Indolines as DDR inhibitors

Abstract

Indoline derivatives as DDR inhibitors The present invention relates to compounds of general formula (I) that inhibit discoidin domain receptors (DDR inhibitors). The present invention relates to methods for preparing such compounds, pharmaceutical compositions containing them and their therapeutic use. The compounds of the present invention may be useful, for example, in the treatment of a number of disorders associated with DDR mechanisms.

Description

[Technical Field]

[0001] The present invention relates to compounds that inhibit discoidin domain receptors (DDR inhibitors), methods for preparing such compounds, pharmaceutical compositions containing them, and their medical uses.

[0002] The compounds of the present invention may be useful, for example, in the treatment of a number of disorders associated with DDR mechanisms. [Background technology]

[0003] Discoidin domain receptors (DDRs) are type I transmembrane receptor tyrosine kinases (RTKs). The DDR family includes two distinct members: DDR1 and DDR2.

[0004] The DDR is a unique receptor among other members of the RTK superfamily in that it is activated by collagen, whereas other members of the RTK superfamily are activated primarily by soluble peptide-like growth factors (see Vogel, W. (1997) Mol. Cell 1, 13-23; Shrivastava A. Mol. Cell. 1997; 1:25-34). Furthermore, the DDR is an unusual RTK because it forms stable, non-covalently associated, ligand-independent dimers (see Noordeen, NA (2006) J. Biol. Chem. 281, 22744-22751; Mihai C. J. Mol. Biol. 2009; 385:432-445).

[0005] The DDR1 subfamily consists of five membrane-anchored isoforms, while the DDR2 subfamily is represented by a single protein. All five DDR1 isoforms share an extracellular domain and a transmembrane domain, but differ in their cytoplasmic regions (see Valiathan, RR (2012) Cancer Metastasis Rev. 31, 295-321; Alves, F. (2001) FASEB J. 15, 1321-1323).

[0006] The DDR receptor family has been implicated in a range of fibrotic diseases, including pulmonary fibrosis, particularly idiopathic pulmonary fibrosis (IPF). The first evidence for a protective role of DDR1 deletion in pulmonary fibrosis was provided by Dr. Vogel's research group in 2006 (see Avivi-Green C, Am J Respir Crit Care Med 2006;174:420-427). The authors showed that DDR1-deficient mice were largely protected from bleomycin (BLM)-induced injury. Furthermore, myofibroblast proliferation and apoptosis were significantly lower in these animals compared with wild-type counterparts. The absence of inflammation in the knockout mice was confirmed by lavage cell counts and cytokine ELISA. These results indicated that DDR1 expression is a prerequisite for the development of lung inflammation and fibrosis.

[0007] Loss or downregulation of DDR2 attenuates bleomycin-induced pulmonary fibrosis (see Zhao H, Bian H, Bu X, Zhang S, Zhang P, Yu J, et al. Mol Ther 2016;24:1734-1744). Zhao et al. demonstrated that DDR2 plays an important role in inducing pulmonary fibrosis and angiogenesis, specifically by synergizing with transforming growth factor (TGF)-β to induce myofibroblast differentiation. Furthermore, they demonstrated that treatment of injured mice with DDR2-specific siRNA showed therapeutic effects on pulmonary fibrosis. In a second publication, Jia et al. demonstrated that DDR2-deficient mice were protected from bleomycin-induced pulmonary fibrosis (see Jia S, Am J Respir Cell Mol Biol 2018;59:295-305). Furthermore, DDR2-null fibroblasts were significantly more prone to apoptosis than wild-type fibroblasts, supporting the paradigm that fibroblast resistance to apoptosis is important for the progression of fibrosis.

[0008] Several compounds have been described in the literature as DDR1 or DDR2 antagonists.

[0009] WO2016064970 (Guangzhou) discloses isoquinoline derivatives as DDR1 inhibitors useful as therapeutic agents for the prevention and treatment of inflammation, liver fibrosis, kidney fibrosis, lung fibrosis, skin scars, atherosclerosis and cancer.

[0010] Of note, inhibiting DDR receptors may be useful in treating fibrosis and diseases, disorders and conditions caused by fibrosis, and further, antagonizing both DDR1 and DDR2 receptors may be particularly effective in treating the above-mentioned diseases, disorders and conditions.

[0011] Over the past few years, several efforts have been made to develop novel DDR1 and DDR2 receptor inhibitors useful for the treatment of several diseases, and some of these compounds have also shown efficacy in humans.

[0012] Notwithstanding the prior art cited above, there remains the possibility of developing selective inhibitors of both the receptors DDR1 and DDR2, useful in the treatment of diseases or conditions associated with dysregulation of DDR receptors in the respiratory field, in particular idiopathic pulmonary fibrosis (IPF), which are administered by the inhalation route and are characterized by a good inhalation profile corresponding to good activity in the lung, good lung retention, and low metabolic stability in order to minimize systemic exposure and associated safety issues.

[0013] In this direction, we have surprisingly found a new series of compounds of general formula (I) as reported herein below, which solve the problem of providing inhibitors of the receptors DDR1 and DDR2 for administration by inhalation and which are active as selective inhibitors of the receptors DDR1 and DDR2 relative to other human protein kinases, exhibiting high potency, a good inhalation profile, low metabolic stability, low systemic exposure, improved safety and tolerability. Summary of the Invention

[0014] In a first aspect, the present invention provides a compound of formula (I): [ka] [In the formula, R is H or -(C1-C4)alkyl; L is selected from the group consisting of -CH2- and -C(O)-; L1 is selected from the group consisting of -C(O)NH- and -NHC(O)-; Hy is -(C1-C4) alkyl, heterocycloalkyl, and -(C1-C4) alkylene-NR A R Bor a bicyclic heteroaryl optionally substituted with one or more groups selected from Hy is a bicyclic semi-saturated heteroaryl; R A is H or -(C1-C4)alkyl; R B is H or -(C1-C4)alkyl; R1 is selected from the group consisting of Het and X, wherein: -Het is -(C1-C4)alkyl, -(C1-C4)haloalkyl, -(C1-C4)alkylene-heterocycloalkyl-NR A R B , -(C1-C4) alkylene-NR A R B and heteroaryl optionally substituted by one or more groups selected from aryl, wherein said aryl is optionally substituted by one or more -(C1-C4)alkyl; -X is a group of the formula: [ka] wherein R2 is selected from the group consisting of —O(C1-C4)haloalkyl, a halogen atom, and —(C1-C4)haloalkyl; R3 is H or -O(C1-C4)alkyl, -C(O)NH-(C1-C4)alkylene-NR A R B , -C(O)-heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted by one or more of -(C1-C4)alkyl, -O-heterocycloalkyl, wherein said heterocycloalkyl is selected from the group consisting of one or more of -(C1-C4)alkyl, -O(C1-C4)alkylene-heterocycloalkyl, -(C1-C4)alkylene-NR A R B, heteroaryl optionally substituted by one or more -(C1-C4)alkyl, and monocyclic heterocycloalkyl-(C1-C4)alkylene-, wherein said heterocycloalkyl is selected from the group consisting of -(C1-C4)alkyl and -NR A R B and optionally substituted with one or more groups selected from is a group represented by the formula: and pharmaceutically acceptable salts thereof.

[0015] In a second aspect, the present invention relates to pharmaceutical compositions comprising compounds of formula (I) and pharmaceutically acceptable salts thereof, together with one or more pharmaceutically acceptable carriers or excipients.

[0016] In a third aspect, the present invention relates to a compound of formula (I) and a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable salt thereof, for use as a medicament.

[0017] In a further aspect, the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising compounds of formula (I) and pharmaceutically acceptable salts thereof, for use in the prevention and / or treatment of diseases, disorders or conditions associated with dysregulation of the DDR.

[0018] In a further aspect, the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising compounds of formula (I) and pharmaceutically acceptable salts thereof, for use in the prevention and / or treatment of fibrosis and / or diseases, disorders or conditions involving fibrosis.

[0019] In a further aspect, the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising compounds of formula (I) and pharmaceutically acceptable salts thereof, for use in the prevention and / or treatment of idiopathic pulmonary fibrosis (IPF).

[0020] Detailed Description of the Invention definition Unless otherwise specified, the compounds of formula (I) of the present invention are intended to include their stereoisomers, tautomers, or pharmaceutically acceptable salts or solvates.

[0021] Unless otherwise specified, the compounds of formula (I) of the present invention are also intended to include compounds of formula (IA), formula (IA'), formula (IA"), formula (IAa), formula (IAa'), formula (IAa'S), formula (IAa"), formula (IAa"S), formula (IAb), formula (IAb'), formula (IAb"), formula (IB), formula (IBa), formula (IBa'), formula (IBa'S), formula (IBa"), formula (IBa"S), formula (IBb), formula (IBb'), and formula (IBb").

[0022] As used herein, the term "pharmaceutically acceptable salts" refers to derivatives of compounds of formula (I) wherein the parent compound is suitably modified by converting any free acid or basic group, if present, into the corresponding addition salt with any base or acid that is conventionally intended to be pharmaceutically acceptable.

[0023] Thus, suitable examples of such salts include mineral acid addition salts or organic acid addition salts of basic residues such as amino groups, and mineral acid addition salts or organic base addition salts of acidic residues such as carboxyl groups.

[0024] Cations of inorganic bases suitable for use in preparing salts include alkali metal or alkaline earth metal ions, such as potassium, sodium, calcium or magnesium.

[0025] Salts formed by reacting the base-functioning main compound with an inorganic or organic acid include, for example, hydrochlorides, hydrobromides, sulfates, phosphates, methanesulfonates, camphorsulfonates, acetates, oxalates, maleates, fumarates, succinates, and citrates.

[0026] The term "solvate" means a physical association of a compound of the present invention with one or more solvent molecules, whether organic or inorganic. This physical association may include hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. The solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules.

[0027] The term "stereoisomer" means isomers of identical constitution that differ in the arrangement of their atoms in space. Enantiomers and diastereomers are examples of stereoisomers.

[0028] The term "enantiomer" refers to one of a pair of molecular species that are mirror images of each other and are not superimposable.

[0029] The term "diastereomer" means a stereoisomer that is not an enantiomer.

[0030] The terms "racemate" or "racemic mixture" refer to a composition of equimolar amounts of two enantiomeric species, devoid of optical activity.

[0031] The term "tautomers" refers to each of two or more isomers of a compound that exist together in equilibrium and are readily interchangeable by shifting atoms or groups within the molecule.

[0032] As used herein, the term "halogen" or "halogen atom" or "halo" includes fluorine, chlorine, bromine and iodine atoms.

[0033] The term “(C x -C y ")Alkyl" (where x and y are integers) means a straight or branched chain alkyl group having from x to y carbon atoms. Thus, for example, if x is 1 and y is 6, the term includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl.

[0034] The term “O(C x -C y )alkyl" (where x and y are integers) means a "(C )alkyl" as defined above, in which a carbon atom is bonded to an oxygen atom. x -C y ) alkyl" groups, e.g., ethoxy.

[0035] The term “(C x -C y (C )haloalkyl" (where x and y are integers) refers to a "(C )haloalkyl" as defined above in which one or more hydrogen atoms have been replaced with one or more halogen atoms, which may be the same or different. x -C y The above-mentioned "(C ) alkyl" group means x -C y Examples of "haloalkyl" groups include halogenated and polyhalogenated alkyl groups, and fully halogenated alkyl groups in which all hydrogen atoms have been replaced with halogen atoms, such as trifluoromethyl.

[0036] The term “O(C x -C y (C )haloalkyl" (where x and y are integers) refers to a "(C )haloalkyl" as defined above, in which a carbon atom is bonded to an oxygen atom. x -C y )haloalkyl" group.

[0037] Therefore, the above "O(C x -C y Examples of "haloalkyl" groups include halogenated O-alkyl groups, poly-halogenated O-alkyl groups, and fully halogenated O-alkyl groups in which all hydrogen atoms have been replaced with halogen atoms, such as trifluoromethoxy.

[0038] The term "aryl" means a monocyclic carbocyclic ring system having 6 ring atoms, in which the ring is aromatic. Examples of suitable aryl monocyclic ring systems include, for example, phenyl.

[0039] The term "heteroaryl" means a monocyclic or bicyclic aromatic group containing one or more heteroatoms selected from S, N, and O, and includes groups having two such monocyclic rings or one such monocyclic ring and one monocyclic aryl ring fused together through a common bond. Examples of suitable heteroaryls include, for example, (imidazo[1,2-a]pyridinyl), 1H-pyrrolo[2,3-b]pyridyl, 1H-pyrazolo[3,4-b]pyridinyl, benzo[d]thiazolyl, 1H-indazolyl, 1H-benzo[d]imidazolyl, isoquinolinyl, imidazo[1,2-a]pyrazinyl, 1H-pyrazolo[3,4-b]pyridinyl, 1H-benzo[d]imidazolyl; 1H-pyrrolo[2,3-b]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, pyrazolo[1,5-a]pyrazinyl, pyrazolyl, pyridinyl, isoxazolyl, and pyrimidinyl.

[0040] The term "semi-saturated heteroaryl" refers to a bicyclic group containing one or more heteroatoms selected from S, N, and O, including a monocyclic heteroaryl fused to one or more monocyclic heterocycloalkyl rings. Examples of suitable semi-saturated heteroaryls include, for example, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl.

[0041] The term "heterocycloalkyl" means a saturated or partially unsaturated monocyclic or bicyclic ring system of 3 to 12 ring atoms containing one or more heteroatoms selected from N, S, or O, e.g., piperazinyl, morpholinyl, pyrrolidinyl, piperidinyl.

[0042] The term "heterocycloalkyl-(C x -C y ) alkylene" refers to a straight or branched (C x -C y ) means a heterocycloalkyl linked to an alkylene group, for example (4-methylpiperazin-1-yl)methyl, morpholinomethyl, pyrrolidin-1-ylmethyl.

[0043] As used in the structural formulas herein [ka] A wavy line or bond pointing to a wavy line, such as indicates a bond that is the point of attachment of a moiety or substituent to a core or backbone structure.

[0044] When referring to a substituent, a dash (“-”) that is not between two letters, words, or symbols is meant to represent a point of attachment for such substituent.

[0045] Carbonyl groups are preferably depicted herein as -C(O)-, as an alternative to other common depictions such as -CO-, -(CO)- or -C(=O)-.

[0046] When referring to the group -C(O)NH- or -NHC(O)- of L1 of formula (I), the left dash ("-") of the group is the bond between the group and the indoline core, and the right dash ("-") of the group is the bond between the group and the R1 group. Thus, when referring to -C(O)NH- of L1 of formula (I), the carbon is bonded to the indoline core and the nitrogen is bonded to the R1 group. When referring to -NHC(O)- of L1 of formula (I), the nitrogen is bonded to the indoline core and the carbon is bonded to the R1 group.

[0047] Whenever a basic amino group is present in the compound of formula (I), a physiologically acceptable anion may be present, selected from chloride, bromide, iodide, trifluoroacetate, formate, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate, p-toluenesulfonate, pamoate, and naphthalenedisulfonate. Similarly, in the presence of an acidic group, the corresponding physiological cation salts may also be present, including, for example, alkali metal or alkaline earth metal ions.

[0048] The term "half maximal inhibitory concentration" (IC50) refers to the concentration of a particular compound or molecule required to inhibit a biological process by 50% in vitro.

[0049] The term "Ki" refers to the dissociation constant of the enzyme-inhibitor complex, expressed in molar units, and is an indicator of the binding affinity between the inhibitor and the DDR1 or DDR2 receptor.

[0050] The present invention relates to novel compounds that differ from the structures disclosed in the art at least in terms of a common new core scaffold. Indeed, the present invention relates to compounds that are indoline derivatives of the general formula (I) detailed below, in which the nitrogen of the indoline is linked to a bicyclic heteroaryl ring Hy via a linker -CH2- or -C(O)-, and that have inhibitory activity against the receptors DDR1 and DDR2.

[0051] As detailed in the following experimental section, the compound of formula (I) of the present invention can act as an antagonist of both DDR1 and DDR2 receptors in a substantial and effective manner.In particular, the following Table 7 shows that the affinity of the compound of the present invention to either DDR1 or DDR2 receptor and the inhibitory activity of either DDR1 or DDR2 receptor are both less than about 80nM in binding (represented as Ki) and cell-based assay (represented as IC50).This confirms that the compound of formula (I) can inhibit the two isoforms of DDR receptors that are mainly involved in fibrosis and diseases caused by fibrosis.Therefore, the compound of formula (I) can be used to treat fibrosis, particularly pulmonary fibrosis, when DDR1 and DDR2 are involved.

[0052] Guangzhou discloses tetrahydroisoquinoline-7-carboxamides as selective DDR1 inhibitors.

[0053] Remarkably, in the compounds of formula (I) according to the present invention, the presence of at least the indoline moiety and the spacer -CH2- or -C(O)- between the nitrogen atom of the pyrrolidine and the heteroaryl group Hy unexpectedly and significantly determines high affinity for both DDR1 and DDR2 receptors and appropriate inhibitory activity against DDR1 and also DDR2 receptors in cellular assays.

[0054] Furthermore, as shown in the experimental section, comparative examples and especially in Table 8, it is shown that, contrary to the compounds of Examples C1 and C2, which feature a -CH2-C(O)- linker between the indoline ring and the Hy group, the presence of a -CH2- or -C(O)- linker at that position in the compounds of the present invention determines an unexpected and significant associated increase in inhibitory activity against both the DDR1 and DDR2 receptors.

[0055] In particular, a direct comparison of Example C1 of the present invention with Examples 14 and 11, which differ only in the linker between the indoline group and Hy, highlights that the presence of the -C(O)- and -CH2- linkers, respectively, in Examples 14 and 11, determines an unexpected and significant increase in activity towards both the DDR1 and DDR2 receptors. Similarly, a direct comparison of the compound of Example C2 of the present invention with the compound of Example 16, which differ only in the linker between the indoline group and Hy, highlights that the presence of the -C(O)- linker determines an unexpected and significant increase in activity towards both the DDR1 and DDR2 receptors.

[0056] Advantageously, the compounds of the present invention have very high potency and can be administered to humans at lower doses than prior art compounds, thereby reducing the adverse events that can occur when high doses of the drug are administered.

[0057] The compounds of the present invention are characterized by being remarkably potent in terms of inhibitory activity against both the DDR1 and DDR2 receptors, as well as being selective inhibitors of the DDR1 and DDR2 receptors with respect to other human protein kinases, by having a good inhalation profile that allows them to act effectively in the pulmonary compartment, and at the same time by having low metabolic stability that allows them to minimize the drawbacks associated with systemic exposure, such as safety and tolerability issues.

[0058] The compounds of the present invention are therefore particularly appreciated by those skilled in the art in view of being suitable and effective compounds useful for the treatment of fibrosis, in particular idiopathic pulmonary fibrosis, which are administered by the inhalation route and are characterized by a good inhalation profile corresponding to good pulmonary activity, good pulmonary retention and low metabolic stability, minimizing systemic exposure and associated safety issues.

[0059] Thus, in one aspect, the present invention provides compounds of general formula (I): [ka] [In the formula, R is H or -(C1-C4)alkyl; L is selected from the group consisting of -CH2- and -C(O)-; L1 is selected from the group consisting of -C(O)NH- and -NHC(O)-; Hy is -(C1-C4) alkyl, heterocycloalkyl, and -(C1-C4) alkylene-NR A R B or Hy is a bicyclic semi-saturated heteroaryl; R A is H or -(C1-C4)alkyl; R B is H or -(C1-C4)alkyl; R1 is selected from the group consisting of Het and X, wherein: -Het is -(C1-C4)alkyl, -(C1-C4)haloalkyl, -(C1-C4)alkylene-heterocycloalkyl-NR A R B , -(C1-C4) alkylene-NR A R B and heteroaryl optionally substituted by one or more groups selected from aryl, wherein said aryl is optionally substituted by one or more -(C1-C4)alkyl, and -X is a group of the formula: [ka] wherein R2 is selected from the group consisting of —O(C1-C4)haloalkyl, a halogen atom, and —(C1-C4)haloalkyl; R3 is H or -O(C1-C4)alkyl, -C(O)NH-(C1-C4)alkylene-NR A R B , -C(O)-heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted by one or more of -(C1-C4)alkyl, -O-heterocycloalkyl, wherein said heterocycloalkyl is selected from the group consisting of one or more of -(C1-C4)alkyl, -O(C1-C4)alkylene-heterocycloalkyl, -(C1-C4)alkylene-NR A R B , heteroaryl optionally substituted by one or more -(C1-C4)alkyl, and monocyclic heterocycloalkyl-(C1-C4)alkylene-, wherein said heterocycloalkyl is selected from the group consisting of -(C1-C4)alkyl and -NR A R B and optionally substituted with one or more groups selected from is a group represented by the formula: or a pharmaceutically acceptable salt thereof.

[0060] In a preferred embodiment, the present invention relates to compounds of general formula (I) in which Hy is a bicyclic heteroaryl, where the heteroatoms are represented by one or more N atoms.

[0061] In another preferred embodiment, the present invention relates to compounds of formula (I), wherein Hy is a bicyclic heteroaryl optionally substituted with one or more groups selected from methyl, (dimethylamino)methyl, and morpholinyl, or Hy is a semi-saturated heteroaryl.

[0062] In another preferred embodiment, the present invention provides a compound of formula (I) wherein Hy is (imidazo[1,2-a]pyridin-3-yl), 1H-pyrrolo[2,3-b]pyridin-5-yl, 1H-pyrazolo[3,4-b]pyridin-5-yl, benzo[d]thiazol-6-yl, 1H-indazol-5-yl, 1H-benzo[d]imidazol-5-yl, isoquinolin-7-yl, imidazo[1,2-a]pyrazin-3-yl, 1H-pyrazolo[3,4-b]pyridin-5-yl, 3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl, 1H-pyrazolo[ 3,4-b]pyridin-5-yl, 1H-benzo[d]imidazol-5-yl, 1H-benzo[d]imidazol-5-yl, 3-((dimethylamino)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl, pyrazolo[1,5-a]pyrimidin-6-yl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl, 3-morpholino-1H-pyrazolo[3,4-b]pyridin-5-yl, pyrazolo[1,5-a]pyrazin-3-yl and pyrazolo[1,5-a]pyrimidin-6-yl].

[0063] In a further preferred embodiment, the present invention provides a compound of formula (I) wherein Het is 3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl, 2-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-6-(trifluoromethyl)pyridin-4-yl, 5-(trifluoromethyl)pyridin-3-yl, 2-((dimethylamino)methyl)-6-(trifluoromethyl)pyridin-4-yl, ((4-methylpiperazin-1-yl) )methyl)-6-(trifluoromethyl)pyridin-4-yl, 3-(tert-butyl)isoxazol-5-yl, 5-(tert-butyl)isoxazol-3-yl, 5-(tert-butyl)-1-methyl-1H-pyrazol-3-yl, 6-(trifluoromethyl)pyrimidin-4-yl and 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl.

