Indoline derivatives as DDR inhibitors

Abstract

Indoline derivatives as DDR inhibitors The present invention relates to compounds of general formula (I) that inhibit DDR1 and DDR2. In particular, the present invention relates to compounds that are indoline derivatives, pharmaceutical compositions containing them and their therapeutic use. The compounds of the present invention can be useful in the treatment of diseases or conditions associated with dysregulation of DDR, particularly fibrosis.

Description

[Technical field]

[0001] The present invention relates to compounds that inhibit discoidin domain receptors (DDR inhibitors), methods for producing 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 many disorders associated with DDR mechanisms. [Background technology]

[0002] Discoidin domain receptors (DDRs) are type I transmembrane receptor tyrosine kinases (RTKs). The DDR family contains two distinct members, DDR1 and DDR2.

[0003] 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 dimers that are non-covalently associated and ligand-independent (see Noordeen, NA (2006) J. Biol. Chem. 281, 22744-22751; Mihai C. J Mol Biol. 2009; 385:432-445).

[0004] The DDR1 subfamily is composed 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).

[0005] The DDR receptor family has been found to be involved in a series of fibrotic diseases, such as pulmonary fibrosis, especially idiopathic pulmonary fibrosis (IPF). The first evidence for a protective role of DDR1 deletion in pulmonary fibrosis was produced in 2006 by Dr. Vogel's research group (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. Moreover, myofibroblast proliferation and apoptosis were much lower in these animals compared to their wild-type counterparts. The absence of inflammation in the knockout mice was confirmed by lavage cell counts and cytokine ELISA. These results showed that DDR1 expression is a prerequisite for the development of lung inflammation and fibrosis.

[0006] Deficiency 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. showed that DDR2 plays an important role in inducing fibrosis and angiogenesis in the lung, in particular, that DDR2 acts synergistically with transforming growth factor (TGF)-β to induce myofibroblast differentiation. Furthermore, they showed that treatment of injured mice with specific siRNA against DDR2 showed therapeutic effects against pulmonary fibrosis. In a second publication, Jia et al. showed 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, fibroblasts lacking DDR2 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.

[0007] Several compounds have been described in the literature as DDR1 or DDR2 antagonists.

[0008] WO2016064970 (Guangzhou) discloses tetrahydroisoquinoline-7-carboxamides as selective DDR1 inhibitors useful as therapeutic agents for the prevention and treatment of inflammation, liver fibrosis, renal fibrosis, pulmonary fibrosis, skin scarring, atherosclerosis and cancer.

[0009] The same inventors from Guangzhou have disclosed tetrahydroisoquinoline-7-carboxamides as selective DDR1 inhibitors in Wang Z. et al. Chem. 2016, 59, 5911-5916.

[0010] In particular, antagonizing DDR receptors is useful in the treatment of fibrosis and diseases, disorders and conditions caused by fibrosis, and further, antagonizing both DDR1 and DDR2 receptors is particularly effective in the treatment of the above-mentioned diseases, disorders and conditions.

[0011] In the past few years, several efforts have been made to develop novel DDR1 and DDR2 receptor antagonists 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 receptors DDR1 and DDR2, useful for the treatment of diseases or conditions associated with dysregulation of DDR receptors in the respiratory field, in particular idiopathic pulmonary fibrosis (IPF), administered by the inhalation route and characterized by a good inhalation profile corresponding to good activity in the lungs, 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) reported herein below, which solve the problem of providing inhibitors for the receptors DDR1 and DDR2 for administration by inhalation and are active as selective inhibitors of the receptors DDR1 and DDR2 relative to other human protein kinases, such compounds 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, R1 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 optionally substituted with one or more groups selected from -(C1-C4)alkyl and oxo -(CH2) n monocyclic heteroaryl optionally substituted by one or more groups selected from NR4R5, -C(O)NR4R5, -(C1-C4)alkyl, -NR4(CO)R5, -(C1-C4)alkylene-O-(C1-C4)alkyl, and -(C4-C7)heterocycloalkyl; n is 0, 1 or 2; R4 is H or -(C1-C4)alkyl; R5 is H or is selected from the group consisting of (C3-C7)cycloalkyl, -(C1-C4)alkyl and heteroaryl, optionally substituted with one or more groups selected from -(C1-C4)alkyl, -(C1-C4)alkylene-NR1R4 and -(C1-C4)alkylene-O-(C1-C4)alkyl; X is [ka] (wherein R2 is selected from the group consisting of -(C1-C4)alkyl, -O(C1-C4)haloalkyl, halogen atoms, -(C1-C4)haloalkyl, -(C3-C7)cycloalkyl and -O(C3-C7)cycloalkyl; R3 is H or is selected from the group consisting of -O(C1-C4)alkyl, heteroaryl optionally substituted with one or more -(C1-C4)alkyl, and (C4-C7)heterocycloalkyl-(C1-C4)alkylene-, where said -(C4-C7)heterocycloalkyl is optionally substituted with one or more groups selected from -(C1-C4)alkyl and -O(C1-C4)alkyl. is] and pharma- ceutically acceptable salts thereof.

