bs, 1H).
Example 139 1-[3,5-difluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)pheny1]-3-(pyridin-2-ylmethypurea N
H H.
F NN) ' F
/ I
N''N/
H
In analogy to example 133 1-{3,5-difluoro-4-[(1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]phenyll-3-(pyridin-2-ylmethypurea (65.0 mg, 124 pmol, intermediate 153) was treated with trifluoroacetic acid (190 pL) in dichloromethane and subsequently with aqueous sodium hydroxide (250 pL, 2.0 M, 490 pmol) in THF to give after preparative HPLC (method 4) the title compound (1.1 mg, 2%).
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 4.43 (d, 2H), 6.28 ¨ 6.30 (m, 1H), 6.40 (d, 1H), 7.22 (t, 1H), 7.28 (ddd, 1H), 7.35 ¨ 7.42 (m, 4H), 7.79 (dt, 1H), 8.07 (d, 1H), 8.52 ¨
8. 54 (m, 1H), 9.53 (bs, 1H), 11.82 (bs, 1H).

Example 140 1-[3,5-difluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)pheny1]-343-(methylsulfonyl)propyl]urea Ho C 3 F N ).rNso-0 * 0 F
/ I
N----N/
H
In analogy to example 133 1-{3,5-difluoro-4-[(1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]pheny11-343-(methylsulfonyl)propyl]urea (73.0 mg, 132 pmol, intermediate 154) was treated with trifluoroacetic acid (250 pL) in dichloromethane and subsequently with aqueous sodium hydroxide (260 pL, 2.0 M, 520 pmol) in THF to give after preparative HPLC (method 4) the title compound (25 mg, 33%).
LC-MS (method 2): Rt = 0.84 min; MS (ESIpos): rrilz = 425 [M+H].
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.83 - 1.91 (m, 2H), 2.99 (s, 3H), 3.11 -3.15 (m, 2H), 3.22 (q, 2H), 6.28 - 6.29 (m, 1H), 6.39 (d, 1H), 6.54 (t, 1H), 7.35 - 7.41 (m, 3H), 8.08 (d, 1H), 9.05 (s, 1H), 11.83 (bs, 1H).
Example 141 1-[3,5-difluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)pheny1]-342-(dimethylamino)ethyl]urea H H
F NyNN,C H3 i . 0 C H3 F
/ I
N----N/
H
In analogy to example 133 1-{3,5-difluoro-4-[(1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]phenyll-342-(dimethylamino)ethyl]urea (56.0 mg, 111 pmol, intermediate 155) was treated with trifluoroacetic acid (170 pL) in dichloromethane and subsequently with aqueous sodium hydroxide (200 pL, 2.0 M, 400 pmol) in THF to give after preparative HPLC (method 4) the title compound (5 mg, 10%).
LC-MS (method 2): Rt = 0.92 min; MS (ESIpos): rrilz = 376 [M+H].
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 2.17 (s, 6H), 2.33 (t, 2H), 3.19 (q, 2H), 6.29 (d, 1H), 6.40 (d, 1H), 6.46 (t, 1H), 7.32 - 7.38 (m, 2H), 7.40 (d, 1H), 8.07 (d, 1H), 9.33 (bs, 1H), 11.82 (bs, 1H).

Example 142 1-[3,5-difluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)pheny1]-343-(piperidin-1-yl)propyl]urea H H
F
0. y v F
/ I
NN/
H
In analogy to example 133 1-{3,5-difluoro-4-[(1 -{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]pheny11-3[3-(piperidin-1-yl)propyl]urea (64.0 mg, 114 pmol, intermediate 156) was treated with trifluoroacetic acid (176 pL) in dichloromethane and subsequently with aqueous sodium hydroxide (220 pL, 2.0 M, 450 pmol) in THF to give after preparative HPLC (method 4) the title compound (13 mg, 19%).
LC-MS (method 2): Rt = 1.12 min; MS (ESIpos): m/z = 430 [M+H].
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.36 ¨ 1.40 (m, 2H), 1.47 ¨ 1.52 (m, 4H), 1.59 (quint, 2H), 2.25 ¨ 2.33 (m, 6H), 3.11 (q, 2H), 6.28 ¨ 6.29 (m, 1H), 6.39 (d, 1H), 6.43 (t, 1H), 7.33 ¨
7.38 (m, 2H), 7.40 (dd, 1H), 8.08 (d, 1H), 8.99 (bs, 1H), 11.82 (bs, 1H).
Example 143 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(3-methoxypropypurea H H
Br F NyNo'C H3 F
/ I
NN/
H
A mixture of crude 1-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(3-methoxypropypurea (223 mg, 381 pmol, intermediate 160) in dichloromethane (2 mL) was treated with trifluoroacetic acid (20 eq., 590 pL, 7.6 mmol) and this mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo and the residue subjected to preparative HPLC (method 4) to give the title compound (76.5 mg, 43%).
LC-MS (method 2): Rt = 1.00 min; MS (ESIpos): m/z = 455/457 [M+H] (Br isotope pattern).
1H-N MR (400 MHz, DMSO-d6) 6 [ppm]: 1.64 ¨ 1.71 (m, 2H), 3.15 (q, 2H), 3.25 (s, 3H), 3.36 (t, 2H), 6.32 (d, 1H), 6.41 (t, 1H), 7.35 ¨ 7.40 (m, 2H), 7.64 (d, 1H), 8.10 (d, 1H), 9.00 (bs, 1H), 12.20 (bs, 1H).

Example 144 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-[(1-methyl-1H-pyrazol-3-y1)methyl]urea N--"Ni F 0 y Brµ 1 F
t...-N N
H
.. In analogy to example 143 crude 1-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-[(1-methyl-1H-pyrazol-3-y1)methyl]urea (231 mg, 380 pmol, intermediate 161) was reacted with trifluoroacetic acid (20 eq., 590 pL, 7.6 mmol) in dichloromethane to give after preparative HPLC (method 4) the title compound (29 mg, 15%).
LC-MS (method 2): Rt = 0.95 min; MS (ESIpos): m/z = 477/479 [M+H] (Br isotope pattern).
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 3.80 (s, 3H), 4.24 (d, 2H), 6.13 (d, 1H), 6.33 (d, 1H), 6.71 (t, 1H), 7.35¨ 7.41 (m, 2H), 7.61 (d, 1H), 7.64 (d, 1H), 8.10 (d, 1H), 9.08 (bs, 1H), 12.21 (bs, 1H).
Example 145 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(1,3-thiazol-2-ylmethyl)urea S---H H$
F NN
.N

Br 0 F
/ I
NN/
H
In analogy to example 143 crude 1-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluoropheny11-3-(1,3-thiazol-2-ylmethypurea (232 mg, 380 pmol, intermediate 162) was reacted with trifluoroacetic acid (20 eq., 590 pL, 7.6 mmol) in dichloromethane to give after preparative HPLC (method 4) the title compound (63 mg, 33%).
LC-MS (method 2): Rt = 0.99 min; MS (ESIpos): m/z = 480/482 [M+H] (Br isotope pattern).
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 4.61 (d, 2H), 6.34 (d, 1H), 7.26 (t, 1H), 7.39 ¨ 7.45 (m, 2H), 7.63 ¨ 7.64 (m, 2H), 7.74(d, 1H), 8.10 (d, 1H), 9.38 (bs, 1H), 12.20 (bs, 1H).

Example 146 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(1H-pyrazol-3-ylmethyl)urea H H.......X
F
N
o401 0 Br F
/ I
N''N/
H
In analogy to example 143 crude 1-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(1H-pyrazol-3-ylmethyl)urea (226 mg, 381 pmol, intermediate 163) was reacted with trifluoroacetic acid (20 eq., 590 pL, 7.6 mmol) in dichloromethane to give after preparative HPLC (method 4) the title compound (8 mg, 4%).
LC-MS (method 2): Rt = 0.91 min; MS (ESIpos): m/z = 463/465 [M+H] (Br isotope pattern).
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 4.30 (d, 2H), 6.17 (d, 1H), 6.33 (d, 1H), 6.72 ¨6.75 (m, 1H), 7.36 ¨ 7.42 (m, 2H), 7.64 (d, 1H), 7.74 (d, 1H), 8.10 (d, 1H), 9.09 (bs, 1H), 12.20 (bs, 1H), 12.65 (bs, 1H).
Example 147 N3-({4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyllcarbamoy1)-beta-alaninamide H H
F Br NNN H 2 F
/ I
N--"N/
H
In analogy to example 143 crude N3-({4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamoy1)-beta-alaninamide (120 mg, 206 pmol, intermediate 164) was reacted with trifluoroacetic acid (20 eq., 320 pL, 4.1 mmol) in dichloromethane to give after preparative HPLC (method 4) the title compound (22 mg, 21%).
LC-MS (method 2): Rt = 0.86 min; MS (ESIpos): m/z = 454/456 [M+H] (Br isotope pattern).
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 2.28 (t, 2H), 3.29 (q, 2H), 6.32 (d, 1H), 6.44 (t, 1H), 6.92 (bs, 1H), 7.33 ¨ 7.40 (m, 3H), 7.64 (d, 1H), 8.10 (d, 1H), 9.15 (bs, 1H), 12.20 (bs, 1H).

Example 148 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-342-(piperidin-1-ypethyl]urea H H
F N N
. y N

Br F
/ I
N----N/
H
In analogy to example 143 crude 1-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-342-(piperidin-1-ypethyl]urea (129 mg, 206 pmol, intermediate 165) was reacted with trifluoroacetic acid (20 eq., 320 pL, 4.1 mmol) in dichloromethane to give after preparative HPLC (method 4) the title compound (33 mg, 31%).
LC-MS (method 2): Rt = 1.17 min; MS (ESIpos): m/z = 494/496 [M+H] (Br isotope pattern).
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.36¨ 1.40 (m, 2H), 1.49¨ 1.54 (m, 4H), 2.32 ¨ 2.37 (m, 6H), 3.20 (q, 2H), 6.28 (t, 1H), 6.32 (d, 1H), 7.33 ¨ 7.39 (m, 2H), 7.64 (d, 1H), 8.10 (d, 1H), 9.20 (bs, 1H), 12.20 (bs, 1H).
Example 149 N-{24({4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyllcarbamoyl)amino]ethyllmethanesulfonamide o H

40 NyNN1' 00 H

Br F
/ I
N----N/
H
In analogy to example 143 crude N-{24({4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyllcarbamoyl)amino]ethyllmethanesulfonamide (131 mg, 206 pmol, intermediate 166) was reacted with trifluoroacetic acid (20 eq., 320 pL, 4.1 mmol) in dichloromethane to give after preparative HPLC (method 4) the title compound (19 mg, 18%).
LC-MS (method 2): Rt = 0.93 min; MS (ESIpos): m/z = 504/506 [M+H] (Br isotope pattern).
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 2.92 (s, 3H), 3.02 ¨ 3.06 (m, 2H), 3.22 (q, 2H), 6.32 (d, 1H), 6.53 ¨ 6.55 (m, 1H), 7.12 (t, 1H), 7.36 ¨ 7.41 (m, 2H), 7.64 (s, 1H), 8.10 (d, 1H), 9.22 (bs, 1H), 12.20 (bs, 1H).

Example 150 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-343-(morpholin-4-y1)propyl]urea H H r0 F . NyNN.) Br F
/ I
N''N/
H
In analogy to example 143 crude 1-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-343-(morpholin-4-y1)propyl]urea (132 mg, 206 pmol, intermediate 167) was reacted with trifluoroacetic acid (20 eq., 320 pL, 4.1 mmol) in dichloromethane to give after preparative HPLC (method 4) the title compound (18 mg, 17%).
LC-MS (method 2): Rt = 0.99 min; MS (ESIpos): m/z = 510/511 [M+H] (Br isotope pattern).
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.60 (quint, 2H), 2.28 ¨ 2.34 (m, 6H), 3.12 (q, 2H), 3.56 ¨ 3.59 (m, 4H), 6.32 (d, 1H), 6.45 (t, 1H), 7.35 ¨ 7.41 (m, 2H), 7.64 (s, 1H), 8.10 (d, 1H), 9.01 (bs, 1H), 12.20 (bs, 1H).
Example 151 N-{24({4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyllcarbamoyl)amino]ethyllacetamide H H
F . NyNN).0 H3 H

Br F
/ I
NN/
H
In analogy to example 143 crude N-{24({4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyllcarbamoyl)amino]ethyllacetamide (123 mg, 206 pmol, intermediate 168) was reacted with trifluoroacetic acid (20 eq., 320 pL, 4.1 mmol) in dichloromethane to give after preparative HPLC (method 4) the title compound (10 mg, 10%).
LC-MS (method 2): Rt = 0.89 min; MS (ESIpos): m/z = 468/470 [M+H] (Br isotope pattern).
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.82 (s, 3H), 3.13 ¨ 3.15 (m, 4H), 6.32 (d, 1H), 6.44 ¨
6.46 (m, 1H), 7.36 ¨ 7.42 (m, 2H), 7.64 (d, 1H), 7.96 ¨ 7.97 (m, 1H), 8.10 (d, 1H), 9.13 (bs, 1H), 12.20 (bs, 1H).

Example 152 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-342-(morpholin-4-y1)-2-oxoethyl]urea F Hs nHN
NN
i Br 0 F
/ I
N----N/
H
In analogy to example 143 crude 1-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-342-(morpholin-4-y1)-2-oxoethyl]urea (132 mg, 206 pmol, intermediate 169) was reacted with trifluoroacetic acid (20 eq., 320 pL, 4.1 mmol) in dichloromethane to give after preparative HPLC (method 4) the title compound (33 mg, 30%).
LC-MS (method 2): Rt = 0.94 min; MS (ESIpos): m/z = 510/512 [M+H] (Br isotope pattern).
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 3.41 - 3.43 (m, 2H), 3.46 - 3.48 (m, 2H), 3.56 - 3.61 (m, 4H), 4.01 (d, 2H), 6.33 (d, 1H), 6.57 (t, 1H), 7.34 - 7.39 (m, 2H), 7.64 (d, 1H), 8.09 (d, 1H), 9.47 (bs, 1H), 12.20 (bs, 1H).
Example 153 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(pyridin-2-ylmethypurea H H I
. N_ y -1\1-Br F N
F
/ I
NN/
H
In analogy to example 143 crude 1-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(pyridin-2-ylmethypurea (125 mg, 206 pmol, intermediate 170) was reacted with trifluoroacetic acid (20 eq., 320 pL, 4.1 mmol) in dichloromethane to give after preparative HPLC (method 4) the title compound (16 mg, 15%).
LC-MS (method 2): Rt = 1.02 min; MS (ESIpos): m/z = 474/476 [M+H] (Br isotope pattern).
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 4.43 (d, 2H), 6.33 (d, 1H), 7.06 (t, 1H), 7.29 (ddd, 1H), 7.35- 7.43 (m, 3H), 7.64 (s, 1H), 7.79 (dt, 1H), 8.10 (d, 1H), 8.54 (ddd, 1H), 9.38 (bs, 1H), 12.20 (bs, 1H).

Example 154 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-[(1,1-dioxidothietan-3-Amethyl]urea ii F H HCIS-..7:0 NN
. 8 Br F
/ I
NN/
H
In analogy to example 143 crude 1-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-[(1,1-dioxidothietan-3-Amethyl]urea (130 mg, 206 pmol, intermediate 171) was reacted with trifluoroacetic acid (20 eq., 320 pL, 4.1 mmol) in dichloromethane to give after preparative HPLC (method 4) the title compound (35 mg, 33%).
LC-MS (method 2): Rt = 0.95 min; MS (ESIpos): m/z = 501/503 [M+H] (Br isotope pattern).
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 2.65 - 2.73 (m, 1H), 3.36 - 3.38 (m, 2H), 3.90 - 3.95 (m, 2H), 4.20 - 4.26 (m, 2H), 6.32 (d, 1H), 6.78 - 6.84 (m, 1H), 7.37 - 7.43 (m, 2H), 7.64 (s, 1H), 8.10 (d, 1H), 9.24- 9.25 (m, 1H), 12.20 (bs, 1H).
Example 155 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(2-methoxyethypurea H H
F N N C H
y ICY 3 Br F
/ I
N---N/
H
In analogy to example 143 crude 1-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(2-methoxyethypurea (118 mg, 206 pmol, intermediate 172) was reacted with trifluoroacetic acid (20 eq., 320 pL, 4.1 mmol) in dichloromethane to give after preparative HPLC (method 4) the title compound (42 mg, 45%).
LC-MS (method 2): Rt = 1.00 min; MS (ESIpos): m/z = 441/443 [M+H] (Br isotope pattern).
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 3.25 - 3.29 (m, 5H), 3.38 - 3.40 (m, 2H), 6.32 (d, 1H), 6.48 (t, 1H), 7.33 - 7.39 (m, 2H), 7.64 (s, 1H), 8.10 (d, 1H), 9.10 (bs, 1H), 12.20 (bs, 1H).

Example 156 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(pyridin-4-ylmethypurea N
H H F NN )J 1101 8 Br F
/ I
N----N/
H
In analogy to example 143 crude 1-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluoropheny11-3-(pyridin-4-ylmethypurea (124 mg, 206 pmol, intermediate 173) was reacted with trifluoroacetic acid (20 eq., 320 pL, 4.1 mmol) in dichloromethane to give after preparative HPLC (method 4) the title compound (20 mg, 18%).
LC-MS (method 2): Rt = 0.98 min; MS (ESIpos): m/z = 474/476 [M+H] (Br isotope pattern).
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 4.35 (d, 2H), 6.32 (d, 1H), 7.07 ¨ 7.11 (m, 1H), 7.29 ¨
7.30 (m, 2H), 7.38¨ 7.44 (m, 2H), 7.64 (bs, 1H), 8.10 (d, 1H), 8.51 ¨8.52 (m, 2H), 9.34 (bs, 1H), 12.20 (bs, 1H).
Example 157 N2-({4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyllcarbamoyl)glycinamide H H j,.
F NN

Br F
/ I
N----N/
H
In analogy to example 143 crude N2-({4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamoyl)glycinamide (117 mg, 206 pmol, intermediate 174) was reacted with trifluoroacetic acid (20 eq., 320 pL, 4.1 mmol) in dichloromethane to give after preparative HPLC (method 4) the title compound (22 mg, 22%).
LC-MS (method 2): Rt = 0.85 min; MS (ESIpos): m/z = 440/442 [M+H] (Br isotope pattern).
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 3.71 (d, 2H), 6.32 (d, 1H), 6.54 (t, 1H), 7.10 (bs, 1H), 7.34 ¨ 7.39 (m, 2H), 7.45 (bs, 1H), 7.64 (d, 1H), 8.10 (d, 1H), 9.34 (bs, 1H), 12.20 (bs, 1H).

Example 158 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-343-(piperidin-1-y1)propyl]urea H H
F N N ...........,,...õN......_..õ..
401 Br 8 F
/ I
N----N/
H
In analogy to example 143 crude 1-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-343-(piperidin-1-y1)propyl]urea (131 mg, 206 pmol, intermediate 175) was reacted with trifluoroacetic acid (20 eq., 320 pL, 4.1 mmol) in dichloromethane to give after preparative HPLC (method 4) the title compound (27 mg, 23%).
LC-MS (method 2): Rt = 1.20 min; MS (ESIpos): m/z = 508/510 [M+H] (Br isotope pattern).
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.34¨ 1.40 (m, 2H), 1.46¨ 1.50 (m, 4H), 1.58 (quint, 2H), 2.23 ¨ 2.30 (m, 6H), 3.11 (q, 2H), 6.32 (d, 1H), 6.46 (t, 1H), 7.35 ¨
7.41 (m, 2H), 7.64 (s, 1H), 8.10 (d, 1H), 9.03 (bs, 1H), 12.20 (bs, 1H).
Example 159 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(1H-1,2,3-triazol-4-ylmethyl)urea H
N, F ill {111 (N,,N
. 8 Br F
/ I
N----N/
H
In analogy to example 143 crude 1-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(1H-1,2,3-triazol-4-ylmethyl)urea (123 mg, 206 pmol, intermediate 176) was reacted with trifluoroacetic acid (20 eq., 320 pL, 4.1 mmol) in dichloromethane to give after preparative HPLC (method 4) the title compound (16 mg, 15%).
LC-MS (method 2): Rt = 0.70 min; MS (ESIpos): m/z = 464/466 [M+H] (Br isotope pattern).
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 4.37 (d, 2H), 6.32 (d, 1H), 6.90 (t, 1H), 7.37 ¨ 7.42 (m, 2H), 7.64 (d, 1H), 7.73 (bs, 1H), 8.10 (d, 1H), 9.15 (bs, 1H), 12.20 (bs, 1H), 14.86 (bs, 1H).

Example 160 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-343-(methylsulfonyl)propyl]urea . Fl% C 3 F S' . N yN 00 Br 0 F
/ I
N----N/
H
In analogy to example 143 crude 1-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-343-(methylsulfonyl)propyl]urea (130 mg, 206 pmol, intermediate 177) was reacted with trifluoroacetic acid (20 eq., 320 pL, 4.1 mmol) in dichloromethane to give after preparative HPLC (method 4) the title compound (9 mg, 9%).
LC-MS (method 2): Rt = 0.93 min; MS (ESIpos): m/z = 503/505 [M+H] (Br isotope pattern).
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.83 ¨ 1.91 (m, 2H), 2.99 (s, 3H), 3.11 ¨3.15 (m, 2H), 3.22 (q, 2H), 6.32 (d, 1H), 6.58 (t, 1H), 7.36 ¨ 7.42 (m, 2H), 7.64 (d, 1H), 8.10 (d, 1H), 9.10 (bs, 1H), 12.20 (bs, 1H).
Example 161 44({4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyllcarbamoyl)amino]butanamide Br .
F
1-1y1-)"N H 2 6 o F
/ I
N----N/
H
In analogy to example 143 crude 44({4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyllcarbamoyl)amino]butanamide (123 mg, .. 206 pmol, intermediate 178) was reacted with trifluoroacetic acid (20 eq., 320 pL, 4.1 mmol) in dichloromethane to give after preparative HPLC (2 consecutive separations, methods 2 and 4) the title compound (13 mg, 10%).
LC-MS (method 2): Rt = 0.93 min; MS (ESIpos): m/z = 468/470 [M+H] (Br isotope pattern).
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.61 ¨1.69 (m, 2H), 2.08 (t, 2H), 3.09 (q, 2H), 6.32 (d, 1H), 6.49 (bs, 1H), 6.77 (bs, 1H), 7.31 (bs, 1H), 7.36 ¨ 7.41 (m, 2H), 7.64 (s, 1H), 8.10 (d, 1H), 9.05 (bs, 1H), 12.20 (bs, 1H).