[0064] In another particularly preferred embodiment, the present invention provides a compound of formula (I) wherein X is 3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl, 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 3-fluoro-5-(trifluoromethyl)phenyl, 4-methoxy-3-(trifluoromethyl)phenyl, 3-(trifluoromethoxy)phenyl, 3-(tert-butyl)- 1-phenyl-1H-pyrazol-5-yl, 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl, 3-fluoro-5-(trifluoromethoxy)phenyl, 4-((tetrahydrofuran-3-yl)oxy)-3-(trifluoromethyl)phenyl, 4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl, 3-(morpholinomethyl)-5-(trifluoromethyl)phenyl, 3-(pyrrolidin-1-ylmethyl)-5-( trifluoromethyl)phenyl, 3-((dimethylamino)methyl)-5-(trifluoromethyl)phenyl, 3-(2-(pyrrolidin-1-yl)ethoxy)-5-(trifluoromethyl)phenyl; 3-(2-morpholinoethoxy)-5-(trifluoromethyl)phenyl, 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl, 4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl, 4-(pyrrolidin-1-ylmethyl) the compound of formula (I) is selected from the group consisting of 3-(trifluoromethyl)phenyl, 3-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-5-(trifluoromethyl)phenyl, 3-((2-(dimethylamino)ethyl)carbamoyl)-5-(trifluoromethyl)phenyl, 3-(4-methylpiperazine-1-carbonyl)-5-(trifluoromethyl)phenyl, and 4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl.

[0065] In a particularly preferred embodiment, the present invention provides compounds of general formula (I) in which L is -C(O)NH-, having the formula (IA): [ka] wherein R, L, Hy and R1 are as defined above.

[0066] In another preferred embodiment, the present invention provides a compound of formula (IA) wherein L is —C(O)—, having formula (IA′): [ka] wherein R, Hy and R1 are as defined above.

[0067] In a further preferred embodiment, the present invention relates to a compound of formula (IA'), wherein R1 is selected from the group consisting of 3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl and 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl, and Hy is selected from the group consisting of imidazo[1,2-a]pyridin-3-yl, imidazo[1,2-a]pyrazin-3-yl, and 1H-pyrazolo[3,4-b]pyridin-5-yl.

[0068] According to a preferred embodiment, the present invention relates to at least one compound of formula (IA') and pharmaceutically acceptable salts thereof as shown in Table 1 below. These compounds are particularly active against the receptors DDR1 and DDR2, as shown in Table 7.

[0069] [Table 1-1] [Table 1-2]

[0070] In another preferred embodiment, the present invention provides a compound of formula (IA) wherein L is -CH-, having formula (IA"): [ka] wherein R, Hy and R1 are as defined above.

[0071] In a further preferred embodiment, the present invention provides a compound of formula (IA″) [wherein R1 is 3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl, 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl), 3-(trifluoromethyl)phenyl, 3-fluoro-5-(trifluoromethyl)phenyl, 4-methoxy-3-(trifluoromethyl)phenyl, 3-(trifluoromethoxy)phenyl; 3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl, 5-(1,1,1-trifluoro-2-methylpropyl)] (pan-2-yl)isoxazol-3-yl, 3-fluoro-5-(trifluoromethoxy)phenyl, 4-((tetrahydrofuran-3-yl)oxy)-3-(trifluoromethyl)phenyl, 4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl, 3-(morpholinomethyl)-5-(trifluoromethyl)phenyl, 3-(pyrrolidin-1-ylmethyl)-5-(trifluoromethyl)phenyl, 3-((dimethylamino)methyl)-5-(trifluoromethyl)phenyl, 3-(2-(pyrrolidin-1-yl)ethoxy)-5-(trifluoromethyl)phenyl;3-(2-morpholinoethoxy)-5-(trifluoromethyl)phenyl, 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl, 4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl, 4-(pyrrolidin-1-ylmethyl)-3-(trifluoromethyl)phenyl, 3-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-5-(trifluoromethyl)phenyl, 3-((2-(dimethylamino)ethyl)carbamoyl)-5-(trifluoromethyl)phenyl, 3-(4-methylpiperazine-1-carbonyl)-5-(trifluoromethyl)phenyl, 2-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-6-(trifluoromethyl)pyridin-4-yl, 5-(trifluoromethyl)pyridin-3-yl, 2-((dimethylamino)methyl)-6-(trifluoromethyl)pyridin-4-yl, 4-methylpiperazin-1-yl)methyl)-6-(trifluoromethyl)pyridin-4-yl, 3-(tert-butyl)isoxazol-5-yl, 5-(tert-butyl)isoxazol-5-yl Hy is selected from the group consisting of imidazo[1,2-a]pyridin-3-yl, 1H-pyrrolo[2,3-b]pyridine, 1H-indazol-5-yl, 1H-benzo[d]imidazol-5-yl, isoquinolin-7-yl, imidazo[1,2-a]pyrazin-3-yl, 1H-pyrrolo[2,3-b]pyridine, 1H-indazol-5-yl, 1H-benzo[d]imidazol-5-yl, isoquinolin-7-yl, imidazo[1,2-a]pyrazin-3-yl, 1H- The present invention relates to a compound selected from the group consisting of pyrazolo[3,4-b]pyridin-5-yl, 3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl, 3-((dimethylamino)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl, pyrazolo[1,5-a]pyrimidin-6-yl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl, 3-morpholino-1H-pyrazolo[3,4-b]pyridin-5-yl, pyrazolo[1,5-a]pyrazin-3-yl, and 1H-benzo[d]imidazol-5-yl;

[0072] According to a preferred embodiment, the present invention relates to at least one compound of formula (IA'') listed in Table 2 below and its pharmaceutically acceptable salts. These compounds are particularly active on the receptors DDR1 and DDR2, as shown in Table 7.

[0073] [Table 2-1]

[0074] [Table 2-2]

[0075] [Table 2-3]

[0076] [Table 2-4]

[0077] [Table 2-5]

[0078] [Table 2-6]

[0079] [Table 2-7]

[0080] [Table 2-8]

[0081] [Table 2-9]

[0082] [Table 2-10]

[0083] [Table 2-11]

[0084] [Table 2-12]

[0085] [Table 2-13]

[0086] [Table 2-14]

[0087] [Table 2-15]

[0088] [Table 2-16]

[0089] [Table 2-17]

[0090] In a particularly preferred embodiment, the present invention provides compounds of general formula (IA), wherein R1 is an X group: [ka] A compound of formula (IAa): [ka] wherein R, L, Hy, R2 and R3 are as defined above.

[0091] In a particularly preferred embodiment, the present invention provides a compound of formula (IAa) wherein L is —C(O)—, having formula (IAa′): [ka] wherein R, Hy, R2 and R3 are as defined above.

[0092] In another particularly preferred embodiment, the present invention provides a compound of general formula (I) wherein L is —C(O)—, L1 is —C(O)NH—, and R1 is X′: [ka] and a compound of formula (IAa'S): [ka] wherein R, Hy, R2 and R3 are as defined above.

[0093] In a further particularly preferred embodiment, the present invention relates to compounds of general formula (IAa) where L is -CH2-, which have the formula (IAa''): [ka] wherein R, Hy, R1, R2 and R3 are as defined above.

[0094] In a further preferred embodiment, the present invention provides a compound of general formula (I) wherein L is —CH—, L is —C(O)NH—, and R is X′: [ka] and a compound of formula (IAa''S): [ka] wherein R, Hy, R2 and R3 are as defined above.

[0095] In a further particularly preferred embodiment, the present invention relates to compounds of general formula (I) in which L1 is -C(O)NH- and R1 is Het, which compounds have the formula (IAb): [ka] wherein R, L, Hy and Het are as defined above.

[0096] In a further preferred embodiment, the present invention provides a compound of general formula (IAb) wherein L is —C(O)—, having formula (IAb′): [ka] wherein R, Hy and Het are as defined above.

[0097] In another particularly preferred embodiment, the present invention provides compounds of general formula (IAb) where L is -CH2-, having formula (IAb''): [ka] wherein R, Hy and Het are as defined above.

[0098] In a further preferred embodiment, the present invention provides compounds of formula (IAb″) wherein Het is 3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl, 2-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-6-(trifluoromethyl)pyridin-4-yl, 5-(trifluoromethyl)pyridin-3-yl, 2-((dimethylamino)methyl)-6-(trifluoromethyl)pyridin-4-yl, 4-methylpiperazin-1-yl )methyl)-6-(trifluoromethyl)pyridin-4-yl, 3-(tert-butyl)isoxazol-5-yl, 5-(tert-butyl)isoxazol-3-yl, 5-(tert-butyl)-1-methyl-1H-pyrazol-3-yl, 6-(trifluoromethyl)pyrimidin-4-yl and 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl).

[0099] In another preferred embodiment, the present invention relates to compounds of formula (IAb″), wherein Hy is selected from the group consisting of 1H-pyrazolo[3,4-b]pyridin-5-yl, imidazo[1,2-a]pyridin-3-yl, 3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl, 3-((dimethylamino)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl and imidazo[1,2-a]pyrazin-3-yl.

[0100] According to a preferred embodiment, the present invention relates to at least one compound of formula (IAb") listed in Table 3 below, and pharmaceutically acceptable salts thereof. These compounds are particularly active on the receptors DDR1 and DDR2, as shown in Table 7.

[0101] [Table 3-1]

[0102] [Table 3-2]

[0103] [Table 3-3]

[0104] [Table 3-4]

[0105] [Table 3-5]

[0106] In another preferred embodiment, the present invention provides a compound of general formula (I) wherein L is -NHC(O)-, having formula (IB): [ka] wherein R, L, Hy and R1 are as defined above.

[0107] According to a preferred embodiment, the present invention relates to at least one compound of formula (IB) and pharmaceutically acceptable salts thereof as listed in Table 4 below. These compounds are particularly active on the receptors DDR1 and DDR2, as shown in Table 7.

[0108] [Table 4-1]

[0109] [Table 4-2]

[0110] In a particularly preferred embodiment, the present invention provides a compound of general formula (I) wherein L1 is -NHC(O)- and R1 is an X group: [ka] and a compound of formula (IBa): [ka] wherein R, L, Hy, R2 and R3 are as defined above.

[0111] In a further preferred embodiment, the present invention provides a compound of general formula (IBa) wherein L is —C(O)—, having formula (IBa′): [ka] wherein R, Hy, R2 and R3 are as defined above.

[0112] In another preferred embodiment, the present invention provides a compound represented by general formula (I), wherein L is -NHC(O)-, L is -C(O)-, and R is X': [ka] and a compound of formula (IBa'S): [ka] wherein R, Hy, R2 and R3 are as defined above.

[0113] In a further preferred embodiment, the present invention relates to compounds of formula (IBa'S), wherein R2 is trifluoromethyl; R3 is 4-methyl-1H-imidazol-1-yl and (4-methylpiperazin-1-yl)methyl; and Hy is selected from the group consisting of 1H-pyrazolo[3,4-b]pyridin-5-yl, imidazo[1,2-a]pyridin-3-yl, and 1-(imidazo[1,2-a]pyrazin-3-yl).

[0114] According to a preferred embodiment, the present invention relates to at least one compound of formula (IBa'S) and its pharmaceutically acceptable salts as listed in Table 5 below. These compounds are particularly active against the receptors DDR1 and DDR2, as shown in Table 7.

[0115] [Table 5]

[0116] In another particularly preferred embodiment, the present invention provides a compound of formula (IBa) wherein L is -CH2-, having formula (IBa''): [ka] wherein R, Hy, R2 and R3 are as defined above.

[0117] In a particularly preferred embodiment, the present invention provides a compound of general formula (I) wherein L1 is -NHC(O)-, L is -CH2-, and R1 is X': [ka] and a compound of formula (IBa''S): [ka] wherein R, Hy, R2 and R3 are as defined above.

[0118] In a further preferred embodiment, the present invention relates to a compound of formula (IBa''S), wherein R2 is trifluoromethyl; R3 is H or selected from the group consisting of 4-methyl-1H-imidazol-1-yl and 4-(methylpiperazin-1-yl)methyl; and Hy is selected from the group consisting of imidazo[1,2-a]pyridin-3-yl; benzo[d]thiazol-6-yl, imidazo[1,2-a]pyrazin-3-yl, and 1H-pyrazolo[3,4-b]pyridin-5-yl.

[0119] According to a preferred embodiment, the present invention relates to at least one compound of formula (IBa''S) and its pharmaceutically acceptable salts as listed in Table 6 below. These compounds are particularly active on the receptors DDR1 and DDR2, as shown in Table 7.

[0120] [Table 6-1] [Table 6-2]

[0121] In a particularly preferred embodiment, the present invention provides compounds of general formula (I) in which L1 is -NHC(O)- and R1 is Het, which compounds have the formula (IBb): [ka] The present invention relates to a compound represented by the formula:

[0122] In another preferred embodiment, the present invention provides a compound of general formula (IBb) wherein L is —C(O)—, having formula (IBb′): [ka] wherein R, Hy and Het are as defined above.

[0123] In another preferred embodiment, the present invention provides a compound of general formula (IBb) wherein L is -CH2-, having formula (IBb''): [ka] wherein R, Hy and Het are as defined above.

[0124] It is clearly understood that any compound of the present invention may be encompassed by more than one general formula. For example, but not limited to, a compound may be encompassed by both formula (IA") and formula (IAb"), both of which have L = CH and L = -C(O)NH-.

[0125] The compounds of the present invention (including all compounds listed herein above) can be prepared from readily available starting materials using the following general methods and procedures, or using slightly modified processes readily available to those of ordinary skill in the art. While specific embodiments of the present invention may be shown or described herein, those of ordinary skill in the art will recognize that all implementations or embodiments of the present invention can be obtained using the methods described herein or using other known methods, reagents, and starting materials. Where typical or preferred process conditions (i.e., reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise specified. Optimum reaction conditions may vary depending on the particular reactants or solvents used, but such conditions can be readily determined by one of ordinary skill in the art by routine optimization procedures.

[0126] In some cases, commonly known protecting groups (PG) can be employed when necessary to mask or protect sensitive or reactive moieties in accordance with general principles of chemistry (Protective groups in organic syntheses, 3rd ed. T.W. Greene, P.G.M. Wuts).

[0127] The compounds of formula (I) of the present invention have surprisingly been found to effectively inhibit both the receptors DDR1 and DDR2. Advantageously, the inhibition of the receptors DDR1 and DDR2 can result in the effective treatment of diseases or conditions in which the DDR receptors are involved.

[0128] In this regard, it has now been found that the compounds of formula (I) of the present invention have inhibitory potencies, expressed as inhibition constants Ki, against DDR1 and DDR2 of less than 80 nM, as shown in the experimental section. Preferably, the compounds of the present invention have Ki of less than 50 nM against DDR1 and DDR2. More preferably, the compounds of the present invention have Ki of less than 25 nM against DDR1 and DDR2.

[0129] Furthermore, as shown in the experimental section, the compounds of formula (I) of the present invention have both an affinity for either DDR1 or DDR2 receptors and an inhibitory activity for either DDR1 or DDR2 receptors in binding (expressed as Ki) and cell-based assays (expressed as IC50), each of which is less than about 80 nM. Preferably, the compounds of the present invention have a Ki and / or IC50 for DDR1 and DDR2 receptors that is less than 50 nM. More preferably, the compounds of the present invention have a Ki and / or IC50 for DDR1 and DDR2 receptors that is less than 25 nM.

[0130] In one aspect, the present invention relates to a compound of formula (I) according to any of the above disclosed embodiments for use as a medicament.

[0131] In a preferred embodiment, the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof for use in the treatment of diseases, disorders or conditions associated with dysregulation of the DDR.

[0132] In another aspect, the present invention relates to the use of a compound of formula (I) as defined above in the preparation of a medicament for the treatment of a disorder associated with dysregulation of the DDR.

[0133] In a preferred embodiment, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the prevention and / or treatment of a disease, disorder or condition associated with a DDR receptor mechanism. In one embodiment, the present invention relates to a compound of formula (I) useful for the prevention and / or treatment of fibrosis and / or a disease, disorder or condition involving fibrosis.

[0134] As used herein, the term "fibrosis" or "fibrotic disorder" means a condition associated with abnormal accumulation of cells and / or fibronectin and / or collagen and / or increased fibroblast recruitment, including, but not limited to, fibrosis of individual organs or tissues such as the heart, kidney, liver, joints, lung, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal and gastrointestinal tract.

[0135] Preferably, the compounds of formula (I) above are useful for the treatment and / or prevention of fibrosis such as pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), liver fibrosis, renal fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis and systemic sclerosis.

[0136] More preferably, the compounds of formula (I) above are for the treatment of idiopathic pulmonary fibrosis (IPF).

[0137] In one aspect, the present invention also relates to a method for preventing and / or treating disorders associated with DDR receptor mechanisms, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) as defined above.

[0138] In a further aspect, the present invention relates to the use of compounds of formula (I) as defined above for treating disorders associated with DDR receptor mechanisms.

[0139] In another aspect, the present invention relates to the use of a compound of formula (I) as defined above in the preparation of a medicament for the treatment of a disorder associated with the DDR receptor mechanism.

[0140] In a further aspect, the present invention relates to a method for preventing and / or treating disorders or conditions associated with dysregulation of DDR receptors 1 and 2, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) as defined above.

[0141] In a further aspect, the present invention relates to the use of a compound of formula (I) as defined above for treating a disease, disorder or condition associated with dysregulation of DDR receptors 1 and 2.

[0142] As used herein, a "safe and effective amount" with respect to a compound of formula (I) or a pharmaceutically acceptable salt thereof or other pharmaceutically active agent means an amount of the compound that is sufficient to treat the patient's condition but low enough to avoid serious side effects, yet can be routinely determined by one of ordinary skill in the art.

[0143] The compounds of formula (I) may be administered in a single dose or according to a dosing regimen in which multiple doses are administered at varying time intervals over a predetermined period of time. Typical daily doses may vary depending on the route of administration selected.

[0144] The present invention also relates to a pharmaceutical composition comprising a compound of formula (I) according to any of its embodiments, together with at least one or more pharmaceutically acceptable carriers or excipients.

[0145] In one embodiment, the present invention relates to pharmaceutical compositions of a compound of formula (I) admixed with one or more pharmaceutically acceptable carriers or excipients, such as those described in Remington's Pharmaceutical Sciences Handbook, XVII Ed., Mack Pub., NY, USA.

[0146] Administration of the compounds of the present invention and pharmaceutical compositions thereof can be achieved, for example, orally, intranasally, parenterally (subcutaneously, intravenously, intramuscularly, intrasternally and by infusion) and by inhalation, depending on the needs of the patient.

[0147] Preferably, the compounds of the present invention are administered orally or by inhalation.

[0148] In a preferred embodiment, the pharmaceutical composition comprising a compound of formula (I) is a solid oral dosage form such as a tablet, gelcap, capsule, caplet, granule, lozenge, and bulk powder.

[0149] In one embodiment, the pharmaceutical composition comprising a compound of Formula (I) is a tablet.

[0150] The compounds of the present invention can be administered alone or in combination with various pharmaceutically acceptable carriers, diluents (sucrose, mannitol, lactose, starch, etc.), and known excipients including suspending agents, solubilizing agents, buffers, binders, disintegrating agents, preservatives, coloring agents, flavoring agents, lubricants, and the like.

[0151] In a further embodiment, the pharmaceutical compositions comprising the compounds of formula (I) are liquid oral dosage forms such as aqueous and non-aqueous solutions, emulsions, suspensions, syrups and elixirs. Such liquid dosage forms may also contain suitable known inert diluents such as water, and suitable known excipients such as preservatives, wetting agents, sweeteners, flavoring agents, and agents for emulsifying and / or suspending the compounds of the present invention.

[0152] In a further embodiment, the pharmaceutical composition comprising a compound of formula (I) is an inhalable preparation, such as an inhalable powder, a propellant-containing metered aerosol, or a propellant-free inhalable formulation.

[0153] When administered as a dry powder, single or multi-dose inhalers known in the art can be utilized, in which case the powder can be filled into gelatin, plastic or other capsules, cartridges or blister packs or reservoirs.

[0154] Diluents or carriers that are chemically inert to the compounds of the invention, such as lactose or other additives suitable for improving the respirable fraction, may be added to the powdered compounds of the invention.

[0155] Inhalation aerosols containing a propellant gas such as a hydrofluoroalkane may contain the compounds of the present invention either in solution or in dispersion form. Propellant-driven formulations may contain other ingredients such as cosolvents, stabilizers, and optionally other excipients.

[0156] Propellant-free inhalable formulations containing the compounds of the invention may be in the form of a solution or suspension in an aqueous, alcoholic or hydroalcoholic medium and may be delivered by jet or ultrasonic or soft mist nebulizers known from the prior art.

[0157] The compounds of the present invention may be administered alone or in combination with other pharmaceutically active ingredients.

[0158] The dosage of the compounds of the present invention will depend on a variety of factors, including, inter alia, the particular disease being treated, the severity of the condition, the route of administration, and the like.

[0159] The present invention is also directed to a device comprising a pharmaceutical composition comprising a compound of formula (I) according to the present invention in the form of a single or multi-dose dry powder inhaler or a metered dose inhaler.

[0160] All preferred groups or embodiments mentioned above for compounds of formula (I) may be combined with one another and apply mutatis mutandis.

[0161] The compounds of the present invention (including all compounds listed herein above) can be prepared from readily available starting materials using the following general methods and procedures, or using slightly modified processes readily available to those of ordinary skill in the art. While specific embodiments of the present invention may be shown or described herein, those of ordinary skill in the art will recognize that all embodiments or aspects of the present invention can be obtained using the methods described herein or using other known methods, reagents, and starting materials. Where typical or preferred process conditions (i.e., reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise specified. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be readily determined by one of ordinary skill in the art by routine optimization procedures.

[0162] Accordingly, the processes described below and reported in the schemes below should not be construed as limiting the scope of synthetic methods available for the preparation of compounds of the present invention.

[0163] Compounds of formula (I), including at least one or all of the compounds listed herein, can be prepared using generally known methods according to the procedures outlined in detail in the schemes shown below.

[0164] In a first embodiment of the present invention, compounds of formula (I) [wherein R1, L, L1, Hy and X are as defined above] can be prepared as described in Scheme 1.

[0165] Compounds of formula (I) can be prepared according to Scheme 1 set forth below, which provides at least one non-limiting synthetic route for the preparation of all examples.

[0166] [ka]

[0167] According to Scheme 1, intermediate V can be prepared via a one-step synthesis starting from intermediate II under suitable amide coupling reaction conditions. For example, intermediate II can be reacted with the appropriate amine III or IV using an organic base such as DIPEA or TEA in the presence of an agent that activates the carboxylic acid partner for subsequent reaction with the amine, such as T3P or HATU, in a suitable organic solvent such as DCM or DMF, typically at temperatures around RT for several hours to overnight. Alternatively, intermediate III can be obtained by reacting intermediate II in the presence of TCFH and 1-methylimidazole in a suitable solvent such as DMF at RT to give a transiently activated acylimidazolinium intermediate that can be reacted with the appropriate amine III or IV.

[0168] In another approach, intermediate V can be obtained by direct transamidation between intermediate IIa and the appropriate amine III using, for example, butyllithium as a base in a suitable organic solvent such as THF or dioxane at temperatures ranging from room temperature to −78° C. for several hours.