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

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

[0017] In a further aspect, the present invention relates to compounds of formula (I) and pharma- ceutically acceptable salts thereof, or pharmaceutical compositions comprising compounds of formula (I) and pharma- ceutically acceptable salts thereof, for use in the prophylaxis 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 pharma- ceutically acceptable salts thereof, or pharmaceutical compositions comprising compounds of formula (I) and pharma- ceutically acceptable salts thereof, for use in the prophylaxis and / or treatment of fibrosis and / or diseases, disorders or conditions involving fibrosis.

[0019] In a further aspect, the present invention relates to a compound of formula (I) and a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) and a pharma-ceutically acceptable salt thereof, for use in the prophylaxis 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 stereoisomers or pharma- ceutically acceptable salts thereof.

[0021] Unless otherwise specified, the compounds of formula (I) of the present invention are also intended to include compounds of formulae (Ia), (Ia1), (Ia1'), (Ia1''), (Ib), (Ib1) and (Ib1').

[0022] As used herein, the term "pharmaceutically acceptable salts" refers to derivatives of the compounds of formula (I) where 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, as well as 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 the preparation of salts include alkali metal or alkaline earth metal ions, such as potassium, sodium, calcium or magnesium.

[0025] Salts obtained by reacting the main compound, which functions as a base, with inorganic or organic acids include, for example, hydrochlorides, hydrobromides, sulfates, phosphates, methanesulfonates, camphorsulfonates, acetates, oxalates, maleates, fumarates, succinates and citrates.

[0026] The term "stereoisomers" means isomers of identical structure that differ in the arrangement of their atoms in space. Enantiomers and diastereomers are examples of stereoisomers.

[0027] The term "enantiomer" refers to one of a pair of molecular species that are mirror images of each other and are not superimposable.

[0028] The term "diastereomer" means a stereoisomer that is not a mirror image.

[0029] The terms "racemate" or "racemic mixture" mean a composition of equimolar amounts of two enantiomeric species, devoid of optical activity.

[0030] As used herein, the terms "halogen" or "halogen atom" or "halo" include fluorine, chlorine, bromine and iodine atoms.

[0031] The term “(C x -C y "(x)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.

[0032] The term “O(C x -C y (C )alkyl" (where x and y are integers) refers to a radical as defined above in which a carbon atom is bonded to an oxygen atom. x -C y ) alkyl groups, such as ethoxy.

[0033] The term “(C x -C y )alkylene" (where x and y are integers) refers to an alkylene having a total of two insufficient valences (C x -C y ) alkyl group.

[0034] The term “(C x -C y (C)haloalkyl" (wherein x and y are integers) refers to a "(C)haloalkyl" as defined above in which one or more hydrogen atoms are replaced by one or more halogen atoms, which may be the same or different. x -C y The above-mentioned "(C x -C y Examples of "haloalkyl" groups include halogenated and polyhalogenated alkyl groups, as well as fully halogenated alkyl groups in which all hydrogen atoms have been replaced with halogen atoms, such as trifluoromethyl.

[0035] The term “O(C x -C y (C)haloalkyl" (wherein 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.

[0036] 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.

[0037] The term “(C x -C y(x and y are integers) means a saturated cyclic hydrocarbon group containing the indicated number of carbon atoms in the ring. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

[0038] The term “O(C x -C y (C)cycloalkyl" (wherein x and y are integers) refers to a cycloalkyl group, as defined above, in which a carbon atom is bonded to an oxygen atom. x -C y )cycloalkyl" group. Examples include, for example, cyclopropyloxy.

[0039] The term "aryl" refers to 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.

[0040] The term "heteroaryl" refers to a monocyclic or bicyclic aromatic group containing one or more heteroatoms selected from S, N and O, including groups in which two such monocyclic rings, or one such monocyclic ring and one monocyclic aryl ring are fused together through a common bond. Examples of suitable heteroaryls include, for example, imidazolyl, pyrimidinyl, pyrazolyl, aminopyrazinyl, and pyridyl.

[0041] The term “-(C x -C y "(X)heterocycloalkyl" (wherein x and y are integers) refers to a saturated or partially unsaturated monocyclic (C)heterocycloalkyl in which at least one ring carbon atom is replaced with at least one heteroatom (e.g., N, S, or O) or which may have an -oxo (=O) substituent. x -C y) cycloalkyl groups. Said heterocycloalkyl may be further optionally substituted at available positions in the ring, i.e., on the carbon atoms or on the heteroatoms available for substitution. Substitution on the carbon atoms includes spirodisubstitution and substitution on two adjacent carbon atoms, in either case thus forming an additional fused 5-6 membered heterocyclic ring. Examples are piperazinyl and oxopiperazinyl.

[0042] The term “(C x -C y )Heterocycloalkyl-(C x -C y "Alkylene" refers to a straight-chain or branched (C x -C y ) alkylene group. For example, (4-methylpiperazin-1-yl)methyl, and the like.