Example 162 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-342-(4-methylpiperazin-1-y1)-2-oxoethyl]urea F H Br 0 H.A
N.{N N

F
/ I
NN/
H
In analogy to example 143 crude 1-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-342-(4-methylpiperazin-1-y1)-2-oxoethyl]urea (137 mg, 206 pmol, intermediate 179) was reacted with trifluoroacetic acid (20 eq., 320 pL, 4.1 mmol) in dichloromethane to give after preparative HPLC (2 consecutive separations, methods 2 and 4) the title compound (10 mg, 7%).
LC-MS (method 2): Rt = 1.00 min; MS (ESIpos): m/z = 523/525 [M+H] (Br isotope pattern).
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 2.19 (s, 3H), 2.25 ¨ 2.28 (m, 2H), 2.31 ¨2.33 (m, 2H), 3.38 ¨ 3.41 (m, 2H), 3.45 ¨ 3.48 (m, 2H), 4.00 (d, 2H), 6.33 (d, 1H), 6.56 (t, 1H), 7.34 ¨ 7.39 (m, 2H), 7.64 (s, 1H), 8.09 (d, 1H), 9.47 (bs, 1H), 12.20 (bs, 1H).
Example 163 1-{3,5-difluoro-4-[(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]pheny11-342-(dimethylamino)ethyl]urea H H
F NI\Iõ,...,...õ,-.....N.,õC H3 I
r, . 8 C H3 H 3C\ I' F
e----n N----N/
H
In analogy to example 143 crude 1-{3,5-difluoro-4-[(3-methyl-1-{[2-(trimethylsilypethoxy]me-thy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]phenyll-342-(dimethylamino)ethyl]urea (59 mg, 114 pmol, intermediate 184) was reacted with trifluoroacetic acid (40 eq., 350 pL, 4.6 mmol) in dichloromethane to give after preparative HPLC (method 4) the title compound (6 mg, 11%).
LC-MS (method 2): R1= 1.10 min; MS (ESIpos): m/z = 390 [M+H].
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 2.17 (s, 6H), 2.32 ¨2.35 (m, 2H), 2.43 (s, 3H), 3.19 (q, 2H), 6.17 (d, 1H), 6.29 (t, 1H), 7.15 ¨ 7.16 (m, 1H), 7.31 ¨7.37 (m, 2H), 7.98 (d, 1H), 9.16 (bs, 1H), 11.43 (bs, 1H).

Example 164 (+/-)-1-{4-[(3-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(tetrahydrofuran-3-yOurea H H
F N N
N . 0 iliQ, ?
F
N---N/
H
In analogy to example 143 crude (+/-)-1-{4-[(3-cyano-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(tetrahydrofuran-3-yOurea (329 mg, 621 pmol, intermediate 189) was reacted with trifluoroacetic acid (40 eq., 1.9 mL, 25 mmol) in dichloromethane to give after preparative HPLC (2 consecutive separations, methods 2 and 4) the title compound (40 mg, 16%).
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.72 ¨ 1.77 (m, 1H), 2.07 ¨2.18 (m, 1H), 3.51 (dd, 1H), 3.68 ¨ 3.83 (m, 3H), 4.18 ¨ 4.25 (m, 1H), 6.52 (d, 1H), 6.72 (d, 1H), 7.37 ¨ 7.43 (m, 2H), 8.23 (d, 1H), 8.45 (s, 1H), 8.87 (s, 1H), 12.99 (bs, 1H).
Example 165 1-{4-[(3-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-342-(dimethylamino)ethyl]urea H H
F opo C H-, i NyN,........../..".....y.., v ?
F
NN/
H
In analogy to example 143 crude 1-{4-[(3-cyano-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-342-(dimethylamino)ethyl]urea (34 mg, .. 63 pmol, intermediate 190) was reacted with trifluoroacetic acid (20 eq., 98 pL, 1.3 mmol) in dichloromethane to give after preparative HPLC (method 4) the title compound (22 mg, 78%).
LC-MS (method 2): Rt = 0.80 min; MS (ESIneg): rrilz = 401 [M+H].
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 2.20 (s, 6H), 2.37 (t, 2H), 3.21 (q, 2H), 6.33 (t, 1H), 6.52 (d, 1H), 7.35 ¨ 7.40 (m, 2H), 8.23 (d, 1H), 8.44 (s, 1H), 9.22 (bs, 1H), 12.97 (bs, 1H).

Example 166 (+/-)-1-{4-[(3-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(tetrahydrofuran-2-ylmethypurea ?
F
NN/
H
In analogy to example 143 crude (+/-)-1-{4-[(3-cyano-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(tetrahydrofuran-2-ylmethypurea (357 mg, 656 pmol, intermediate 191) was reacted with trifluoroacetic acid (40 eq., 2.0 mL, 26 mmol) in dichloromethane to give after preparative HPLC (2 consecutive separations, methods 2 and 4) the title compound (27 mg, 9%).
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.48¨ 1.56 (m, 1H), 1.77¨ 1.94 (m, 3H), 3.08 ¨ 3.14 (m, 1H), 3.22 ¨ 3.28 (m, 1H), 3.61 ¨3.68 (m, 1H), 3.76 ¨ 3.81 (m, 1H), 3.84 ¨
3.91 (m, 1H), 6.44 (t, 1H), 6.52 (d, 1H), 7.35 ¨ 7.41 (m, 2H), 8.23 (d, 1H), 8.44 (s, 1H), 9.06 (s, 1H), 12.98 (bs, 1H).
.. Example 167 1-{4-[(3-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(3-methoxypropypurea H H
F
fa NyNo'CH3 ? W
F
N----N/
H
In analogy to example 143 crude 1-{4-[(3-cyano-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(3-methoxypropypurea (316 mg, 594 pmol, intermediate 192) was reacted with trifluoroacetic acid (40 eq., 1.8 mL, 24 mmol) in dichloromethane to give after preparative HPLC (2 consecutive separations, methods 2 and 4) the title compound (23 mg, 10%).
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.68 (quint, 2H), 3.15 (q, 2H), 3.24 (s, 3H), 3.37 (t, 2H), 6.42 (t, 1H), 6.52 (d, 1H), 7.37 ¨ 7.43 (m, 2H), 8.23 (d, 1H), 8.44 (s, 1H), 9.02 (bs, 1H), 12.98 (bs, 1H).

Example 168 1-{4-[(3-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-343-(morpholin-4-y1)propyl]urea H H (0 F N NN) N\ ? (101 Yo F
NN/
H
In analogy to example 143 crude 1-{4-[(3-cyano-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-343-(morpholin-4-y1)propyl]urea (37 mg, 64 pmol, intermediate 193) was reacted with trifluoroacetic acid (20 eq., 98 pL, 1.3 mmol) in dichloromethane to give after preparative HPLC (method 4) the title compound (17 mg, 54%).
LC-MS (method 2): Rt = 0.78 min; MS (ESIpos): rniz = 457 [M+H].
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.63 (bs, 2H), 2.35 (bs, 4H), 3.14 (q, 2H), 3.59 (bs, 4H), 6.44 (bs, 1H), 6.51 (d, 1H), 7.37 ¨ 7.43 (m, 2H), 8.23 (d, 1H), 8.45 (s, 1H), 9.02 (bs, 1H), 12.99 (bs, 1H).
Example 169 1-{4-[(3-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-[(1-methyl-1H-pyrazol-3-yl)methyl]urea F0H H N ? ---NNC,N¨C H 3 ri F
N----N/
H
In analogy to example 143 crude 1-{4-[(3-cyano-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-[(1-methyl-1H-pyrazol-3-y1)methyl]urea (332 mg, 600 pmol, intermediate 194) was reacted with trifluoroacetic acid (40 eq., 1.8 mL, 24 mmol) in dichloromethane to give after preparative HPLC (method 4) the title compound (63 mg, 20%).
LC-MS (method 2): Rt = 0.75 min; MS (ESIpos): rniz = 424 [M+H].
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 3.80 (s, 3H), 4.24 (d, 2H), 6.14 (d, 1H), 6.52 (d, 1H), 6.73 (t, 1H), 7.38 ¨ 7.43 (m, 2H), 7.61 (d, 1H), 8.23 (d, 1H), 8.44 (s, 1H), 9.10 (bs, 1H), 12.98 (bs, 1H).

Example 170 1-{4-[(3-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(1,3-thiazol-2-ylmethyl)urea H
S H

N
? 1101 8 F
N----N/
H
In analogy to example 143 crude 1-{4-[(3-cyano-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(1,3-thiazol-2-ylmethypurea (363 mg, 652 pmol, intermediate 195) was reacted with trifluoroacetic acid (40 eq., 2.0 mL, 26 mmol) in dichloromethane to give after preparative HPLC (method 4) the title compound (38 mg, 12%).
LC-MS (method 2): Rt = 0.77 min; MS (ESIpos): rniz = 427 [M+H].
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 4.61 (d, 2H), 6.54 (d, 1H), 7.26 (t, 1H), 7.43 ¨ 7.45 (m, 2H), 7.64 (d, 1H), 7.75 (d, 1H), 8.23 (d, 1H), 8.45 (s, 1H), 9.40 (bs, 1H), 12.99 (bs, 1H).
Example 171 1-{4-[(3-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(pyridin-4-ylmethypurea N
F

?
F
N---N/
H
In analogy to example 143 crude 1-{4-[(3-cyano-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(pyridin-4-ylmethypurea (144 mg, 261 pmol, intermediate 196) was reacted with trifluoroacetic acid (40 eq., 800 pL, 10 mmol) in dichloromethane to give after preparative HPLC (method 4) the title compound (59 mg, 54%).
LC-MS (method 2): Rt = 0.74 min; MS (ESIpos): rniz = 421 [M+H].
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 4.35 (d, 2H), 6.52 (d, 1H), 7.04 (t, 1H), 7.29 ¨ 7.31 (m, 2H), 7.40 ¨ 7.45 (m, 2H), 8.23 (d, 1H), 8.44 (d, 1H), 8.51 ¨8.52 (m, 2H), 9.30 (bs, 1H), 12.99 (bs, 1H).

Example 172 1-{4-[(3-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(2-methoxyethypurea H H
F & N yNO'C H 3 ?
F
N---N/
H
In analogy to example 143 crude 1-{4-[(3-cyano-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluoropheny11-3-(2-methoxyethypurea (343 mg, 663 pmol, intermediate 197) was reacted with trifluoroacetic acid (40 eq., 2.0 mL, 27 mmol) in dichloromethane to give after preparative HPLC (method 4) the title compound (72 mg, 27%).
LC-MS (method 2): Rt = 0.75 min; MS (ESIpos): rrilz = 388 [M+H].
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 3.25 ¨ 3.29 (m, 5H), 3.38 ¨ 3.41 (m, 2H), 6.45 (t, 1H), 6.52 (d, 1H), 7.36 ¨ 7.41 (m, 2H), 8.23 (d, 1H), 8.44 (s, 1H), 9.08 (bs, 1H), 12.98 (bs, 1H).
Example 173 1-{4-[(3-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(1H-pyrazol-3-ylmethyl)urea H
N¨N
F 11\11{W
N
? 1101 8 F
N---N/
H
In analogy to example 143 crude 1-{4-[(3-cyano-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(1H-pyrazol-3-ylmethyl)urea (282 mg, 522 pmol, intermediate 198) was reacted with trifluoroacetic acid (40 eq., 1.6 mL, 21 mmol) in dichloromethane to give after preparative HPLC (method 4) the title compound (69 mg, 29%).
.. LC-MS (method 2): Rt = 0.71 min; MS (ESIpos): rrilz = 410 [M+H].
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 4.30 (d, 2H), 6.17 (s, 1H), 6.52 (d, 1H), 6.76 (bs, 1H), 7.40 ¨ 7.42 (m, 2H), 7.63 (bs, 1H), 8.23 (d, 1H), 8.44 (s, 1H), 9.11 (s, 1H), 12.64 (bs, 1H), 12.99 (bs, 1H).

Example 174 (+/-)-1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(tetrahydrofuran-3-yOurea H H
F N N
o 110 lr kiC
Br F
/ I
N---"N
H
A solution of (+/-)-1-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(tetrahydrofuran-3-yOurea (100 mg, 171 pmol, intermediate 200) in dichloromethane (2 mL) was treated with trifluoroacetic acid (20 eq., 260 pL, 3.4 mmol) and stirred at room temperature overnight. The reaction mixture was evaporated in vacuo to give (+/-)-1-(4-{[3-bromo-1-(hyd roxymethyl)-1 H-pyrrolo[2,3-b]pyrid in-4-yl]oxy}-3 ,5-d ifl uoropheny1)-3-(tetrahydrofuran-3-yl)urea trifluoroacetate (1:1). A part of this crude intermediate (55 mg) was dissolved in THF (1.0 mL), aqueous sodium hydroxide (5.0 eq., 280 pL, 2.0 M, 570 pmol) was added and the mixture stirred at 60 C for 24 hours. The reaction mixture was evaporated in vacuo and the obtained residue subjected to preparative HPLC (method 4) to give the title compound (9 mg).
.. LC-MS (method 2): Rt =0.96 min; MS (ES1pos): m/z = 453/455 [M+H] (Br isotope pattern).
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.71 ¨ 1.78 (m, 1H), 2.09 ¨2.18 (m, 1H), 3.51 (dd, 1H), 3.68 ¨ 3.83 (m, 3H), 4.18 ¨ 4.25 (m, 1H), 6.52 (d, 1H), 6.72 (d, 1H), 7.35 ¨ 7.40 (m, 2H), 7.64 (s, 1H), 8.10 (d, 1H), 8.86 (bs, 1H), 12.20 (bs, 1H).
Example 175 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(6-methoxypyridazin-3-yOurea H H
F N N
F F .Y `r F 0 Ni C HF4'? 1\10' 3 F
t----N----N/
H
In analogy to example 1, 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(6-methoxypyridazin-3-yOurea (85.0 mg, 139 pmol, intermediate 201) was stirred with trifluoroacetic acid (320 pL, 4.2 mmol) in dichloromethane (450 pL) to afford after preperative HPLC
purification the title compound (8 mg, 11% yield).
LC-MS (method 2): Rt = 1.11 min; MS (ESIpos): rrilz = 481 [M+H]
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 3.98 (s, 3 H), 6.49 (d, 1 H), 7.28 (d, 1 H), 7.53 (d, 2 H), 7.97 (d, 1 H), 8.11 (d, 1 H), 8.22 (d, 1 H).
Example 176 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(6,7-dihydro-5H-cyclopenta[c]pyridazin-3-y1)urea N' ' I
N
H
F NyNH

F
,------NN/
H
In analogy to example 1, 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(6,7-dihydro-5H-cyclopenta[c]pyridazin-3-y1)urea (55.0 mg, 88.6 pmol, intermediate 202) was stirred with trifluoroacetic acid (200 pL, 2.7 mmol) in dichloromethane (290 pL) to afford after preperative HPLC purification the title compound (5 mg, 11 % yield).
LC-MS (method 2): Rt = 1.14 min; MS (ESIpos): rrilz = 491 [M+H]
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 2.03 - 2.13 (m, 2 H), 2.95 (t, 2 H), 3.01 (t, 2 H), 6.51 (d, 1 H), 7.51 (d, 3 H), 7.79 (s, 1 H), 8.13 (s, 1 H), 8.23 (d, 1 H), 9.87 (br s, 1 H), 10.43 (br s, 1 H).
Example 177 1-(6-bromopyridazin-3-yI)-3-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyllurea H H
F N N
Y `r Cl 0 'I\1 Br F
/ I
NN/
H

In analogy to example 1, 1-(6-bromopyridazin-3-y1)-3-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyllurea (120 mg, 192 pmol, intermediate 203) was stirred with trifluoroacetic acid (740 pL, 9.6 mmol) in dichloromethane (1.2 mL) to afford after preperative HPLC purification the title compound (1 mg, 1 % yield).
LC-MS (method 3): Rt = 1.16 min; MS (ESIpos): rrilz = 495 [M+H]
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 6.36 (d, 1 H), 7.51 (br d, 2 H), 7.63 (s, 1 H), 7.96 (d, 1 H), 8.06 -8.13 (m, 2 H), 9.89 (br s, 1 H), 12.15 (br s, 1 H).
.. Example 178 (+/-)-1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(tetrahydrofuran-2-ylmethyl)urea H H
F* NyNa.e0 Cl 0 F
/ I
NN/
H
To a solution of (+/-)-1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluoropheny11-3-[tetrahydrofuran-2-ylmethyl]urea (130 mg, 235 pmol, intermediate 204) in dichloromethane (5.0 mL) was added trifluoroacetic acid (1.0 mL, 13 mmol). The resulting mixture was stirred overnight at room temperature, at which time the mixture was slowly basified with a 1M aqueous solution of sodium hydroxide.
The basified mixture was stirred for 5 minutes at room temperature, at which time ethyl acetate was added and the layers were separated. The aqueous phase was extracted twice with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, and evaporated to afford the crude urea. The crude product was purified by preperative HPLC to afford the title compound (33 mg, 33 % yield).
LC-MS (method 2): Rt = 1.04 min; MS (ESIpos): rrilz = 423 [M+H]
.. 1H NMR (400 MHz, DMSO-c16) 6 ppm 1.47 - 1.57 (m, 1 H), 1.77 - 1.95 (m, 3 H), 3.07 - 3.15 (m, 1 H), 3.21 - 3.28 (m, 1 H), 3.61 - 3.68 (m, 1 H), 3.74 - 3.82 (m, 1 H), 3.84 -3.91 (m, 1 H), 6.32 (d, 1 H), 6.44 (t, 1 H), 7.36 (d, 2 H), 7.61 (s, 1 H), 8.10 (d, 1 H), 9.05 (s, 1 H), 12.12 (br d, 1 H) Example 179 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-[(3S)-tetrahydrofuran-3-yl]urea H H
F N N,,, (101 YO .3 CI
F
/ I
N----N/
H
In analogy to example 178, 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-[(3S)-tetrahydrofuran-3-yl]urea (145 mg, 269 pmol, intermediate 205) was stirred with trifluoroacetic acid (1.0 mL, 13 mmol) in dichloromethane (5.0 mL) to afford after preperative HPLC purification the title compound (33 mg, 30 % yield).
LC-MS (method 2): R1= 1.04 min; MS (ESIpos): rniz = 409 [M+H]
1H NMR (400 MHz, DMSO-c16) 6 ppm 1.70 - 1.79 (m, 1 H), 2.13 (dq, 1 H), 3.50 (dd, 1 H), 3.67 -3.84 (m, 3 H), 4.18 -4.26 (m, 1 H), 6.32 (d, 1 H), 6.71 (d, 1 H), 7.37 (d, 2 H), 7.61 (s, 1 H), 8.10 (d, 1 H), 8.85 (s, 1 H), 12.12 (br s, 1 H) Example 180 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-[(1-methyl-1H-pyrazol-3-y1)methyl]urea H H.....
F N N .....r ,N-C H3 N
T, .
Cl 0 F
/ I
N--"N/
H
To a solution of 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-[(1-methyl-1H-pyrazol-3-y1)methyl]urea (130 mg, 231 pmol, intermediate 207) in dichloromethane (5.0 mL) was added trifluoroacetic acid (1.0 mL, 13 mmol). The reaction mixture was stirred at room temperature overnight at which time the mixture was basified with a 1M aqueous solution of sodium hydroxide. The resulting precipitate was collected by filtration and dried to yield the title compound (19 mg, 19 %
yield) LC-MS (method 2): Rt = 0.98 min; MS (ESIpos): rniz = 433 [M+H]
1H NMR (400 MHz, DMSO-c16) 6 ppm 3.79 (s, 3 H), 4.24 (d, 2 H), 6.13 (d, 1 H), 6.32 (d, 1 H), 6.72 (br t, 1 H), 7.38 (d, 2 H), 7.61 (s, 2 H), 8.10 (d, 1 H), 9.09 (s, 1 H), 12.12 (br s, 1 H) Example 181 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(2-oxaspiro[3.3]hept-6-yOurea H H
F NN
F
/ I
N---N/
H
A solution of 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1 H-pyrrolo[2,3-b]pyrid in-4-yl)oxy]-3,5-difluoropheny11-3-(2-oxaspiro[3.3]hept-6-yOurea (150 mg, 265 pmol, intermediate 206) in DMF (2.0 mL) was treated with ceasium fluoride (80.6 mg, 531 pmol) and stirred at 90 C overnight. An additional charge of ceasium fluoride (80.6 mg, 531 pmol) was added and stirred at 100 C overnight. Water and ethyl acetate were added and the layers were separated.
The aqueous phase was extracted twice with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated to afford the crude product. The crude product was purified by preparativeHPLC (method 7), to obtain 5 mg (4 %
yield) of the title compound.
LC-MS (method 2): Rt = 1.00 min; MS (ESIpos): rniz = 435 [M+H]
1H NMR (400 MHz, DMSO-c16) 6 ppm 2.03 -2.12 (m, 2 H), 2.53 -2.57 (m, 2 H), 3.94 (sxt, 1 H), 4.49 (s, 2 H), 4.60 (s, 2 H), 6.31 (d, 1 H), 6.73 (d, 1 H), 7.36 (d, 2 H), 7.61 (d, 1 H), 8.09 (d, 1 H), 9.03 (s, 1 H), 12.13 (br s, 1 H) Example 182 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-346-(difluoromethyppyridazin-3-yl]urea H H
F N N
. Y
Cl 0 0 I\1 F
`N
F F
/ I
N---"N/
H
In analogy to example 178, 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-346-(difluoromethyppyridazin-3-yl]urea (120 mg, 201 pmol, intermediate 208) was stirred with trifluoroacetic acid (770 pL, 10 mmol) in dichloromethane (1.3 mL) to afford after preperative HPLC purification the title compound (10 mg, 10 % yield).
LC-MS (method 2): Rt = 1.14 min; MS (ESIneg): rrilz = 467 [M+H]
1H NMR (400 MHz, DMSO-c16) 6 ppm 6.37 (d, 1 H), 7.19 (t, 1 H), 7.53 (d, 2 H), 7.63 (s, 1 H), 8.01 (d, 1 H), 8.11 (d, 1 H), 8.30 (d, 1 H).
Example 183 (+/-)-1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(tetrahydrofuran-3-yOurea H H
F NN
Cl 0 F
/ I
N----N/
H
In analogy to example 178, (+/-)-1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-[tetrahydrofuran-3-yl]urea (125 mg, 232 pmol, intermediate 209) was stirred with trifluoroacetic acid (1.0 mL, 13 mmol) in dichloromethane (5.0 mL) to afford after preperative HPLC purification the title compound (19 mg, 20% yield).
LC-MS (method 2): Rt = 0.98 min; MS (ESIpos): rrilz = 409 [M+H]
1H NMR (400 MHz, DMSO-c16) 6 ppm 1.70 - 1.79 (m, 1 H), 2.13 (dq, 1 H), 3.50 (dd, 1 H), 3.66 -3.84 (m, 3 H), 4.17 - 4.26 (m, 1 H), 6.32 (d, 1 H), 6.71 (d, 1 H), 7.37 (d, 2 H), 7.61 (d, 1 H), 8.10 (d, 1 H), 8.84 (s, 1 H), 12.13 (br s, 1 H) Example 184 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(3-methoxypropypurea H H
F
40 Cl NyNo'C H3 F
/ I
NN/
H
In analogy to example 178, 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluoropheny11-3-(3-methoxypropypurea (125 mg, 231 pmol, intermediate 210) was stirred with trifluoroacetic acid (1.0 mL, 13 mmol) in dichloromethane (5.0 mL) to afford after preperative HPLC purification the title compound (35 mg, 37 % yield).
LC-MS (method 2): Rt = 1.02 min; MS (ESIpos): rrilz = 411 [M+H]
1H NMR (400 MHz, DMSO-c16) 6 ppm 1.67 (quin, 2 H), 3.11 -3.18 (m, 2 H), 3.24 (s, 3 H), 3.36 (t, 2 H), 6.32 (d, 1 H), 6.41 (t, 1 H), 7.38 (d, 2 H), 7.61 (s, 1 H), 8.10 (d, 1 H), 9.00 (s, 1 H), 12.12 (s, 1 H) Example 185 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-[(3R)-tetrahydrofuran-3-yl]urea H H
F NN
. 8 `Co Cl 0 F
/ I
NN/
H
In analogy to example 178, 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-[(3R)-tetrahydrofuran-3-yl]urea (145 mg, 269 pmol, intermediate 211) was stirred with trifluoroacetic acid (1.0 mL, 13 mmol) in dichloromethane (5.0 mL) to afford after preperative HPLC purification the title compound (43 mg, 39 % yield).
LC-MS (method 2): R1= 1.03 min; MS (ESIpos): rniz = 409 [M+H]
1H NMR (400 MHz, DMSO-c16) 6 ppm 1.70 - 1.79 (m, 1 H), 2.13 (dq, 1 H), 3.50 (dd, 1 H), 3.66 -3.84 (m, 3 H), 4.17 - 4.26 (m, 1 H), 6.32 (d, 1 H), 6.71 (d, 1 H), 7.37 (d, 2 H), 7.61 (d, 1 H), 8.10 (d, 1 H), 8.84 (s, 1 H), 12.13 (br s, 1 H) Example 186 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(1H-pyrazol-3-ylmethyl)urea H
N-N
F ill {111 . 8 Cl 0 F
/ I
N----N/
H