[0169] Intermediate V can be converted to intermediate VI by deprotecting the BOC-protected amine under acidic conditions such as trifluoroacetic acid in a suitable solvent such as, but not limited to, DCM at room temperature for several hours, and intermediate VI can then be converted to compounds of formula (I) bearing the appropriate aldehyde VII by applying reductive amination conditions using a suitable reducing agent such as Na(OAc)BH or NaCNBH, and if necessary, a suitable dehydrating agent such as MgSO, in a suitable solvent such as DCM or EtOH in the presence of an acid such as acetic acid and a coordinating agent such as titanium tetrahydroisopropoxide, if necessary, at room temperature.

[0170] Alternatively, compounds of formula (I) can be prepared from intermediate VI via amidation conditions with an appropriate carboxylic acid X in the presence of an organic base such as DIPEA or TEA and an agent that activates the carboxylic acid partner such as TBTU or HATU or T3P in a suitable organic solvent such as DCM or DMF, typically at around room temperature.

[0171] In a different approach, compounds of formula (I) can be prepared from intermediate VI by applying reductive amination conditions, as described above, with a suitable bromo-aldehyde VIII to give intermediate IX, followed by It can be obtained by applying palladium catalyzed cross-coupling conditions with a suitable amine using a suitable palladium catalyst such as RuPhos Pd G3 in a suitable solvent such as dioxane and a suitable base such as LiHMDS at a suitable temperature, e.g. 80°C.

[0172] Intermediate XII can be prepared from intermediate IIb by protecting the amine with a suitable protecting agent, such as, but not limited to, Boc anhydride, with a suitable promoter, such as DMAP, in a suitable solvent, such as DCM or DMF, and a suitable base, such as DIPEA or TEA, at room temperature, followed by reduction of the nitro group with a suitable hydrogen source, such as H, with a suitable catalyst, such as palladium on carbon, in a suitable solvent, such as ethyl acetate, at room temperature. Intermediate XII can undergo amidation using a suitable carboxylic acid and applying the appropriate amidation conditions described above, followed by Boc deprotection, performed as described above, to provide intermediate XIV, which can be reacted with a suitable aldehyde VII under reductive amination conditions, as described above, to provide compounds of formula (I).

[0173] Alternatively, intermediate XIV can undergo amidation with an appropriate carboxylic acid X using the conditions described above to give compounds of formula (I).

[0174] In another embodiment, compounds of formula (I) can be prepared according to Scheme 2.

[0175] [ka]

[0176] According to Scheme 2, intermediate XV can be prepared from intermediate IIc by reducing conditions using a suitable hydrogen source, for example, triethylsilane, under acidic conditions such as trifluoroacetic acid in a suitable organic solvent such as THF, typically at a temperature around 0° C. for a period ranging from several hours to overnight. Intermediate XV can be subjected to amine protection using a suitable organic base such as DIPEA or TEA, a suitable activating agent such as DMAP, in the presence of a suitable protecting group such as BOC anhydride, typically in a suitable organic solvent such as DCM, at a temperature around RT for a period ranging from several hours to overnight, to give intermediate XVI.

[0177] Hydrolysis of ester XVI can be carried out under basic conditions, such as lithium hydroxide, in a suitable organic solvent, such as MeOH, typically at about room temperature. Intermediate XVIII can be prepared from intermediate XVI under suitable amide coupling reaction conditions. For example, intermediate XVII can be reacted with the appropriate amine III or IV using an organic base, such as DIPEA or TEA, in the presence of an agent that activates the carboxylic acid partner for subsequent reaction with an amine, such as T3P or HATU, in a suitable organic solvent, such as DCM or DMF, typically at about room temperature for a period ranging from several hours to overnight.

[0178] Intermediate XVIII can be converted to intermediate XIX by deprotecting the BOC-protected amine under suitable acidic conditions, such as trifluoroacetic acid, in a suitable solvent, such as, but not limited to, DCM, at room temperature for several hours.

[0179] Compounds of formula (I) can then be obtained from intermediate XIX using the appropriate carboxylic acid X under suitable amide coupling conditions as described above. Alternatively, intermediate XIX can be converted to compounds of formula (I) using the appropriate aldehyde VII by applying reductive amination conditions at room temperature using a suitable reducing agent such as Na(OAc)BH or NaCNBH, and optionally using a suitable dehydrating agent such as MgSO, in the presence of an acid such as acetic acid and optionally a coordinating agent such as titanium tetrahydroisopropoxide.

[0180] In another approach, intermediate XXI can be prepared from intermediate Iid by reductive amination with an appropriate aldehyde VII using the conditions described above, followed by hydrolysis of the ester using a suitable aqueous inorganic base such as LiOH or NaOH in a suitable solvent such as MeOH or EtOH at room temperature.

[0181] Compounds of formula (I) can be obtained from intermediate XX by applying transamidation conditions with the appropriate amine III or IV using a suitable base such as butyllithium or LDA in a suitable organic solvent such as THF or dioxane for several hours at a temperature in the range of −78° C. Alternatively, compounds of formula (I) can be obtained from intermediate XXI under suitable amide coupling reaction conditions with the appropriate amine III or IV using an organic base such as DIPEA or TEA in the presence of an agent that activates the carboxylic acid partner for subsequent reaction with an amine such as T3P or HATU, in a suitable organic solvent such as DCM or DMF for a time generally ranging from several hours to overnight at a temperature around RT. In another approach, compounds of formula (I) can be obtained from intermediate XXI by applying acyl chloride forming conditions, for example using a suitable chlorinating agent such as thionyl chloride or oxalyl chloride in a suitable solvent such as DCM at a temperature ranging from 0° C. to room temperature, followed by amidation such as treating amine IV with LiHMDS in a suitable solvent such as THF at a suitable temperature such as −78° C.

[0182] In a further embodiment, compounds of formula I can be prepared according to Scheme 3.

[0183] [ka]

[0184] According to Scheme 3, intermediate XXIII can be prepared from intermediate IIe by applying Friedel-Crafts acylation conditions using an appropriate acyl chloride, such as acetyl chloride, with a suitable Lewis acid, such as AlCl3, in a suitable solvent, such as DCM. Intermediate XXIII can be reduced to intermediate XXIV with a suitable hydrogen source, such as triethylsilane, under acidic conditions, such as trifluoroacetic acid, in a suitable organic solvent, such as THF, typically at a temperature around 0 °C overnight. Intermediate XXIV can be converted to intermediate XXV with an appropriate aldehyde VII by reductive amination conditions, using a suitable reducing agent, such as Na(OAc)3BH or NaCNBH3, and optionally a suitable dehydrating agent, such as Mg2SO4, in a suitable solvent, such as DCM or EtOH, in the presence of an acid, such as acetic acid, and optionally a coordinating agent, such as titanium tetrahydroisopropoxide, at room temperature. Hydrolysis of ester XXV can be carried out under basic conditions, such as lithium hydroxide, in a suitable organic solvent, such as MeOH, typically at a temperature around room temperature. Compounds of formula (I) can be obtained starting from intermediate XXVI by the presence of a suitable chlorinating reagent such as POCl or thionyl chloride in a solvent such as pyridine or DCM at 5° C. or room temperature to give the corresponding acyl chloride, which can then be directly treated with an appropriate amine III in a suitable solvent such as DCM at room temperature.

[0185] Various aspects of the invention described in this application are illustrated by the following examples, which should not be construed as limiting the invention in any way.

[0186] Preparation of Intermediates and Examples

[0187] Chemical names of compounds were generated using Structure To Name Place IUPAC Name by PerkinElmer ChemDraw Professional 19.1.1.21.

[0188] All reagents whose synthesis is not described in the experimental section are commercially available, are known compounds, or can be formed from known compounds by known methods by one skilled in the art.

[0189] In the following procedures, some of the starting materials are designated with "Intermediate" or "Example" numbers and step numbers, which are provided solely for the assistance of the skilled chemist.

[0190] By "similar" or "analogous" procedures, it is meant that such procedures may involve minor variations, e.g., reaction temperatures, amounts of reagents / solvents, reaction times, work-up conditions, chromatographic purification conditions, etc.

[0191] Abbreviation-Meaning t R= retention time; Boc = tert-butoxycarbonyl; (BOC)2O = Boc anhydride, di-tert-butyl dicarbonate; TEA = triethylamine; HATU = (dimethylamino)-N,N-dimethyl(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methaniminium hexafluorophosphate; TBTU = O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; DMAP = 4-dimethylaminopyridine; DMF = dimethylformamide; EtOAc = ethyl acetate; ee = enantiomeric excess; RT or rt = room temperature; THF = tetrahydrofuran; SOCl2 = thionyl chloride; DCM = dichloromethane; MeOH = methyl alcohol; LCMS = liquid chromatography / mass spectrometry; HPLC = high-performance liquid chromatography; PrepHPLC = preparative high-performance liquid chromatography; Int. = intermediate; TLC = thin-layer chromatography; d-DMSO = deuterated dimethyl sulfoxide; NMR = nuclear magnetic resonance; DIPEA = N,N-diisopropylethylamine; UPLC = ultra-high performance liquid chromatography; tBu XPhos = 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl; PdCl 2( dppf) = [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); STAB = sodium triacetoxyborohydride; Pd(OAc)2 = palladium(II) acetate; AcOH = acetic acid; Py = pyridine; T3P = propanephosphonic anhydride; NaBH3CN = sodium cyanoborohydride; Na2SO4 = sodium sulfate; pTLC = preparative thin-layer chromatography; FCC = flash column chromatography; nBuLi = n-butyllithium; ACN = acetonitrile; NaHCO3 = 15% or saturated solution of sodium bicarbonate (sat.aq.sol.); RuPhos Pd G3: (2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, 3rd generation. SCX = strong cation exchange; SFC = supercritical fluid chromatography; SM = starting material; eq. = equivalent.

[0192] Xphos Pd G2 = (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, 2nd generation; Xphos Pd G3 = (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, 3rd generation.

[0193] General experimental details and methods NMR characterization 1 H NMR spectra were recorded on a Varian MR-400 spectrometer operating at 400 MHz (proton frequency) equipped with a 5 mm 1H / nX broadband probehead with a self-shielded Z gradient coil for inverse detection, a deuterium digital lock channel unit, and a quadrature digital detection unit with transmitter offset frequency shift, or 1 H NMR spectra were recorded on a Bruker Avance III HD 400 MHz or a Bruker Fourier 300 MHz. Chemical shifts are reported in ppm relative to trimethylsilane (TMS) as the internal standard. Coupling constants (J values) are given in Hertz (Hz), and multiplicities are reported using the following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br. s = broad singlet, nd = undetermined.

[0194] The NH signal of an amide or amine bond (exchangeable proton) may not be visible. The CH2 signal of the indoline ring may be hidden under the water or DMSO signal. The CH2 signal of the pyrrolidine or 1-methylpiperazine ring may be hidden under the water or DMSO signal. The CH3 group signal may be hidden under the water or DMSO signal.

[0195] LC / UV / MS analysis method LC / MS retention times are estimated to be subject to an experimental error of ±0.5 min.

[0196] Method 1: Kinetex® XB-C18 column, 4.6 x 50 mm, 2.6 μm, maintained at 25°C. Mobile phase: water (0.1% formic acid) in MeCN (0.1% formic acid), 80% to 5% in 3.90 min; flow rate: 1.0 ml / min; wavelength: 190-340 nm DAD. Dionex UHPLC Ultimate 3000 / Thermo Scientific MSQ Plus with DAD detector.

[0197] Method 2: Acquity UPLC HSS C18 column, 100x2.1mm, 1.8µm (Plus guard cartridge), maintained at 40°C. Mobile phase: MeCN (0.1% formic acid) in water (0.1% formic acid) from 5% to 95% in 5.6 minutes. Flow rate: 0.4ml / min. Wavelength: 210-400nm DAD. UPLC + Waters DAD + Waters SQD2, single quadrupole UPLC-MS.

[0198] Method 3: Kinetex® XB-C18 column, 4.6 x 50 mm, 2.6 μm, maintained at 25°C. Mobile phase: water (0.1% formic acid) in MeCN (0.1% formic acid), 95% to 20% in 4.75 min; flow rate: 1.0 ml / min; wavelength: 190-340 nm DAD. Dionex UHPLC Ultimate 3000 / Thermo Scientific MSQ Plus with DAD detector.

[0199] Method 4: Kinetex® XB-C18 column, 4.6 x 50 mm, 2.6 μm, maintained at 25°C. Mobile phase: water (0.1% formic acid) in MeCN (0.1% formic acid), 90% to 5% in 3.90 min; flow rate: 1.0 ml / min; wavelength: 190-340 nm DAD. Dionex UHPLC Ultimate 3000 / Thermo Scientific MSQ Plus with DAD detector.

[0200] Method 5: Kinetex® XB-C18 column, 4.6 x 50 mm, 2.6 μm, maintained at 25°C. Mobile phase: water (0.1% formic acid) in MeCN (0.1% formic acid), 70% to 5% in 3.90 min; flow rate: 1.0 ml / min; wavelength: 190-340 nm DAD. Dionex UHPLC Ultimate 3000 / Thermo Scientific MSQ Plus with DAD detector.

[0201] Method 6: Acquity CSH C18 column, 50 mm x 2.1 mm, 1.7 μm, maintained at 40 °C; Mobile phase: Eluent B (MeCN / water 95:5 + 0.05% HCOOH) in Eluent A (water / MeCN 95:5 + 0.05% HCOOH), from 1% to 99.9% in 1.5 min. Flow rate: 1 mL / min. Wavelength: 210-400 nm. UPLC + Waters PDA + Waters QDA.

[0202] Method 7: Kinetex® XB-C18 column, 4.6 x 50 mm, 2.6 μm, maintained at 25°C. Mobile phase: water (0.1% formic acid) in MeCN (0.1% formic acid), 80% to 5% in 3.90 min; flow rate: 1.0 ml / min; wavelength: 190-340 nm DAD. Dionex UHPLC Ultimate 3000 / Thermo Scientific MSQ Plus with DAD detector.

[0203] Method 8: Kinetex® XB-C18 column, 4.6 x 50 mm, 2.6 μm, maintained at 25°C. Mobile phase: water (without formic acid) in MeCN (without formic acid), 60% to 5% in 3.90 min; flow rate: 1.0 ml / min; wavelength: 190-340 nm DAD. Dionex UHPLC Ultimate 3000 / Thermo Scientific MSQ Plus with DAD detector.

[0204] Method 9: Kinetex® XB-C18 column, 4.6 x 50 mm, 2.6 μm, maintained at 25°C. Mobile phase: water (0.1% formic acid) in MeCN (0.1% formic acid), 60% to 5% in 3.90 min; flow rate: 1.0 ml / min; wavelength: 190-350 nm DAD. Dionex UHPLC Ultimate 3000 / Thermo Scientific ISQ EC mass spectrometer with DAD detector.

[0205] Method 10: Kinetex® XB-C18 column, 4.6 x 50 mm, 2.6 μm, maintained at 25°C. Mobile phase: water (0.1% formic acid) in MeCN (0.1% formic acid), 70% to 5% in 3.90 min; flow rate: 1.0 ml / min; wavelength: 190-350 nm DAD. Dionex UHPLC Ultimate 3000 / Thermo Scientific ISQ EC mass spectrometer with DAD detector.

[0206] Method 11: Kinetex® XB-C18 column, 4.6 x 50 mm, 2.6 μm, maintained at 25°C. Mobile phase: water (0.1% formic acid) in MeCN (0.1% formic acid), 80% to 5% in 3.90 min; flow rate: 1.0 ml / min; wavelength: 190-340 nm DAD. Dionex UHPLC Ultimate 3000 / Thermo Scientific MSQ Plus with DAD detector.

[0207] Method 12: Kinetex® XB-C18 column, 4.6 x 50 mm, 2.6 μm, maintained at 25°C. Mobile phase: water (0.1% formic acid) in MeCN (0.1% formic acid), 75% to 5% within 3.90 min; flow rate: 1.0 ml / min; wavelength: 190-340 nm DAD. Dionex UHPLC Ultimate 3000 / Thermo Scientific MSQ Plus with DAD detector.

[0208] Method 13: ACQUITY UPLC BEH C8 column, 42.1 x 150 mm, 1.7 μm, maintained at 55 °C. Mobile phase: Water (0.1% formic acid) in MeCN (0.1% formic acid), 80% to 10% in 7.00 min; flow rate: 0.5 ml / min; wavelength: 190-340 nm DAD. Dionex UHPLC Ultimate 3000 / Thermo Scientific MSQ Plus with DAD detector.

[0209] Method 14: Kinetex® XB-C18 column, 4.6 x 50 mm, 2.6 μm, maintained at 25°C. Mobile phase: water (0.1% formic acid) in MeCN (0.1% formic acid), 50% to 5% in 3.90 min; flow rate: 1.0 ml / min; wavelength: 190-350 nm DAD. Dionex UHPLC Ultimate 3000 / Thermo Scientific ISQ EC-Mass Spectrometer with DAD detector.

[0210] Method 15: Gemini-NX C18 column, 4.6 x 150 mm, 3 μm, maintained at 35 °C. Mobile phase: Water (0.1% formic acid) in MeCN (0.1% formic acid), 80% to 5% in 8.50 min; flow rate: 1.0 ml / min; wavelength: 190-340 nm DAD. Dionex UHPLC Ultimate 3000 / Thermo Scientific MSQ Plus with DAD detector.

[0211] Method 16: Kinetex® XB-C18 column, 4.6 x 50 mm, 2.6 μm, maintained at 25°C. Mobile phase: water (0.1% formic acid) in MeCN (0.1% formic acid), 60% to 5% in 3.90 min; flow rate: 1.0 ml / min; wavelength: 190-340 nm DAD. Dionex UHPLC Ultimate 3000 / Thermo Scientific ISQ EC mass spectrometer with DAD detector.

[0212] Method 20: Acquity UPLC BEH C18, 100x2.1mm, 1.7µm, maintained at 40°C. Mobile phase: MeCN (0.1% formic acid) in water (0.1% formic acid), 5% to 80% in 1.5 minutes; flow rate: 1.5ml / min; wavelength: 210-400nm DAD. Acquity H-Class UPLC with PDA detector and Qda.

[0213] Method 21: Acquity BEH UPLC column, 2.1 x 50 mm, 1.7 μm, maintained at 40 °C. Mobile phase: MeCN (0.03% ammonia) in water (0.03% ammonia), from 8% to 97% in 1.5 min; flow rate: 0.8 ml / min; wavelength: 210-400 nm. Acquity H-Class UPLC with PDA detector and QDa.

[0214] Method 22: Waters Sunfire C18 column, 4.6 x 50 mm, 3.5 μm, maintained at 40 °C. Mobile phase: MeCN + 10 mM ammonium bicarbonate in water, 5 to 95% in 2.5 min. Flow rate: 2.0 ml / min. Wavelength: 210-400 nm DAD. Waters 2795 Separation Module + Waters DAD + Micromass ZQ, single quadrupole LC-MS.

[0215] Chiral Supercritical Fluid Chromatography (SFC) Separation Protocol Diastereomeric separation of compounds was achieved by supercritical fluid chromatography (SFC) using a Waters Thar Prep100 preparative SFC system (P200 CO2 pump, 2545 modifier pump, 2998 UV / VIS detector, and 2767 liquid handler with stacked injection module). The Waters 2767 liquid handler served as the autosampler and fraction collector. Appropriate isocratic methods were selected under unmodified or basic conditions based on methanol, ethanol, or isopropanol solvent systems. The standard SFC method used the modifier CO2 at 100 mL / min, 120 bar backpressure, and 40 °C column temperature. The modifier used under basic conditions was diethylamine (0.1% v / v). The modifier used under acidic conditions was formic acid (0.1% v / v) or trifluoroacetic acid (0.1% v / v). SFC purification was controlled by Waters Fractionlynx software, monitoring from 210 to 400 nm and triggering at a threshold collection value (usually 260 nm). Collected fractions were analyzed by SFC (Waters / Thar SFC system with Waters SQD). Fractions containing the desired product were concentrated by vacuum centrifugation.

[0216] Supercritical fluid chromatography-mass spectrometry analysis conditions:

[0217] Method 17: SFC-MS was performed on a Waters / Thar SFC system equipped with a Waters SQD using a YMC AMYLOSE-C column (45% IPA / CO2 (containing 0.1% diethylamine) isocratic run at 100 mL / min, 120 Bar backpressure, and 40 °C column temperature).

[0218] Method 18: SFC-MS was performed on a Gilson preparative LC system (Gilson Pump - 333; Gilson 151; Gilson Valvemate 6 position) using a Lux C1 (21.2 mm x 250 mm, 5 μm) column (isocratic run (50:50 hexane:EtOH, 0.2% v / v NH3) at 21 mL / min, column temperature 30 °C).

[0219] Method 19: SFC-MS was performed on a Gilson preparative LC system using a Lux C1 (4.6 mm x 250 mm, 5 μm) column (isocratic run (50:50 HEX:EtOH (0.2% v / v NH3) at 1 mL / min, column temperature 30 °C).

[0220] Where the preparation of starting materials is not described, these are either commercially available, known in the literature, or readily available to those skilled in the art using standard procedures. All solvents were commercially available and used without purification.

[0221] Preparative HPLC was performed using reverse-phase (C18) preparative HPLC under both basic (ACN + 0.1% NH, HO + 0.1% NH) and acidic (ACN + 0.1% FA, HO + 0.1% FA) conditions; in the latter case, unless otherwise noted, the residue was triturated with NaHCO (15% aq. sol.), and the precipitate was filtered through a Schottky funnel, rinsed with water, transferred to a vial, and dried under high vacuum overnight at room temperature; alternatively, the free base of the product was obtained using SCX(NH).

[0222] Thin layer chromatography was performed on Merck silica gel 60 F254 TLC plates. Preparative thin layer chromatography (pTLC) was performed on Uniplate 1000 micron or 500 micron silica gel plates.

[0223] Flash chromatography (FCC) was performed using Interchim PuriFlash 450 and 520Plus systems or Isolera unless otherwise specified in the text. TM A flash purification system was used, using pre-packed silica gel cartridges.

[0224] Preparation of intermediates Preparation of Lithio 3-[(4-methylpiperazin-1-yl)methyl]-5-(trifluoromethyl)benzoate - Intermediate 1 [ka]

[0225] Step 1: Methyl 3-bromo-5-(trifluoromethyl)benzoate - Intermediate 2 [ka]

[0226] To a solution of 3-bromo-5-(trifluoromethyl)benzoic acid (75.0 g, 279 mmol) in MeOH (282 mL) at 0 °C, SOCl (81.0 mL, 1115 mmol) was added dropwise. The reaction mixture was then stirred under reflux overnight, after which the volatiles were removed under vacuum. Water (200 mL) was added to the residue, and the aqueous phase was extracted with EtOAc (2 x 250 mL). The organic phases were combined, washed with a saturated solution of NaHCO, dried over NaSO, and concentrated under vacuum to give the title compound (74.5 g, 94%).

[0227] 1 H NMR (300 MHz, DMSO-d6) δ 8.30 (dt, J = 1.8, 0.8 Hz, 2H), 8.13 (td, J = 1.6, 0.8 Hz, 1H), 3.90 (s, 3H).

[0228] Step 2: Methyl 3-[(4-methylpiperazin-1-yl)methyl]-5-(trifluoromethyl)benzoate - Intermediate 3 [ka]

[0229] Intermediate 2 (47.5 g, 168 mmol), CsCO (164 g, 503 mmol), potassium 1-methyl-4-trifluoroborate methylpiperazine (40.6 g, 184.6 mmol) were suspended in a mixture of THF (100 mL) and water (11 mL). The suspension was degassed, and then Pd(OAc) (3.76 g, 16.8 mmol) and XPhos (16.0 g, 33.5 mmol) were added, and the reaction was carried out at 80 °C for 24 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 × 150 mL). The organic phases were combined, concentrated, and dried under vacuum to give the crude product, which was purified by column chromatography eluting with DCM / MeOH (9:1) to give the title compound (25.3 g, 48%).

[0230] 1 H NMR (300 MHz, DMSO-d6) δ 8.16 (d, J = 1.7 Hz, 1H), 8.07 (t, J = 1.8 Hz, 1H), 7.97 - 7.86 (m, 1H), 3.90 (s, 3H), 3.62 (s, 2H), 2.38 (s, 8H), 2.15 (s, 3H).

[0231] Step 3: Lithio 3-[(4-methylpiperazin-1-yl)methyl]-5-(trifluoromethyl)benzoate - Intermediate 1 Intermediate 3 (25.3 g, 80.0 mmol) was dissolved in MeOH (700 mL). 1 M LiOH solution (3.8 g, 160 mL) was added to the reaction mixture and stirred at RT overnight. The solvent was removed in vacuo, and the crude material was triturated with diethyl ether (2x) and filtered. The solid was collected to give the title compound (26.0 g, 100%).

[0232] 1H NMR (300 MHz, DMSO-d6) δ 8.02 (s, 2H), 7.49 (s, 1H), 3.51 (s, 2H), 2.32 (s, 8H), 2.14 (s, 3H).

[0233] Preparation of 2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine-5-carbaldehyde - Intermediate 4 [ka]

[0234] Step 1: 2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine-5-carbaldehyde - Intermediate 4

[0235] 2-Chloropyrimidine-5-carbaldehyde (50 mg, 0.351 mmol) was dissolved in THF (3.5 ml), followed by the addition of 1-methyl-1H-pyrazol-4-amine (41 mg, 0.421 mmol), TEA (0.1 ml, 0.719 mmol), and THF (3.5 ml). The reaction mixture was stirred at room temperature overnight. The mixture was quenched by adding DCM and brine. The phases were separated, and the aqueous phase was washed with DCM (x2). All organic phases were combined, dried over Na2SO4, filtered, and concentrated. The crude material was purified by FCC eluting with hexane / ethyl acetate (1:1) to give the title compound (35 mg, 39%).

[0236] 1 H NMR (300 MHz, DMSO-d6) δ 10.45 (s, 1H), 9.80 (s, 1H), 8.92 - 8.79 (m, 2H), 7.99 (d, J = 0.8 Hz, 1H), 7.56 (d, J = 0.8 Hz, 1H), 3.83 (s, 3H).

[0237] 3-(morpholinomethyl)-5-(trifluoromethyl)aniline - Preparation of intermediate 5 [ka]

[0238] Step 1: 4-(3-nitro-5-(trifluoromethyl)benzyl)morpholine - Intermediate 6 [ka]

[0239] 3-Nitro-5-(trifluoromethyl)benzaldehyde (150 mg, 0.685 mmol) and morpholine (0.066 mL, 0.753 mmol) were dissolved in DCM (6.8 mL), and titanium(IV) isopropoxide (389.4 mg, 1.37 mmol) and acetic acid were added. The reaction mixture was stirred at room temperature for 1 h. STAB (290 mg, 1.37 mmol) was added, and the reaction mixture was stirred at room temperature until LCMS showed the consumption of the starting material. The reaction mixture was diluted with DCM and saturated NaHCO3 (aq) The mixture was partitioned between 1000 ml of ethyl acetate and 1000 ml of ethyl acetate, and the mixture was filtered through a bed of Celite. The aqueous phase was extracted 2x with DCM, and the organic phases were combined and washed with saturated aqueous NaCl. (aq) The extract was washed with HCl, separated and concentrated in vacuo to give the title compound (197 mg, 99%).

[0240] 1 H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 8.40 (s, 1H), 7.96 (s, 1H), 3.76 - 3.73 (m, 4H), 3.66 (s, 2H), 2.51 - 2.48 (m, 4H)

[0241] The following compounds were prepared by reacting the appropriate corresponding amine as described for Step 1 of Intermediate 6.

[0242] [Table 7-1] [Table 7-2]

[0243] Step 2: 3-(morpholinomethyl)-5-(trifluoromethyl)aniline - Intermediate 5 To palladium on carbon 10% (10 wt%) was added a solution of intermediate 6 (153 mg, 0.527 mmol) in ethanol (5 ml). The flask was evacuated and purged with argon (x3), then evacuated and purged with hydrogen (x3). The reaction mixture was stirred at room temperature until LCMS showed consumption of the starting material. The reaction mixture was diluted with DCM and filtered through Celite. The filter cake was washed with DCM and the filtrates were combined and concentrated in vacuo to give the title compound (134 mg, 98%).

[0244] 1 H NMR (400 MHz, CDCl3) δ 6.95 (s, 1H), 6.84 (s, 2H), 6.79 (s, 1H), 3.82 (s, 2H), 3.74 - 3.69 (m, 4H), 3.44 - 3.43 (m, 2H), 2.46 - 2.43 (m, 4H).

[0245] The following compounds were prepared as described for Step 2 of Intermediate 5, starting from the appropriate corresponding Intermediates 7 and 8 described above in Step 1.

[0246] [Table 8]

[0247] 3-(Pyrrolidin-1-ylmethyl)-5-(trifluoromethyl)aniline - Preparation of intermediate 11 [ka]

[0248] Step 1: 3-(trifluoromethyl)-5-vinyl-aniline - intermediate 12 [ka]

[0249] A mixture of 3-amino-5-bromobenzotrifluoride (2.50 g, 10.4 mmol, 1.00 eq), vinylboronic acid pinacol ester (2.10 mL, 12.5 mmol, 1.20 eq), XPhos Pd G3 (441 mg, 0.521 mmol, 0.05 eq), XPhos (497 mg, 1.04 mmol, 0.1 eq), and K3PO4 (5527 mg, 26.0 mmol, 2.5 eq) was suspended in 1,4-dioxane (45 mL) and water (5 mL). The reaction mixture was sparged with argon for 15 min and stirred at 80 °C for 1.5 h. The reaction mixture was allowed to cool to room temperature and partitioned between water and EtOAc. The aqueous phase was extracted 2x with EtOAc, and the organic phases were combined, washed with saturated NaCl(aq), dried (MgSO4), and concentrated. The residue was purified by FCC eluting with 0-30% EtOAc in cyclohexane to give the title compound (1.54 g, 79%).

[0250] 1 H NMR (400 MHz, CDCl3) δ 7.04 (s, 1H), 6.85 (s, 1H), 6.79 (s, 1H), 6.64 (dd, J=11.0, 17.5 Hz, 1H), 5.75 (d, J=17.5 Hz, 1H), 5.30 (d, J=11.0 Hz, 1H), 3.86 (br s, 2H)

[0251] The following intermediate C was prepared by reacting the appropriate corresponding bromide as described for intermediate 12 in step 1. This procedure may involve slight variations. In some cases, variations in chromatographic purification conditions (e.g., prep HPLC or flash chromatography) or catalysts (e.g., XPhos Pd G3 or XPhos Pd G2) were involved, and such variations are reported in the table.

[0252] [Table 9]

[0253] Step 2: tert-butyl N-[3-(trifluoromethyl)-5-vinyl-phenyl]carbamate - Intermediate 13 [ka]

[0254] To a mixture of intermediate 12 (500 mg, 2.67 mmol, 1.00 eq) and di-tert-butyl dicarbonate (0.77 mL, 3.34 mmol, 1.25 eq), toluene (5 mL) was added. The reaction mixture was stirred at 100 °C for 19 h, allowed to cool to RT, and concentrated in vacuo. The residue was diluted with heptane and partially concentrated, resulting in the formation of a thick precipitate. The suspension was filtered in vacuo to give the title compound (488 mg, 64%). The filtrate was concentrated in vacuo, and the residue was purified by FCC eluting with EtOAc (0-10%) in cyclohexane to give the title compound (150 mg, 20%). Combined yield = 638 mg, 84%.

[0255] 1 H NMR (400 MHz, CDCl3) δ 7.59 - 7.54 (m, 2H), 7.32 (s, 1H), 6.69 (dd, J=11.0, 17.5 Hz, 1H), 6.56 (s, 1H), 5.81 (d, J=17.5 Hz, 1H), 5.35 (d, J=11.0 Hz, 1H), 1.53 (s, 9H)

[0256] The following intermediate 47 was prepared as described for intermediate 13 in step 2.

[0257] [Table 10]

[0258] Step 3: tert-butyl N-[3-formyl-5-(trifluoromethyl)phenyl]carbamate - Intermediate 14 [ka]

[0259] Ozone was passed through a solution of intermediate 13 (488 mg, 1.70 mmol, 1.00 eq) in DCM (20 mL) at -78 °C for 30 min, at which point a light blue color was observed. Dimethyl sulfide (0.62 mL, 8.49 mmol, 5.00 eq) was added, and the reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel (ethyl acetate / cyclohexane, 0-20%) to give the title compound (278 mg, 57%).

[0260] 1 H NMR (400 MHz, CDCl3) δ 10.02 (s, 1H), 8.06 (s, 1H), 7.98 (s, 1H), 7.80 (s, 1H), 6.76 (s, 1H), 1.54 (s, 9H).

[0261] The following intermediate 48 was prepared as described for intermediate 14 in step 3.

[0262] [Table 11]

[0263] Step 4: tert-butyl N-[3-(pyrrolidin-1-ylmethyl)-5-(trifluoromethyl)phenyl]carbamate - Intermediate 15 [ka]

[0264] To a solution of intermediate 14 (140 mg, 0.484 mmol, 1.00 eq) in DCM (3.5 mL) was added pyrrolidine (440 μL, 0.532 mmol, 1.10 eq), acetic acid (83 μL, 1.45 mmol, 3.00 eq), and titanium(IV) isopropoxide (290 μL, 0.968 mmol, 2.00 eq). The reaction mixture was stirred at room temperature for 1 h. STAB (205 mg, 0.968 mmol, 2.00 eq) was added, and the reaction mixture was stirred at room temperature for an additional 1.5 h. The reaction mixture was diluted with saturated NaHCO 3(aq) The aqueous phase was re-extracted 3x with EtOAc and the organic phases were combined and partitioned between water, saturated NaCl (aq) The mixture was washed with HCl, separated and concentrated in vacuo to give the title compound.

[0265] 1 H NMR (400 MHz, CDCl3) δ 7.65 (s, 1H), 7.44 (s, 1H), 7.27 (s, 1H), 6.58 (s, 1H), 3.63 (s, 2H), 2.55 - 2.50 (m, 4H), 1.81 - 1.77 (m, 4H), 1.52 (s, 9H).

[0266] The following intermediate 49 was prepared as described for intermediate 15 in step 4. Intermediate 49 was used in the next step without further purification.

[0267] [Table 12]

[0268] Step 5: 3-(pyrrolidin-1-ylmethyl)-5-(trifluoromethyl)aniline - Intermediate 11 To a solution of intermediate 15 (186 mg, 0.540 mmol, 1.0 eq) in MeOH (3.0 ml) was added 4 M HCl in dioxane (0.41 ml, 1.62 mmol, 3.0 eq). The reaction mixture was stirred at room temperature for 2 h. An additional 4 M HCl in dioxane (0.41 mL, 1.62 mmol, 3.00 eq) was added and the reaction mixture was stirred at room temperature for an additional 4 h. An additional 4 M HCl in dioxane (0.41 mL, 1.62 mmol, 3.00 eq) was added and the reaction mixture was stirred for an additional 12 h. The reaction mixture was concentrated in vacuo to give the HCl salt of the title compound (140 mg, 90%).

[0269] 1 H NMR (400 MHz, DMSO) δ 10.64 (s, 1H), 7.12 (s, 1H), 6.98 (s, 1H), 6.96 (s, 1H), 4.27 (d, J=6.0 Hz, 2H), 3.37 - 3.31 (m, 2H), 3.07 - 2.98 (m, 2H), 2.03 - 1.96 (m, 2H), 1.91 - 1.86 (m, 2H)

[0270] The following intermediate 50 was prepared as described for intermediate 11 in step 5.

[0271] [Table 13]

[0272] 4-((tetrahydrofuran-3-yl)oxy)-3-(trifluoromethyl)aniline - Preparation of intermediate 16 [ka]

[0273] Step 1: 3-(4-nitro-2-(trifluoromethyl)phenoxy)tetrahydrofuran - Intermediate 17 [ka]

[0274] To a stirred solution of 3-hydroxytetrahydrofuran (0.53 g, 6.00 mmol) in acetonitrile (13 mL) under an inert atmosphere was added sodium hydride (60% in mineral oil, 158 mg, 6.60 mmol). The reaction mixture was stirred for 1 h, and then 2-fluoro-5-nitrobenzotrifluoride (0.69 mL, 5.00 mmol) was added in one portion. The reaction mixture was stirred at room temperature until LCMS indicated consumption of the starting material. The reaction mixture was partitioned between water and DCM, and the aqueous phase was re-extracted with DCM (x2). The organic phases were combined, separated, and concentrated in vacuo to give the title compound (1.52 g, 99%).

[0275] 1 H NMR (400 MHz, CDCl3) δ 8.52 (d, J=3.0 Hz, 1H), 8.42 (dd, J=3.0, 9.0 Hz, 1H), 7.03 (d, J=9.0 Hz, 1H), 5.16 - 5.12 (m, 1H), 4.15 - 4.11 (m, 1H), 4.03 - 3.97 (m, 3H), 2.35 - 2.19 (m, 2H)

[0276] The following compounds were prepared as described for step 1 in intermediate 17, starting from the appropriate corresponding alcohol.

[0277] [Table 14]

[0278] Step 2: 4-((tetrahydrofuran-3-yl)oxy)-3-(trifluoromethyl)aniline - Intermediate 16

[0279] The required intermediate 17 (1.52 g, 5.48 mmol) and iron powder (1.53 g, 27.4 mmol) were combined in acetic acid (18 ml) and methyl alcohol (18 ml). The reaction mixture was stirred at 50 °C until LCMS showed consumption of the starting material. The stirred mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was partitioned between DCM and saturated Na2CO3(aq). The organic phases were combined, separated, and concentrated in vacuo. The residue was loaded onto an Isolute SCX cartridge, washed with DCM / MeOH, and then eluted with 2M NH3 / MeOH. The eluate was concentrated to give the title compound (1.10 g, 75%).

[0280] 1 H NMR (400 MHz, CDCl3) δ 6.91 (d, J=2.0 Hz, 1H), 6.79-6.79 (m, 2H), 4.92 - 4.87 (m, 1H), 4.04 - 3.90 (m, 4H), 3.56 (s, 2H), 2.18 - 2.10 (m, 2H)

[0281] The following compounds were prepared starting from the appropriate corresponding nitro derivative via reduction of the nitro residue as described for intermediate 16.

[0282] [Table 15]

[0283] 3-(2-morpholinoethoxy)-5-(trifluoromethyl)aniline - Preparation of intermediate 20 [ka]

[0284] Step 1: 4-(2-(3-nitro-5-(trifluoromethyl)phenoxy)ethyl)morpholine - Intermediate 21 [ka]

[0285] To a solution of 3-nitro-5-(trifluoromethyl)phenol (480.5 mg, 2.32 mmol) in N,N-dimethylformamide (12 ml) was added 4-(2-chloroethyl)morpholine hydrochloride (431 mg, 2.32 mmol) (1.20 eq), followed by cesium carbonate (1.5 g, 4.64 mmol). The mixture was stirred at 80° C. until LCMS showed consumption of the starting material. The reaction mixture was diluted with water and extracted with DCM (×2). The organic phases were combined and concentrated.

[0286] The residue was purified by FCC eluting with EtOAc in cyclohexane (0-100%) to give the title compound (0.6 g, 97%).

[0287] 1 H NMR (400 MHz, DMSO) δ 8.05 (d, J=2.5 Hz, 2H), 7.81 (s, 1H), 4.34 (dd, J=5.6, 5.6 Hz, 2H), 3.58 (dd, J=4.6, 4.6 Hz, 4H), 2.74 (dd, J=5.6, 5.6 Hz, 2H), 2.52 (s, 4H), 2.51 (ddd, J=5.5, 5.5, 4.3 Hz, 4H).

[0288] The following intermediate 51 was prepared as described for intermediate 21 in step 1.

[0289] [Table 16]

[0290] Step 2: 3-(2-morpholinoethoxy)-5-(trifluoromethyl)aniline - Intermediate 20

[0291] To Intermediate 21 (100 mg, 0.312 mmol) in ethanol (3 mL) under a nitrogen atmosphere were added 1-methyl-1,4-cyclohexadiene (881 mg, 9.36 mmol) and palladium on carbon (10%) (33 mg, 0.312 mmol) sequentially, and the reaction mixture was stirred at 80 °C until LCMS showed the consumption of the starting material. The reaction mixture was allowed to cool to room temperature and filtered through a pad of Celite, which was washed with ethanol and ethyl acetate. The filtrate was concentrated under reduced pressure to give the title compound (84 mg, 93%).

[0292] 1 H NMR (400 MHz, CDCl3) δ 6.52 (d, J=9.5 Hz, 2H), 6.36 (t, J=2.0 Hz, 1H), 4.09 (t, J=5.6 Hz, 2H), 3.83 (s, 2H), 3.75 - 3.72 (m, 4H), 2.79 (t, J=5.7 Hz, 2H), 2.59 - 2.55 (m, 4H).

[0293] The following intermediate 52 was prepared as described for intermediate 20 in step 2.

[0294] [Table 17]

[0295] Preparation of 3-((dimethylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde

[0296] Intermediate 53 Step 1: 3-((dimethylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde [ka]

[0297] 1H-Pyrrolo[2,3-b]pyridine-5-carbaldehyde (100 mg, 0.684 mmol, 1.00 eq) and N,N-dimethylmethyleneiminium iodide (190 mg, 1.03 mmol, 1.50 eq) were combined in acetonitrile (5.00 mL) and heated with stirring at 80° C. overnight. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water (20.00 mL), the pH adjusted to 12 with 1N NaOH, and extracted with DCM. The organic phases were combined, filtered through a hydrophobic frit, and the solvent was concentrated under reduced pressure. The resulting material was washed with 1:1 cyclohexane / diethyl ether and filtered to give the title compound (64 mg, 46%).

[0298] 1 H NMR (400 MHz, CDCl3) d 10.14 (s, 1H), 10.05 - 10.05 (m, 1H), 8.84 (s, 1H), 8.59 (s, 1H), 7.39 (s, 1H), 3.66 (s, 2H), 2.30 (s, 6H)

[0299] Preparation of 3-bromo-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde intermediate 54

[0300] Step 1: 3-Bromo-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde [ka]

[0301] To a solution of 1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (650 mg, 4.42 mmol, 1.00 eq) in N,N-dimethylformamide (20 mL) at 20 °C was added N-bromosuccinimide (983 mg, 5.52 mmol, 1.25 eq). The reaction mixture was stirred at room temperature for 18 h. The mixture was diluted with saturated aqueous NHCl (100 mL) and extracted with EtOAc. The organic phases were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The material was triturated with water and dried under reduced pressure to give the title compound (1.02 g, 99.2% yield).

[0302] 1 H NMR (400 MHz, DMSO) δ 14.61 - 14.58 (m, 1H), 10.23 (s, 1H), 9.13 (d, J=1.8 Hz, 1H), 8.73 (d, J=1.5 Hz, 1H)

[0303] Preparation of 2-((4-methylpiperazin-1-yl)methyl)-6-(trifluoromethyl)pyridin-4-amine

[0304] Intermediate 55 [ka]

[0305] Step 1: 4-amino-N-methoxy-N-methyl-6-(trifluoromethyl)picolinamide Intermediate 56 [ka]

[0306] To a mixture of 4-amino-6-(trifluoromethyl)picolinic acid (445 mg, 2.16 mmol) and HATU (1.6 g, 4.32 mmol) in DMF (0.1 M concentration) was added N,N-diisopropylethylamine (2.9 mL, 17.98 mmol). The reaction mixture was stirred at room temperature for 15 min, and then N,O-dimethylhydroxylamine hydrochloride (232 mg, 2.37 mmol) was added. The reaction mixture was stirred until LCMS indicated consumption of the starting material, then concentrated. Purification by column silica gel chromatography (80 g cartridge, 0–50% EtOAc in cyclohexane (+0.1% NEt)) afforded the title compound (369 mg, 68%).

[0307] 1H NMR (400 MHz, DMSO) δ 6.96 (d, J=2.1 Hz, 1H), 6.84 - 6.78 (m, 3H), 3.67 (s, 3H), 3.24 (s, 3H)

[0308] Step 2: 4-Amino-6-(trifluoromethyl)picolinaldehyde

[0309] Intermediate 57 [ka]

[0310] To a stirred solution of intermediate 56 (308 mg, 1.24 mmol) in THF (4.82 mL) cooled in an ice / water bath was added LiAlH4 (2 M in THF, 0.62 mL, 1.24 mmol) dropwise while maintaining an internal temperature of 6 °C. The reaction mixture was stirred for 1 h and diluted with anhydrous diethyl ether (5 mL). Water (47 μL), 15% NaOH (aq) (47 μL) and water (141 μL) were added, and the reaction mixture was warmed to room temperature and stirred for 15 min. Anhydrous MgSO was added, and the reaction mixture was stirred for 15 min, filtered, and the filtrate was concentrated under reduced pressure to give intermediate 57 (252 mg, >100%), which was used in the next step without purification.

[0311] LCMS (Method 21) R : 0.95 min, m / z (M+1); 191

[0312] Step 3: 2-((4-methylpiperazin-1-yl)methyl)-6-(trifluoromethyl)pyridin-4-amine

[0313] Intermediate 55 To a solution of intermediate 57 (126 mg, 0.663 mmol) in DCM (0.1 M concentration) was added methylpiperazine (0.074 mL, 0.663 mmol), titanium(IV) isopropoxide (376.87 mg, 1.326 mmol, 2.00 eq), and acetic acid (114 μL, 1.988 mmol eq). The reaction mixture was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (281 mg, 1.325 mmol) was added, and the reaction mixture was stirred at room temperature until LCMS indicated consumption of the starting material. Purification by column silica gel chromatography (0–10% 2M NH3 / MeOH in DCM) gave the title compound (85 mg, 46%).

[0314] The following intermediates were prepared as described for intermediate 55 in step 3, starting from intermediate 57 using the appropriate commercially available amine.

[0315] [Table 18]

[0316] Preparation of 3-amino-N-[2-(dimethylamino)ethyl]-5-(trifluoromethyl)benzamide

[0317] Intermediate 60 [ka]

[0318] Step 1: 3-amino-N-[2-(dimethylamino)ethyl]-5-(trifluoromethyl)benzamide Intermediate 60

[0319] To a mixture of the required carboxylic acid (0.25 g, 1.21 mmol) and HATU (0.9 g, 2.43 mmol) in DMF (0.1 M concentration) was added N,N-diisopropylethylamine (639 μL, 3.66). The reaction mixture was stirred at rt for 15 min, and then N,N-dimethylethylenediamine (0.13 g mg, 1.46 mmol) was added. The reaction mixture was stirred at rt until LCMS indicated consumption of the starting material, then concentrated. The residue was purified by column silica gel chromatography (12 g cartridge, 0–10% 2M NH3 / MeOH in DCM) to give the title compound (237 mg, 71%).