In analogy to example 178, 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(1H-pyrazol-3-ylmethyl)urea (150 mg, 273 pmol, intermediate 212) was stirred with trifluoroacetic acid (1.0 mL, 13 mmol) in dichloromethane (5.0 mL) to afford after preperative HPLC purification the title compound (4 mg, 3 % yield).
LC-MS (method 2): Rt = 0.95 min; MS (ESIpos): rniz = 419 [M+H]
1H NMR (400 MHz, DMSO-c16) 6 ppm 4.29 (br d, 2 H), 6.17 (s, 1 H), 6.32 (d, 1 H), 6.75 (br s, 1 H), 7.39 (d, 2 H), 7.61 (s, 1 H), 7.65 (br s, 1 H), 8.10 (d, 1 H), 9.10 (s, 1 H), 12.12 (br s, 1 H), 12.65 (br s, 1 H) .. Example 187 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(2,2,2-trifluoroethypurea F
H H.)<F
F NN
F

Cl 0 F
/ I
N----N/
H
In analogy to example 178, 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(2,2,2-trifluoroethypurea (150 mg, 272 pmol, intermediate 213) was stirred with trifluoroacetic acid (1.0 mL, 13 mmol) in dichloromethane (5.0 mL) to afford after preperative HPLC purification the title compound (27 mg, 23 % yield).
LC-MS (method 2): Rt = 1.14 min; MS (ESIpos): rniz = 421 [M+H]
1H NMR (400 MHz, DMSO-c16) 6 ppm 3.94 (qd, 2 H), 6.33 (d, 1 H), 7.05 (t, 1 H), 7.41 (d, 2 H), 7.62 (s, 1 H), 8.10 (d, 1 H), 9.30 (s, 1 H), 12.13 (br s, 1 H) Example 188 (+/-)-N-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-[(dimethylamino)methyl]pyrrolidine-1-carboxamide H
Cl F . NN1f-a-AA\
,N¨C H 3 F
/ I
N---"N/
H
In analogy to example 178, (+/-)-N-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-[(dimethylamino)methyl]pyrrolidine-1-carboxamide (155 mg, 267 pmol, intermediate 214) was stirred with trifluoroacetic acid (1.0 mL, 13 mmol) in dichloromethane (5.0 mL) to afford after preperative HPLC
purification the title compound (56 mg, 46 % yield).
LC-MS (method 2): Rt = 1.11 min; MS (ESIpos): rrilz = 450 [M+H]
1H NMR (400 MHz, DMSO-c16) 6 ppm 1.57 (dq, 1 H), 1.93 - 2.02 (m, 1 H), 2.16 (s, 6 H), 2.18 -2.29 (m, 2 H), 2.39 - 2.47 (m, 1 H), 3.09 (dd, 1 H), 3.30 - 3.38 (m, 1 H), 3.49 (dq, 1 H), 3.57 (dd, 1 H), 6.31 (d, 1 H), 7.57 - 7.63 (m, 3 H), 8.10 (d, 1 H), 8.63 (s, 1 H), 12.12 (br s, 1 H) Example 189 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-[(4-methyl-1,2,5-oxadiazol-3-Amethyl]urea H H
F Cl NN-\ IC H 3 . r\li i/ µC
F
/ I
NN/
H
In analogy to example 178, 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-[(4-methyl-1,2,5-oxadiazol-3-Amethyl]urea (150 mg, 265 pmol, intermediate 215) was stirred with trifluoroacetic acid (1.0 mL, 13 mmol) in dichloromethane (5.0 mL) to afford after preperative HPLC purification the title compound (41 mg, 35 % yield).
LC-MS (method 2): Rt = 1.11 min; MS (ESIpos): rrilz = 435 [M+H]
1H NMR (400 MHz, DMSO-c16) 6 ppm 2.40 (s, 3 H), 4.52 (d, 2 H), 6.32 (d, 1 H), 7.08 (t, 1 H), 7.39 (d, 2 H), 7.61 (d, 1 H), 8.09 (d, 1 H), 9.29 (s, 1 H), 12.13 (br s, 1 H) Example 190 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(2-fluoroethypurea H H
F N N
/10 y F

Cl 0 F
/ I
NN/
H
In analogy to example 178, 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(2-fluoroethypurea (140 mg, 272 pmol, intermediate 216) was stirred with trifluoroacetic acid (1.0 mL, 13 mmol) in dichloromethane (5.0 mL) to afford after preperative HPLC purification the title compound (39 mg, 37 %
yield).
LC-MS (method 2): Rt= 1.01 min; MS (ESIpos): rrilz = 385 [M+H]
1H NMR (400 MHz, DMSO-c16) 6 ppm 3.41 (dq, 2 H), 4.47 (dt, 2 H), 6.32 (d, 1 H), 6.66 (t, 1 H), 7.39 (d, 2 H), 7.61 (s, 1 H), 8.10 (d, 1 H), 9.12 (s, 1 H), 12.13 (br s, 1 H) Example 191 N-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-2-oxa-7-azaspiro[3.5]nonane-7-carboxamide F

Cl F
/ I
N''N/
H
In analogy to example 178, N-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-2-oxa-7-azaspiro[3.5]nonane-7-carboxamide (155 mg, 268 pmol, intermediate 217) was stirred with trifluoroacetic acid (1.0 mL, 13 mmol) in dichloromethane (5.0 mL) to afford after preperative HPLC purification the title compound (40 mg, 30 % yield).
LC-MS (method 2): Rt = 1.03 min; MS (ESIpos): rrilz = 449 [M+H]
1H NMR (400 MHz, DMSO-c16) 6 ppm 1.77- 1.82 (m, 4 H), 3.37 - 3.41 (m, 4 H), 4.34 (s, 4 H), 6.31 (d, 1 H), 7.50 (d, 2 H), 7.61 (s, 1 H), 8.10 (d, 1 H), 8.97 (s, 1 H), 12.12 (br s, 1 H) Example 192 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(2,2-difluoroethypurea F
H HL
F Cl NN

F
/ I
NN/
H
In analogy to example 1, 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(2,2-difluoroethypurea (140 mg, 263 pmol, intermediate 218) was stirred with trifluoroacetic acid (1.0 mL, 13 mmol) in dichloromethane (5.0 mL) to afford after preperative HPLC purification the title compound (47 mg, 44 % yield).
LC-MS (method 2): Rt = 1.05 min; MS (ESIpos): rrilz = 403 [M+H]
1H NMR (400 MHz, DMSO-c16) 6 ppm 3.54 (tdd, 2 H), 6.07 (tt, 1 H), 6.33 (d, 1 H), 6.77 (t, 1 H), 7.40 (d, 2 H), 7.61 (s, 1 H), 8.10 (d, 1 H), 9.23 (s, 1 H), 12.13 (br s, 1 H) Example 193 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-[(4-methyl-1H-imidazol-2-y1)methyl]urea H N
H H
F NNN

Cl 0 F
/ I
N----N/
H
In analogy to example 178, 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-[(4-methyl-1H-imidazol-2-y1)methyl]urea (150 mg, 266 pmol, intermediate 219) was stirred with trifluoroacetic acid (1.0 mL, 13 mmol) in dichloromethane (5.0 mL) to afford after preperative HPLC purification the title compound (45 mg, 37 % yield).
LC-MS (method 2): Rt = 0.99 min; MS (ESIpos): rrilz = 433 [M+H]
1H NMR (400 MHz, DMSO-c16) 6 ppm 2.10 (s, 3 H), 4.25 (d, 2 H), 6.32 (d, 1 H), 6.64 (br s, 1 H), 6.79 (t, 1 H), 7.39 (d, 2 H), 7.61 (s, 1 H), 8.10 (d, 1 H), 9.22 (s, 1 H), 11.57 (br s, 1 H), 12.13 (br s, 1 H) Example 194 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(6-methoxypyridazin-3-yOurea H H
N
Y
CI F N.

1\j'NO-F
/ I
N'N
H

In analogy to example 178, 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(6-methoxypyridazin-3-yOurea (120 mg, 208 pmol, intermediate 220) was stirred with trifluoroacetic acid (800 pL, 10 mmol) in dichloromethane (1.3 mL) to afford after preperative HPLC purification the title compound (11 mg, 12 % yield).
LC-MS (method 2): Rt = 1.11 min; MS (ESIpos): rrilz = 447 [M+H]
1H NMR (400 MHz, DMSO-c16) 6 ppm 3.97 (s, 3 H), 6.36 (d, 1 H), 7.27 (d, 1 H), 7.51 (d, 2 H), 7.60 (s, 1 H), 7.94 (d, 1 H), 8.11 (d, 1 H) Example 195 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(1,3,4-thiadiazol-2-yOurea H H
F .
Cl NõN, _N
- IVr ' 0 S....../

F
/ I
NN/
H
In analogy to example 178, 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(1,3,4-thiadiazol-2-yOurea (150 mg, 271 pmol, intermediate 221) was stirred with trifluoroacetic acid (1.0 mL, 13 mmol) in dichloromethane (5.0 mL) to afford after preperative HPLC purification the title compound (5 mg, 4 % yield over two steps).
LC-MS (method 2): Rt = 0.70 min; MS (ESIpos): rrilz = 423 [M+H]
1H NMR (400 MHz, DMSO-c16) 6 ppm 6.35 (d, 1 H), 7.55 (br d, 2 H), 7.63 (d, 1 H), 8.11 (d, 1 H), 9.05 (br s, 1 H), 9.65 (br s, 1 H), 12.15 (br s, 1 H) Example 196 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(1,3-thiazol-2-ylmethyl)urea N\>
F 11\1111-\11s\
. 8 a 0 F
/ I
N----N/
H

In analogy to example 178, 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(1,3-thiazol-2-ylmethypurea (150 mg, 265 pmol, intermediate 222) was stirred with trifluoroacetic acid (1.0 mL, 13 mmol) in dichloromethane (5.0 mL) to afford after preperative HPLC purification the title compound (60 mg, 51 % yield over two steps).
LC-MS (method 2): Rt = 1.02 min; MS (ESIpos): rrilz = 436 [M+H]
1H NMR (400 MHz, DMSO-c16) 6 ppm 4.61 (d, 2 H), 6.34 (d, 1 H), 7.26 (t, 1 H), 7.42 (d, 2 H), 7.61 (s, 1 H), 7.63 (d, 1 H), 7.74 (d, 1 H), 8.09 (d, 1 H), 9.39 (s, 1 H), 12.13 (br s, 1 H) Example 197 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(6-iodopyridazin-3-yOurea H H
F N N
Y
4 0 I 0 0 N, j=
F
/ I
N'N/
H
In analogy to example 178, 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluoropheny11-3-(6-iodopyridazin-3-yOurea (120 mg, 178 pmol, intermediate 223) was stirred with trifluoroacetic acid (690 pL, 8.9 mmol) in dichloromethane (1.1 mL) to afford after preperative HPLC purification the title compound (4 mg, 4 % yield).
LC-MS (method 2): R1= 1.15 min; MS (ESIpos): rrilz = 541 [M]
1H NMR (400 MHz, DMSO-c16) 6 ppm 6.32 (d, 1 H), 6.38 (d, 1 H), 6.99 (d, 1 H), 7.11 (d, 2 H), 7.61 (s, 1 H), 8.10 (d, 1 H) Example 198 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-346-(morpholin-4-yppyridazin-3-yl]urea H H
F
40o II\I 1 NY N1\k Cl 0 N
F L.o / I
N----N/
H
In analogy to example 178, 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-346-(morpholin-4-y1)pyridazin-3-yl]urea (120 mg, 190 pmol, intermediate 224) was stirred with trifluoroacetic acid (730 pL, 9.5 mmol) in dichloromethane (1.2 mL) to afford after preperative HPLC purification the title compound (31 mg, 32 % yield).
LC-MS (method 2): Rt = 1.06 min; MS (ESIpos): rrilz = 502 [M+H]
1H NMR (400 MHz, DMSO-c16) 6 ppm 3.43 - 3.48 (m, 4 H), 3.71 - 3.76 (m, 4 H), 6.36 (d, 1 H), 7.43 (d, 1 H), 7.50 (d, 2 H), 7.63 (s, 1 H), 7.79 (d, 1 H), 8.11 (d, 1 H), 9.62 (s, 1 H), 10.15 (br s, 1 H), 12.14 (br s, 1 H) Example 199 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(5-methylpyridazin-3-yOurea H H
F N N N
01 y "I\I
0 0 ,I) cl / I
N----N/
H
In analogy to example 178, 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(5-methylpyridazin-3-yOurea (80.0 mg, 143 pmol, intermediate 225) was stirred with trifluoroacetic acid (550 pL, 7.1 mmol) in dichloromethane (920 pL) to afford after preperative HPLC purification the title compound (11 mg, 17 % yield).
LC-MS (method 2): Rt = 1.07 min; MS (ESIpos): rrilz = 431 [M+H]
1H NMR (400 MHz, DMSO-c16) 6 ppm 2.33 (s, 3 H), 6.37 (d, 1 H), 7.52 (d, 2 H), 7.63 (s, 1 H), 7.86 (s, 1 H), 8.11 (d, 1 H), 8.80 (d, 1 H), 9.92 (br s, 1 H), 10.22 (br s, 1 H), 12.15 (br s, 1 H) Example 200 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(6-cyclopropylpyridazin-3-yOurea H H
NY N N;N, Cl F0 F
/ I
N'N/
H
In analogy to example 178, 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(6-cyclopropylpyridazin-3-yOurea (120 mg, 204 pmol, intermediate 226) was stirred with trifluoroacetic acid (790 pL, 10 mmol) in dichloromethane (1.3 mL) to afford after preperative HPLC purification the title compound (25 mg, 26 % yield).
LC-MS (method 2): R1= 1.16 min; MS (ESIpos): rrilz = 457 [M+H]
1H NMR (400 MHz, DMSO-d6) 6 ppm 0.95- 1.00 (m, 2 H), 1.04 (dt, 2 H), 2.17 -2.24 (m, 1 H), 6.36 (d, 1 H), 7.50 (m, 3 H), 7.63 (s, 1 H), 7.89 (d, 1 H), 8.11 (d, 1 H), 9.92 (br s, 1 H), 10.21 (br s, 1 H), 12.14 (br s, 1 H) Example 201 (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(1-methyl-5-oxopyrrolidin-3-yl)urea H H
F 40 NN 8 't-cro F
F-......F
F
/ I
N'N/
H
In analogy to example 1, (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(1-methyl-5-oxopyrrolidin-3-yOurea (110 mg, 183 pmol, intermediate 227) was stirred with trifluoroacetic acid (0.9 mL, 12 mmol) in dichloromethane (1.8 mL). After purification using a Biotage chromatography system we obtained 65.6 mg (95 % purity, 72 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 2.17 (dd, 1H), 2.61 (dd, 1H), 2.73 (s, 3H), 3.19 (dd, 1H), 3.64 (dd, 1H), 4.22 - 4.32 (m, 1H), 6.46 (d, 1H), 6.96 (d, 1H), 7.35 -7.42 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 9.00 (s, 1H), 12.63 (s, 1H).
Example 202 N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-4,4-difluoropiperidine-1-carboxamide F
H ri--F
F YN
F,.....01F F 0 N 0 F
/ I
N'N/
H

In analogy to example 1, N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-4,4-difluoropiperidine-1-carboxamide (158 mg, 260 pmol, intermediate 228) was stirred with trifluoroacetic acid (0.9 mL, 12 mmol) in dichloromethane (1.8 mL). After purification using a Biotage chromatography system we obtained 72.9 mg (95 % purity, 56 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.95 - 2.08 (m, 4H), 3.55 - 3.64 (m, 4H), 6.46 (d, 1H), 7.45 - 7.53 (m, 2H), 8.11 (s, 1H), 8.22 (d, 1H), 9.15 (s, 1H), 12.64 (br s, 1H).
Example 203 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-343-(propan-2-yloxy)propyl]urea H H
F
FF F . NYO NOYCH3 CH3 -........01 F
/ I
N--"N/
H
In analogy to example 1, 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-343-(propan-2-yloxy)propyl]urea (140 mg, 233 pmol, intermediate 229) was stirred with trifluoroacetic acid (0.9 mL, 12 mmol) in dichloromethane (1.8 mL). After purification using a Biotage chromatography system we obtained 69.9 mg (95 % purity, 60 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.09 (d, 6H), 1.64 (quin, 2H), 3.15 (q, 2H), 3.39 (t, 2H), 3.52 (spt, 1H), 6.41 (t, 1H), 6.46 (d, 1H), 7.34 - 7.42 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 9.01 (s, 1H), 12.63 (br s, 1H).
Example 204 N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-methoxyazetidine-1-carboxam id e H /ycl,C H3 F NN
F F . 8 F-...........) F
/ I
N'N/
H

In analogy to example 1, N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-methoxyazetidine-1-carboxamide (151 mg, 264 pmol, intermediate 230) was stirred with trifluoroacetic acid (0.9 mL, 12 mmol) in dichloromethane (1.8 mL). After purification using a Biotage chromatography system we obtained 70.3 mg (95 % purity, 57 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 3.33 (s, 3H), 3.79 (dd, 2H), 4.14 - 4.24 (m, 3H), 6.46 (d, 1H), 7.46 - 7.54 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 8.97 (s, 1H), 12.63 (br s, 1H).
Example 205 N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-1-oxa-6-azaspiro[3.3]heptane-6-carboxamide H
F
F F 110 NI(NI/D
F.¨k ?
F
NN/
H
In analogy to example 1, N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-1-oxa-azaspiro[3.3]heptane-6-carboxamide (67.2 mg, 115 pmol, intermediate 231) was stirred with trifluoroacetic acid (0.9 mL, 12 mmol) in dichloromethane (1.8 mL). After purification using a Biotage chromatography system we obtained 31.5 mg (90 % purity, 54 % yield) of the desired title compound.
.. 1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 2.84 (t, 2H), 4.07 (dd, 2H), 4.23 (dd, 2H), 4.38 - 4.46 (m, 2H), 6.46 (d, 1H), 7.45 - 7.53 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 9.00 (s, 1H), 12.63 (br s, 1H).

Example 206 N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-2-oxa-6-azaspiro[3.5]nonane-6-carboxamide H
F . NN 8 ` Co F F

...___01 F
/ I
N''N/
H
In analogy to example 1, N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-2-oxa-azaspiro[3.5]nonane-6-carboxamide (159 mg, 260 pmol, intermediate 232) was stirred with trifluoroacetic acid (0.9 mL, 12 mmol) in dichloromethane (1.8 mL). After purification using a Biotage chromatography system we obtained 70.2 mg (90 % purity, 50 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.41 - 1.52 (m, 2H), 1.77 - 1.87 (m, 2H), 3.35- 3.41 (m, 2H), 3.69 (s, 2H), 4.24 - 4.31 (m, 4H), 6.47 (d, 1H), 7.48 - 7.55 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 9.02 (s, 1H), 12.63 (br s, 1H).
Example 207 N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-N'-{[3-(propan-2-ypoxetan-3-yl]methyllurea n C H3 F F
F-...011101 0 H
..3C
F
/ I
N--"N/
H
In two independent experiments to a solution of N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-N'-{[3-(propan-2-ypoxetan-3-yl]methyllurea (200 mg, 325 pmol) (50 + 200 mg, 81 pmol + 325 pmol, intermediate 233) and ethylenediamine (22 + 89 pL, 334 + 1300pm01) in DMF (1.0 + 4.0 mL) was added a solution of 1N tetrabutylammoniume fluoride in THF (325 + 1300pL, 325 +
1300pmol) and this mixture was stirred at 45 C overnight. After cooling to room temperature the two mixtures were combined and poured into water and extracted two times with ethyl acetate. The combined organic phase was washed with brine, filtrated over a hydrophobic phase separation filter paper and concentrated in vacuo. The obtained residue was purified via a Biotage chromatography system (11g snap KP-NH column, ethyl acetate! 0 ¨ 80%
ethanol) to obtain a crude product, which was solved in ethyl acetate, washed two times with water, filtrated over a hydrophobic phase separation filter paper and concentrated in vacuo. The resulting residue was then purified via HPLC to obtain 59 mg (97 % purity, 30 % yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 0.91 (d, 6H), 2.01 (quin, 1H), 3.32 (d, 2H), 4.28 - 4.34 (m, 4H), 6.48 (d, 1H), 6.71 (t, 1H), 7.36 - 7.43 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 9.08 (s, 1H), 12.62 (br s, 1H).
Example 208 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-343-methyl-3-(morpholin-4-yl)butyl]urea H H (0 F NyN(N.) F F . 0 HC C H3 F.........___ F
/ I
N''N/
H
In analogy to example 1, 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-343-methyl-3-(morpholin-4-y1)butyl]urea (150 mg, 228 pmol, intermediate 234) was stirred with trifluoroacetic acid (0.9 mL, 12 mmol) in dichloromethane (1.8 mL). After purification using a Biotage chromatography system we obtained 92.7 mg (95 % purity, 73 % yield) of the desired title compound.
LC-MS (method 2): R1= 1.16 min; MS (ESIpos): m/z = 528 [M+H]
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 0.98 (s, 6H), 1.52- 1.59 (m, 2H), 2.43 -2.48 (m, 4H), 3.13 (dt, 2H), 3.53 - 3.62 (m, 4H), 6.38 (t, 1H), 6.46 (d, 1H), 7.33 - 7.41 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 9.05 (s, 1H), 12.63 (br s, 1H).

Example 209 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-[(4-methyl-1,2,5-oxadiazol-3-Amethyl]urea N-0 .
#
H r\L)1.,./(N
F Ny Brµ t F

N N
H
In analogy to example 143, crude 1-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-[(4-methyl-1,2,5-oxadiazol-3-y1)methyl]urea (232 mg, 381 pmol, intermediate 235) was reacted with trifluoroacetic acid (40 eq., 1.2 mL, mmol) in dichloromethane for 2 days to give after preparative HPLC (method 4) the title compound (83 mg, 43%).
10 LC-MS (method 2): Rt = 1.04 min; MS (ESIpos): m/z = 479/481 [M+H] (Br isotope pattern).
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 2.39 (s, 3H), 4.52 (d, 2H), 6.33 (d, 1H), 7.10 (t, 1H), 7.37 ¨ 7.42 (m, 2H), 7.64(d, 1H), 8.09 (d, 1H), 9.30 (bs, 1H), 12.20 (bs, 1H).
Example 210 15 (+/-) 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(tetrahydrofuran-2-ylmethyl)urea H H.,,,0 F N N
0 *
Br F
/ I
N F\j/
H
In analogy to example 143, crude (+/-) 1-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(tetrahydrofuran-2-ylmethypurea (228 mg, 381 pmol, intermediate 236) was reacted with trifluoroacetic acid (40 eq., 1.2 mL, 15 mmol) in dichloromethane for 2 days to give after preparative HPLC (method 4) the title compound (59 mg, 32%).
LC-MS (method 2): Rt = 1.02 min; MS (ESIpos): m/z = 467/469 [M+H] (Br isotope pattern).
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.48¨ 1.56 (m, 1H), 1.78¨ 1.92 (m, 3H), 3.08 ¨ 3.14 (m, 1H), 3.21 ¨3.28 (m, 1H), 3.61 ¨3.67 (m, 1H), 3.76 ¨ 3.81 (m, 1H), 3.84 ¨
3.90 (m, 1H), 6.32 (d, 1H), 6.45 (t, 1H), 7.33 ¨ 7.39 (m, 2H), 7.64 (s, 1H), 8.10 (d, 1H), 9.06 (bs, 1H), 12.20 (bs, 1H).

Example 211 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-pyridazin-3-ylurea H H
F N N
Y `r Br 'N
F
/ I
N----N/
H
In analogy to example 143 crude 1-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluoropheny11-3-pyridazin-3-ylurea (225 mg, 380 pmol, intermediate 237) was reacted with trifluoroacetic acid (40 eq., 1.2 mL, 15 mmol) in dichloromethane for 2 days to give after preparative HPLC (method 4) the title compound (0.3 mg, 0.2%).
LC-MS (method 2): Rt = 0.99 min; MS (ESIpos): m/z = 461/463 [M+H] (Br isotope pattern).
1H-N MR (400 MHz, DMSO-d6) 6 [ppm]: 6.37 (d, 1H), 7.49 ¨ 7.54 (m, 2H), 7.66 ¨
7.70 (m, 2H), 8.05 (dd, 1H), 8.11 (d, 1H), 8.93 (dd, 1H), 9.97 (bs, 1H), 10.10 (bs, 1H), 12.23 (bs, 1H).
Example 212 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(6-methylpyridazin-3-yl)urea H H
F N N
Y `r (001 0 N
Br 'N C H 3 F
/ I
N----N/
H
In analogy to example 143 crude 1-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(6-methylpyridazin-3-yOurea (230 mg, 380 pmol, intermediate 238) was reacted with trifluoroacetic acid (40 eq., 1.2 mL, 15 mmol) in dichloromethane for 2 days to give after preparative HPLC (method 4) the title compound (0.1 mg, 0.1%).
LC-MS (method 2): Rt = 1.06 min; MS (ESIpos): m/z = 475/477 [M+H] (Br isotope pattern).
1H-N MR (400 MHz, DMSO-d6) 6 [ppm]: 2.55 (s, 3H), 6.36 (d, 1H), 7.48 ¨ 7.54 (m, 2H), 7.57 (d, 1H), 7.66 (d, 1H), 7.92 (d, 1H), 8.11 (d, 1H), 9.90 (bs, 1H), 10.18 (bs, 1H), 12.23 (bs, 1H).

Example 213 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(1,3,4-thiadiazol-2-yOurea H H
Tr r 'N
Br F
/ I
N----N/
H
In analogy to example 143 crude 1-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(1,3,4-thiadiazol-2-yOurea (227 mg, 380 pmol, intermediate 239) was reacted with trifluoroacetic acid (40 eq., 1.2 mL, 15 mmol) in dichloromethane for 2 days to give after preparative HPLC (method 4) the title compound (7 mg, 4%).
LC-MS (method 2): Rt = 0.63 min; MS (ESIpos): m/z = 467/469 [M+H] (Br isotope pattern).
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 6.35 (d, 1H), 7.54 ¨ 7.56 (m, 2H), 7.66 (d, 1H), 8.11 (d, 1H), 9.04 (bs, 1H), 9.64 (bs, 1H), 11.53 (bs, 1H), 12.23 (bs, 1H).
Example 214 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-[(4-methyl-1H-imidazol-2-y1)methyl]urea N
F 11\11{11\116 r, 0 8 N
H
F
N----N/
H
In analogy to example 143 1-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-[(4-methyl-1H-imidazol-2-y1)methyl]urea (43 mg, 71 pmol, intermediate 240) was reacted with trifluoroacetic acid (40 eq., 220 pL, 2.8 mmol) in dichloromethane for 2 days to give after preparative HPLC (method 4) the title compound (6 mg, 16%).
LC-MS (method 2): Rt = 0.93 min; MS (ESIpos): m/z = 477/479 [M+H] (Br isotope pattern).
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 2.10 (s, 3H), 4.25 (d, 2H), 6.32 (d, 1H), 6.62 (bs, 1H), 6.79 (t, 1H), 7.36 ¨ 7.42 (m, 2H), 7.64 (d, 1H), 8.10 (d, 1H), 9.23 (bs, 1H), 11.59 (bs, 1H), 12.21 (bs, 1H).

Example 215 1-{4-[(3-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(6-methylpyridazin-3-yOurea H H
N N
Yo _ `1\1-C H3 In analogy to example 143 1-{4-[(3-cyano-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-(6-methylpyridazin-3-yOurea (53 mg, 95 pmol, intermediate 241) was reacted with trifluoroacetic acid (40 eq., 290 pL, 3.8 mmol) in dichloromethane to give after preparative HPLC (method 4) the title compound (1.4 mg, 3%).
LC-MS (method 2): Rt = 0.82 min; MS (ESIpos): rniz = 422 [M+H].
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 2.55 (s, 3H), 6.56 (d, 1H), 7.50 - 7.58 (m, 3H), 7.92 (d, 1H), 8.25 (d, 1H), 8.46 (s, 1H), 9.95 (bs, 1H), 10.23 (bs, 1H), 12.95 (bs, 1H).
Example 216 1-{4-[(3-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-pyridazin-3-ylurea H H
N N
Y `r ?
NN/
In analogy to example 143 1-{4-[(3-cyano-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-pyridazin-3-ylurea (28 mg, 52 pmol, intermediate 242) was reacted with trifluoroacetic acid (40 eq., 160 pL, 2.1 mmol) in dichloromethane to give after preparative HPLC (method 4) the title compound (0.8 mg, 3%).
LC-MS (method 2): Rt = 0.78 min; MS (ESIpos): rniz = 408 [M+H].
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 6.35 - 6.57 (m, 1H), 7.50 - 7.57 (m, 2H), 7.66 - 7.70 (m, 1H), 7.91 -8.07 (m, 1H), 8.10 - 8.25 (m, 1H), 8.46(s, 1H), 8.93 (dd, 1H), 9.93- 10.03(m, 1H), 10.16 - 10.21 (m, 1H), 12.23 - 12.96 (m, 1H).

Example 217 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-{1-[(4-methylpiperazin-1-y1)carbonyl]cyclopropyllurea H H.
F N N
40 T _____________________________________________ Nn .N, F
/ I
N---N/
H
In analogy to example 178, 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-{1-[(4-methylpiperazin-1-y1)carbonyl]cyclopropyllurea (80.0 mg, 126 pmol, intermediate 245) was stirred with trifluoroacetic acid (490 pL, 6.3 mmol) in dichloromethane (810 pL, 13 mmol) to afford after preperative HPLC
purification the title compound (21 mg, 33 % yield).
.. LC-MS (method 2): Rt = 0.99 min; MS (ESIneg): rrilz = 503 [M-1-1]-1H NMR (400 MHz, DMSO-c16) 6 ppm 0.93 - 0.97 (m, 2 H), 1.17 - 1.21 (m, 2 H), 2.16 (s, 3 H), 2.26 (br t, 4 H), 3.54 (br s, 4 H), 6.32 (d, 1 H), 7.38 (d, 3 H), 7.61 (d, 1 H), 8.09 (d, 1 H), 8.88 (s, 1 H), 12.13 (br s, 1 H) Example 218 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-341-(morpholin-4-ylcarbonyl)cyclopropyl]urea F NN
N
0 1101 on A 0 CI
F
/ I
N--"N/
H
In analogy to example 178, 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-.. b]pyridin-4-yl)oxy]-3,5-difluoropheny11-341-(morpholin-4-ylcarbonyl)cyclopropyl]urea (100 mg, 161 pmol, intermediate 246) was stirred with trifluoroacetic acid (620 pL, 8.0 mmol) in dichloromethane (1.0 mL, 16 mmol) to afford after preperative HPLC
purification the title compound (4 mg, 5 % yield).
LC-MS (method 2): Rt = 0.98 min; MS (ESIneg): rrilz = 492 [M+H]
1H NMR (400 MHz, DMSO-c16) 6 ppm 0.92 (br s, 2 H), 1.16 - 1.21 (m, 2 H), 3.54 (br s, 8 H), 6.32 (d, 1 H), 7.40 (br d, 2 H), 7.60 (s, 1 H), 8.09 (d, 1 H), 8.26 (br s, 1 H), 9.86 (br s, 1 H), 12.04 (br s, 1 H) Example 219 14({4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyllcarbamoyl)amino]-N,N-dimethylcyclopropanecarboxamide F 1101 NN,.= C H, 8 __________ N' -i CI
F
/ I
N----N/
H
In analogy to example 178, 14({4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamoyl)amino]-N,N-dimethylcyclopropanecarboxamide (80.0 mg, 138 pmol, intermediate 247) was stirred with trifluoroacetic acid (530 pL, 6.9 mmol) in dichloromethane (890 pL, 14 mmol) to afford after preperative HPLC purification the title compound (17 mg, 27 % yield).
LC-MS (method 2): R1= 1.00 min; MS (ESIpos): rniz = 450 [M+H]
1H NMR (400 MHz, DMSO-d6) 6 ppm 0.90 -0.97 (m, 2 H), 1.17- 1.24 (m, 2 H), 2.96 (br s, 6 H), 6.32 (d, 1 H), 7.39 (d, 2 H), 7.58 - 7.65 (m, 2 H), 8.09 (d, 1 H), 9.19 (br s, 1 H) Example 220 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-341-(piperidin-1-ylcarbonyl)cyclopropyl]urea H H, N
F NN
(101 8 Cl 0 F
/ I
N---N/
H
In analogy to example 178, 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-341-(piperidin-1-ylcarbonyl)cyclopropyl]urea (80.0 mg, 129 pmol, intermediate 248) was stirred with trifluoroacetic acid (500 pL, 6.4 mmol) in dichloromethane (830 pL, 13 mmol) to afford after preperative HPLC
purification the title compound (27 mg, 42 % yield).
LC-MS (method 2): Rt = 1.12 min; MS (ESIpos): rniz = 490 [M+H]
1H NMR (400 MHz, DMSO-d6) 6 ppm 0.90 - 0.94 (m, 2 H), 1.17 (br d, 2 H), 1.44 (br s, 4 H), 1.57 (br d, 2 H), 3.50 (br s, 4 H), 6.32 (d, 1 H), 7.39 (d, 2 H), 7.60 (s, 1 H), 7.87 (br s, 1 H), 8.09 (d, 1 H), 9.39 (br s, 1 H), 12.11 (br s, 1 H) Example 221 (+/-)1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(1-methoxypropan-2-yOurea H H
F 01 NyNy-0,C H3 CI
F
/ I
N----N/
H
In analogy to example 178, (+1-) 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-34-1-methoxypropan-2-yl]urea (145 mg, 268 pmol, intermediate 249) was stirred with trifluoroacetic acid (1.0 mL, 13 mmol) in dichloromethane (5.0 mL) to afford after preperative HPLC purification the title compound (42 mg, 38 % yield).
LC-MS (method 2): R1= 1.07 min; MS (ESIpos): rrilz = 411 [M+H]
1H NMR (400 MHz, DMSO-c16) 6 ppm 1.10 (d, 3 H), 3.25 - 3.31 (m, 4 H), 3.34 -3.36 (m, 1 H), 3.81 - 3.92 (m, 1 H), 6.30 - 6.36 (m, 2 H), 7.35 (d, 2 H), 7.61 (d, 1 H), 8.10 (d, 1 H), 8.95 (s, 1 H), 12.12 (br s, 1 H) Example 222 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-341-(methoxymethyl)cyclopropyl]urea H H
Cl 0 F 401 NN,co,C H 3 8 _______________________________________________ F
/ I
NN/
H
In analogy to example 178, 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluoropheny11-341-(methoxymethyl)cyclopropyl]urea (150 mg, 271 pmol, intermediate 250) was stirred with trifluoroacetic acid (1.0 mL, 13 mmol) in dichloromethane (4.0 mL, 62 mmol) to afford after preperative HPLC
purification the title compound (37 mg, 32 % yield).
LC-MS (method 2): Rt = 1.07 min; MS (ESIpos): rrilz = 423 [M+H]
1H NMR (400 MHz, DMSO-c16) 6 ppm 0.72 (s, 4 H), 3.28 (s, 3 H), 3.37 (s, 2 H), 6.32 (d, 1 H), 6.81 (s, 1 H), 7.37 (d, 2 H), 7.61 (d, 1 H), 8.10 (d, 1 H), 8.82 (s, 1 H), 12.12 (br s, 1 H) Example 223 (+1-) 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(2,2-dimethyltetrahydrofuran-3-yOurea H H
F NN
Cl 0 H3C CH3 F
/ I
N---"N
H
In analogy to example 178, (+/-)1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-[(3S)-2,2-dimethyltetrahydrofuran-3-yl]urea (150 mg, 264 pmol, intermediate 251) was stirred with trifluoroacetic acid (1.0 mL, 13 mmol) in dichloromethane (4.0 mL, 62 mmol) to afford after preperative HPLC
purification the title compound (33 mg, 28 % yield).
LC-MS (method 2): R1= 1.08 min; MS (ESIpos): rrilz = 437 [M+H]
1H NMR (400 MHz, DMSO-d6) 6 ppm 1.07 (s, 3 H), 1.17 (s, 3 H), 1.70 - 1.79 (m, 1 H), 2.25 -2.35 (m, 1 H), 3.67 - 3.81 (m, 2 H), 3.93 - 4.01 (m, 1 H), 6.32 (d, 1 H), 6.54 (d, 1 H), 7.37 (d, 2 H), 7.61 (s, 1 H), 8.10 (d, 1 H), 8.87 (s, 1 H), 12.12 (br s, 1 H) Example 224 (+1-) 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(5-oxaspiro[3.4]oct-7-yOurea H H
F N N
Cl F
/ I
NN/
H
In analogy to example 178, (+1-) 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluoropheny11-3-[(7R)-5-oxaspiro[3.4]oct-7-yl]urea (150 mg, 259 pmol, intermediate 252) was stirred with trifluoroacetic acid (1.0 mL, 13 mmol) in dichloromethane (4.0 mL, 62 mmol) to afford after preperative HPLC
purification the title compound (39 mg, 33 % yield).
LC-MS (method 2): Rt = 1.14 min; MS (ESIpos): rrilz = 449 [M+H]
1H NMR (400 MHz, DMSO-d6) 6 ppm 1.45- 1.58 (m, 1 H), 1.58- 1.68 (m, 1 H), 1.90 (dd, 1 H), 1.98 (ddt, 1 H), 2.05 - 2.21 (m, 3 H), 2.25 (dd, 1 H), 3.48 (dd, 1 H), 3.86 (dd, 1 H), 4.17 - 4.26 (m, 1 H), 6.32 (d, 1 H), 6.63 (d, 1 H), 7.37 (d, 2 H), 7.61 (d, 1 H), 8.10 (d, 1 H), 8.90 (s, 1 H), 12.12 (br s, 1 H) Example 225 (+1-) 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-[(trans)-4-(pyrrolidin-1-yptetrahydrofuran-3-yl]urea Om H H -F
/ I
N----N
H
.. In analogy to example 178, (+1-) 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-3-[(trans)-4-(pyrrolidin-1-yptetrahydrofuran-3-yl]urea (160 mg, 263 pmol, intermediate 253) was stirred with trifluoroacetic acid (1.0 mL, 13 mmol) in dichloromethane (4.0 mL, 62 mmol) to afford after preperative HPLC
purification the title compound (35 mg, 28 % yield).
.. LC-MS (method 2): R1= 1.04 min; MS (ESIpos): rrilz = 478 [M+H]
1H NMR (400 MHz, DMSO-c16) 6 ppm 1.67 (br s, 5 H), 2.66 - 2.72 (m, 1 H), 3.51 (dd, 1 H), 3.60 (dd, 1 H), 3.89 (td, 2 H), 4.14 - 4.22 (m, 1 H), 6.31 (d, 1 H), 6.96 (br d, 1 H), 7.39 (d, 2 H), 7.61 (s, 1 H), 8.09 (d, 1 H), 9.08 (br s, 1 H), 12.10 (br s, 1 H) Example 226 N2-({4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyllcarbamoy1)-N,N-dimethylalaninamide H H
F N Ny= H3 F
/ I
N'N/
H
In analogy to example 178, N2-({4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyllcarbamoyI)-N,N-dimethylalaninamide (60.0 mg, 106 pmol, intermediate 254) was stirred with trifluoroacetic acid (410 pL, 5.3 mmol) in dichloromethane (680 pL, 11 mmol) to afford after preperative HPLC
purification the title compound (20 mg, 39 % yield).
LC-MS (method 2): Rt = 1.01 min; MS (ESIpos): rrilz = 438 [M+H]
1H NMR (400 MHz, DMSO-c16) 6 ppm 1.21 (d, 3 H), 2.86 (s, 3 H), 3.05 (s, 3 H), 4.68 (quin, 1 H), 6.32 (d, 1 H), 6.72 (d, 1 H), 7.34 (d, 2 H), 7.61 (s, 1 H), 8.09 (d, 1 H), 9.29 (s, 1 H), 12.12 (br s, 1 H) Example 227 N2-({4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyllcarbamoy1)-N,N-dimethylvalinamide NN CH, F
/ I
N----N/
H
In analogy to example 178, N2-({4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyllcarbamoy1)-N,N-dimethylvalinamide (60.0 mg, 101 pmol, intermediate 255) was stirred with trifluoroacetic acid (390 pL, 5.0 mmol) in dichloromethane (650 pL, 10 mmol) to afford after preperative HPLC
purification the title compound (30 mg, 59 % yield).
LC-MS (method 2): R1= 1.12 min; MS (ESIpos): rrilz = 466 [M+H]
1H NMR (400 MHz, DMSO-c16) 6 ppm 0.86 (d, 3 H), 0.90 (d, 3 H), 2.86 (s, 3 H), 3.08 (s, 3 H), 4.57 (dd, 1 H), 6.32 (d, 1 H), 6.61 (d, 1 H), 7.34 (d, 2 H), 7.61 (s, 1 H), 8.09 (d, 1 H), 9.22 (s, 1 H), 12.12 (br s, 1 H) Example 228 (+/-)1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(3-methyltetrahydrofuran-3-yOurea F NN
1.1 8 to a 0 -F
/ I
NN/
H
In analogy to example 178, (+/-)-1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluoropheny11-343-methyltetrahydrofuran-3-yl]urea (150 mg, 271 pmol, intermediate 256) was stirred with trifluoroacetic acid (1.0 mL, 13 mmol) in dichloromethane (4.0 mL, 62 mmol) to afford after preperative HPLC
purification the title compound (15 mg, 13 % yield).
LC-MS (method 2): Rt = 1.07 min; MS (ESIpos): rrilz = 423 [M+H]
1H NMR (400 MHz, DMSO-c16) 6 ppm 1.43 (s, 3 H), 1.86 (dt, 1 H), 2.17 (dt, 1 H), 3.53 (d, 1 H), 3.78 -3.85 (m, 3 H), 6.32 (d, 1 H), 6.63 (s, 1 H), 7.35 (d, 2 H), 7.61 (d, 1 H), 8.10 (d, 1 H), 8.83 (s, 1 H), 12.12 (br s, 1 H) Example 229 (+/-)1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-oxabicyclo[2.2.1]hept-2-yl]urea - mixture of isomers H H
F N N
. YO 0 Cl 0 F
/ I
N---N/
H
In analogy to example 178, (+/-)1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-347-oxabicyclo[2.2.1]hept-2-yl]urea (150 mg, 265 pmol, intermediate 257, mixture of isomers) was stirred with trifluoroacetic acid (1.0 mL, 13 mmol) in dichloromethane (4.0 mL, 62 mmol) to afford after preperative HPLC
purification the title compound (12 mg, 10 % yield).
LC-MS (method 2): Rt = 1.07 min; MS (ESIpos): rrilz = 435 [M+H]
1H NMR (400 MHz, DMSO-d6) 6 ppm 1.30- 1.60 (m, 5 H), 1.93 (dd, 1 H), 3.76 (td, 1 H), 4.26 (d, 1 H), 4.53 -4.58 (m, 1 H), 6.32 (d, 1 H), 6.48 (d, 1 H), 7.35 (d, 2 H), 7.61 (s, 1 H), 8.10 (d, 1 H), 8.85 (s, 1 H), 12.12 (br s, 1 H) Example 230 (+/-)-1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-3-(1-methyl-2-oxopyrrolidin-3-yOurea H H
F NN
. 8 a 0 0 F CH 3 / I
NN/
H
In analogy to example 178, (+/-)-1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluoropheny11-3-(1-methyl-2-oxopyrrolidin-3-yOurea (60.0 mg, 106 pmol, intermediate 258) was stirred with trifluoroacetic acid (410 pL, 5.3 mmol) in dichloromethane (680 pL, 11 mmol) to afford after preperative HPLC
purification the title compound (11 mg, 22 % yield).
LC-MS (method 2): Rt = 0.96 min; MS (ESIpos): rrilz = 436 [M+H]
1H NMR (400 MHz, DMSO-d6) 6 ppm 1.83 (dq, 1 H), 2.38 (dddd, 1 H), 2.77 (s, 3 H), 3.27 - 3.32 (m, 2 H), 4.20 -4.27 (m, 1 H), 6.32 (d, 1 H), 6.75 (d, 1 H), 7.38 (d, 2 H), 7.61 (s, 1 H), 8.10 (d, 1 H), 9.21 (s, 1 H), 12.12 (br s, 1 H) Example 231 N-(3,5-difluoro-4-{[3-(trifluoromethyI)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)azetidine-1-carboxamide H
F NI\D
F F
F-.......01110 8 F
/ I
N'N/
H
In analogy to example 1, N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)azetidine-1-carboxamide (132 mg, 243 pmol, intermediate 259) was stirred with trifluoroacetic acid (1.7 mL, 22 mmol) in dichloromethane (3.4 mL). After purification using a Biotage chromatography system (11 g snap KP-NH column, ethyl acetate / 0 ¨ 50% ethanol) we obtained 82.3 mg (97 %
purity, 80 %
yield) of the desired title compound.
LC-MS (method 2): R1= 1.08 min; MS (ESIpos): m/z = 413 [M+H]
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 2.17 -2.25 (m, 2H), 3.96- 4.01 (m, 4H), 6.46 (d, 1H), 7.47 - 7.57 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 8.85 (s, 1H), 12.63 (br s, 1H).
Example 232 N-(3,5-difluoro-4-{[3-(trifluoromethyI)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)pyrrolidine-1-carboxamide H
F N.{NrD
F F
¨F........01 1101 8 F
/ I
N'N/
H
In analogy to example 1, N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)pyrrolidine-1-carboxamide (130 mg, 234 pmol, intermediate 260) was stirred with trifluoroacetic acid (1.6 mL, 21 mmol) in dichloromethane (3.2 mL). After purification using a Biotage chromatography system we obtained 66.2 mg (97 % purity, 64 % yield) of the desired title compound.
LC-MS (method 2): R1= 1.13 min; MS (ESIpos): m/z = 427 [M+H]
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.82 - 1.92 (m, 4H), 3.35 - 3.42 (m, 4H), 6.46 (d, 1H), 7.54 -7.6i (m, 2H), 8.11 (s, 1H), 8.22 (d, 1H), 8.61 (s, 1H), 12.63 (s, 1H).