[0320] 1 H NMR (300 MHz, DMSO) δ 8.51 (t, J=5.5 Hz, 1H), 7.28 - 7.25 (m, 1H), 7.25 - 7.21 (m, 1H), 6.99 - 6.96 (m, 1H), 5.78 (s, 2H), 3.44 (q, J=6.3 Hz, assumed 2H, overlapping with water peak), 2.75 (t, J=6.2 Hz, 2H), 2.46 (s, 6H)

[0321] The following intermediates were prepared as described for intermediate 60, varying the corresponding commercially available amine.

[0322] [Table 19]

[0323] Preparation of Examples

[0324] Example 1: Preparation of compound 1-(imidazo[1,2-a]pyridin-3-ylmethyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide [ka]

[0325] Step 1: tert-butyl 6-((3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)carbamoyl)indoline-1-carboxylate - Intermediate 22 [ka]

[0326] 1-(tert-Butoxycarbonyl)indoline-6-carboxylic acid (1 g, 3.80 mmol) and 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (0.916 g, 3.80 mmol) were dissolved in DCM (2 mL). DIPEA (1.990 mL, 11.39 mmol) and 50% T3P (4.48 mL, 7.60 mmol) in ethyl acetate were added. The reaction mixture was stirred at 20 °C for 20 h. The reaction mixture was diluted with DCM (10 mL), and then water (5 mL) was added. The phases were separated, and the organic phase was washed with citric acid (5% aq.sol., 2 × 10 mL), dried over Na2SO4, filtered, and concentrated to dryness. The crude material was purified via column chromatography eluting with DCM / MeOH, going from 100% DCM to 5% MeOH in DCM. 200 mg of pure desired product was obtained. 1.4 g of a mixture of the desired product and starting material (acid) was obtained. This material was dissolved in DCM (100 ml) and washed with Na2CO3 (3 x 50 ml) and brine (100 ml) to remove residual acid. The organic phase was dried over Na2SO4, filtered, and evaporated to dryness to give the title compound (1.01 g, 55%).

[0327] 1H NMR (300 MHz, DMSO-d6) δ 10.66 (s, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.20 (d, J = 1.4 Hz, 1H), 8.14 (s, 1H), 7.71 (d, J = 2.1 Hz, 1H), 7.58 (dd, J = 7.7, 1.7 Hz, 1H), 7.49 (t, J = 1.3 Hz, 1H), 7.37 (d, J = 7.8 Hz, 1H), 3.98 (t, J = 8.7 Hz, 2H), 3.15 (t, J = 8.7 Hz, 2H), 2.18 (d, J = 1.0 Hz, 3H), 1.53 (s, 8H).

[0328] Step 2: N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide - Intermediate 23 [ka]

[0329] Intermediate 22 (1.01 g, 2.076 mmol) was dissolved in DCM (5 ml), and then trifluoroacetic acid (1.440 ml, 18.68 mmol) was added. The reaction mixture was stirred at RT overnight. The reaction mixture was diluted with DCM (10 ml), and NaHCO3 (sat. aq. sol.) was added. The mixture was stirred at RT for 30 min (bubbles were observed). The phases were partitioned. The organic phase was washed with NaHCO3, dried over Na2SO4, and evaporated in vacuo. The material was used without further purification. The title compound was obtained as the free base (900 mg, 100%).

[0330] 1H NMR (300 MHz, DMSO-d6) δ 10.49 (s, 1H), 8.31 (dd, J = 4.2, 2.1 Hz, 2H), 8.17 (d, J = 1.7 Hz, 1H), 7.71 (d, J = 1.8 Hz, 1H), 7.53 (d, J = 1.4 Hz, 1H), 7.25 - 7.13 (m, 2H), 7.06 (d, J = 1.3 Hz, 1H), 3.47 (d, J = 8.5 Hz, 3H), 2.98 (t, J = 8.5 Hz, 2H), 2.20 (d, J = 1.0 Hz, 3H).

[0331] Step 3: 1-(Imidazo[1,2-a]pyridin-3-ylmethyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide (Example 1)

[0332] N-(3-(4-Methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide (0.1 g, 0.259 mmol) was dissolved in DCM (2 ml), then imidazo[1,2-a]pyridine-3-carbaldehyde (0.038 g, 0.259 mmol), NaCNBH (0.024 g, 0.388 mmol) and AcOH (0.030 ml, 0.518 mmol) were added. The reaction mixture was stirred at 20 °C for 18 h. The reaction mixture was evaporated, then diluted with DCM (5 ml), and then water (5 ml) was added. The phases were separated and the organic phase was washed with 2 × 10 ml of KCO (aq. sat. sol.), dried over NaSO, filtered and concentrated under reduced pressure. The crude material was purified via preparative HPLC eluting with ACN+0.1% NH3, H2O+0.1% NH3 to afford the title compound (28 mg, 21%).

[0333] [Table 20]

[0334] The following compounds were prepared by reductive amination as described for steps 1-3 of Example 1, starting from the appropriate corresponding commercially available carbaldehyde in step 3; equivalents (eq.) are indicated in the table when STAB was used instead of NaCNBH as the reducing agent.

[0335] [Table 21-1]

[0336] [Table 21-2]

[0337] [Table 21-3]

[0338] [Table 21-4]

[0339] Example 9 Preparation of 1-((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide [ka]

[0340] Step 1: tert-butyl 6-((3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)carbamoyl)indoline-1-carboxylate - Intermediate 24 [ka]

[0341] In a dry (heat gun / vacuum / N2 cycle) two-necked 25 mL flask, 3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)aniline (0.542 g, 1.983 mmol) was dissolved in anhydrous THF (15 mL) and cooled to -78 °C, followed by the dropwise addition of butyllithium (0.793 mL, 1.983 mmol). The solution was stirred for 15 min, followed by the dropwise addition of a solution of 1-(tert-butyl) 6-methylindoline-1,6-dicarboxylate (0.275 g, 0.992 mmol) in anhydrous THF (1 mL). The mixture was stirred for 16 h, warming from -78 °C to room temperature. Water (50 mL) was added, followed by extraction with EtOAc (3 x 10 mL). The organic phase was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to dryness. The crude material was purified on an FCC (Biotage® Sfar KP-Amino D-Duo) system eluting with DCM / MeOH (100:0 to 90:10) to give the title compound (518 mg, 100%).

[0342] 1 H NMR (DMSO-d6, 400MHz): δ = 10.48 (s, 1H), 8.15 (s, 1H), 7.99 (s, 1H), 7.57 (d, 1H, J = 7.7 Hz), 7.36-7.32 (m, 2H), 6.76 (s, 1H), 5.51 (s, 2H), 3.97 (t, 2H, J = 8.7 Hz), 3.14 (t, 2H, J = 8.7 Hz), 2.33 (bs, 8H), 2.15 (s, 3H), 1.53 (s, 9H) ppm

[0343] The following intermediate 62 was prepared following the same procedure used for the synthesis of intermediate 24, varying the corresponding commercially available amine.

[0344] [Table 22]

[0345] Step 2: N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide - Intermediate 25 [ka]

[0346] Intermediate 24 (0.514 g, 0.991 mmol) was dissolved in a 3:1 mixture of DCM (12 mL) and 2,2,2-trifluoroacetic acid (3.04 mL, 39.6 mmol). The solution was stirred at room temperature for 1 h. The solvent was evaporated. The crude material was diluted with water (20 mL), and the pH was then adjusted to approximately 7-8. The product was extracted with DCM (2 x 20 mL) via a phase separator. The organic phase was concentrated to dryness to give the title compound (415 mg, 100%).

[0347] 1 H NMR (DMSO-d6, 400MHz): δ = 10.25 (s, 1H), 8.13 (s, 1H), 7.96 (s, 1H), 7.28 (s, 1H), 7.15 (d, 1H, J = 7.5 Hz), 7.11 (d, 1H, J = 7.5 Hz), 7.01 (s, 1H), 4.04 (q, 1H, J = 5.1 Hz), 3.49 (s, 2H), 3.44 (t, 2H, J = 8.7 Hz), 2.94 (t, 2H, J = 8.7 Hz), 2.34-2.27 (m, 8H), 2.13 (s, 3H)ppm The following intermediate 63 was prepared following the same procedure as reported for intermediate 25. Variations in chromatographic purification conditions are reported in the table.

[0348] [Table 23]

[0349] Step 3: 1-((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide (Example 9)

[0350] Intermediate 25 (0.1 g, 0.239 mmol) was dissolved in DCM (2 ml), followed by the addition of 1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (0.035 g, 0.239 mmol), NaCNBH (0.023 g, 0.358 mmol), and AcOH (0.027 ml, 0.478 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with DCM (5 ml) and washed with water (5 ml). The organic phase was washed with KCO (aq. sat. sol., 2 × 10 ml), dried over NaSO, filtered, and concentrated under reduced pressure.

[0351] The crude material was purified via preparative HPLC eluting with ACN+0.1% FA, HO+0.1% FA. The residue was triturated with NaHCO (15% aq.sol.), and the precipitate was filtered through a Schottky funnel, rinsed with water, transferred to a vial, and dried overnight under high vacuum at room temperature to give the title compound (17 mg, 13%).

[0352] [Table 24]

[0353] The following compounds were prepared via reductive amination using NaCNBH or STAB as the reducing agent as described for steps 1-3 of Example 9, starting from the appropriate corresponding commercially available or synthetic carbaldehyde in step 3. In some cases, titanium(IV) isopropoxide was used as the reducing agent. These modifications are reported in the tables.

[0354] [Table 25-1] [Table 25-2]

[0355] Example 12: Preparation of 1-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide [ka]

[0356] Step 1: N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-1-(2-(methylcarbamoyl)isonicotinoyl)indoline-6-carboxamide (Example 12)

[0357] Imidazo[1,2-a]pyridine-3-carboxylic acid (0.040 g, 0.246 mmol) was dissolved in DMF (2.5 mL), followed by the addition of TBTU (0.079 g, 0.246 mmol) and TEA (0.069 mL, 0.492 mmol). The mixture was stirred at room temperature for approximately 15 minutes, followed by the addition of Intermediate 23 (0.095 g, 0.246 mmol). The reaction mixture was stirred at room temperature overnight.

[0358] The reaction mixture was diluted with DCM (5 ml) and water (5 ml). The mixture was stirred at room temperature for 15 minutes, then the phases were separated, and the organic phase was washed with water (2 x 15 ml) and brine (2 x 5 ml), then dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure. The crude material has low solubility in organic solvents. The residue was triturated with H2O overnight, filtered, and dried under high vacuum to give the title compound (43 mg, 33%).

[0359] [Table 26]

[0360] The following compounds were prepared via amidation as described for Step 1 of Example 12, starting from the appropriate corresponding commercially available acid in Step 1.

[0361] [Table 27]

[0362] Example 14: Preparation of 1-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide [ka]

[0363] Step 1: 1-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide

[0364] Imidazo[1,2-a]pyridine-3-carboxylic acid (0.012 g, 0.072 mmol) and HATU (0.030 g, 0.079 mmol) were dissolved in a 3:1 solution of anhydrous DCM (3 mL) and DMF (1.000 mL), followed by the addition of N-ethyl-N-isopropylpropan-2-amine (0.027 mL, 0.158 mmol) in one portion. The solution was stirred at room temperature for 10 min, followed by the addition of Intermediate 25 (0.03 g, 0.072 mmol) in one portion. Stirring was maintained at room temperature for 16 h. After dilution with DCM (10 mL), the mixture was washed with sat. NH4Cl (10 mL), sat. NaHCO3 (10 mL), and brine (10 mL). The organic phase was separated, dried over Na2SO4, filtered, and concentrated to dryness. The crude material was purified by reverse-phase chromatography eluting with H2O / MeCNH / HC02H (95:5:0.1 to 5:95:0.1) to afford the title compound as the formate salt (9 mg, 22%).

[0365] [Table 28]

[0366] The following compounds were prepared via amidation using TBTU as the coupling agent as described for Step 1 of Example 14, starting from the appropriate corresponding commercially available acid in Step 1.

[0367] [Table 29]

[0368] Example 16 Preparation of N-(1-(imidazo[1,2-a]pyridine-3-carbonyl)indolin-6-yl)-3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamide [ka]

[0369] Step 1: tert-Butyl 6-nitroindoline-1-carboxylate - Intermediate 26 [ka]

[0370] A flask was charged with BOC-anhydride (26.6 g, 122 mmol), 6-nitroindoline (20 g, 122 mmol), DMAP (1.5 g, 12.18 mmol), TEA (51 ml, 365 mmol), and DCM (244 ml). The reaction mixture was stirred at room temperature overnight. The solvent was removed under vacuum. Extraction was performed with DCM. The solvent was removed once more. The crude product was purified by FCC eluting with hexane / ethyl acetate (9:1) to give the title compound (29 g, 90%).

[0371] 1H NMR (300 MHz, DMSO-d6) δ 8.42 (s, 1H), 7.84 (dd, J = 8.2, 2.3 Hz, 1H), 7.49 - 7.40 (m, 1H), 4.01 (dd, J = 9.2, 8.2 Hz, 2H), 3.19 (t, J = 8.7 Hz, 2H), 1.54 (s, 9H).

[0372] Step 2: tert-Butyl 6-aminoindoline-1-carboxylate - Intermediate 27 [ka]

[0373] Intermediate 26 (29.13 g, 110 mmol) was placed in a three-neck round button. The air was evacuated using a water pump and purged with Ar—a process repeated three times. Then, 10 wt.% palladium on carbon (2.91 g, 27.3 mmol) and ethyl acetate (551 ml) were added. The reaction mixture was purged with argon, removed using a water pump, and then purged with H. The mixture was stirred under a hydrogen atmosphere at rt overnight. The reaction mixture was filtered through a Celite pad and concentrated to give the title compound (27 g, 100%).

[0374] 1 H NMR (300 MHz, DMSO-d6) δ 7.05 (s, 1H), 6.80 (d, J = 7.9 Hz, 1H), 6.13 (dd, J = 7.9, 2.1 Hz, 1H), 4.92 (d, J = 6.6 Hz, 2H), 3.82 (dd, J = 9.2, 7.9 Hz, 2H), 2.86 (t, J = 8.5 Hz, 2H), 1.50 (s, 9H).

[0375] Step 3: tert-butyl 6-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamido)indoline-1-carboxylate - Intermediate 28 [ka]

[0376] Intermediate 27 (6.45 g, 21.34 mmol) was placed in a flask, followed by the addition of HATU (16.23 g, 42.7 mmol), DIPEA (14.91 ml, 85 mmol), DMF (53.4 ml), and dichloromethane (160 ml). The reaction mixture was stirred at rt for 30 min. tert-Butyl 6-aminoindoline-1-carboxylate (5 g, 21.34 mmol) was then added. Stirring was continued overnight. Extraction with water and DCM was performed. The organic phase was removed under reduced pressure. The crude product was purified by FCC eluting with hexane / ethyl acetate (9:1) to give the title compound (10.4 g, 92%).

[0377] 1 H NMR (300 MHz, DMSO-d6) δ 10.40 (s, 1H), 9.32 (s, 1H), 8.24 (d, J = 17.0 Hz, 2H), 8.15 (d, J = 1.9 Hz, 1H), 7.90 (s, 1H), 7.18 (d, J = 8.0 Hz, 1H), 3.94 (t, J = 8.5 Hz, 2H), 3.78 (s, 2H), 3.05 (t, J = 8.6 Hz, 2H), 2.70 (s, 3H), 2.40 (s, 8H), 1.52 (s, 9H).

[0378] Step 4: N-(indolin-6-yl)-3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamide - Intermediate 29 [ka]

[0379] Intermediate 28 (1.938 g, 3.74 mmol) was dissolved in DCM (37.4 ml) and TFA (2.59 ml, 33.6 mmol) was added. The reaction mixture was stirred at rt overnight. The mixture was washed with sat. NaHCO3 and brine (10 mL). The organic phase was separated, dried over Na2SO4, filtered, and concentrated to dryness. The crude material was purified by FCC eluting with DCM / MeOH (95:5). The pure fractions were washed with water, brine, and 5% citric acid, and finally, the organic phase was dried over Na2SO4 and evaporated under vacuum to give the title compound (770 mg, 48%).

[0380] 1 H NMR (300 MHz, DMSO-d6) δ 10.16 (s, 1H), 8.14 (d, J = 6.8 Hz, 2H), 7.83 (s, 1H), 7.04 (d, J = 1.9 Hz, 1H), 6.98 (d, J = 7.9 Hz, 1H), 6.92 - 6.82 (m, 1H), 5.61 (s, 1H), 3.63 (s, 2H), 3.48 - 3.39 (m, 2H), 2.88 (t, J = 8.4 Hz, 2H), 2.37 (d, J = 22.8 Hz, 8H), 2.16 (s, 3H).

[0381] Step 5: N-(1-(imidazo[1,2-a]pyridine-3-carbonyl)indolin-6-yl)-3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamide (Example 16)

[0382] Imidazo[1,2-a]pyridine-3-carboxylic acid (0.012 g, 0.072 mmol) and HATU (0.030 g, 0.079 mmol) were dissolved in a 3:1 solution of anhydrous DCM / DMF (5 mL / 1 mL), and then N-ethyl-N-isopropylpropan-2-amine (0.027 mL, 0.158 mmol) was added in one portion. The solution was stirred at room temperature for 10 min, and then Intermediate 29 (0.03 g, 0.072 mmol) was added in one portion. Stirring was maintained at room temperature for 16 h. The mixture was diluted with DCM (10 mL) and then washed with sat. NH4Cl (10 mL), sat. NaHCO3 (10 mL), and brine (10 mL). The organic phase was separated, dried over Na2SO4, filtered, and concentrated to dryness. The crude material was purified by reverse-phase column chromatography eluting with HO / MeCNH / HC0H (95:5:0.1 to 5:95:0.1) to afford the title compound as the formate salt (31 mg, 71%).

[0383] [Table 30]

[0384] Example 17: Preparation of N-(1-(benzo[d]thiazol-6-ylmethyl)indolin-6-yl)-3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamide [ka]

[0385] Intermediate 29 (0.1 g, 0.239 mmol) was dissolved in anhydrous DCM (2.4 ml), and then benzo[d]thiazole-6-carbaldehyde (0.039 g, 0.239 mmol) was added, followed by AcOH (0.027 ml, 0.478 mmol). The reaction mixture was stirred at rt for 30 min. NaBHCN (0.023 g, 0.35) was then added, and the reaction mixture was stirred at rt overnight. The mixture was quenched by the addition of a sat. aq. solution of NaHCO. The phases were separated, and the aqueous phase was washed with DCM (x2). The organic phases were collected, dried over NaSO, and the solvent was removed in vacuo. The crude material was purified by column chromatography eluting with DCM / MeOH (9:1) and preparative HPLC eluting with ACN, HO + 0.05% NH to give the title compound (20 mg, 15%).

[0386] [Table 31]

[0387] The following compounds were prepared via reductive amination using STAB as the reducing agent as described for Step 1 of Example 17, starting from the appropriate corresponding commercially available aldehyde in Step 1.

[0388] [Table 32]

[0389] Example 19: Preparation of N-(1-(imidazo[1,2-a]pyridine-3-carbonyl)indolin-6-yl)-3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzamide [ka]

[0390] Step 1: tert-butyl 6-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzamido)indoline-1-carboxylate - Intermediate 30 [ka]

[0391] 3-(4-Methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid (1.15 g, 4.27 mmol), tert-butyl 6-aminoindoline-1-carboxylate (1.0 g, 4.27 mmol), HATU (4.87 g, 12.80 mmol), and DIPEA (4.47 mL, 25.6 mmol) were placed in a flask, followed by the addition of DMF (0.907 mL) and DCM (2.721 mL). The reaction mixture was stirred at room temperature overnight.

[0392] Extraction was performed with water and DCM. The solvent was dried over Na2SO4 and removed under reduced pressure. The crude material was purified by FCC eluting with hexane / ethyl acetate (1:1) to give the title compound (2.2 g, 90%).

[0393] 1 H NMR (300 MHz, DMSO-d6) δ 10.52 (s, 1H), 9.55 (s, 1H), 8.58 (s, 1H), 8.43 (d, J = 8.1 Hz, 2H), 8.15 (s, 2H), 7.21 (d, J = 8.0 Hz, 1H), 4.01 - 3.90 (m, 2H), 3.06 (t, J = 8.5 Hz, 2H), 2.36 (d, J = 1.2 Hz, 3H), 1.52 (s, 9H).

[0394] Step 2: N-(indolin-6-yl)-3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzamide - Intermediate 31 [ka]

[0395] Intermediate 30 (1.87 g, 3.84 mmol) was dissolved in DCM (38.4 ml). Then, TFA (2.67 ml, 34.6 mmol) was added. The reaction mixture was stirred at rt overnight. After washing with NaHCO, the DCM was dried over NaSO. The solvent was removed under reduced pressure. The crude product was purified by FCC eluting with DCM / MeOH (95:5). Subsequent extraction with water, brine, and 5% citric acid gave the title compound (1.09 g, 53%).

[0396] 1 H NMR (300 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.40 (d, J = 1.5 Hz, 2H), 8.22 (s, 1H), 8.13 (s, 1H), 7.72 (d, J = 1.4 Hz, 1H), 7.05 (d, J = 1.9 Hz, 1H), 7.00 (d, J = 7.8 Hz, 1H), 6.89 (d, J = 8.0 Hz, 1H), 5.64 (s, 1H), 3.44 (d, J = 8.4 Hz, 2H), 2.89 (t, J = 8.4 Hz, 2H), 2.20 (s, 3H).

[0397] Step 3: N-(1-(imidazo[1,2-a]pyridine-3-carbonyl)indolin-6-yl)-3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzamide (Example 19)

[0398] Imidazo[1,2-a]pyridine-3-carboxylic acid (42.0 mg, 0.259 mmol), Intermediate 31 (100 mg, 0.259 mmol), TBTU (0.083 g, 0.259 mmol), and TEA (72.1 μl, 0.518 mmol) were placed in a vial, and DMF (2.5 ml) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was made basic with saturated NaHCO. Extraction was performed with DCM. The solvent was dried over NaSO and removed under reduced pressure. The crude product was purified by FCC eluting with DCM / MeOH (95:5) to give the title compound (98 mg, 69%).

[0399] [Table 33]

[0400] The following compounds were prepared via amidation as described for steps 1-3 of Example 19, starting from the appropriate corresponding commercially available acid in step 3.