Example 233 N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-N'-[(3-fluorooxetan-3-y1)methyl]urea H H.
F N
F
F F

F
/ I
N---N/
H
In analogy to intermediate 67, in two experiments using N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-N'-[(3-fluorooxetan-3-y1)methyl]urea (50 + 268 mg, 85 + 454 pmol, intermediate 261) were reacted with 1N tetra-N-butylammoniumfluoride in tetrahydrofurane (0.34 + 1.8 mL, 1.0 M, 0.34 +
1.8 mmol) and ethylenediamine (0.9 + 120 pL, 0.35 + 1.9 mmol) in DMF (1.0 +
5.4 mL) to give after purification via a Biotage chromatography system, a subsequent HPLC
chromatography followed by a preparative thin layer chromatography using dichloromethane /
methanol (8:2) 110 mg (95% purity, 43% yield) of the desired title compound.
LC-MS (method 2): Rt = 1.02 min; MS (ESIpos): m/z = 461 [M+H]
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 3.66 (dd, 2H), 4.55 -4.67 (m, 4H), 6.47 (d, 1H), 6.89 (t, 1H), 7.36 -7.42 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 9.22 (s, 1H), 12.63 (br s, 1H).
Example 234 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(2-hydroxy-2-methylpropyl)urea CH
H H.)C H3\_ 3 F

F F . N N 8 F-___,....s. F
/ I
N----N/
H
In analogy to example 77, 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(2-hydroxy-2-methylpropypurea (130 mg, 226 pmol, intermediate 262) was stirred with trifluoroacetic acid .. (1.6 mL, 20 mmol) in dichloromethane (3.1 mL). After purification using a Biotage chromatography system and a subsequent preparative HPLC we obtained 18.4 mg (90 %
purity, 16% yield) of the desired title compound.
LC-MS (method 2): Rt = 1.02 min; MS (ESIpos): rniz = 445 [M+H]
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.10 (s, 6H), 3.05 (d, 2H), 4.58 (s, 1H), 6.34 (t, 1H), 6.47 (d, 1H), 7.31 - 7.40 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 9.14 (s, 1H), 12.63 (br s, 1H).
Example 235 (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-342-hydroxy-2-methyl-3-(morpholin-4-y1)propyl]urea H H HO CH3r0 F
NNOc.N.) F - F F 01. 8 F
/ I
N''N/
H
In analogy to example 114, (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-342-hydroxy-2-methyl-3-(morpholin-4-y1)propyl]urea (230 mg, 348 pmol, intermediate 270) was stirred with trifluoroacetic acid (1.6 mL, 21 mmol) in dichloromethane (3.2 mL). After purification using a preparative HPLC (according to method 1), we obtained 55.8 mg (97 % purity, 29 % yield) of the desired title compound.
LC-MS (method 2): Rt = 1.05 min; MS (ESIpos): rniz = 530 [M+H]
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.07 (s, 3H), 2.08 - 2.09 (m, 2H), 2.20 -2.29 (m, 2H), 3.07 - 3.20 (m, 2H), 3.53 - 3.60 (m, 4H), 4.55 (s, 1H), 6.27 (t, 1H), 6.47 (d, 1H), 7.31 -7.38 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 9.16 (s, 1H), 12.63 (br s, 1H).
Example 236 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(3-hydroxy-3-methylbutypurea H H OH
F

F F 1.1 8 CH
F........) F
/ I
N--"N/
H

In analogy to example 77, 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-3-(3-hydroxy-3-methylbutypurea (110 mg, 187 pmol, intermediate 264) was stirred with trifluoroacetic acid (0.9 mL, 12 mmol) in dichloromethane (1.8 mL). After purification using a Biotage chromatography system (11 g snap KP-NH column, hexane /0 - 100% ethylacetate, then ethyl acetate /0 - 80% ethanol) followed by a preparative HPLC (according to method 1) we obtained 24.0 mg (95 % purity, 27 % yield) of the desired title compound.
LC-MS (method 2): Rt = 1.04 min; MS (ESIpos): m/z = 459 [M+H]
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.13 (s, 6H), 1.52- 1.59 (m, 2H), 3.16 -3.23 (m, 2H), 4.39 (s, 1H), 6.35 (t, 1H), 6.46 (d, 1H), 7.34 - 7.41 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 9.07 (s, 1H), 12.62 (br s, 1H).
Example 237 64({4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyllcarbamoyl)amino]-N-methylpyridazine-3-carboxamide H H
F N N N

F H N
/ I 'C H3 N----N/
H
In analogy example 178, 64({4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyllcarbamoyl)amino]-N-methylpyridazine-3-carboxamide (100 mg, 166 pmol, intermediate 265) was stirred with trifluoroacetic acid (640 pL, 8.3 mmol) in dichloromethane (1.1 mL, 17 mmol) to afford after preperative HPLC
purification the title compound (5 mg, 6 % yield).
LC-MS (method 2): Rt = 1.01 min; MS (ESIpos): m/z = 474 [M+H]
1H NMR (400 MHz, DMSO-c16) 6 ppm 2.85 (d, 3 H), 6.37 (d, 1 H), 7.50 (d, 2 H), 7.63 (d, 1 H), 8.11 (d, 1 H), 8.18 (d, 1 H), 8.25 - 8.31 (m, 1 H), 9.05 (q, 1 H), 9.93 (s, 1 H), 10.30 (s, 1 H), 12.15 (br d, 1 H) Example 238 1-(6-tert-butylpyridazin-3-yI)-3-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyllurea H H
F N N N
. 0 i<C H3 CI CH

/ I
NN/
H
In analogy to example 178, 1-(6-tert-butylpyridazin-3-y1)-3-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyllurea (100 mg, 166 pmol, intermediate 266) was stirred with trifluoroacetic acid (640 pL, 8.3 mmol) in dichloromethane (1.1 mL, 17 mmol) to afford after preperative HPLC
purification the title compound (5 mg, 6 % yield).
LC-MS (method 2): R1= 1.28 min; MS (ESIpos): rrilz = 473 [M+H]
1H NMR (400 MHz, DMSO-c16) 6 ppm 1.36 (s, 9 H), 6.36 (d, 1 H), 7.52 (d, 2 H), 7.62 (d, 1 H), 7.81 (d, 1 H), 7.94 (d, 1 H), 8.11 (d, 1 H), 9.89 (s, 1 H), 10.21 (s, 1 H), 12.15 (br s, 1 H) Example 239 64({4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyllcarbamoyl)amino]-N,N-dimethylpyridazine-3-carboxamide H H
F N y N N -N
. 0 0 CI
F N

N----N/
H
In analogy to example 178, 64({4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyllcarbamoyl)amino]-N,N-dimethylpyridazine-carboxamide (100 mg, 162 pmol, intermediate 267) was stirred with trifluoroacetic acid (620 pL, 8.1 mmol) in dichloromethane (1.0 mL, 16 mmol) to afford after preperative HPLC
purification the title compound (3 mg, 4 % yield).
LC-MS (method 2): Rt = 1.00 min; MS (ESIpos): rrilz = 488 [M+H]
1H NMR (400 MHz, DMSO-c16) 6 ppm 3.04 (s, 3 H), 3.05 (s, 3 H), 6.37 (d, 1 H), 7.52 (d, 2 H), 7.63 (d, 1 H), 7.85 (d, 1 H), 8.11 (d, 1 H), 8.19 (d, 1 H), 10.07 (s, 1 H), 10.21 (s, 1 H), 12.15 (br d, 1 H) Example 240 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-346-(trifluoromethyppyridazin-3-yl]urea H H
F . NY N N' CI 0 ' 0 i ,,I,,F<F
F
F
(I
NN/
H
In analogy to example 178, 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-346-(trifluoromethyppyridazin-3-yl]urea (20.0 mg, 32.5 pmol, intermediate 268) was stirred with trifluoroacetic acid (130 pL, 1.6 mmol) in dichloromethane (210 pL, 3.3 mmol) to afford after preperative HPLC
purification the title compound 1.60 mg (98% purity, 10% yield).
LC-MS (method 2): Rt = 1.21 min; MS (ESIpos): rrilz = 485 [M+H]
1H NMR (400 MHz, DMSO-c16) 6 ppm 6.37 (d, 1 H), 7.53 (d, 2 H), 7.63 (s, 1 H), 8.11 (d, 1 H), 8.20 (d, 1 H), 8.37 (d, 1 H), 9.91 (br d, 1 H), 10.53 (br s, 1 H), 12.15 (br s, 1 H) Example 241 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyll-346-(methylsulfonyl)pyridazin-3-yl]urea H H
F . N N N y -N
0 )Ls,:j Cl 0 / I
N----N/
H
In analogy to example 179, 1-{4-[(3-chloro-1-{[2-(trimethylsilypethoxy]methyll-1H-pyrrolo[2,3-b]pyridin-4-ypoxy]-3,5-difluorophenyll-346-(methylsulfonyl)pyridazin-3-yl]urea (90.0 mg, 144 pmol, intermediate 269) was stirred with trifluoroacetic acid (550 pL, 7.2 mmol) in dichloromethane (930 pL, 14 mmol) to afford after preperative HPLC
purification the title compound (1.2 mg, 2 % yield).
LC-MS (method 2): Rt = 0.99 min; MS (ESIpos): rrilz = 495 [M+H]
1H NMR (400 MHz, DMSO-c16) 6 ppm 3.36 (s, 3 H), 6.36 (d, 1 H), 7.57 (d, 2 H), 7.62 (s, 1 H), 7.98 - 8.06 (m, 1 H), 8.11 (d, 1 H), 8.35 (d, 1 H) Example 242 (+/-)-N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-N'-(2-fluoro-3-methoxypropypurea F
F 11\1111-\110C H 3 F F . 8 F-.....,.) F
/ I
N----N/
H
In analogy to example 1, (+/-)-N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-N'-(2-fluoro-3-methoxypropypurea (107 mg, 181 pmol, intermediate 270) was reacted with trifluoroacetic acid (900 pL, 12 mmol) in dichloromethane (1.8 mL) to obtain 62.0 mg (95% purity, 71 % yield) of the desired title compound.
LC-MS (method 2): R1= 1.07 min; MS (ESIpos): rrilz = 463 [M+H]
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 3.30 (s, 3H), 3.31 - 3.60 (m, 4H), 4.59 -4.79 (m, 1H), 6.47 (d, 1H), 6.66 (t, 1H), 7.34 - 7.42 (m, 2H), 8.09 -8.13 (m, 1H), 8.21 (d, 1H), 9.14 (s, 1H), 12.63 (br s, 1H).
Example 243 (+/-)-N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-N'-[(4,4-dimethyloxetan-2-y1)methyl]urea H H,,,,,CL C H 3 F NN
F F

F
/ I
1\1---N/
H
In analogy to example 67, (+/-)-N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-N'-[(4,4-dimethyloxetan-2-y1)methyl]urea (112 mg, 186 pmol, intermediate 271) was reacted with tetra-N-butylammonium fluoride in THF (750 pL, 1.0 M, 750 pmol) and ethylene diamine (51 pL, 760 pmol) in DMF (2.2 mL) to obtain 37.1 mg (92% purity, 39% yield) of the desired title compound.
LC-MS (method 2): Rt = 1.11 min; MS (ESIpos): rrilz = 471 [M+H]

11-I-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.33 (s, 3H), 1.38 (s, 3H), 2.14 (dd, 1H), 2.27 -2.34 (m, 1H), 3.29 (t, 2H), 4.49 - 4.57 (m, 1H), 6.47 (d, 1H), 6.57 (br t, 1H), 7.33 - 7.41 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 9.15 (s, 1H), 12.62 (br s, 1H).
Example 244 (+/-)-N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-N'-(2-fluoro-3-methoxy-2-methylpropypurea F F NN.)0 'C H3 F .¨k F ? . 8 F
N----N/
H
In analogy to example 1, (+/-)-N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-N'-(2-fluoro-3-methoxy-2-methylpropypurea (107 mg, 176 pmol, intermediate 272) was reacted with TFA
(900 pL, 12 mmol) in dichloromethane (1.8 mL) to obtain 60.6 mg (95% purity, 69% yield) of the desired title compound.
LC-MS (method 2): Rt = 1.11 min; MS (ESIpos): rrilz = 477 [M+H]
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.26 (d, 3H), 3.32 (s, 3H), 3.34 - 3.47 (m, 4H), 6.47 (d, 1H), 6.57 (t, 1H), 7.34 -7.41 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 9.05 (s, 1H), 12.63 (s, 1H).
Example 245 N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-N'-{[3-(hydroxymethyl)oxetan-3-yl]methyllurea OH
H H
F N N*0 F-, F F
/ I
N----N/
H
In analogy to example 67, N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-N'-{[3-(hydroxymethypoxetan-3-yl]methyllurea (65.5 mg, 109 pmol, intermediate 273) was reacted with (430 pL, 1.0 M, 430 pmol) and ethylene diamine (30 pL, 450 pmol) in DMF
(1.3 mL) to obtain 11.1 mg (95 % purity, 21 % yield) of the desired title compound.
LC-MS (method 2): Rt = 0.94 min; MS (ESIpos): rrilz = 473 [M+H]
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 3.36 - 3.41 (m, 2H), 3.59 (d, 2H), 4.26 -4.34 (m, 4H), .. 4.98 (t, 1H), 6.47 (d, 1H), 6.99 (br s, 1H), 7.36 - 7.43 (m, 2H), 8.11 (s, 1H), 8.21 (d, 1H), 9.48 (br s, 1H), 12.63 (br s, 1H).
Example 246 N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-N'-[(3-hydroxyoxetan-3-yl)methyl]urea F NN
F F

F
/ I
N--"N/
H
In analogy to example 67, N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-N'-[(3-hydroxyoxetan-3-y1)methyl]urea (50.9 mg, 86.5 pmol, intermediate 274) was reacted with (350 pL, 1.0 M, 350 pmol) and ethylene diamine (24 pL, 350 pmol) in DMF (1.0 mL) to obtain 8.4 mg (90 %
purity, 19% yield) of the desired title compound.
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 3.42 (d, 2H), 4.36 - 4.42 (m, 4H), 6.00 (s, 1H), 6.47 (d, 1H), 6.74 (t, 1H), 7.34 - 7.41 (m, 2H), 8.09 - 8.12 (m, 1H), 8.21 (d, 1H), 9.36 (s, 1H), 12.63 (br s, 1H).
Example 247 N-(2,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-N'-[(3-methyloxetan-3-y1)methyl]urea F
F F . N N
yo 0 F-C), F
/ I
N----N/
H

In analogy to intermediate 67, N-(2,5-difluoro-4-{[3-(trifluoromethyl)-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-N'-[(3-methyloxetan-3-y1)methyl]urea (120 mg, 205 pmol, intermediate 275) was reacted with 1N tetra-N-butylammoniumfluoride in tetrahydrofurane (820 pL, 1.0 M, 820 pmol) and ethylenediamine (56 pL, 840 pmol) in DMF (2.5 mL) to give after purification via a Biotage chromatography system and a subsequent HPLC chromatography 41.2 mg (95 % purity, 42 % yield) of the desired title compound.
LC-MS (method 2): Rt = 1.04 min; MS (ESIneg): rrilz = 455 [M-H]-1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.24 (s, 3H), 3.33 (d, 2H), 4.23 (d, 2H), 4.36 (d, 2H), 6.47 (d, 1H), 6.98 (t, 1H), 7.50 (dd, 1H), 8.10 (s, 1H), 8.20 (d, 1H), 8.26 (dd, 1H), 8.65 (s, 1H), 12.58 (br s, 1H).
Example 248 N-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)sulfanyl]-3,5-difluorophenyll-N'42-(morpholin-4-y1)-2-oxoethyl]urea H

=/10 )(-) H N.
S N
Br / I
N----N/
H
In analogy to example 1, N-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-y1)sulfanyl]-3,5-difluorophenyll-N'42-(morpholin-4-y1)-2-oxoethyl]urea (180 mg, 274 pmol, intermediate 280) was reacted with TFA (1.9 mL, 24 mmol) in dichloromethane (5.0 mL) to obtain 146 mg (90% purity, 91 % yield) of the desired title compound.
LC-MS (method 3): Rt = 1.02 min; MS (ESIneg): rrilz = 524 [M-H]-1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 3.39 - 3.49 (m, 4H), 3.59 (dt, 4H), 4.03 (d, 2H), 6.22 (d, 1H), 6.69 (t, 1H), 7.37 -7.42 (m, 2H), 7.71 (s, 1H), 7.99 (d, 1H), 9.73 (s, 1H), 12.21 (br s, 1H).