[0401] [Table 34]

[0402] Example 22: Preparation of N-(1-(imidazo[1,2-a]pyrazin-3-ylmethyl)indolin-6-yl)-3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzamide [ka]

[0403] Step 1: N-(1-(imidazo[1,2-a]pyrazin-3-ylmethyl)indolin-6-yl)-3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzamide (Example 22)

[0404] A flask was charged with Intermediate 31 (100 mg, 0.259 mmol), imidazo[1,2-a]pyrazine-3-carbaldehyde (38.1 mg, 0.259 mmol), magnesium sulfate (62.3 mg, 0.518 mmol), and DCM (2.6 ml). Acetic acid (29.6 μl, 0.518 mmol) was added. The reaction mixture was stirred at rt for 2 h, then STAB (110 mg, 0.518 mmol) was added, and the mixture was stirred overnight. Fresh STAB (110 mg, 0.518 mmol) was added, and stirring was continued for another day. The mixture was quenched by the addition of sat. NaHCO3. The phases were separated, and the aqueous phase was washed with DCM (x2). All organic phases were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography eluting with DCM / MeOH (95:05) to give the title compound (75 mg, 53%).

[0405] [Table 35]

[0406] The following compounds were prepared starting from the appropriate corresponding commercially available aldehyde via amidation using NaBH3CN as the reducing agent as described for Step 1 of Example 22.

[0407] [Table 36]

[0408] Example 24: 1-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-3-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide [ka]

[0409] Step 1: Methyl 3-methylindoline-6-carboxylate - Intermediate 32 [ka]

[0410] Methyl 3-methyl-1H-indole-6-carboxylate (1.5 g, 7.93 mmol), trifluoroacetic acid (4.86 mL, 63.1 mmol), and triethylsilane (5.06 mL, 31.7 mmol) were placed in a flask, and THF (30 mL) was added. The reaction mixture was stirred at 0 °C overnight. A saturated solution of NaHCO was added, and extraction was performed with DCM. The solvent was dried over NaSO and removed under reduced pressure. The crude material was purified by FCC eluting with hexane / ethyl acetate (9:1) to give the title compound (950 mg, 62%).

[0411] 1 H NMR (300 MHz, DMSO-d6) δ 7.20 (dd, J = 7.6, 1.5 Hz, 1H), 7.11 (d, J = 7.6 Hz, 1H), 7.02 (d, J = 1.5 Hz, 1H), 5.72 (s, 1H), 3.79 (s, 3H), 3.63 (td, J = 8.9, 1.3 Hz, 1H), 3.31 - 3.23 (m, 1H), 3.02 (td, J = 8.6, 2.5 Hz, 1H), 1.24 (d, J = 6.8 Hz, 3H).

[0412] Step 2: 1-(tert-butyl) 6-methyl 3-methylindoline-1,6-dicarboxylate - Intermediate 33 [ka]

[0413] Intermediate 32 (950 mg, 4.97 mmol), BOC-anhydride (1084 mg, 4.97 mmol), DMAP (61 mg, 0.497 mmol), and triethylamine (2.077 ml, 14.90 mmol) were placed in a flask, and DCM (50 ml) was added. The reaction mixture was stirred at rt overnight. Extraction was performed with DCM. The solvent was dried over Na2SO4 and removed under reduced pressure. The crude material was purified by FCC eluting with hexane: / ethyl acetate (4:1) to give the title compound (970 mg, 67%).

[0414] 1 H NMR (300 MHz, DMSO-d6) δ 8.26 (s, 1H), 7.60 (dd, J = 7.8, 1.6 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 4.13 (d, J = 12.5 Hz, 1H), 3.84 (s, 3H), 3.48 (d, J = 8.1 Hz, 2H), 1.52 (s, 9H), 1.28 (d, J = 6.5 Hz, 3H).

[0415] Step 3: 1-(tert-butoxycarbonyl)-3-methylindoline-6-carboxylic acid - Intermediate 34 [ka]

[0416] Intermediate 33 (0.95 g, 3.26 mmol), 1M lithium hydroxide (4.89 ml, 4.89 mmol), and MeOH (32.6 ml) were added to a flask and stirred overnight at room temperature. An additional 0.7 eq of 1M LiOH was then added, and stirring was continued until the next day. The solvent was removed under reduced pressure. The crude material as the lithium salt was used in the next step without further purification (1.09 g, 100%). Alternatively, the chloride was removed by extraction with 5% aqueous citric acid to give the title compound in quantitative yield.

[0417] 1H NMR (300 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.51 (dd, J = 7.6, 1.4 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 4.18 - 4.02 (m, 1H), 3.41 (t, J = 6.1 Hz, 2H), 1.51 (s, 9H), 1.24 (d, J = 6.5 Hz, 3H).

[0418] Step 4: tert-butyl 3-methyl-6-((3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)carbamoyl)indoline-1-carboxylate - Intermediate 35 [ka]

[0419] To a solution of intermediate 34 (1.5 g, 5.41 mmol), 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (1.305 g, 5.41 mmol) and DIPEA (5.67 ml, 32.5 mmol) in anhydrous DCM (54.1 ml) was added T3P (4.83 ml, 8.11 mmol). The reaction was stirred at rt overnight. The reaction mixture was diluted with DCM (5 ml) and water was added. The phases were separated and the organic phase was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by FCC eluting with DCM / MeOH (95:5) to give the title compound (1.7 g, 61%).

[0420] 1H NMR (300 MHz, DMSO-d6) δ 10.67 (s, 1H), 8.28 (s, 1H), 8.20 (d, J = 1.4 Hz, 1H), 8.14 (s, 1H), 7.72 (s, 1H), 7.61 (dd, J = 7.8, 1.6 Hz, 1H), 7.52 - 7.46 (m, 1H), 7.41 (d, J = 7.8 Hz, 1H), 4.16 (d, J = 11.1 Hz, 1H), 3.50 (q, J = 8.7, 7.8 Hz, 2H), 2.18 (d, J = 1.0 Hz, 3H), 1.53 (s, 9H), 1.31 (d, J = 6.5 Hz, 3H).

[0421] The next intermediate 64 was prepared via amidation as described for step 4 of intermediate 35, starting from intermediate 34 and varying the corresponding amine. Such procedures may involve minor variations. In some cases, if changes were involved in the coupling agent (e.g., TCFH and 1-methylimidazole instead of T3P) or chromatographic purification conditions (e.g., prep HPLC or flash chromatography), such variations were reported in the table.

[0422] [Table 37]

[0423] Step 5: 3-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide - Intermediate 36 [ka]

[0424] Intermediate 35 (1.71 g, 3.42 mmol) was dissolved in DCM (34.2 ml). TFA (2.369 ml, 30.7 mmol) was then added. The reaction mixture was stirred at rt for 2 days. The reaction mixture was diluted with DCM (5 ml) and an aqueous solution of NaHCO was added. The phases were then separated and the organic phase was dried over NaSO and concentrated in vacuo. The crude product was purified by FCC eluting with DCM:MeOH (95:5) to give the title compound (1.07 g, 76%).

[0425] 1 H NMR (300 MHz, DMSO-d6) δ 10.48 (s, 1H), 8.33 - 8.26 (m, 1H), 8.22 - 8.15 (m, 2H), 7.70 (s, 1H), 7.48 (t, J = 1.3 Hz, 1H), 7.26 - 7.14 (m, 2H), 7.05 (d, J = 1.4 Hz, 1H), 3.66 (t, J = 8.9 Hz, 1H), 3.10 - 3.01 (m, 1H), 2.19 (d, J = 1.0 Hz, 3H), 1.27 (d, J = 6.8 Hz, 3H).

[0426] The next intermediate 65 was prepared via acidic cleavage as described for intermediate 36 in step 5. Such procedures may involve slight variations. In some cases, changes in chromatographic purification conditions (e.g., replacing FCC with SCX) were included, and such variations are reported in the tables.

[0427] [Table 38]

[0428] Step 6: 1-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-3-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide (Example 24)

[0429] A flask was charged with 1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (36.7 mg, 0.250 mmol), Intermediate 36 (100 mg, 0.250 mmol), acetic acid (28.6 μl, 0.499 mmol), magnesium sulfate (60.1 mg, 0.499 mmol), and DCM (2.5 ml). The reaction mixture was stirred at rt for 2 h. Then, STAB (212 mg, 0.999 mmol) was added. Stirring was continued until the next day. The reaction mixture was diluted with DCM, and an aqueous solution of NaHCO was added. The phases were then separated, and the organic phase was dried over NaSO and concentrated in vacuo. The crude material was purified by FCC eluting with DCM:MeOH (9:1) to give the title compound (105 mg, 77%).

[0430] [Table 39]

[0431] The following compounds were prepared via reductive amination as described for steps 1-6 of Example 24, starting from the appropriate corresponding commercially available aldehyde in step 6 and the corresponding amine in step 5. In some cases, this involved the addition of titanium(IV) isopropoxide or modifications to chromatographic purification conditions (e.g., prep HPLC or flash chromatography), and such modifications are reported in the table.

[0432] [Table 40-1] [Table 40-2]

[0433] Example 27: Preparation of 1-(imidazo[1,2-a]pyrazin-3-ylmethyl)-3-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide (single enantiomer) [ka]

[0434] Step 1: Preparation of 1-(imidazo[1,2-a]pyrazin-3-ylmethyl)-3-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide (Example 27)

[0435] A quantity of isolated racemic Example 26 (65 mg) was dissolved in EtOH at 5 mg / mL and then purified by chiral HPLC (SFC chiral separation) according to Method 18. Fractions of the second eluting enantiomer were combined and evaporated to near dryness using a rotary evaporator. The resulting solid was transferred to a final container with DCM removed under a stream of compressed air at 35°C and then stored in a vacuum oven at 35°C and 5 mbar to give the title compound (23.10 mg).

[0436] [Table 41]

[0437] Example 28: Preparation of 3-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-1-(1H-pyrazolo[3,4-b]pyridine-5-carbonyl)indoline-6-carboxamide [ka]

[0438] Intermediate 36 (0.1 g, 0.250 mmol), 1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (0.041 g, 0.250 mmol), TEA (69.6 μl, 500 mmol), and TBTU (0.08 g, 0.250 mmol) were placed in a vial, and DMF (2.5 ml) was added. The reaction mixture was stirred at room temperature overnight, then the temperature was raised to 80 °C, and stirring was continued until the next day. Extraction was performed with water and DCM. The organic phase was separated, dried over Na SO , and removed under reduced pressure. The crude product was purified by preparative HPLC eluting with FCC DCM / MeOH (9:1) and ACN, HO + 0.05% NH to give the title compound (15 mg, 11%).

[0439] [Table 42]

[0440] The following compounds were prepared via amidation as described for Step 1 of Example 28, starting from the appropriate corresponding commercially available acid in Step 1.

[0441] [Table 43]

[0442] Example 30: Preparation of 1-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-3-methyl-N-(3-(trifluoromethyl)phenyl)indoline-6-carboxamide [ka]

[0443] Step 1: tert-butyl 3-methyl-6-((3-(trifluoromethyl)phenyl)carbamoyl)indoline-1-carboxylate - Intermediate 37 [ka]

[0444] To a solution of 1-(tert-butoxycarbonyl)-3-methylindoline-6-carboxylic acid (935 mg, 3.37 mmol), 3-(trifluoromethyl)aniline (543 mg, 3.37 mmol), and DIPEA (3.53 ml, 20.23 mmol) in anhydrous DCM (33.7 ml) was added T3P (3.01 ml, 5.06 mmol). The reaction was stirred at rt overnight. Water was added to the reaction mixture, and the mixture was extracted with DCM (2 x 20 ml). The organic solvent was dried over Na2SO4 and removed under reduced pressure. The crude material was purified by FCC eluting with DCM / MeOH (95:5) to give the title compound (560 mg, 39%).

[0445] 1 H NMR (300 MHz, DMSO-d6) δ 10.53 (s, 1H), 8.23 ​​(s, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.58 (dd, J = 7.7, 1.6 Hz, 2H), 7.45 (d, J = 7.8 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 4.15 (d, J = 11.3 Hz, 1H), 3.54 - 3.44 (m, 2H), 1.53 (s, 9H), 1.30 (d, J = 6.5 Hz, 3H).

[0446] Step 2: 3-Methyl-N-(3-(trifluoromethyl)phenyl)indoline-6-carboxamide - Intermediate 38 [ka]

[0447] Intermediate 37 (560 mg, 1.332 mmol) was dissolved in DCM (13.32 ml) and TFA (0.924 ml, 11.99 mmol) was added. The reaction mixture was stirred at rt overnight. The reaction mixture was diluted with DCM and an aqueous saturated solution of NaHCO was added. The phases were then separated and the organic phase was dried over NaSO and concentrated in vacuo. The crude material was purified by FCC eluting with DCM:MeOH (99:1) to give the title compound (375 mg, 86%).

[0448] 1 H NMR (300 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.25 (s, 1H), 8.03 (d, J = 8.2 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.42 (d, J = 7.8 Hz, 1H), 7.19 (dd, J = 7.6, 1.5 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H), 7.03 (d, J = 1.4 Hz, 1H), 5.73 (s, 1H), 3.64 (td, J = 8.9, 1.3 Hz, 1H), 3.27 (d, J = 7.8 Hz, 1H), 3.04 (td, J = 8.6, 2.5 Hz, 1H), 1.26 (d, J = 6.8 Hz, 3H).

[0449] Step 3: 1-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-3-methyl-N-(3-(trifluoromethyl)phenyl)indoline-6-carboxamide (Example 30)

[0450] A flask was charged with 1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (32.2 mg, 0.219 mmol), Intermediate 38 (70 mg, 0.219 mmol), acetic acid (25.02 μL, 0.437 mmol), magnesium sulfate (52.6 mg, 0.437 mmol), and DCM (2185 μL). The reaction mixture was stirred at rt for 2 h. STAB (185 mg, 0.874 mmol) was then added. Stirring was continued until the next day. The reaction was made basic with NaHCO3. Extraction was performed with DCM. The phases were then separated, and the organic phase was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by FCC eluting with DCM / MeOH (95:5) to give the title compound (17 mg, 89%).

[0451] [Table 44]

[0452] The following compounds were prepared via reductive amination as described for steps 1-3 of Example 30, starting from the appropriate corresponding commercially available aldehyde in step 3.

[0453] [Table 45-1] [Table 45-2]

[0454] Example 34: Preparation of 1-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-3-methyl-N-(3-(trifluoromethyl)phenyl)indoline-6-carboxamide (single enantiomer) [ka]

[0455] Step 1: 1-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-3-methyl-N-(3-(trifluoromethyl)phenyl)indoline-6-carboxamide (Example 34)

[0456] Chiral preparative SFC separation of 70 mg of racemic Example 30 afforded the title compound as a single isomer. After preparative chiral separation, the combined fractions of the second eluting enantiomer were evaporated to dryness on a rotary evaporator to afford the title compound (11 mg, 15.6%).

[0457] [Table 46]

[0458] Example 35: Preparation of 1-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-(trifluoromethyl)phenyl)indoline-6-carboxamide [ka]

[0459] Step 1: Methyl 1-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)indoline-6-carboxylate - Intermediate 39 [ka]

[0460] Methyl indoline-6-carboxylate (1 g, 5.64 mmol), 1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (0.830 g, 5.64 mmol), acetic acid (0.646 mL, 11.29 mmol), and magnesium sulfate (1.358 g, 11.29 mmol) were dissolved in DCM (56.4 mL). The reaction mixture was stirred at rt for 2 h. STAB (2.392 g, 11.29 mmol) was then added. Stirring was continued overnight. A saturated solution of NaHCO was added and extracted with DCM. The organic phase was dried over NaSO and removed under reduced pressure. The crude material was purified by FCC eluting with hexane / ethyl acetate (0-100%) to give the title compound (571 mg, 32.7%).

[0461] 1 H NMR (300 MHz, DMSO-d6) δ 13.64 (s, 1H), 8.54 (d, J = 2.1 Hz, 1H), 8.17 (d, J = 2.0 Hz, 1H), 8.13 (s, 1H), 7.27 (dd, J = 7.5, 1.4 Hz, 1H), 7.19 - 7.14 (m, 2H), 4.49 (s, 2H), 3.79 (s, 3H), 2.97 (t, J = 8.4 Hz, 2H).

[0462] Step 2: 1-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-(trifluoromethyl)phenyl)indoline-6-carboxamide (Example 35)

[0463] A solution of 3-(trifluoromethyl)aniline (85 μL, 0.681 mmol) in anhydrous THF (1135 μL) was cooled to −78° C. under a stream of argon. Then, nBuLi (2.5 M in hexanes) (272 μL, 0.681 mmol) was added. The mixture was stirred for 25 min, and then a solution of intermediate 39 (70 mg, 0.227 mmol) in anhydrous THF (1135 μL) was added dropwise. The mixture was stirred at −78° C. for 0.5 h and then allowed to warm slowly to room temperature. The reaction mixture was stirred at room temperature overnight. Water was added and extraction was carried out with DCM. The organic phase was separated, dried over NaSO, and removed under reduced pressure. The crude material was purified by FCC eluting with DCM / MeOH (95:5) to give the title compound (77.4 mg, 77%).

[0464] [Table 47]

[0465] The following compounds were prepared via transamidation as described for steps 1-2 of Example 35, starting from the appropriate corresponding commercially available amine in step 2.

[0466] [Table 48-1] [Table 48-2]

[0467] Example 41: Preparation of N-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(imidazo[1,2-a]pyrazin-3-ylmethyl)indoline-6-carboxamide [ka]

[0468] Step 1: Methyl 1-(imidazo[1,2-a]pyrazin-3-ylmethyl)indoline-6-carboxylate - Intermediate 40 [ka]

[0469] Ethyl indoline-6-carboxylate hydrochloride (0.5 g, 2.340 mmol), imidazo[1,2-a]pyrazine-3-carbaldehyde (0.344 g, 2.340 mmol), and magnesium sulfate (0.563 g, 4.68 mmol) were placed in a flask under argon. Anhydrous DCM (23.40 mL) was added, followed by AcOH (0.268 mL, 4.68 mmol). The reaction mixture was stirred at RT for 2 h. STAB (1.736 g, 8.19 mmol) was then added, and the reaction mixture was stirred at RT overnight. The reaction mixture was diluted with DCM, and a 10% aqueous solution of NaHSO3 was added. The mixture was stirred for 20 min, and the phases were separated. The organic phase was washed three times with a 10% aqueous solution of NaHSO3 to remove residual aldehyde. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by FCC eluting with DCM / MeOH (1:0 to 1:1) to give the title compound (0.319 g, 44.2%).

[0470] 1 H NMR (300 MHz, DMSO-d6) δ 9.08 (d, J = 1.5 Hz, 1H), 8.46 (dd, J = 4.7, 1.5 Hz, 1H), 7.94 (d, J = 4.7 Hz, 1H), 7.81 (s, 1H), 7.33 (d, J = 7.1 Hz, 2H), 7.22 - 7.16 (m, 1H), 4.76 (s, 2H), 3.82 (s, 3H), 3.22 (t, J = 8.3 Hz, 2H), 2.92 (t, J = 8.3 Hz, 2H).

[0471] Step 2: N-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(imidazo[1,2-a]pyrazin-3-ylmethyl)indoline-6-carboxamide (Example 41)

[0472] A solution of 3-fluoro-5-(trifluoromethyl)aniline (0.095 ml, 0.730 mmol) in anhydrous THF (1.216 ml) was cooled to −78° C. Then, nBuLi (2.5 M in hexanes) (0.243 ml, 0.608 mmol) was added. The mixture was stirred for 25 minutes, and then a solution of Intermediate 40 (0.075 g, 0.243 mmol) in anhydrous THF (1.2 ml) was added dropwise. The mixture was stirred at −78° C. and allowed to warm slowly to room temperature. The reaction mixture was stirred at room temperature overnight. Water and ethyl acetate were added to the reaction mixture. The two phases were separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried over Na2SO4, filtered, and concentrated to dryness. The crude product was purified by preparative HPLC eluting with ACN, H2O+0.05% NH3 to give the title compound (0.061 g, 55% yield).

[0473] [Table 49]

[0474] The following compounds were prepared via transamidation as described for steps 1-2 of Example 41, starting from the appropriate corresponding commercially available amine in step 2.

[0475] [Table 50-1] [Table 50-2] [Table 50-3]

[0476] Example 47: 1-(imidazo[1,2-a]pyrazin-3-ylmethyl)-N-[4-(oxetan-3-ylmethoxy)-3-(trifluoromethyl)phenyl]indoline-6-carboxamide [ka]

[0477] Step 1: 1-(imidazo[1,2-a]pyrazin-3-ylmethyl)indoline-6-carboxylic acid - intermediate 41 [ka]

[0478] Intermediate 40 (68 mg, 0.21 mmol) and NaOH 1N (0.6 ml) were stirred at rt for 2 h. The mixture was concentrated under reduced pressure. The residue was washed with water, filtered, and dried under vacuum to give the title compound (65 mg, 100%).

[0479] Step 2: 1-(Imidazo[1,2-a]pyrazin-3-ylmethyl)-N-[4-(oxetan-3-ylmethoxy)-3-(trifluoromethyl)phenyl]indoline-6-carboxamide (Example 47)

[0480] To a mixture of intermediate 41 (65 mg, 0.221 mmol) and HATU (100.8 mg, 0.26) in DMF (0.6 ml) was added N,N-diisopropylethylamine (85.68 mg, 129.2 mmol). The reaction mixture was stirred at room temperature for 15 minutes, and intermediate 16 (55 mg, 0.221 mmol) was added. The reaction mixture was stirred at room temperature until LCMS showed the consumption of the starting material and concentrated. Water and ethyl acetate were added to the reaction mixture. The two phases were separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried over Na2SO4, filtered, and concentrated to dryness. The crude product was purified by reverse-phase preparative HPLC eluting with ACN / H2O (10 mM NH4CO3) to give the title compound (15.28 mg, 13.1%).

[0481] [Table 51]

[0482] The following compounds were prepared via amidation as described for Steps 1-2 of Example 47, starting from the appropriate corresponding amine in Step 2.

[0483] [Table 52-1] [Table 52-2] [Table 52-3]

[0484] Example 55: Preparation of 1-(imidazo[1,2-a]pyridin-3-ylmethyl)-N-(3-(trifluoromethoxy)phenyl)indoline-6-carboxamide [ka]

[0485] Step 1: Methyl 1-(imidazo[1,2-a]pyridin-3-ylmethyl)indoline-6-carboxylate - Intermediate 42 [ka]

[0486] Methyl indoline-6-carboxylate (1 g, 5.64 mmol), imidazo[1,2-a]pyridine-3-carbaldehyde (0.825 g, 5.64 mmol), acetic acid (0.646 ml, 11.29 mmol), magnesium sulfate (1.358 g, 11.29 mmol), and DCM (56.4 ml) were placed in a flask. The reaction mixture was stirred at rt for 2 h, and then STAB (2.392 g, 11.29 mmol) was added. Stirring was continued until the next day. Saturated NaHCO3 solution was added. Extraction was performed with DCM. The solvent was removed under reduced pressure. The crude material was purified by FCC eluting with DCM / MeOH 95.5 to give the title compound (760 mg, 43%).

[0487] 1 H NMR (300 MHz, DMSO-d6) δ 8.36 (dt, J = 6.9, 1.2 Hz, 1H), 7.60 (dt, J = 9.1, 1.1 Hz, 1H), 7.56 (s, 1H), 7.35 (d, J = 1.4 Hz, 1H), 7.34 - 7.24 (m, 2H), 7.18 (d, J = 7.5 Hz, 1H), 6.96 (td, J = 6.8, 1.2 Hz, 1H), 4.69 (s, 2H), 3.82 (s, 3H), 3.20 (t, J = 8.3 Hz, 2H), 2.91 (t, J = 8.3 Hz, 2H).