Example 249 N-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)sulfanyl]-3,5-difluorophenyll-W-(2-methoxyethypurea H
FNO
(101 H NO'C H 3 Br S
F
/ I
N----N/
H
In analogy to example 1, N-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-y1)sulfanyl]-3,5-difluorophenyll-W-(2-methoxyethypurea (160 mg, 272 pmol) intermediate 281) was reacted with TFA (1.8 mL, 24 mmol) in dichloromethane (5.0 mL) to obtain 100 mg (92% purity, 74% yield) of the desired title compound.
LC-MS (method 3): Rt = 1.08 min; MS (ESIpos): rrilz = 457 [M+H]
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 3.25 - 3.31 (m, 5H), 3.37 - 3.43 (m, 2H), 6.21 (d, 1H), 6.57 (t, 1H), 7.36 -7.42 (m, 2H), 7.71 (s, 1H), 8.00 (d, 1H), 9.33 (s, 1H), 12.21 (s, 1H).
Example 250 N-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)sulfanyl]-3,5-difluorophenyll-W-ethylurea H
FNO
. HNCH3 S
Br F
/ I
NN/
H
In analogy to example 77, N-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-y1)sulfanyl]-3,5-difluorophenyll-W-ethylurea (160 mg, 287 pmol, intermediate 282) was reacted with TFA (1.9 mL, 24 mmol) in dichloromethane (5.0 mL) to obtain 35 mg (97 %
purity, 28 % yield) of the desired title compound.
LC-MS (method 3): Rt = 1.11 min; MS (ESIpos): rrilz = 427 [M+H]
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.07 (t, 3H), 3.13 (dt, 2H), 6.21 (d, 1H), 6.53 (t, 1H), 7.38 - 7.44 (m, 2H), 7.71 (s, 1H), 8.00 (d, 1H), 9.28 (s, 1H), 12.20 (br s, 1H).

Example 251 N-{4-[(3-bromo-1 H-pyrrolo[2,3-b]pyrid in-4-yl)sulfanyI]-3,5-d ifl uorophenyllmorpholine-4-carboxamide H

(101 N
S
Br N----N/
H
In analogy to example 77, N-{4-[(3-bromo-1-{[2-(trimethylsilypethoxy]methy11-1H-pyrrolo[2,3-b]pyridin-4-y1)sulfanyl]-3,5-difluorophenyllmorpholine-4-carboxamide (185 mg, 309 pmol, intermediate 283) was reacted with TFA (2.1 mL, 27 mmol) in dichloromethane (5.0 mL) to obtain 66 mg (97 % purity, 44 % yield) of the desired title compound.
LC-MS (method 3): R1= 1.10 min; MS (ESIpos): rrilz = 469 [M+H]
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 3.44 - 3.50 (m, 4H), 3.60 - 3.66 (m, 4H), 6.20 (d, 1H), 7.49 - 7.55 (m, 2H), 7.71 (s, 1H), 8.00 (d, 1H), 9.25 (br s, 1H), 12.21 (br s, 1H).
Example 252 N-(3 ,5-d ifl uoro-4-{[3-(propan-2-yI)-1 H-pyrrolo[2,3-b]pyrid in-4-yl]oxylphenyI)-N'-[(3-fluorooxetan-3-yl)methyl]urea F NN
n F
H 3 . 0 H 3C --C?
F
N--"N/
H
To a solution of N-(3,5-difluoro-4-{[1-(4-methylbenzene-1-sulfony1)-3-(propan-2-y1)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylpheny1)-N'-[(3-fluorooxetan-3-y1)methyl]urea (250 mg, 425 pmol, intermediate 291) in methanol (7.0 mL) was added sodium hydroxide (34 mg, 849 pmol). The resulting mixture was stirred at room temperature overnight, at which time water and ethyl acetate were added and the layers were separated. The aqueous phase was extracted twice with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate and evaporated to give the crude product. The crude product was purified by preperative HPLC to afford the title compound (5 mg, 3% yield).
LC-MS (method 2): Rt = 1.11 min; MS (ESIpos): rrilz = 436 [M+H]

1H NMR (400 MHz, DMSO-d6) 6 ppm 1.32 (d, 6 H), 3.29 - 3.36 (m, 1 H), 3.65 (dd, 2 H), 4.56 -4.66 (m, 4 H), 6.19 (d, 1 H), 7.01 (br s, 1 H), 7.15 (s, 1 H), 7.39 (d, 2 H), 7.99 (d, 1 H), 9.34 (br s, 1 H), 11.46 (br s, 1 H) Example 253 N-(3 ,5-d ifl uoro-4-{[3-(3 ,3,3-trifluoropropyI)-1 H-pyrrolo[2,3-b]pyrid in-4-yl]oxylphenyI)-N'-[(3-fluorooxetan-3-yl)methyl]urea H H.$\) F F
F
NN/
H
In analogy to example 252, N-(3,5-difluoro-4-{[1-(4-methylbenzene-1-sulfonyI)-3-(3,3,3-trifluoropropyI)-1 H-pyrrolo[2,3-b]pyrid in-4-yl]oxylphenyI)-N '-[(3-fluorooxetan-3-yl)methyl]u rea (230 mg, 358 pmol, intermediate 295) was reacted with sodium hydroxide (28.6 mg, 716 pmol) in methanol (5.0 mL), to afford after preperative HPLC purification the title compound (13 mg, 7 % yield).
LC-MS (method 2): R1= 1.10 min; MS (ESIpos): rrilz = 489 [M+H]
1H NMR (400 MHz, DMSO-d6) 6 ppm 2.59 -2.73 (m, 2 H), 3.03 - 3.09 (m, 2 H), 3.66 (dd, 2 H), 4.61 (ddd, 4 H), 6.24 (d, 1 H), 6.79 (t, 1 H), 7.32 (d, 1 H), 7.39 (d, 2 H), 8.03 (d, 1 H), 9.10 (s, 1 H), 11.62 (d, 1 H) Example 254 (+/-)-N43,5-difluoro-4-({341,1,1-trifluoropropan-2-y1]-1H-pyrrolo[2,3-b]pyridin-4-ylloxy)phenyl]-N'-[(3-fluorooxetan-3-yl)methyl]urea H H.
F NN5\) F n F
F......-130 01 0 F F
/ I
N----N/
H
To a solution of (+/-)-N-{3 ,5-d ifl uoro-4-[(341,1,1-trifluoropropan-2-y1]-1-{[2-(tri methylsilypethoxy]methy11-1 H-pyrrolo[2,3-b]pyrid in-4-yl)oxy]phenyll-N'-[(3-fluorooxetan-3-yl)methyl]urea (600 mg, 50 % purity, 485 pmol, intermediate 298) in DMF (15 mL) was added DEMANDE OU BREVET VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.

NOTE : Pour les tomes additionels, veuillez contacter le Bureau canadien des brevets JUMBO APPLICATIONS/PATENTS
THIS SECTION OF THE APPLICATION/PATENT CONTAINS MORE THAN ONE
VOLUME

NOTE: For additional volumes, please contact the Canadian Patent Office NOM DU FICHIER / FILE NAME:
NOTE POUR LE TOME / VOLUME NOTE:

Claims (16)

Claims

1. A compounds of formula (l) in which X represents a nitrogen, a sulphur or an oxygene atom, Y represents a sulphur or an oxygene atom, R1 represents hydrogen, halogen, C1-C6-alkyl, halo-C1-C6-alkyl or cyano, R2 represents fluorine or chlorine, R3 represents hydrogen or C1-C6-alkyl, R4 represents hydrogen or represents C1-C6-alkyl-, which may optionally be mono-or polysubstituted by identical or different substituents from the group consisting of halogen, cyano, hydroxy, C1-C3-alkoxy-, -NH2, -NH-(C1-C6-alkyl), -N(C1-C6-alkyl)2, -NH-(C1-C6-alkyl)-C1-C6-alkoxy, C1-C6-alkyl-, C1-C6-alkoxy-, -S(=O)2NH2, -C(=O)-R9, -C(=O)NH-R x, -C(=O)-NR5R6, -NH-C(=O)-R9, -NH-S(=O)2-R9, -S(=O)2-R9, -S(=O)(=NR y)-R x, -S(=O)-R x, C3-C10-cycloalkyl- which itself may optionally be mono- or polysubstituted by dentical or different substituents from the group consisting of of halogen, cyano, nitro, hydroxy, amino, oxo, carboxy, C1-C6-alkyl-, C1-C6-alkoxy-, C1-C6-alkoxy-C1-C6-alkyl-, hydroxy-C1-C6-alkyl-, C1-C6-alkylamino-, C1-C6-alkylcarbonylamino-, amino-C1-C6-alkyl-, C1-C6-alkylamino-C1-C6-alkyl-, halo-C1-C6-alkyl-, halo-C1-C6-alkoxy-, C3-C10-cycloalkyl-, phenyl-, halophenyl-, phenyl-C1-C6-alkyl-, phenoxy-, pyridinyl-, -C(=O)-NR5R6, -NH-C(=O)-R3, -C(=O)-R7, -S(=O)2-NR5R6, -S(=O)-R3, -S(=O)(=NR5)-R6, -S(=O)2-R3, -NH-S(=O)2-R3, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, monocyclic heteroaryl- having 5 or 6 ring atoms which itself may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, cyano, nitro, carboxy, C1-C6-alkyl-, C1-C6-alkoxy-, C1-C6- alkoxy-C1-C6-alkyl-, hydroxy-C1-C6-alkyl-, C1-C6-alkylamino-, amino-C1-C6-alkyl-, C1-C6-alkylamino-C1-C6-alkyl, halo-C1-alkyl-, halo-C1-C6-alkoxy-, C3-C10-cycloalkyl and a monocyclic heterocyclyl radical having 3 to 8 ring atoms, monocyclic heterocyclyl- having 3 to 8 ring atoms which itself may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, cyano, oxo, carboxy, C1-C6-alkyl-, -carboxy-C1-C6-alkyl-, C1-C6-alkoxy-, C1-C6-alkoxy-C1-C6-alkyl-, C1-C6-alkylamino-, amino-C1-C6-alkyl-, C1-C6-alkylamino-C1-C6-alkyl-, hydroxy-C1-C6-alkyl-, halo-C1-C6-alkyl-, halo-C1-C6-alkoxy-, C3-C10-cycloalkyl-and a monocyclic heterocyclyl radical having 3 to 8 ring atoms, phenyl- which itself may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, cyano, nitro, carboxy, C1-C6-alkyl-, C1-C6-alkoxy-, C1-C6-alkoxy-C1-C6-alkyl-, C1-C6-alkyl-amino-, amino-C1-C6-alkyl-, C1-C6-alkylaminocarbonyl-, C1-C6-alkyl-aminosulphonyl-, C1-C6-alkylamino-C1-C6-alkyl-, hydroxy-C1-C6-alkyl-, halo-C1-C6-alkyl-, halo-C1-C6-alkoxy-, C3-C10-cycloalkyl- and a monocyclic heterocyclyl radical having 3 to 8 ring atoms, spirocycloalkyl, 5 to 12 membered heterospirocycloalkyl, bicycloalkyl-, heterobicycloalkyl-, bridged cycloalkyl or a bridged heterocycloalkyl, naphthyl or bicyclic heteroaryl, or partially saturated bicyclic aryl- or heteroaryl, each of which mentioned supra may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, cyano, nitro, hydroxy, amino, oxo, carboxy, C1-C6-alkyl-, C1-C6-alkoxy-, C1-C6-alkoxy-C1-C6-alkyl-, hydroxy-C1-C6-alkyl-, C1-C6-alkylamino-, C1-C6-alkylcarbonylamino-, amino-C1-C6-alkyl-, C1-C6-alkylamino-C1-C6-alkyl-, halo-C1-C6-alkyl-, halo-C1-C6-alkoxy-, C3-C10-cycloalkyl-, phenyl-, halophenyl-, phenyl-C1-C6-alkyl-, phenoxy-, pyridinyl-, -C(=O)-NR5R6, -NH-C(=O)-R8, -C(=O)-1R7, -S(=O)2-NR5R6, -S(=O)-R8, -S(=O)(=NR5)-R6, -S(=O)2-R8, -NH-S(=O)2-R8, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, or R4 represents C3-C10-cycloalkyl- which may optionally be mono- or polysubstituted by dentical or different substituents from the group consisting of of of halogen, cyano, nitro, hydroxy, amino, oxo, carboxy, C1-C6-alkyl-, C1-C6-alkoxy-, C1-C6-alkoxy-C1-C6-alkyl-, hydroxy-C1-C6-alkyl-, C1-C6-alkylamino-, C1-C6-alkylcarbonylamino-, amino-C1-C6-alkyl-, C1-C6-alkylamino-C1-C6-alkyl-, halo-C1-C6-alkyl-, halo-C1-C6-alkoxy-, C3-C10-cycloalkyl-, phenyl-, halophenyl-, phenyl-C1-C6-alkyl-, phenoxy-, pyridinyl-, -C(=O)-NR5R6, -NH-C(=O)-R8, -C(=O)-R7,-S(=O)2-NR5R6, -S(=O)-R8, -S(=O)(=NR5)-R6,-S(=O)2-R8, -NH-S(=O)2-R8, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, or represents monocyclic heteroaryl- having 5 or 6 ring atoms which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of of halogen, cyano, nitro, hydroxy, amino, carboxy, C1-C6-alkyl-, C1-C6-alkoxy-, C1-C6-alkoxy-C1-C6-alkyl-, hydroxy-C1-C6-alkyl-, C1-C6-alkylamino-, C1-C6-alkylcarbonylamino-, amino-C1-C6-alkyl-, C1-C6-alkylamino-C1-C6-alkyl-, halo-C1-C6-alkyl-, halo-C1-C6-alkoxy-, C3-C10-cycloalkyl-, phenyl-, halophenyl-, phenyl-C1-C6-alkyl-, phenoxy-, pyridinyl-, -C(=O)-NR5R6, -NH-C(=O)-R8, -C(=O)-R7,-S(=O)2-NR5R6, -S(=O)-R8, -S(=O)(=NR5)-R6,-S(=O)2-R8, -NH-S(=O)2-R8, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, or represents monocyclic heterocyclyl- having 3 to 8 ring atoms which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of of halogen, cyano, nitro, hydroxy, amino, oxo, carboxy, C1-C6-alkyl-, C1-C6-alkoxy-, C1-C6-alkoxy-C1-C6-alkyl-, hydroxy-C1-C6-alkyl-, C1-C6-alkylamino-, C1-C6-alkylcarbonylamino-, amino-C1-C6-alkyl-, C1-C6-alkylamino-C1-C6-alkyl-, halo-C1-C6-alkyl-, halo-C1-C6-alkoxy-, C3-C10-cycloalkyl-, phenyl-, halophenyl-, phenyl-C1-C6-alkyl-, phenoxy-, pyridinyl-, -C(=O)-NR5R6, -NH-C(=O)-R8, -C(=O)-R7, -S(=O)2-NR5R6, -S(=O)-R8, -S(=O)(=NR5)-R6, -S(=O)2-R8, -NH-S(=O)2-R8, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, or represents phenyl- which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of of halogen, cyano, nitro, hydroxy, amino, carboxy, C1-C6-alkyl-, C1-C6-alkoxy-, C1-C6-alkoxy-C1-alkyl-, hydroxy-C1-C6-alkyl-, C1-C6-alkylamino-, C1-C6-alkylcarbonylamino-, amino-C1-C6-alkyl-, C1-C6-alkylamino-C1-C6-alkyl-, halo-C1-C6-alkyl-, halo-C1-alkoxy-, C3-C10-cycloalkyl-, phenyl-, halophenyl-, phenyl-C1-C6-alkyl-, phenoxy-, pyridinyl-, -C(=O)-NR5R6, -NH-C(=O)-R8, -C(=O)-R7,-S(=O)2-NR5R6, -S(=O)-R8, -S(=O)(=NR5)-R6, -S(=O)2-R8, -NH-S(=O)2-R8, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, or represents a spirocycloalkyl radical, a 5 to 12 membered heterospirocycloalkyl radical, a bicycloalkyl, a heterobicycloalkyl radical, a bridged cycloalkyl radical or a bridged heterocycloalkyl radical, a naphthyl radical or a bicyclic heteroaryl radical, or a partially saturated bicyclic aryl- or heteroaryl radical, where the radicals mentioned may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of of halogen, cyano, nitro, hydroxy, amino, oxo, carboxy, C1-C6-alkyl-, C1-C6-alkoxy-, C1-C6-alkoxy-C1-C6-alkyl-, hydroxy-C1-C6-alkyl-, C1-C6-alkylamino-, C1-C6-alkylcarbonylamino-, amino-C1-C6-alkyl-, C1-C6-alkylamino-C1-C6-alkyl-, halo-C1-C6-alkyl-, halo-C1-alkoxy-, C3-C10-cycloalkyl-, phenyl-, halophenyl-, phenyl-C1-C6-alkyl-, phenoxy-, pyridinyl-, -C(=O)-NR5R6, -NH-C(=O)-R8, -C(=O)-R7, -S(=O)2-NR5R6, -S(=O)-R8, -S(=O)(=NR5)-R6, -S(=O)2-R8, -NH-S(=O)2-R8, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, or R3 and R4 together with the nitrogen atom form a 4 to 10 membered heterocycloalkyl or a to 12 membered heterospirocycloalkyl, which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of of halogen, cyano, nitro, hydroxy, amino, oxo, carboxy, C1-C6-alkyl-, C1-C6-alkoxy-, C1-C6-alkoxy-C1-C6-alkyl-, hydroxy-C1-C6-alkyl-, C1-C6-alkylamino-, C1-C6-alkylcarbonylamino-, amino-C1-C6-alkyl-, C1-C6-alkylamino-C1-C6-alkyl-, halo-C1-C6-alkyl-, halo-C1-C6-alkoxy-, C3-C10-cycloalkyl-, phenyl-, halophenyl-, phenyl-C1-C6-alkyl-, phenoxy-, pyridinyl-, -C(=O)-NR5R6, -NH-C(=O)-R8, -C(=O)-R7, -S(=O)2-NR5R6, -S(=O)-R8, -S(=O)(=NR5)-R6, -S(=O)2-R8, -NH-S(=O)2-R8, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, R5 and R6 independently of one another represent hydrogen, C1-C3-alkyl-, cyclopropyl- or di-C1-C3-alkylamino-C1-C3-alkyl-, or R5 and R6 together with the nitrogen atom form a monocyclic heterocyclyl-having 3 to 8 ring atoms which itself may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, cyano, oxo, C1-C6-alkyl-, C1-C6-alkoxy-, C1-C6-alkylamino-, halo-C1-C6-alkyl-, halo-C1-C6-alkoxy-, R7 represents hydroxy, C1-C6-alkyl-, C1-C6-alkoxy-, halo-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, C3-C8-cycloalkyl-, phenyl-, monocyclic heterocyclyl- having 3 to 8 ring atoms or monocyclic heteroaryl- having 5 or 6 ring atoms where phenyl-, heteroaryl- and heterocyclyl- may optionally be mono- or disubstituted by halogen, C1-C3-alkoxy- or C1-C3-alkyl-, R8 represents C1-C6-alkyl-, R9 represents C1-C6-alkyl-, -NH2, -NH-C1-C6-alkyl, -N(C1-C6-alkyl)2, or C1-C6-alkoxy-C1-C6-alkyl-, or represents monocyclic heterocyclyl- having 3 to 8 ring atoms which itself may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of of halogen, cyano, nitro, hydroxy, amino, oxo, carboxy, C1-C6-alkyl-, C1-C6-alkoxy-, C1-C6-alkoxy-C1-C6-alkyl-, hydroxy-C1-C6-alkyl-, C1-C6-alkylamino-, C1-C6-alkylcarbonylamino-, amino-C1-C6-alkyl-, C1-C6-alkylamino-C1-C6-alkyl-, halo-C1-C6-alkyl-, halo-C1-C6-alkoxy-, C3-Cio-cycloalkyl-, phenyl-, halophenyl-, phenyl-C1-C6-alkyl-, phenoxy-, pyridinyl-, -C(=O)-NR5R6, -NH-C(=O)-R8, -C(=O)-R7, -S(=O)2-NR5R6, -S(=O)-R8, -S(=O)(=NR5)-R6, -S(=O)2-R8, -NH-S(=O)2-R8, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, R x represents C1-C6-alkyl- or C1-C6-alkoxy-C1-C6-alkyl-, R y represents hydrogen, halo-C1-C6-alkyl, C1-C6-alkyl, C1-C6-alkyl substituted with C3-C6-cycloalkyl, and their polymorphs, enantiomers, diastereomers, racemates, tautomers, solvates, physiologically acceptable salts and solvates of these salts.

2. Compounds of formula (l), according to claim 1, in which X represents an oxygene atom, Y represents a sulphur or an oxygene atom, R1 represents hydrogen, halogen, C1-C6-alkyl, halo-C1-C6-alkyl and cyano, R2 represents fluorine, R3 represents hydrogen or C1-C6-alkyl, R4 represents hydrogen or represents C1-C6-alkyl-, which may optionally be mono- or disubstituted by identical or different substituents from the group consisting of halogen, cyano, hydroxy, C1-C3-alkoxy-, -NH2, -NH-(C1-C6-alkyl), -N(C1-C6-alkyl)2, -NH-(C1-C6-alkyl)-C1-C6-alkoxy, C1-C6-alkyl-, C1-C6-alkoxy-, -S(=O)2NH2, -C(=O)-R9, -C(=O)NH-R x, -NH-C(=O)-R9, -NH-S(=O)2-R9, -S(=O)2-R9, -S(=O)(=NR y)-R x, -S(=O)-R x, C3-C10-cycloalkyl-, monocyclic heteroaryl- having 5 or 6 ring atoms which itself may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, cyano, nitro, hydroxy, amino, carboxy, C1-C6-alkyl-, C1-C6-alkoxy-, C1-C6-alkoxy-C1-C6-alkyl-, hydroxy-C1-C6-alkyl-, C1-C6-alkylamino-, C1-C6-alkylcarbonylamino-, amino-C1-C6-alkyl-, C1-C6-alkylamino-C1-C6-alkyl-, halo-C1-C6-alkyl-, halo-C1-C6-alkoxy-, C3-C10-cycloalkyl-, phenyl-, halophenyl-, phenyl-C1-C6-alkyl-, phenoxy-, pyridinyl-, -C(=O)-NR5R6, -NH-C(=O)-R8, -C(=O)-R7, -S(=O)2-NR5R6, -S(=O)-R8, -S(=O)(=NR5)-R6, -S(=O)2-R8, -NH-S(=O)2-R8, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, monocyclic heterocyclyl- having 4 to 8 ring atoms which itself may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, cyano, nitro, hydroxy, amino, oxo, carboxy, C1-C6-alkyl-, C1-C6-alkoxy-, C1-C6-alkoxy-C1-C6-alkyl-, hydroxy-C1-C6-alkyl-, C1-C6-alkylamino-, C1-C6-alkylcarbonylamino-, amino-C1-C6-alkyl-, C1-C6-alkylamino-C1-C6-alkyl-, halo-C1-C6-alkyl-, halo-C1-C6-alkoxy-, C3-C10-cycloalkyl-, phenyl-, halophenyl-, phenyl-C1-C6-alkyl-, phenoxy-, pyridinyl-, -C(=O)-NR5R6, -NH-C(=O)-R8, -C(=O)-R7,-S(=O)2-NR5R6, -S(=O)-R8, -S(=O)(=NR5)-R6, -S(=O)2-R8, -NH-S(=O)2-R8, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, phenyl- which itself may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, cyano, nitro, hydroxy, amino, carboxy, C1-C6-alkyl-, C1-C6-alkoxy-, C1-C6-alkoxy-C1-C6-alkyl-, hydroxy-C1-C6-alkyl-, C1-C6-alkylamino-, C1-C6-alkylcarbonylamino-, amino-C1-C6-alkyl-, C1-C6-alkylamino-C1-C6-alkyl-, halo-C1-C6-alkyl-, halo-C1-C6-alkoxy-, C3-C10-cycloalkyl-, phenyl-, halophenyl-, phenyl-C1-C6-alkyl-, phenoxy-, pyridinyl-, -C(=O)-NR5R6, -NH-C(=O)-R8, -C(=O)-R7,-S(=O)2-NR5R6, -S(=O)-R8, -S(=O)(=NR5)-R6, -S(=O)2-R8, -NH-S(=O)2-R8, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, spirocycloalkyl-, heterospirocycloalkyl-, bicycloalkyl-, heterobicycloalkyl-, bridged cycloalkyl or a bridged heterocycloalkyl, naphthyl or bicyclic heteroaryl, or partially saturated bicyclic aryl- or heteroaryl, each of which mentioned may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, cyano, nitro, hydroxy, amino, oxo, carboxy, C1-C6-alkyl-, C1-C6-alkoxy-, C1-C6-alkoxy-C1-C6-alkyl-, hydroxy-C1-C6-alkyl-, C1-C6-alkylamino-, C1-C6-alkylcarbonylamino-, amino-C1-C6-alkyl-, C1-C6-alkylamino-C1-C6-alkyl-, halo-C1-C6-alkyl-, halo-C1-C6-alkoxy-, C3-C10-cycloalkyl-, phenyl-, halophenyl-, phenyl-C1-C6-alkyl-, phenoxy-, pyridinyl-, -C(=O)-NR5R6, -NH-C(=O)-R8, -C(=O)-R7, -S(=O)2-NR5R6, -S(=O)-R8, -S(=O)(=NR5)-R6, -S(=O)2-R8, -NH-S(=O)2-R8, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, or R4 represents monocyclic heterocyclyl- having 3 to 8 ring atoms which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, cyano, nitro, hydroxy, amino, oxo, carboxy, C1-C6-alkyl-, C1-C6-alkoxy-, C1-C6-alkoxy-C1-C6-alkyl-, hydroxy-C1-C6-alkyl-, C1-C6-alkylamino-, C1-C6-alkylcarbonylamino-, amino-C1-C6-alkyl-, C1-C6-alkylamino-C1-C6-alkyl-, halo-C1-C6-alkyl-, halo-C1-C6-alkoxy-, C3-C10-cycloalkyl-, phenyl-, halophenyl-, phenyl-C1-C6-alkyl-, phenoxy-, pyridinyl-, -C(=O)-NR5R6, -NH-C(=O)-R8, -C(=O)-R7, -S(=O)2-NR5R6, -S(=O)-R8, -S(=O)(=NR5)-R6, -S(=O)2-R8, -NH-S(=O)2-R8, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, or represents phenyl- which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, cyano, nitro, hydroxy, amino, carboxy, C1-C6-alkyl-, C1-C6-alkoxy-, C1-C6-alkoxy-C1-C6-alkyl-, hydroxy-C1-C6-alkyl-, C1-C6-alkylamino-, C1-C6-alkylcarbonylamino-, amino-C1-C6-alkyl-, C1-C6-alkylamino-C1-C6-alkyl-, halo-C1-C6-alkyl-, halo-C1-C6-alkoxy-, C3-C10-cycloalkyl-, phenyl-, halophenyl-, phenyl-C1-C6-alkyl-, phenoxy-, pyridinyl-, -C(=O)-NR5R6, -NH-C(=O)-R8, -C(=O)-R7, -S(=O)2-NR5R6, -S(=O)-R8, -S(=O)(=NR5)-R6, -S(=O)2-R8, -NH-S(=O)2-R8, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, or R3 and R4 together with the nitrogen atom form a 4 to 10 membered heterocycloalkyl ring, which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, cyano, nitro, hydroxy, amino, oxo, carboxy, C1-C6-alkyl-, C1-C6-alkoxy-, C1-C6-alkoxy-C1-C6-alkyl-, hydroxy-C1-C6-alkyl-, C1-C6-alkylamino-, C1-C6-alkylcarbonylamino-, amino-C1-C6-alkyl-, C1-C6-alkylamino-C1-C6-alkyl-, halo-C1-C6-alkyl-, halo-C1-C6-alkoxy-, C3-C10-cycloalkyl-, phenyl-, halophenyl-, phenyl-C1-C6-alkyl-, phenoxy-, pyridinyl-, -C(=O)-NR5R6, -NH-C(=O)-R8, -C(=O)-R7, -S(=O)2-NR5R6, -S(=O)-R8, -S(=O)(=NR5)-R6, -S(=O)2-R8, -NH-S(=O)2-R8, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, or together with the nitrogen atom form a heterospirocycloalkyl or heterobicycloalkyl group, each of which mentioned may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, cyano, nitro, hydroxy, amino, oxo, carboxy, C1-C6-alkyl-, C1-C6-alkoxy-, C1-C6-alkoxy-C1-C6-alkyl-, hydroxy-C1-C6-alkyl-, C1-C6-alkylamino-, C1-C6-alkylcarbonylamino-, amino-C1-C6-alkyl-, C1-C6-alkylamino-C1-C6-alkyl-, halo-C1-C6-alkyl-, halo-C1-C6-alkoxy-, C3-C410-cycloalkyl-, phenyl-, halophenyl-, phenyl-C1-C6-alkyl-, phenoxy-, pyridinyl-, -C(=O)-NR5R6, -NH-C(=O)-R8, -C(=O)-R7, -S(=O)2-NR5R6, -S(=O)-R8, -S(=O)(=NR5)-R6, -S(=O)2-R8, -NH-S(=O)2-R8, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, R5 and R6 independently of one another represent hydrogen, C1-C3-alkyl-, cyclopropyl- or di-C1-C3-alkylamino-C1-C3-alkyl-, R7 represents hydroxy, C1-C6-alkyl-, C1-C6-alkoxy-, halo-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, C3-C8-cycloalkyl-, phenyl-, monocyclic heterocyclyl- having 3 to 8 ring atoms or monocyclic heteroaryl- having 5 or 6 ring atoms where phenyl-, heteroaryl- and heterocyclyl- may optionally be mono- or disubstituted by halogen, C1-C3-alkoxy- or C1-C3-alkyl-, R8 represents C1-C6-alkyl-, R9 represents C1-C6-alkyl-, -NH2, -NH-C1-C6-alkyl, -N(C1-C6-alkyl)2, alkoxy-C1-C6-alkyl-, or represents monocyclic heterocyclyl- having 3 to 8 ring atoms which itself may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, cyano, nitro, hydroxy, amino, oxo, carboxy, C1-C6-alkyl-, C1-C6-alkoxy-, C1-C6-alkoxy-C1-C6-alkyl-, hydroxy-C1-C6-alkyl-, C1-C6-alkylamino-, C1-C6-alkylcarbonylamino-, amino-C1-C6-alkyl-, C1-C6-alkylamino-C1-C6-alkyl-, halo-C1-C6-alkyl-, halo-C1-C6-alkoxy-, C3-C10-cycloalkyl-, phenyl-, halophenyl-, phenyl-C1-C6-alkyl-, phenoxy-, pyridinyl-, -C(=O)-NR5R6, -NH-C(=O)-R8, -C(=O)-R7, -S(=O)2-NR5R6, -S(=O)-R8, -S(=O)(=NR5)-R6, -S(=O)2-R8, -NH-S(=O)2-R8, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, R x represents C1-C6-alkyl- or C1-C6-alkoxy-C1-C6-alkyl-, R y represents hydrogen, halo-C1-C6-alkyl, C1-C6-alkyl, C1-C6-alkyl substituted with C3-C6-cycloalkyl, and their polymorphs, enantiomers, diastereomers, racemates, tautomers, solvates, physiologically acceptable salts and solvates of these salts.

3. Compounds of formula (l), according to claim 1 or 2, in which X represents a sulphur or an oxygene atom, Y represents a sulphur or an oxygene atom, R1 represents hydrogen, halogen, C1-C6-alkyl, halo-C1-C6-alkyl or cyano, R2 represents fluorine, R3 represents hydrogen or C1-C6-alkyl, R4 represents hydrogen or represents C1-C6-alkyl-, which may optionally be mono-or polysubstituted by identical or different substituents from the group consisting of halogen, cyano, hydroxy, C1-C3-alkoxy-, -N(C1-C6-alkyl)2, -C(=O)-R9, -C(=O)NH-R x, -C(=O)-NR5R6, -NH-C(=O)-R9, -NH-S(=O)2-R9 or -S(=O)2-R9, or a C3-C10-cycloalkyl- which itself may optionally substituted by hydroxy, or a monocyclic heteroaryl- having 5 or 6 ring atoms which itself may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of cyano, C1-C6-alkyl-, C1-C6-alkoxy- or C1-C6-alkoxy-C1-C6-alkyl-, or a monocyclic heterocyclyl- having 3 to 8 ring atoms which itself may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, hydroxyl, carboxy, C1-C6-alkyl- or hydroxy-C1-C6-alkyl-, or a phenyl, 5 to 12 membered heterospirocycloalkyl or partially saturated bicyclic heteroaryl, each of which mentioned supra may optionally be substituted by -C(=O)-NR5R6, or R4 represents a C3-C10-cycloalkyl- which may optionally substituted by -C(=O)-NR5R6 or C1-C6-alkoxy-C1-C6-alkyl-or represents a monocyclic heteroaryl- having 5 or 6 ring atoms which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, C1-C6-alkyl-, halo-C1-C6-alkyl-, C3-C10-cycloalkyl-,-C(=O)-NR5R6, -S(=O)2-R8 or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, or represents a monocyclic heterocyclyl- having 3 to 8 ring atoms which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, oxo, C1-C6-alkylamino-C1-C6-alkyl or monocyclic heterocyclyl radical having 3 to 8 ring atoms or represents a phenyl- which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, C1-C6-alkoxy- or halo-C1-C6-alkyl-, or represents a 5 to 12 membered heterospirocycloalkyl radical, or a bridged heterocycloalkyl radical, or R3 and R4 together with the nitrogen atom form a 4 to 10 membered heterocycloalkyl or a to 12 membered heterospirocycloalkyl, which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, C1-C6-alkyl-, C1-C6-alkoxy- or hydroxy-C1-C6-alkyl-, R5 and R6 independently of one another represent hydrogen or C1-C3-alkyl-, R5 and R6 together with the nitrogen atom form a monocyclic heterocyclyl-having 3 to 8 ring atoms which itself may optionally be substituted by C1-C6-alkyl-, R8 represents C1-C6-alkyl-, R9 represents C1-C6-alkyl- or -NH2, R x represents C1-C6-alkoxy-C1-C6-alkyl-, and their polymorphs, enantiomers, diastereomers, racemates, tautomers, solvates, physiologically acceptable salts and solvates of these salts.

4. Compounds of formula (l), according to any one of claim 1 to 3, in which X represents a sulphur or an oxygene atom, Y represents a sulphur or an oxygene atom, R1 represents hydrogen, halogen, C1-C6-alkyl, halo-C1-C6-alkyl or cyano, R2 represents fluorine, R3 represents hydrogen or C1-C3-alkyl, R4 represents hydrogen or represents C1-C6-alkyl-, which may optionally be mono-or polysubstituted by identical or different substituents from the group consisting of halogen, cyano, hydroxy, C1-C3-alkoxy-, -N(C1-C3-alkyl)2, -C(=O)-R9, -C(=O)NH-R x, -C(=O)-NR5R6, -NH-C(=O)-R9, -NH-S(=O)2-R9, -S(=O)2-R9, or a C3-C7-cycloalkyl- which itself may optionally substituted by hydroxy, or a monocyclic heteroaryl- having 5 or 6 ring atoms which itself may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of cyano, C1-C6-alkyl-, C1-C6-alkoxy- or C1-C6-alkoxy-C1-C6-alkyl-, or a monocyclic heterocyclyl- having 4 to 6 ring atoms which itself may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, hydroxyl, carboxy, C1-C6-alkyl- or hydroxy-C1-C6-alkyl-, or a phenyl, 7 to 9 membered heterospirocycloalkyl or partially saturated bicyclic heteroaryl, each of which mentioned supra may optionally be substituted by -C(=O)-NR5R6, or R4 represents a C3-C7-cycloalkyl- which may optionally substituted by -C(=O)-NR5R6 or C1-C6-alkoxy-C1-C6-alkyl-or represents a monocyclic heteroaryl- having 5 or 6 ring atoms which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, C1-C3-alkyl-, halo-C1-C3-alkyl-, C3-C7-cycloalkyl-, -C(=O)-NR5R6, -S(=O)2-R8 or a monocyclic heterocyclyl radical having 4 to 6 ring atoms, or represents a monocyclic heterocyclyl- having 4 to 6 ring atoms which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, oxo, C1-C3-alkylamino-C1-C3-alkyl or monocyclic heterocyclyl radical having 4 to 6 ring atoms or represents a phenyl- which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, C1-C3-alkoxy- or halo-C1-C3-alkyl-, or represents a 7 to 9 membered heterospirocycloalkyl radical, or a bridged heterocycloalkyl radical, or R3 and R4 together with the nitrogen atom form a 4 to 6 membered heterocycloalkyl or a 7 to 9 membered heterospirocycloalkyl, which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, C1-C3-alkyl-, C1-C3-alkoxy-, hydroxy-C1-C3-alkyl-, R5 and R6 independently of one another represent hydrogen or C1-C3-alkyl-, R5 and R6 together with the nitrogen atom form a monocyclic heterocyclyl-having 4 to 6 ring atoms which itself may optionally be substituted by C1-C3-alkyl-, R3 represents C1-C3-alkyl-, R9 represents C1-C3-alkyl- or -NH2, R x represents C1-C3-alkoxy-C1-C3-alkyl-, and their polymorphs, enantiomers, diastereomers, racemates, tautomers, solvates, physiologically acceptable salts and solvates of these salts.

5. Compounds of formula (l), according to any one of claims 1 to 4, in which X represents an oxygene atom, Y represents a sulphur or an oxygene atom, R1 represents hydrogen, chlorine, bromine, methyl-, trifluoromethyl and cyano, R2 represents fluorine, R3 represents hydrogen or methyl, R4 represents hydrogen, C1-C6-alkyl-, which may optionally be mono- or disubstituted by identical or different substituents from the group consisting of halogen, cyano, hydroxy, C1-C3-alkoxy-, -NH2, -NH-(C1-C6-alkyl), -N(C1-C6-alkyl)2, -NH-(C1-C6-alkyl)-C1-C6-alkoxy, C1-C6-alkyl-, C1-C6-alkoxy-, -S(=O)2NH2, -C(=O)-R9, -C(=O)-NH-R9, -NH-C(=O)-R x, -NH-S(=O)2-R9, -S(=O)2-R9, or R4 represents or R3 and R4 together with the nitrogen atom form the group R9 represents methyl, -NH2 or -CH2-CH2-O-CH3 or R x represents methyl or -CH2-CH2-O-CH3, R10 represents hydrogen, methyl, methoxy and cyano R11 represents hydrogen and trifluoromethyl, R12 represents hydrogen, fluorine and methoxy, R13 represents hydrogen and methyl, R14 represents hydrogen and -CH2-O-CH3, where "*" denotes the point of attachment to the remainder of the molecule, and their polymorphs, enantiomers, diastereomers, racemates, tautomers, solvates, physiologically acceptable salts and solvates of these salts.

6. Compounds of formula (l), according to any one of claims 1 to 5, in which X represents an oxygene atom, Y represents an oxygene atom, R1 represents hydrogen, chlorine, bromine, methyl-, trifluoromethyl and cyano, R2 represents fluorine, R3 represents hydrogen or methyl, R4 represents hydrogen, C1-C6-alkyl-, which may optionally be mono- or disubstituted by identical or different substituents from the group consisting of halogen, cyano, hydroxy, C1-C3-alkoxy-, -NH2, -NH-(C1-C6-alkyl), -N(C1-C6-alkyl)2, -NH-(C1-C6-alkyl)-C1-C6-alkoxy, C1-C6-alkyl-, C1-C6-alkoxy-, -S(=O)2NH2, -C(=O)-R9, -C(=O)NH-R x, -NH-C(=O)-R9, -NH-S(=O)2-R9, -S(=O)2-R9, or R4 represents or R3 and R4 together with the nitrogen atom form the group R9 represents methyl, -NH2 or -CH2-CH2-O-CH3 or R x represents methyl or -CH2-CH2-O-CH3, R10 represents hydrogen, methyl, methoxy and cyano R11 represents hydrogen and trifluoromethyl, R12 represents hydrogen, fluorine and methoxy, R13 represents hydrogen and methyl, R14 represents hydrogen and -CH2-O-CH3, where "*" denotes the point of attachment to the remainder of the molecule, and their polymorphs, enantiomers, diastereomers, racemates, tautomers, solvates, physiologically acceptable salts and solvates of these salts.