[0488] Step 2: 1-(Imidazo[1,2-a]pyridin-3-ylmethyl)-N-(3-(trifluoromethoxy)phenyl)indoline-6-carboxamide (Example 55)

[0489] A solution of 3-(trifluoromethoxy)aniline (121 mg, 0.683 mmol) in anhydrous THF (1139 μl) was cooled to −78° C. Then, nBuLi (2.5 M in hexanes) (228 μl, 0.569 mmol) was added. The mixture was stirred for 25 min, and then a solution of intermediate 42 (70 mg, 0.228 mmol) in anhydrous THF (1139 μl) was added dropwise. The mixture was stirred at −78° C. and slowly warmed to room temperature. The reaction mixture was stirred at room temperature overnight. Water and DCM were added to the reaction mixture. The two phases were separated, and the aqueous phase was extracted once more with DCM. The organic phases were combined, dried over Na2SO4, filtered, and concentrated to dryness. The crude material was purified by FCC eluting with DCM / MeOH (95:5) to give the title compound (87 mg, 84%).

[0490] [Table 53]

[0491] The following compounds were prepared via transamidation as described for steps 1-2 of Example 55, starting from the appropriate corresponding commercially available amine in step 2.

[0492] [Table 54-1] [Table 54-2]

[0493] Example 60: Preparation of 1-((1H-benzo[d]imidazol-5-yl)methyl)-N-(3-(trifluoromethyl)phenyl)indoline-6-carboxamide [ka]

[0494] Step 1: Methyl 1-((1H-benzo[d]imidazol-5-yl)methyl)indoline-6-carboxylate - Intermediate 43 [ka]

[0495] Methyl indoline-6-carboxylate hydrochloride (1.5 g, 7.02 mmol), 1H-benzo[d]imidazole-5-carbaldehyde (1.026 g, 7.02 mmol), and magnesium sulfate (1.690 g, 14.04 mmol) were placed in a flask under argon. Anhydrous DCM (46.8 mL) was added, followed by AcOH (0.804 mL, 14.04 mmol). The reaction mixture was stirred at RT for 2 h. STAB (5.21 g, 24.57 mmol) was then added, and the reaction mixture was stirred at RT overnight. The reaction mixture was diluted with DCM, and a 10% aqueous solution of NaHSO was added. The mixture was stirred for 20 min, and the phases were separated. The organic phase was washed three times with a 10% aqueous solution of NaHSO. The organic phase was dried over NaSO, filtered, and concentrated in vacuo. The crude product was purified via flash column chromatography eluting with DCM / MeOH (1:0 to 1:1). The resulting solid was triturated with water to give the title compound (1.068 g, 49.5% yield).

[0496] 1 H NMR (300 MHz, DMSO-d6) δ 8.32 (s, 1H), 7.58 (d, J = 8.3 Hz, 1H), 7.54 (d, J = 1.5 Hz, 1H), 7.23 (td, J = 7.9, 1.5 Hz, 2H), 7.15 (d, J = 7.6 Hz, 1H), 7.07 (d, J = 1.4 Hz, 1H), 4.45 (s, 2H), 3.78 (s, 3H), 3.37 (t, 2H), 2.97 (t, J = 8.5 Hz, 2H).

[0497] Step 2: 1-((1H-benzo[d]imidazol-5-yl)methyl)-N-(3-(trifluoromethyl)phenyl)indoline-6-carboxamide (Example 60)

[0498] A solution of 3-(trifluoromethyl)aniline (0.091 ml, 0.732 mmol) in anhydrous THF (1.220 ml) was cooled to −78° C. Next, nBuLi (2.5 M in hexanes) (0.244 ml, 0.610 mmol) was added. The mixture was stirred for 25 minutes, and then a solution of Intermediate 43 (0.075 g, 0.244 mmol) in anhydrous THF (1.2 ml) was added dropwise. The mixture was stirred at −78° C. and slowly warmed to room temperature. The reaction mixture was stirred at room temperature overnight. Water and ethyl acetate were added to the reaction mixture. The two phases were separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried over NaSO, filtered, and concentrated to dryness. The crude product was purified via preparative HPLC eluting with ACN, HO+0.05% NH to give the title compound (0.044 g, 41.3% yield).

[0499] [Table 55]

[0500] The following compounds were prepared via transamidation as described for steps 1-2 of Example 60, starting from the appropriate corresponding commercially available amine in step 2.

[0501] [Table 56]

[0502] Example 63: Preparation of 1-(pyrazolo[1,5-a]pyrimidin-6-ylmethyl)-N-(3-(trifluoromethyl)phenyl)indoline-6-carboxamide [ka]

[0503] Step 1: 1-(pyrazolo[1,5-a]pyrimidin-6-ylmethyl)-N-(3-(trifluoromethyl)phenyl)indoline-6-carboxamide (Example 63)

[0504] To a solution of pyrazolo[1,5-a]pyrimidine-6-carbaldehyde (24 mg, 0.163 mmol) and N-(3-(trifluoromethyl)phenyl)indoline-6-carboxamide (50 mg, 0.163 mmol), prepared as described in Steps 1-2 of Example 32 starting from 1-(tert-butoxycarbonyl)-indoline-6-carboxylic acid, in MeOH (5 ml) was added titanium(IV) isopropoxide (139 mg, 0.489 mmol), and the mixture was refluxed for 2 h. The reaction was cooled to room temperature, NaBHCN (26 mg, 0.407 mmol) was added, and stirring was continued overnight at room temperature. The reaction was quenched with water, filtered through Celite, and concentrated in vacuo. The residue was purified by reverse-phase preparative HPLC eluting with ACN / HO (0.1% FA) to give the title compound (15 mg, 39%).

[0505] [Table 57]

[0506] Example 64: Preparation of 3-ethyl-1-(imidazo[1,2-a]pyrazin-3-ylmethyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide [ka]

[0507] Step 1: Methyl 3-acetyl-1H indole-6-carboxylate - Intermediate 66 [ka]

[0508] To a suspension of aluminum chloride (9.13 g, 68.5 mmol, 2.40 eq) and acetyl chloride (2.4 mL, 34.3 mmol, 1.20 eq) in DCM (100.00 mL) was added methyl indole-6-carboxylate (5.00 g, 28.5 mmol, 1.00 eq) and the mixture was stirred at room temperature for 1 h. The mixture was poured onto ice and extracted with ethyl acetate (x3) (filtration through Celite required). The organic extracts were combined, washed with brine, and dried (Na2SO4). The solvent was evaporated, and the residue was triturated with ether and filtered to give the title compound (1.19 g, 18%).

[0509] LCMS (Method 21 Report) R =1.04 min, m / z (M+1)= 218.1

[0510] Step 2: Methyl 3-ethylindoline-6-carboxylate - Intermediate 67 [ka]

[0511] Triethylsilane (14 mL, 90.3 mmol, 18.0 eq) was added to a suspension of intermediate 66 (1.09 g, 5.02 mmol, 1.00 eq) in TFA (16 mL, 0.214 mol, 42.6 eq) and the mixture was stirred for 18 h. The mixture was concentrated under reduced pressure and the residue was partitioned between NaHCO3 solution and DCM. The organic extracts were combined, dried (Na2SO4) and evaporated. The residue was purified by FCC eluting with 50% EtOAc in cyclohexane to give the title compound (0.31 g, 29%).

[0512] 1H NMR (400 MHz, CDCl3) d 7.43 (d, J=7.6 Hz, 1H), 7.25 (s, 1H), 7.13 - 7.10 (m, 1H), 3.87 (s, 3H), 3.81 (s, 1H), 3.74 - 3.69 (m, 1H), 3.30 - 3.19 (m, 2H), 1.91 - 1.80 (m, 1H), 1.65 - 1.52 (m, 1H), 1.01 - 0.96 (m, 3H).

[0513] Step 3: Methyl 3-ethyl-1-(imidazo[1,2-a]pyrazin-3-ylmethyl)indoline-6-carboxylate Intermediate-68 [ka]

[0514] STAB (613 mg, 2.89 mmol, 2.00 eq) was added to a mixture of imidazo[1,2-a]pyrazine-3-carbaldehyde (266 mg, 1.81 mmol, 1.25 eq), Intermediate 67 (297 mg, 1.45 mmol, 1.00 eq), acetic acid (15 uL), and magnesium sulfate (697 mg, 5.79 mmol, 4.00 eq) in DCM (5.00 mL), and the mixture was stirred for 5 h. The mixture was partitioned between NaHCO3 solution and DCM (x3). The organic extracts were combined, dried (Na2SO4), and evaporated. The residue was purified by FCC eluting with 1% MeOH in DCM to give the title compound (382 mg, 83%).

[0515] 1H NMR (400 MHz, CDCl3) d 9.14 (s, 1H), 8.08 (d, J=4.6 Hz, 1H), 7.90 (d, J=4.6 Hz, 1H), 7.79 - 7.78 (m, 1H), 7.53 (d, J=7.6 Hz, 1H), 7.36 - 7.35 (m, 1H), 7.17 - 7.14 (m, 1H), 4.70 - 4.65 (m, 1H), 4.56 - 4.51 (m, 1H), 3.92 - 3.91 (s, 3H), 3.32 - 3.26 (m, 1H), 3.18 - 3.09 (m, 1H), 2.84 - 2.78 (m, 1H), 1.87 - 1.76 (m, 1H), 1.56 - 1.44 (m, 1H), 0.89 (t, J=7.4 Hz, 3H).

[0516] Step 4: Ethyl-1-(imidazo[1,2-a]pyrazin-3-ylmethyl)indoline-6-carboxylic acid - Intermediate 69 [ka]

[0517] LiOH (54 mg, 2.27 mmol, 2.00 eq) was added to a solution of intermediate 68 (382 mg, 1.14 mmol, 1.00 eq) in MeOH (2.00 mL) and water (0.50 mL), and the mixture was stirred at 50 °C for 64 h. The mixture was cooled to room temperature, and HCl (1 M; 2.27 mL, 2.27 mmol) was added. The reaction mixture was lyophilized. The resulting material was purified by FCC on silica gel (40 g cartridge, 0-100% DCM / MeOH 1:5 in DCM) to give the title compound (249 mg, 61%).

[0518] 1H NMR (400 MHz, DMSO) d 9.38 (d, J=1.0 Hz, 1H), 8.69 - 8.67 (m, 1H), 8.21 (d, J=4.8 Hz, 1H), 8.15 (s, 1H), 7.37 - 7.35 (m, 2H), 7.20 - 7.17 (m, 1H), 4.93 - 4.86 (m, 1H), 4.75 - 4.69 (m, 1H), 3.70 (br s, 1H), 3.42 (s, 1H), 3.45 - 3.39 (m, 1H), 3.16 - 3.07 (m, 1H), 2.93 (t, J=8.1 Hz, 1H), 1.86 - 1.72 (m, 1H), 0.89 - 0.83 (m, 3H).

[0519] Step 5: 3-Ethyl-1-(imidazo[1,2-a]pyrazin-3-ylmethyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide - Intermediate 70 [ka]

[0520] Thionyl chloride (0.79 mL, 10.9 mmol, 50.0 eq) was added to Intermediate 69 (70 mg, 0.217 mmol, 1.00 eq) and the mixture was stirred for 10 minutes. The mixture was dried under reduced pressure to give the intermediate acid chloride. The material was suspended in DCM (2 mL) and 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (105 mg, 0.434 mmol, 2.00 eq) was added. The mixture was stirred for 20 minutes and left overnight. The mixture was dried under reduced pressure, and the residue was passed through an SCX-2 (10 g) cartridge and eluted with MeOH (30 mL) followed by 2M methanolic ammonia solution (50 mL). The ammonia solution eluents were combined and concentrated under reduced pressure. Purification by reverse-phase preparative HPLC gave the title compound (7.96 mg, 6.7%).

[0521] 1H NMR (400 MHz, DMSO) d 10.54 (s, 1H), 9.11 (d, J=1.5 Hz, 1H), 8.49 - 8.47 (m, 1H), 8.31 (d, J=1.8 Hz, 1H), 8.21 (d, J=1.4 Hz, 1H), 8.16 (s, 1H), 7.98 (d, J=4.6 Hz, 1H), 7.86 (s, 1H), 7.73 (s, 1H), 7.50 - 7.50 (m, 1H), 7.39 - 7.35 (m, 2H), 7.26 (d, J=7.4 Hz, 1H), 4.87 (d, J=15.3 Hz, 1H), 4.73 (d, J=15.3 Hz, 1H), 3.45 - 3.39 (m, 1H), 3.20 - 3.12 (m, 1H), 2.98 - 2.93 (m, 1H), 2.19 (s, 3H), 1.83 - 1.76 (m, 1H), 1.53 - 1.45 (m, 1H), 0.91 - 0.85 (m, 3H).

[0522] Step 6: 3-Ethyl-1-(imidazo[1,2-a]pyrazin-3-ylmethyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide (Example 64)

[0523] Example 64 was obtained as a single enantiomer (second elution) by chiral preparative SFC purification of the racemic mixture of Intermediate 70 (Waters / Thar SFC system, YMC Cellulose-C column, 40 / 60 IPA (0.1% diethylamine) / heptane isocratic run, 1.0 ml / min).

[0524] [Table 58]

[0525] Example 65: Preparation of 3-ethyl-1-(imidazo[1,2-a]pyrazin-3-ylmethyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide [ka]

[0526] Step 1: Ethyl 1-((3-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl)methyl)indoline-6-carboxylate acid - Intermediate 71 [ka]

[0527] STAB (1108 mg, 5.23 mmol, 2.00 eq) was added to a mixture of 3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (527 mg, 3.27 mmol, 1.25 eq), ethyl indoline-6-carboxylate (500 mg, 2.61 mmol, 1.00 eq), acetic acid (15 μL), and magnesium sulfate (1259 mg, 10.5 mmol, 4.00 eq) in DCM (15.00 mL), and the mixture was stirred at room temperature for 5 h. The mixture was partitioned between NaHCO3 solution and DCM (x3). The organic extracts were combined, dried (Na2SO4), and evaporated. The residue was triturated with ether and filtered to give the title compound (785 mg, 89%).

[0528] LCMS (Method 21) R =1.41 min, m / z (M+1)= 337.2

[0529] Step 2: 1-((3-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl)methyl)indoline-6-carboxylic acid - Intermediate 72 [ka]

[0530] NaOH (192 mg, 4.80 mmol, 2.13 eq) was added to a solution of intermediate 71 (758 mg, 2.25 mmol, 1.00 eq) in MeOH (10.00 mL) and water (0.50 mL), and the mixture was stirred at 50° C. for 64 h. The mixture was cooled to rt, and 1 M HCl (4.8 mL, 4.80 mmol, 2.13 eq) was added dropwise, giving a solid precipitate that was filtered and washed with acetone (4 mL) to give the title compound (652 mg, 94%).

[0531] LCMS (Method 21) R 0.77 min, m / z (M+1) = 309.2

[0532] Step 3: 1-((3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)indoline-6-carboxamide (Example 65)

[0533] To a mixture of Intermediate 72 (50 mg, 0.162 mmol) and HATU (74 mg, 0.194 mmol) in DMF (0.1 M concentration) was added N,N-diisopropylethylamine (84 μL, 0.480 mmol). The reaction mixture was stirred at room temperature for 15 min, and then 4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)aniline (53 mg, 0.195 mmol eq) was added. The reaction mixture was applied to a 5 g Isolute SCX-II cartridge pre-conditioned with MeOH, washed with MeOH, and then eluted with 2 M NH3 / MeOH. The 2 M NH3 / MeOH eluate was concentrated under reduced pressure. Purification by reverse-phase preparative HPLC (Xbridge Phenyl 19x150 mm, 10 μm 40-100% MeOH / H2O (10 mM NH4HCO3), 20 mL / min, RT) gave the title compound (33.59 mg, 36%).

[0534] [Table 59]

[0535] The following compounds were prepared via amidation as described for Steps 1-3 of Example 65, using previously synthesized or commercially available amines in Step 3. Such procedures may involve minor variations. In some cases, if changes were involved in coupling agents (e.g., TCFH and methylimidazole), solvents, or chromatographic purification conditions, such changes are reported in the tables.

[0536] [Table 60-1] [Table 60-2] [Table 60-3] [Table 60-4]

[0537] Example 75: Preparation of 1-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)indoline-6-carboxamide [ka]

[0538] Step 1: tert-butyl 6-((4-((4-methylpiperazin-1-yl)methyl)-3-trifluoromethyl)phenyl)carbamoyl)indoline-1-carboxamide - Intermediate 73 [ka]

[0539] To a suspension of 1-tert-butoxycarbonylindoline-6-carboxylic acid (1.00 g, 3.80 mmol) and 4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)aniline (1.25 g, 4.56 mmol) in DMF (10 mL) was added 1-methylimidazole (1.1 mL, 13.3 mmol) and TCFH (1.60 g, 5.70 mmol). The reaction mixture was stirred at rt for 24 h. The mixture was partitioned between brine (3 × 10 mL) and EtOAc (10 mL). The organic phase was dried (NaSO) and concentrated. The residue was purified by FCC eluting with 10% 2M NH / MeOH in DCM to give the title compound (2.22 g, 100%). LCMS (Method 21) R =1.72 min, m / z (M+1)= 519

[0540] The following intermediates were prepared via amidation as described for Step 1 of Intermediate 73, using the appropriate commercially available or previously synthesized amines. Such procedures may involve minor variations. In some cases, changes in coupling agents (e.g., TCFH and 1-methylimidazole were replaced with HATU and DIPEA), solvents (DMF was replaced with ACN), or chromatographic purification conditions (e.g., prep HPLC or flash chromatography) were included, and such variations are reported in the tables.

[0541] [Table 61-1] [Table 61-2] [Table 61-3]

[0542] Step 2: N-((4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)indoline-6-carboxamide (Intermediate 80) [ka]

[0543] Trifluoroacetic acid (3.3 mL, 42.8 mmol) was added to a solution of Intermediate 73 (2.22 g, 4.28 mmol) in DCM (15 mL), and the mixture was stirred for 4 h. The mixture was concentrated under reduced pressure, and the residue was passed through an SCX-2 (25 g) cartridge and eluted with MeOH (30 mL) followed by 2 M methanolic ammonia solution (50 mL). The ammonia solution eluate was concentrated under reduced pressure to give a residue that was triturated with ether and filtered to give the title compound (1.47 g, 82%).

[0544] 1 H NMR (400 MHz, DMSO) δ 10.28 - 10.26 (m, 1H), 8.21 - 8.19 (m, 1H), 8.01 (dd, J=1.9, 8.5 Hz, 1H), 7.68 - 7.65 (m, 1H), 7.16 - 7.15 (m, 2H), 7.03 (s, 1H), 5.75 (s, 1H), 3.55 (s, 2H), 3.48 (dt, J=1.4, 8.6 Hz, 2H), 3.00 - 2.94 (m, 2H), 2.38 - 2.33 (m, 8H), 2.16 - 2.15 (m, 3H)

[0545] The following intermediates were prepared by acidic cleavage as described for step 2 of Intermediate 80. Such procedures may involve slight variations. In some cases, variations in chromatographic purification conditions (e.g., prep HPLC or flash chromatography) were included, and such variations are reported in the tables.

[0546] [Table 62-1] [Table 62-2] [Table 62-3]

[0547] Step 3: 1-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)indoline-6-carboxamide, Example 75

[0548] Sodium triacetoxyborohydride (50.4 mg, 0.238 mmol) was added to a mixture of 1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (22 mg, 0.149 mmol), Intermediate 80 (50 mg, 0.119 mmol), acetic acid (0.0001 mmol, 7 μL eq), and MgSO (117.32 mg, 0.476 mmol) in DCM (15.00 mL), and the mixture was stirred at room temperature until LCMS indicated consumption of the starting material. The mixture was partitioned between saturated NaHCO (aq) and DCM and then re-extracted with DCM. The organic extracts were combined, dried (NaSO), and concentrated under reduced pressure. The crude product was purified by reverse phase HPLC (Xbridge Phenyl 19x150mm, 10um 40-100% MeOH / H2O (10mM NH4CO3), 20ml / min, RT) to give the title compound (50mg, 76%).

[0549] [Table 63]

[0550] The following compounds were prepared via reductive amination starting from the corresponding intermediates described in step 2 and using the appropriate corresponding commercially available or synthesized carbaldehyde in step 3 as described for steps 1-3 of Example 75. If there were changes in the reducing agent (e.g., NaBHCN was substituted for STAB), solvent (MeOH was substituted for DCM), use of titanium(IV) isopropoxide, or chromatographic purification conditions (e.g., prepHPLC or flash chromatography), such changes are reported in the table.

[0551] [Table 64-1] [Table 64-2] [Table 64-3] [Table 64-4] [Table 64-5] [Table 64-6]

[0552] Example 87: Preparation of N-(5-(tert-butyl)-1-methyl-1H-pyrazol-3-yl)-1-(imidazo[1,2-a]pyrazin-3-ylmethyl)indoline-6-carboxamide [ka]

[0553] Intermediate 41 (40%, 100 mg, 0.136 mmol) was suspended in thionyl chloride (6.42 mmol, 0.46 mL), and the reaction mixture was stirred at 50 °C for 2 h. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was suspended in toluene and reconcentrated to give the intermediate acyl chloride.

[0554] To a solution of 5-tert-butyl-1-methyl-pyrazol-3-amine (31 mg, 0.204 mmol) in pyridine (0.1 M concentration) was added the acyl chloride. The reaction mixture was stirred at 40 °C until LCMS showed consumption of the starting material. The reaction mixture was evaporated, dissolved in MeOH (1 mL), and loaded onto an SCX-2 (5 g) cartridge, which was washed with MeOH. The compound was eluted with methanolic ammonia (2 M), and the basic solution was evaporated. Purification by reverse-phase preparative HPLC Sunfire C18 19 x 150 mm, 10 μm 20-80% acetonitrile / water (10 mM NH4HCO3), 20 mL / min, RT, followed by lyophilization gave the title compound (3.3 mg, 6%).

[0555] [Table 65]

[0556] Example 88: Preparation of -(imidazo[1,2-a]pyrazin-3-ylmethyl)-N-(6-trifluoromethyl)pyrimidin-4-yl)indoline-6-carboxamide [ka]

[0557] Thionyl chloride (0.40 mL, 5.44 mmol, 40.0 eq) was added to Intermediate 41, and the mixture was stirred at room temperature for 15 min. The mixture was evaporated under reduced pressure, and the residue was suspended in dry DCM (2.00 mL). In a separate flask, 1 M lithium bis(trimethylsilyl)amide in THF (0.30 mL, 0.299 mmol, 2.20 eq) was added dropwise to a solution of 6-(trifluoromethyl)pyrimidin-4-amine (27 mg, 0.163 mmol, 1.20 eq) in dry tetrahydrofuran (2.00 mL) at 78 °C, and the mixture was stirred for 15 min and then added dropwise to the suspension of acid chloride at −78 °C. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The solvent was evaporated, and the residue was dissolved in MeOH (1 mL) and passed through an SCX-2 (10 g) cartridge, eluting with MeOH (30 mL) followed by 2 M methanolic ammonia solution (20 mL). The ammonia solution eluents were combined and concentrated under reduced pressure. The residue (113 mg) was dissolved in 9:1 DMSO:water (1.0 mL) and purified by reverse-phase preparative HPLC (Xbridge Phenyl 19x150 mm, 10 μm 40-100% MeOH / HO (10 mM NH4CO3), 20 mL / min) to give the title compound (13.04 mg, 21.04%).