7. Compounds of formula (l), according to any one of claims 1 to 6, in which X represents an oxygene atom, Y represents an oxygene atom, R1 represents chlorine, bromine, cyano and trifluoromethyl, R2 represents fluorine, R3 represents hydrogen, R4 represents hydrogen, C1-C6-alkyl-, which may optionally be mono- or disubstituted by identical or different substituents from the group consisting of halogen, cyano, hydroxy, C1-C3-alkoxy-, -NH2, -NH-(C1-C6-alkyl), -N(C1-C6-alkyl)2, -NH-(C1-C6-alkyl)-C1-C6-alkoxy, C1-C6-alkyl-, C1-C6-alkoxy-, -S(=O)2NH2, -C(=O)-R9, -C(=O)NH-R x, -NH-C(=O)-R9, -NH-S(=O)2-R9, -S(=O)2-R9, or or R4 represents R9 represents methyl, -NH2 or -CH2-CH2-O-CH3 or R x represents methyl or -CH2-CH2-O-CH3, R10 represents hydrogen, R13 represents hydrogen, where "*" denotes the point of attachment to the remainder of the molecule, and their polymorphs, enantiomers, diastereomers, racemates, tautomers, solvates, physiologically acceptable salts and solvates of these salts.

8. Compounds of formula (l), according to any of the former claims as follows:
- 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-[3-(morpholin-4-yl)propyl]urea;
- 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-(2-methoxyethyl)urea;
- 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-[3-(methylsulfonyl)propyl]urea;
- 1-(2,2-difluoroethyl)-3-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)urea;
- N3-[(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)carbamoyl]-beta-alaninamide;
- 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-(pyridin-4-ylmethyl)urea;
- 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-[(1-hydroxycyclopropyl)methyl]urea;
- 4-{[(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)carbamoyl]amino}butanamide;
- 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-(3-methoxypropyl)urea;
- 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-[2-(morpholin-4-yl)-2-oxoethyl]urea;
- 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-(pyridin-3-ylmethyl)urea;
- 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-(pyridin-2-ylmethyl)urea;
- 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-[2-(pyridin-4-yl)ethyl]urea;
- (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-[2-hydroxy-3-(morpholin-4-yl)propyl]urea;
- (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-(tetrahydrofuran-2-ylmethyl)urea;
- 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-(tetrahydro-2H-pyran-4-ylmethyl)urea;
- 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-(1H-1,2,3-triazol-5-ylmethyl)urea;

- N2-[(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)carbamoyl]glycinamide;
- 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-[2-(morpholin-4-yl)ethyl]urea;
- 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-[2-(piperidin-1-yl)ethyl]urea;
- 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-[3-(piperidin-1-yl)propyl]urea;
- 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-[3-(dimethylamino)propyl]urea;
- 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-[2-(dimethylamino)ethyl]urea;
- 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-[(1,1-dioxidothietan-3-yl)methyl]urea;
- N-(2-{[(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)carbamoyl]amino}ethyl)acetamide;
- (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-[1-(morpholin-4-yl)propan-2-yl]urea;
- (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-[2-(morpholin-4-yl)propyl]urea;
- 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-[2-(methylsulfonyl)ethyl]urea;
- 3-{[(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)carbamoyl]amino}propane-1-sulfonamide;
- 3-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-1-methyl-1-[2-(morpholin-4-yl)ethyl]urea;
- N-(2-{[(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)carbamoyl]amino}ethyl)methanesulfonamide;
- 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-pyridin-3-ylurea;
- 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-[3-(trifluoromethyl)phenyl]urea;
- 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-(1,3,4-thiadiazol-2-yl)urea;

- 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea;
- 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-pyridazin-3-ylurea;
- 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-(2-methoxyphenyl)urea;
- 1-(2,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-[3-(morpholin-4-yl)propyl]urea;
- 1-(2,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-[2-(morpholin-4-yl)ethyl]urea;
- 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-[3-(piperidin-1-yl)propyl]urea;
- 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-[2-(dimethylamino)ethyl]urea;
- 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-[2-(piperidin-1-yl)ethyl]urea;
- 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-[3-(morpholin-4-yl)propyl]urea;
- 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-(2-methoxyethyl)urea;
- 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-ethylurea;
- 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-[2-(morpholin-4-yl)ethyl]urea;
- 1-benzyl-3-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}urea - 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-(pyrimidin-5-ylmethyl)urea;
- 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-(pyridin-4-ylmethyl)urea;
- 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-(2-cyanoethyl)urea;
- 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-(3-methylbutyl)urea;
- 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-(1,2-oxazol-3-yl)urea;

- 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-pyridazin-3-ylurea;
- 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}urea;
- N-{2-[({4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}carbamoyl)-amino]ethyl}acetamide;
- 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-[2-(dimethylamino)ethyl]urea;
- 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-[3-(dimethylamino)propyl]urea;
- 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-butylurea;
- 1-benzyl-3-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}urea;
- 1-(2,3-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-[3-(morpholin-4-yl)propyl]urea;
- 1-(2,3-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-[2-(morpholin-4-yl)ethyl]urea;
- 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-[2-(dimethylamino)ethyl]thiourea;
- 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-[2-(morpholin-4-yl)ethyl]thiourea;
- 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-(2-methoxyethyl)thiourea;
- 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-ethylthiourea and - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-[3-(morpholin-4-yl)propyl]thiourea, 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-(oxetan-3-ylmethyl)urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-methylurea - 3-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-1,1-dimethylurea - N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)morpholine-4-carboxamide - N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-4-methylpiperazine-1 -carboxamide - 1 -(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-342-(4-methylpiperazin-1-yl)-2-oxoethyl]urea - N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide - N2-[(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)carbamoyl]-N-methylglycinamide - 1 -(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-(1 ,2-thiazol-4-yl)urea - 1 -(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-(1 -methyl-1H-pyrazol-4-yl)urea - 1 -(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-(6-methylpyridin-3-yl)urea - 1 -[(1 -acetylazetidin-3-yl)methyl]-3-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)urea - N2-[(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)carbamoyl]-N-(2-methoxyethyl)glycinamide - (+/-)-1 -(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-[(1 ,1-dioxidothietan-2-yl)methyl]urea - 1 -(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-(2-methylpyrimidin-5-yl)urea - 1 -(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-(1H-pyrazol-4-yl)urea - 1 -(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-[2-(1-oxa-6-azaspiro[3.3]hept-6-yl)ethyl]urea - 1 -(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-[2-(1 ,1-dioxido-1-thia-6-azaspiro[3.3]hept-6-yl)ethyl]urea - (+/-)-1 -(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-(2-oxopyrrolidin-3-yl)urea - (+/-)-1 -(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-(1 ,1-dioxidotetrahydrothiophen-3-yl)urea - (+/-)-1 -(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-(5-oxopyrrolidin-3-yl)urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-(1H-pyrazol-3-ylmethyl)urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-(1H-imidazol-2-ylmethyl)urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-[(1-methyl-1H-pyrazol-3-yl)methyl]urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-(1,3-thiazol-2-ylmethyl)urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-(pyrimidin-4-ylmethyl)urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-[(2-methylpyridin-4-yl)methyl]urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-(pyridazin-3-ylmethyl)urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-[(5-methyl-1H-imidazol-2-yl)methyl]urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-{[3-(methoxymethyl)-1,2,4-oxadiazol-5-yl]methyl}urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-[(5-methyl-4H-1,2,4-triazol-3-yl)methyl]urea - (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-(tetrahydrofuran-3-yl)urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-[(3R)-tetrahydrofuran-3-yl]urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-[(3S)-tetrahydrofuran-3-yl]urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-{3-[(2R,6R)-2,6-dimethylmorpholin-4-yl]propyl}urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-[(1-methyl-1H-imidazol-2-yl)methyl]urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-[(2-methoxypyridin-4-yl)methyl]urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-[(1-methyl-1H-imidazol-4-yl)methyl]urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-{2-[(2RS,6RS)-2,6-dimethylmorpholin-4-yl]ethyl}urea - 1-[(2-cyanopyridin-4-yl)methyl]-3-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-(pyridazin-4-ylmethyl)urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-(1,2,4-oxadiazol-3-ylmethyl)urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-(1,3-oxazol-2-ylmethyl)urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-(1,3-thiazol-5-ylmethyl)urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-[2-(2-oxa-6-azaspiro[3.3]hept-6-yl)ethyl]urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]urea - N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-N'-[(3-methyloxetan-3-yl)methyl]urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-(5-methylpyridazin-3-yl)urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-[(2R)-tetrahydrofuran-2-ylmethyl]urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-[(2S)-tetrahydrofuran-2-ylmethyl]urea - (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-[(5,5-dimethyltetrahydrofuran-2-yl)methyl]urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-(tetrahydro-2H-pyran-4-yl)urea - (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-(tetrahydro-2H-pyran-2-ylmethyl)urea - (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-(tetrahydro-2H-pyran-3-yl)urea - (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-[(2-methyltetrahydrofuran-2-yl)methyl]urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-(2-methoxy-2-methylpropyl)urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-[2-methyl-2-(morpholin-4-yl)propyl]urea - (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-(tetrahydro-2H-pyran-3-ylmethyl)urea - (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-(tetrahydrofuran-3-ylmethyl)urea - 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-pyridazin-4-ylurea - 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-(6-methylpyridazin-3-yl)urea - 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-pyridin-3-ylurea - 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-pyridin-2-ylurea - 1-[3,5-difluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]-3-[2-(piperidin-1-yl)ethyl]urea - N3-{[3,5-difluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]carbamoyl}-beta-alaninamide - 1-[3,5-difluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]-3-(1H-1,2,3-triazol-5-ylmethyl)urea - 1-[3,5-difluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]-3-[3-(dimethylamino)propyl]urea - 4-({[3,5-difluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]carbamoyl}amino)butanamide - 1-[3,5-difluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]-3-(2-methoxyethyl)urea - 1-[3,5-difluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]-3-(pyridin-2-ylmethyl)urea - 1-[3,5-difluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]-3-[3-(methylsulfonyl)propyl]urea - 1-[3,5-difluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]-3-[2-(dimethylamino)ethyl]urea - 1-[3,5-difluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]-3-[3-(piperidin-1-yl)propyl]urea - 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-(3-methoxypropyl)urea - 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-[(1-methyl-1H-pyrazol-3-yl)methyl]urea - 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-(1,3-thiazol-2-ylmethyl)urea - 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-(1H-pyrazol-3-ylmethyl)urea - N3-({4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}carbamoyI)-beta-alaninamide - 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-[2-(piperidin-1-yl)ethyl]urea - N-{2-[({4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}carbamoyl)amino]ethyl}methanesulfonamide - 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-[3-(morpholin-4-yl)propyl]urea - N-{2-[({4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}carbamoyl)amino]ethyl}acetamide - 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-[2-(morpholin-4-yl)-2-oxoethyl]urea - 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-(pyridin-2-ylmethyl)urea - 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-[(1,1-dioxidothietan-3-yl)methyl]urea - 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-(2-methoxyethyl)urea - 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-(pyridin-4-ylmethyl)urea - N2-({4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}carbamoyl)glycinamide - 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-[3-(piperidin-1-yl)propyl]urea - 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-(1H-1,2,3-triazol-4-ylmethyl)urea - 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-[3-(methylsulfonyl)propyl]urea - 4-[4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}carbamoyl)amino]butanamide - 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-[(4-methylpiperazin-1-yl-2-oxoethyl]urea - 1-{3,5-difluoro-4-[(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]phenyl}-3-[2-(dimethylamino)ethyl]urea - (+/-)-1-{4-[(3-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-(tetrahydrofuran-3-yl)urea - 1-{4-[(3-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-[2-(dimethylamino)ethyl]urea - (+/-)-1-{4-[(3-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-(tetrahydrofuran-2-ylmethyl)urea - 1-{4-[(3-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-(3-methoxypropyl)urea - 1-{4-[(3-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-[3-(morpholin-4-yl)propyl]urea - 1-{4-[(3-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-[(1-methyl-1H-pyrazol-3-yl)methyl]urea - 1-{4-[(3-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-(1,3-thiazol-2-ylmethyl)urea - 1-{4-[(3-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-(pyridin-4-ylmethyl)urea - 1-{4-[(3-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-(2-methoxyethyl)urea - 1-{4-[(3-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-(1H-pyrazol-3-ylmethyl)urea - (+/-)-1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-(tetrahydrofuran-3-yl)urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-(6-methoxypyridazin-3-yl)urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-(6,7-dihydro-5H-cyclopenta[c]pyridazin-3-yl)urea - 1-(6-bromopyridazin-3-yl)-3-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}urea - (+/-)-1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-(tetrahydrofuran-2-ylmethyl)urea - 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-[(3S)-tetrahydrofuran-3-yl]urea - 1 -{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluoropheny}-3-[(1-methyl-1H-pyrazol-3-yl)methyl]urea - 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-(2-oxaspiro[3.3]hept-6-yl)urea - 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-[6-(difluoromethyl)pyridazin-3-yl]urea - (+/-)-1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-(tetrahydrofuran-3-yl)urea - 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-(3-methoxypropyl)urea - 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-[(3R)-tetrahydrofuran-3-yl]urea - 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-(1H-pyrazol-3-ylmethyl)urea - 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-(2,2,2-trifluoroethyl)urea - (+/-)-N-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-[(dimethylamino)methyl]pyrrolidine-1-carboxamide - 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]urea - 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-(2-fluoroethyl)urea - N-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-2-oxa-7-azaspiro[3.5]nonane-7-carboxamide - 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-(2,2-difluoroethyl)urea - 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-[(4-methyl-1H-imidazol-2-yl)methyl]urea - 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-(6-methoxypyridazin-3-yl)urea - 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-(1,3,4-thiadiazol-2-yl)urea - 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-(1,3-thiazol-2-ylmethyl)urea - 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-(6-iodopyridazin-3-yl)urea - 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-[6-(morpholin-4-yl)pyridazin-3-yl]urea - 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-(5-methylpyridazin-3-yl)urea - 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-(6-cyclopropylpyridazin-3-yl)urea - (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-(1-methyl-5-oxopyrrolidin-3-yl)urea - N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-4,4-difluoropiperidine-1-carboxamide - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-[3-(propan-2-yloxy)propyl]urea - N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-methoxyazetidine-1-carboxamide - N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-1-oxa-6-azaspiro[3.3]heptane-6-carboxamide - N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-2-oxa-6-azaspiro[3.5]nonane-6-carboxamide - N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-N'-{[3-(propan-2-yl)oxetan-3-yl]methyl}urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-3-[3-methyl-3-(morpholin-4-yl)butyl]urea - 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]urea - (+/-) 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-(tetrahydrofuran-2-ylmethyl)urea - 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-pyridazin-3-ylurea - 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-(6-methylpyridazin-3-yl)urea - 1-{4-[(3-bromo-1 H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-(1,3,4-thiadiazol-2-yl)urea - 1-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-[(4-methyl-1H-imidazol-2-yl)methyl]urea - 1-{4-[(3-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-(6-methylpyridazin-3-yl)urea - 1-{4-[(3-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-pyridazin-3-ylurea - 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-{1-[(4-methylpiperazin-1-yl)carbonyl]cyclopropyl}urea - 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-[1-(morpholin-4-ylcarbonyl)cyclopropyl]urea - 1-[({4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}carbamoyl)amino]-N,N-dimethylcyclopropanecarboxamide - 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-[1-(piperidin-1-ylcarbonyl)cyclopropyl]urea - (+/-)1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-(1-methoxypropan-2-yl)urea - 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-[1-(methoxymethyl)cyclopropyl]urea - (+/-) 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-(2,2-dimethyltetrahydrofuran-3-yl)urea - (+/-) 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-(5-oxaspiro[3.4]oct-7-yl)urea - (+/-) 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-[(trans)-4-(pyrrolidin-1-yl)tetrahydrofuran-3-yl]urea - N2-({4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}carbamoyI)-N,N-dimethylalaninamide - N2-({4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}carbamoyI)-N,N-dimethylvalinamide - (+/-)1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-(3-methyltetrahydrofuran-3-yl)urea - (+/-)1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-347-oxabicyclo[2.2.1]hept-2-yl]urea - mixture of isomers - (+/-)-1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-(1-methyl-2-oxopyrrolidin-3-yl)urea - N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)azetidine-1-carboxamide - N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)pyrrolidine-1-carboxamide - N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)-N'-[(3-fluorooxetan-3-yl)methyl]urea - 1 -(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)-3-(2-hydroxy-2-methylpropyl)urea - (+/-)-1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)-3-(2-hydroxy-2-methy1-3-(morpholin-4-yl)propyl]urea - 1-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)-3-(3-hydroxy-3-methylbutyl)urea - 6-[({4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}carbamoyl)amino]-N-methylpyridazine-3-carboxamide - 1-(6-tert-butylpyridazin-3-yl)-3-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}urea - 6-[({4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}carbamoyl)amino]-N,N-dimethylpyridazine-3-carboxamide - 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-[6-(trifluoromethyl)pyridazin-3-yl]urea - 1-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-3-[6-(methylsulfonyl)pyridazin-3-yl]urea - (+/-)-N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)-N'-(2-fluoro-3-methoxypropyl)urea - (+/-)-N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)-N'-[(4,4-dimethyloxetan-2-yl)methyl]urea - (+/-)-N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxylphenyl)-N'-(2-fluoro-3-methoxy-2-methylpropyl)urea - N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-N'-{[3-(hydroxymethyl)oxetan-3-yl]methyl}urea - N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-N'-[(3-hydroxyoxetan-3-yl)methyl]urea - N-(2,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-N'-[(3-methyloxetan-3-yl)methyl]urea - N-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)sulfanyl]-3,5-difluorophenyl}-N'-[2-(morpholin-4-yl)-2-oxoethyl]urea - N-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)sulfanyl]-3,5-difluorophenyl}-N'-(2-methoxyethyl)urea - N-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)sulfanyl]-3,5-difluorophenyl}-N'-ethylurea - N-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)sulfanyl]-3,5-difluorophenyl}morpholine-4-carboxamide - N-(3,5-difluoro-4-{[3-(propan-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-N'-[(3-fluorooxetan-3-yl)methyl]urea - N-(3,5-difluoro-4-{[3-(3,3,3-trifluoropropyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-N'-[(3-fluorooxetan-3-yl)methyl]urea - (+/-)-N-[3,5-difluoro-4-({3-[1,1,1-trifluoropropan-2-yl]-1H-pyrrolo[2,3-b]pyridin-4-yl}oxy)phenyl]-N'-[(3-fluorooxetan-3-yl)methyl]urea - N-(3,5-difluoro-4-{[3-(propan-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-N'-(2-methoxyethyl)urea - N-(3,5-difluoro-4-{[3-(propan-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-N'-[(3-methyloxetan-3-yl)methyl]urea - N-(3,5-difluoro-4-{[3-(propan-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-N'-{[3-(propan-2-yl)oxetan-3-yl]methyl}urea - N-(3,5-difluoro-4-{[3-(propan-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)morpholine-4-carboxamide - N-(3,5-difluoro-4-{[3-(propan-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-N'-[2-(morpholin-4-yl)-2-oxoethyl]urea - (+/-)-N-[3,5-difluoro-4-({3-[1,1,1-trifluoropropan-2-yl]-1H-pyrrolo[2,3-b]pyridin-4-yl}oxy)phenyl]-N'-(2-methoxyethyl)urea - (+/-)-N-[4-({3-(butan-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl}oxy)-3,5-difluorophenyl]-N'-(2-methoxyethy)urea - (+/-)-N-[3,5-difluoro-4-({3-(3-methylbutan-2-yl)-1H-pyrrolo[2,3-b]pyridin-yl}oxy)phenyl]-N'-(2-methoxyethyl)urea ¨ N-(3,5-difluoro-4-{[3-(pentan-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-N'-(2-methoxyethyl)urea ¨ N-(3,5-difluoro-4-{[3-(2-methylpropyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-N'-(2-methoxyethyl)urea ¨ (+/-)-N-[3,5-difluoro-4-({3-[4,4,4-trifluorobutan-2-yl]-1H-pyrrolo[2,3-b]pyridin-4-yl}oxy)phenyl]-N'-(2-methoxyethyl)urea ¨ N-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-2-methylazetidine-1-carboxamide ¨ N-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}azetidine-1-carboxamide ¨ N'-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-N,N-dimethylurea ¨ (+/-)-N-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-4,4-difluoro-3-(hydroxymethyl)piperidine-1-carboxamide ¨ N-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-N'-(1-methoxy-2-methylpropan-2-yl)urea ¨ (+/-)-N-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-N'-1-oxaspiro[4.4]nonan-6-ylurea ¨ mixture of isomers ¨ (+/-)-N-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-N'-[1-(morpholin-4-yl)-1-oxopropan-2-yl]urea and their polymorphs, enantiomers, diastereomers, racemates, tautomers, solvates, physiologically acceptable salts and solvates of these salts.

9. A compound of general formula (l) according to any one of claims 1 to 8 for use in the treatment or prophylaxis of a disease.

10. A pharmaceutical composition comprising a compound of general formula (l) according to any one of claims 1 to 8 and one or more pharmaceutically acceptable excipients.

11. A pharmaceutical combination comprising:
.cndot. one or more first active ingredients, in particular compounds of general formula (l) according to any one of claims 1 to 8, and .cndot. one or more pharmaceutical active anti cancer compounds or .cndot. one or more pharmaceutical active immune checkpoint inhibitors.

12. A pharmaceutical combination according to claim 11, characterized in that the pharmaceutical active immune checkpoint inhibitor is an antibody.

13. Use of a compound of general formula (l) according to any one of claims 1 to 8 for the treatment or prophylaxis of a disease.

14. Use of a compound of general formula (l) according to any one of claims 1 to 8 for the preparation of a medicament for the treatment or prophylaxis of a disease.

15. Use according to claim 13 or 14, wherein the disease is cancer or conditions with dysregulated immune responses or other disorders associated with aberrant signaling, such as liquid and solid tumours, for example.

16. Use according to claim 13 or 14, wherein the diseases, respectively the disorders are benign hyperplasias, atherosclerotic disorders, sepsis, autoimmune disorders, vascular disorders, viral infections, neurodegenerative disorders, in inflammatory disorders, and male fertility control.