[0558] [Table 66]

[0559] Example 89: Preparation of N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-1-[(3-morpholino-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl]indoline-6-carboxamide [ka]

[0560] Step 1: 1-[(3-bromo-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl]-N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]indoline-6-carboxamide - Intermediate 87 [ka]

[0561] To a solution of intermediate 54 (74 mg, 0.33 mmol, 1.1 eq) in DCM (0.1 M concentration) was added intermediate 80 (125 mg, 0.30 mmol, 1 eq), titanium(IV) isopropoxide (170.53 mg, 0.060 mmol), and acetic acid (63 μL, 0.90 mmol). The reaction mixture was stirred at room temperature for 1 h. STAB (127.16 mg, 0.6 mmol) was added, and the reaction mixture was stirred at room temperature until LCMS showed the consumption of the starting material, giving intermediate 87 (180 mg, 0.229 mmol, 77%). Carried on to the next step without further purification.

[0562] LCMS (Method 22): R =1.69 min, m / z (M+1)= 628 / 630

[0563] Step 2: N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-1-[(3-morpholino-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl]indoline-6-carboxamide (Example 75)

[0564] A solution of intermediate 87 (80%, 70 mg, 0.0891 mmol) and morpholine (0.0086 mL, 0.0980 mmol) in 1,4-dioxane (3.00 mL) was sparged with N. 1 M lithium bis(trimethylsilyl)amide (0.45 mL, 0.446 mmol) was added dropwise, and the resulting solution was degassed before adding RuPhos Pd G (7.5 mg, 8.91 μmol, 0.1000 eq). The mixture was capped and heated to 80 °C for 1 h. The sample was cooled to room temperature and quenched with HO (1 mL). The mixture was extracted with EtOAc (3 × 5 mL), and the organic phases were combined, dried (MgSO), and evaporated. The residue was purified by preparative HPLC (Sunfire C18 19x150mm, 10µm 5-60% ACN / HO (0.1% FA), 20ml / min, RT). The resulting material was dissolved in 10% MeOH in DCM and applied to a 2g SCX cartridge. The cartridge was washed with 50:50 MeOH:DCM, and then the product was eluted with 1N NH3 in MeOH (20mL). The solvent was evaporated under high vacuum to give the title compound (12mg, 21%).

[0565] [Table 67]

[0566] When L1 is -C(O)NH- or -NHC(O)-, the comparative newly synthesized compounds have a -C(O)CH2- linker between the indoline ring and the Hy group instead of a -C(O) or CH2- linker.

[0567] Example C1: 1-(2-(Imidazo[1,2-a]pyridin-3-yl)acetyl)-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide [ka]

[0568] 2-(Imidazo[1,2-a]pyridin-3-yl)acetic acid (0.042 g, 0.239 mmol) was dissolved in DMF (2.4 ml), followed by the addition of TBTU (0.077 g, 0.239 mmol) and TEA (0.067 ml, 0.478 mmol). The mixture was stirred at room temperature for 15 minutes, followed by the addition of Intermediate 25 (0.1 g, 0.239 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM (5 ml) and water (5 ml). The mixture was stirred at room temperature for 15 minutes, followed by the phase separation, and the organic phase was washed with brine (2 x 15 ml), dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure. The crude material was triturated with a mixture of pentane and DCM (97 / 3). The residue was purified by preparative HPLC eluting with ACN+0.1% NH3, H2O+0.1% NH3 to give the title compound (26 mg, 19%).

[0569] [Table 68]

[0570] Example C2: N-(1-(2-(imidazo[1,2-a]pyridin-3-yl)acetyl)indolin-6-yl)-3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamide [ka]

[0571] 2-(Imidazo[1,2-a]pyridin-3-yl)acetic acid (37.9 mg, 0.215 mmol), Intermediate 29 (90 mg, 0.215 mmol), and TEA (0.060 mL, 0.430 mmol) were dissolved in DMF (0.2 mL) and DCM (0.6 mL), and then TBTU (69.1 mg, 0.215 mmol) was added. The reaction was carried out at RT for 16 h. The reaction mixture was diluted with DCM and then extracted with water (1 × 5 mL) and brine (1 × 5 mL). The aqueous phases were combined and extracted with DCM. The organic phases were combined, dried over Na2SO4, filtered, and concentrated to dryness in vacuo. The crude material was purified by FCC eluting with DCM / MeOH (100:0 to 80:20) to give the title compound (83 mg, 67%).

[0572] [Table 69]

[0573] Pharmacological activity of the compounds of the present invention In vitro assay Binding assay

[0574] DDR1 and DDR2 binding assays were performed using LanthaScreen from Life Technologies TMThe Europium Kinase Binding assay was performed. Compounds were incubated with 5 nM DDR1 (Carna Biosciences) or 5 nM DDR2 (Life Technologies) in assay buffer (50 mM HEPES pH 7.5, 10 mM MgCl2, 1 mM EGTA, 0.01% BRIJ35) in white 384-well OptiPlates (PerkinElmer) containing 20 nM or 10 nM kinase tracer 178 and 2 nM europium-labeled anti-GST antibody (Life Technologies) for 1 h at room temperature. The fluorescence emission 665 nm / 615 nm ratio after excitation at 340 nm was determined using a Tecan Spark 20M plate reader. IC50 values ​​were determined using a four-parameter model: log(inhibitor) vs. response, using GraphPad Prism 7.0 software. IC50 values ​​were converted to Ki using the Cheng-Prusoff equation (Ki=IC50 / (1+[tracer] / Kd)).

[0575] DDR1 cell-based assay Inhibition of DDR1 receptor activation by compounds was assessed using the PathHunter® U2OS DDR1 Assay (Eurofins DiscoverX) according to the manufacturer's instructions. Briefly, U2OS-DDR1 cells were seeded into white 384-well plates at a density of 5000 cells / well and incubated at 37°C and 5% CO2 for 2 hours. Cells were then treated with various concentrations of compounds, incubated for 30 minutes, and then stimulated with 20 μg / ml bovine type II collagen and incubated overnight at 37°C and 5% CO2. PathHunter detection reagent was prepared according to the protocol provided by DiscoverX, and this mix was added to each well at 20 μl / well. Plates were incubated in the dark at room temperature for 1 hour, after which luminescence signals were acquired using a plate reader. Raw data were normalized to vehicle control (normalized to 0%) and positive control (normalized to 100%; cells treated with 20 μg / ml collagen II), and IC50 parameters were calculated using sigmoidal dose-response curve fitting with variable slope in GraphPad Prism 8.0 software.

[0576] DDR2 cell-based assay Inhibition of DDR2 phosphorylation by compounds was assessed by phospho-ELISA assay using HEK293T-DDR2 recombinant cells. Briefly, HEK293T-DDR2 cells were seeded at a density of 250,000 cells / well on poly-D-lysine-coated 24-well plates and incubated in DMEM + 10% FBS at 37°C and 5% CO2 for 1.5 hours. The medium was then changed to serum-free DMEM, and the cells were incubated for 3 hours. Test compounds were then added at different concentrations 30 minutes before stimulation with 50 μg / ml bovine type II collagen for an additional 3 hours. For the DDR2 phospho-ELISA assay (DuoSet IC Human Phospho-DDR2; R&D Systems), protein extracts were obtained by adding 60 μl / well of lysis buffer prepared according to the manufacturer's instructions. Protein concentrations in the samples were measured by BCA assay, and phospho-DDR2 levels were measured according to R&D Systems' instructions. Raw data were normalized to the maximum inhibition control (0% normalization) and positive control (100% normalization; cells treated with 20 μg / ml collagen II), and IC50 parameters were calculated using sigmoidal dose-response curve fitting with variable slope in GraphPad Prism 8.0 software.

[0577] The results for individual compounds are shown in Table 7, sorted in terms of binding affinity (Ki) for DDR1 and DDR2 receptors, and potency (IC50) for inhibitory activity against DDR1 and DDR2 receptors.

[0578] [Table 70-1] [Table 70-2] [Table 70-3]

[0579] As can be seen, the compounds in Table 7, i.e., the compounds of the present invention, show good activity as antagonists of DDR1 and DDR2 receptors. Therefore, the compounds of the present invention can be effectively used in the treatment of diseases, disorders or conditions associated with DDR receptors, such as fibrosis, for example, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), liver fibrosis, renal fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis and systemic sclerosis.

[0580] Comparative Example The compounds of Examples C1 and C2 were tested in the same binding assay as above.

[0581] [Table 71]

[0582] As shown in Table 7, the compounds of the present invention have both binding affinities, expressed as Ki, for the DDR1 and DDR2 receptors and inhibitory potencies, expressed as IC50s for the DDR1 and DDR2 receptors, of less than 80 nM, with most compounds being less than 50 nM, or even less than 25 nM. Conversely, as shown in Table 8, Comparative Examples C1 and C2 have binding affinities for the DDR1 receptor of greater than 600 nM, C1 has a binding affinity of 58,000, and both C1 and C2 have a binding affinity of 58,000 for the DDR2 receptor. These data demonstrate that, contrary to the compounds of Examples C1 and C2, which feature a -CH2-C(O)- linker between the indoline ring and the Hy group, the presence of a -CH2- or -C(O)- linker at this position in the compounds of the present invention unexpectedly and surprisingly determines an appropriate increase in inhibitory activity for the DDR1 and DDR2 receptors. In particular, a direct comparison of the compound of Example C1 of the present invention, which differs only in the linker between the indoline group and Hy, with the compounds of Examples 14 and 11, highlights that the presence of the -C(O)- and -CH2- linkers in Examples 14 and 11, respectively, determines an unexpectedly significant increase in activity towards both the DDR1 and DDR2 receptors.

[0583] Similarly, a direct comparison of the compound of Example C2 of the present invention with the compound of Example 16, which differs only in the linker between the indoline group and Hy, highlights that the presence of the -C(O)- linker determines an unexpected and valuable increase in activity towards both the DDR1 and DDR2 receptors.

Claims

1. Formula (I): 【Chemistry 1】 [In the formula, R is H or -(C 1 -C 4 ) alkyl; L is -CH 2 - and -C(O)-; L 1 is selected from the group consisting of -C(O)NH- and -NHC(O)-; Hy is -(C 1 -C 4 ) alkyl, heterocycloalkyl and -(C 1 -C 4 ) Alkylene-NR A R B or Hy is a bicyclic semi-saturated heteroaryl; R A is H or -(C 1 -C 4 ) alkyl; R B is H or -(C 1 -C 4 ) alkyl; R 1 is selected from the group consisting of Het and X, -Het is -(C 1 -C 4 ) alkyl, -(C 1 -C 4 ) haloalkyl, -(C 1 -C 4 ) Alkylene-heterocycloalkyl-NR A R B , -(C 1 -C 4 ) Alkylene-NR A R B and aryl, wherein said aryl is one or more of -(C 1 -C 4 ) optionally substituted with alkyl; -X is a group represented by the formula: 【Chemistry 2】 (In the formula, R 2 is -O(C 1 -C 4 ) haloalkyl, halogen atoms and -(C 1 -C 4 ) haloalkyl; R 3 is H or -O(C 1 -C 4 ) alkyl, -C(O)NH-(C 1 -C 4 ) Alkylene-NR A R B , —C(O)-heterocycloalkyl, wherein said heterocycloalkyl is selected from the group consisting of one or more —(C 1 -C 4 )alkyl, -O-heterocycloalkyl, where said heterocycloalkyl is optionally substituted with one or more -(C 1 -C 4 ) alkyl, -O(C 1 -C 4 ) alkylene-heterocycloalkyl, -(C 1 -C 4 ) Alkylene-NR A R B , one or more -(C 1 -C 4 ) Heteroaryl optionally substituted by alkyl, and monocyclic heterocycloalkyl-(C 1 -C 4 )alkylene-, where the heterocycloalkyl is optionally substituted by -(C 1 -C 4 ) alkyl and -NR A R B and optionally substituted with one or more groups selected from is a group represented by the formula: or a pharma- ceutically acceptable salt thereof.

2. L 1 is -C(O)NH-, formula (IA): 【Chemistry 3】 2. The compound of formula (I) according to claim 1,

3. Formula (IA'), wherein L is -C(O)-: 【Chemistry 4】 3. The compound of claim 2 having the formula (IA): or a pharma- ceutically acceptable salt thereof.

4. 1-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide; 1-(imidazo[1,2-a]pyrazine-3-carbonyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide; 1-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide; 1-(Imidazo[1,2-a]pyrazine-3-carbonyl)-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide; 3-Methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-1-(1H-pyrazolo[3,4-b]pyridine-5-carbonyl)indoline-6-carboxamide; and 1-(imidazo[1,2-a]pyrazine-3-carbonyl)-3-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide, or a pharma- ceutically acceptable salt thereof.

5. L is -CH 2 -, wherein the compound of formula (IA'') is 【Chemistry 5】 3. The compound of claim 2 having the formula (IA): or a pharma- ceutically acceptable salt thereof.

6. 1-(imidazo[1,2-a]pyridin-3-ylmethyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide; 1-((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide; 1-(imidazo[1,2-a]pyrazin-3-ylmethyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide; 1-((1H-benzo[d]imidazol-5-yl)methyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide; 1-(isoquinolin-7-ylmethyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide; 1-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide; N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-1-((3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)indoline-6-carboxamide; 1-((1H-indazol-5-yl)methyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide; 1-((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide; 1-(imidazo[1,2-a]pyrazin-3-ylmethyl)-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide; 1-(imidazo[1,2-a]pyridin-3-ylmethyl)-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide; 1-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-3-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide; 1-(imidazo[1,2-a]pyridin-3-ylmethyl)-3-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide; 1-(imidazo[1,2-a]pyrazin-3-ylmethyl)-3-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide; 1-(imidazo[1,2-a]pyrazin-3-ylmethyl)-3-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide; 1-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-3-methyl-N-(3-(trifluoromethyl)phenyl)indoline-6-carboxamide; 1-(Imidazo[1,2-a]pyrazin-3-ylmethyl)-3-methyl-N-(3-(trifluoromethyl)phenyl)indoline-6-carboxamide; 1-((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-3-methyl-N-(3-(trifluoromethyl)phenyl)indoline-6-carboxamide; 1-(imidazo[1,2-a]pyridin-3-ylmethyl)-3-methyl-N-(3-(trifluoromethyl)phenyl)indoline-6-carboxamide; 1-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-3-methyl-N-(3-(trifluoromethyl)phenyl)indoline-6-carboxamide; 1-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)indoline-6-carboxamide; 1-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-(trifluoromethoxy)phenyl)indoline-6-carboxamide; 1-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)indoline-6-carboxamide; 1-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)indoline-6-carboxamide; N-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(imidazo[1,2-a]pyrazin-3-ylmethyl)indoline-6-carboxamide; 1-(Imidazo[1,2-a]pyrazin-3-ylmethyl)-N-(3-(trifluoromethyl)phenyl)indoline-6-carboxamide; 1-(imidazo[1,2-a]pyrazin-3-ylmethyl)-N-(3-(trifluoromethoxy)phenyl)indoline-6-carboxamide; N-(3-fluoro-5-(trifluoromethoxy)phenyl)-1-(imidazo[1,2-a]pyrazin-3-ylmethyl)indoline-6-carboxamide; 1-(imidazo[1,2-a]pyrazin-3-ylmethyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)indoline-6-carboxamide; 1-(imidazo[1,2-a]pyrazin-3-ylmethyl)-N-(4-methoxy-3-(trifluoromethyl)phenyl)indoline-6-carboxamide; 1-(imidazo[1,2-a]pyrazin-3-ylmethyl)-N-(4-((tetrahydrofuran-3-yl)oxy)-3-(trifluoromethyl)phenyl)indoline-6-carboxamide; N-(4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl)-1-(imidazo[1,2-a]pyrazin-3-ylmethyl)indoline-6-carboxamide; 1-(imidazo[1,2-a]pyrazin-3-ylmethyl)-N-(3-(morpholinomethyl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide; 1-(imidazo[1,2-a]pyrazin-3-ylmethyl)-N-(3-(pyrrolidin-1-ylmethyl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide; N-(3-((dimethylamino)methyl)-5-(trifluoromethyl)phenyl)-1-(imidazo[1,2-a]pyrazin-3-ylmethyl)indoline-6-carboxamide; 1-(imidazo[1,2-a]pyrazin-3-ylmethyl)-N-(3-(2-(pyrrolidin-1-yl)ethoxy)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide; 1-(imidazo[1,2-a]pyrazin-3-ylmethyl)-N-(3-(2-morpholinoethoxy)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide; 1-(imidazo[1,2-a]pyrazin-3-ylmethyl)-N-(4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)indoline-6-carboxamide; 1-(imidazo[1,2-a]pyridin-3-ylmethyl)-N-(3-(trifluoromethoxy)phenyl)indoline-6-carboxamide; N-(3-fluoro-5-(trifluoromethoxy)phenyl)-1-(imidazo[1,2-a]pyridin-3-ylmethyl)indoline-6-carboxamide; 1-(imidazo[1,2-a]pyridin-3-ylmethyl)-N-(3-(trifluoromethyl)phenyl)indoline-6-carboxamide; 1-(imidazo[1,2-a]pyridin-3-ylmethyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)indoline-6-carboxamide; N-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(imidazo[1,2-a]pyridin-3-ylmethyl)indoline-6-carboxamide; 1-((1H-benzo[d]imidazol-5-yl)methyl)-N-(3-(trifluoromethyl)phenyl)indoline-6-carboxamide; 1-((1H-Benz[d]imidazol-5-yl)methyl)-N-(3-(trifluoromethoxy)phenyl)indoline-6-carboxamide; 1-((1H-benzo[d]imidazol-5-yl)methyl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)indoline-6-carboxamide; 1-(pyrazolo[1,5-a]pyrimidin-6-ylmethyl)-N-(3-(trifluoromethyl)phenyl)indoline-6-carboxamide; 3-Ethyl-1-(imidazo[1,2-a]pyrazin-3-ylmethyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide; 1-((3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)indoline-6-carboxamide; 1-((3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-(pyrrolidin-1-ylmethyl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide; N-(5-(tert-butyl)isoxazol-3-yl)-1-((3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)indoline-6-carboxamide; 1-((3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide; N-(4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl)-1-((3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)indoline-6-carboxamide; 1-((3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(4-(pyrrolidin-1-ylmethyl)-3-(trifluoromethyl)phenyl)indoline-6-carboxamide; 1-((3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(5-(trifluoromethyl)pyridin-3-yl)indoline-6-carboxamide; (R)—N-(3-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-1-((3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)indoline-6-carboxamide; N-(3-((2-(dimethylamino)ethyl)carbamoyl)-5-(trifluoromethyl)phenyl)-1-((3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)indoline-6-carboxamide; 1-((3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-(4-methylpiperazine-1-carbonyl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide; 1-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)indoline-6-carboxamide; N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-1-(pyrazolo[1,5-a]pyrimidin-6-ylmethyl)indoline-6-carboxamide; 1-((2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)indoline-6-carboxamide; 1-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-(tert-butyl)isoxazol-5-yl)indoline-6-carboxamide; N-(3-(tert-butyl)isoxazol-5-yl)-1-(imidazo[1,2-a]pyrazin-3-ylmethyl)indoline-6-carboxamide; N-(3-(tert-butyl)isoxazol-5-yl)-1-((3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)indoline-6-carboxamide; 1-((3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(2-((4-methylpiperazin-1-yl)methyl)-6-(trifluoromethyl)pyridin-4-yl)indoline-6-carboxamide; N-(2-((dimethylamino)methyl)-6-(trifluoromethyl)pyridin-4-yl)-1-((3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)indoline-6-carboxamide; 1-((3-((dimethylamino)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-N-(5-(trifluoromethyl)pyridin-3-yl)indoline-6-carboxamide; (R)—N-(2-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-6-(trifluoromethyl)pyridin-4-yl)-1-((3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)indoline-6-carboxamide; 1-((3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-(2-(pyrrolidin-1-yl)ethoxy)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide; N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-1-(pyrazolo[1,5-a]pyrazin-3-ylmethyl)indoline-6-carboxamide; N-(5-(tert-butyl)-1-methyl-1H-pyrazol-3-yl)-1-(imidazo[1,2-a]pyrazin-3-ylmethyl)indoline-6-carboxamide; 1-(imidazo[1,2-a]pyrazin-3-ylmethyl)-N-(6-(trifluoromethyl)pyrimidin-4-yl)indoline-6-carboxamide; N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-1-((3-morpholino-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)indoline-6-carboxamide; 1-((3-((dimethylamino)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-N-(3-(trifluoromethyl)phenyl)indoline-6-carboxamide; 1-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-3-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)indoline-6-carboxamide; and 1-(imidazo[1,2-a]pyrazin-3-ylmethyl)-3-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)indoline-6-carboxamide, or a pharma- ceutically acceptable salt thereof.

7. L 1 is -NHC(O)-, formula (IB): 【Chemistry 6】 2. The compound of formula (I) according to claim 1, wherein:

8. N-(1-(imidazo[1,2-a]pyridine-3-carbonyl)indolin-6-yl)-3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamide; N-(1-(benzo[d]thiazol-6-ylmethyl)indolin-6-yl)-3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamide; N-(1-(imidazo[1,2-a]pyrazin-3-ylmethyl)indolin-6-yl)-3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamide; N-(1-(imidazo[1,2-a]pyridine-3-carbonyl)indolin-6-yl)-3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzamide; N-(1-(imidazo[1,2-a]pyrazine-3-carbonyl)indolin-6-yl)-3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzamide; N-(1-(1H-pyrazolo[3,4-b]pyridine-5-carbonyl)indolin-6-yl)-3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzamide; N-(1-(imidazo[1,2-a]pyrazin-3-ylmethyl)indolin-6-yl)-3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzamide; N-(1-(imidazo[1,2-a]pyridin-3-ylmethyl)indolin-6-yl)-3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzamide; N-(1-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)indolin-6-yl)-3-(trifluoromethyl)benzamide; and N-(1-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)indolin-6-yl)-3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzamide, or a pharma- ceutically acceptable salt thereof.

9. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 8, or a pharma- ceutically acceptable salt thereof, together with one or more pharma- ceutically acceptable carriers or excipients.

10. 10. The pharmaceutical composition of claim 9, for administration by inhalation.

11. A medicine comprising a compound of formula (I) according to any one of claims 1 to 8 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 9 or 10.

12. The pharmaceutical according to claim 11 for preventing and / or treating a disease, disorder or condition associated with dysregulation of the DDR.

13. A medicament according to claim 11 or 12 for the prevention and / or treatment of fibrosis and / or a disease, disorder or condition in which fibrosis is involved.

14. 14. The medicament according to claim 13 for the prevention and / or treatment of fibrosis, including pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), liver fibrosis, renal fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis and systemic sclerosis.

15. The pharmaceutical composition according to claim 14 for preventing and / or treating idiopathic pulmonary fibrosis (IPF).

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