[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)-, instead of other common representations 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] In the case where a basic amino group is present in the compound of formula (I), a physiologically acceptable anion may be present, selected from among 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 case of an acidic group, the corresponding physiological cation salts may also be present, including, for example, alkali metal ions 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 are different from the structures disclosed in the art at least on a common new core scaffold.Indeed, the present invention relates to compounds that are indoline derivatives, in which the nitrogen of indoline is linked to the monocyclic heteroaryl ring Hy via the linker -CH2- or -C(O)-, as shown in the general formula (I) detailed below, and have inhibitory activity against the receptors DDR1 and DDR2.

[0051] The compounds of the invention are active as selective inhibitors of the DDR1 and DDR2 receptors versus other human protein kinases, and exhibit potency, good inhalation profile, low metabolic stability, low systemic exposure, improved safety and tolerability.

[0052] In this regard, the art has neither described nor suggested the indoline derivatives of general formula (I) of the present invention, having inhibitory activity towards the receptors DDR1 and DDR2, which provide a solution to the aforementioned need.

[0053] Guangzhou and Wang disclose tetrahydroisoquinoline-7-carboxamides as selective DDR1 inhibitors.

[0054] 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 surprisingly determines high affinity for both the DDR1 and DDR2 receptors and suitable inhibitory activity against the DDR1 and further DDR2 receptors in cellular assays.

[0055] In fact, as detailed in the experimental section below, 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 5 shows that for the compound of the present invention, both the affinity to either DDR1 or DDR2 receptor and the inhibitory activity to either DDR1 or DDR2 receptor are less than about 80nM in binding (expressed as Ki) and cell-based assay (expressed as IC50), respectively.This confirms that the compound of formula (I) can inhibit the two isoforms of DDR receptors that are mainly involved in fibrosis and fibrosis-related diseases.Therefore, the compound of formula (I) can be used for the treatment of fibrosis, particularly pulmonary fibrosis, when DDR1 and DDR2 are involved.

[0056] Moreover, as shown in the experimental section, and in particular in the comparative examples of Table 6, it is shown that the presence of a -CH2- or -C(O)- linker at this position in the compounds of the invention, contrary to the compounds of Examples C1 to C3, which are characterized by the lack of a linker between the indoline ring and the Hy group, surprisingly and significantly determines an appropriate increase in the inhibitory activity against DDR1 and DDR2.

[0057] Advantageously, the compounds of the present invention have extremely high affinity and potency for DDR1 and DDR2, as shown in binding assays and cell-based assays, respectively, and therefore can be administered to humans at lower doses relative to prior art compounds, thereby reducing adverse events that may occur when high doses of the drugs are administered.

[0058] The compounds of the present invention, in addition to having high affinity for the DDR1 and DDR2 receptors and being remarkably potent in exerting inhibitory activity against both DDR1 and DDR2 receptors, are also characterized by a good inhalation profile that allows them to act effectively on the pulmonary compartment, while at the same time having low metabolic stability that allows them to minimize the drawbacks associated with systemic exposure, such as safety and tolerability issues.

[0059] The compounds of the present invention will therefore be particularly appreciated by those skilled in the art when looking for suitable and effective compounds that are useful for the treatment of fibrosis, in particular idiopathic pulmonary fibrosis, administered by the inhalation route and that 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.

[0060] Thus, in one aspect, the present invention provides a compound of general formula (I): [ka] [In the ceremony R1 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 optionally substituted with one or more groups selected from -(C1-C4)alkyl and oxo -(CH2) n monocyclic heteroaryl optionally substituted by one or more groups selected from NR4R5, -C(O)NR4R5, -(C1-C4)alkyl, -NR4(CO)R5, -(C1-C4)alkylene-O-(C1-C4)alkyl, and -(C4-C7)heterocycloalkyl; n is 0, 1 or 2; R4 is H or -(C1-C4)alkyl; R5 is H or is selected from the group consisting of (C3-C7)cycloalkyl, -(C1-C4)alkyl and heteroaryl, optionally substituted with one or more groups selected from -(C1-C4)alkyl, -(C1-C4)alkylene-NR1R4 and -(C1-C4)alkylene-O-(C1-C4)alkyl; X is [ka] (wherein R2 is selected from the group consisting of -(C1-C4)alkyl, -O(C1-C4)haloalkyl, halogen atoms, -(C1-C4)haloalkyl, -(C3-C7)cycloalkyl and -O(C3-C7)cycloalkyl; R3 is H or selected from the group consisting of -O(C1-C4)alkyl, heteroaryl optionally substituted with one or more -(C1-C4)alkyl, and (C4-C7)heterocycloalkyl-(C1-C4)alkylene-, wherein said -(C4-C7)heterocycloalkyl is optionally substituted with one or more groups selected from -(C1-C4)alkyl and -O(C1-C4)alkyl. and pharma- ceutically acceptable salts thereof.

[0061] In a preferred embodiment, R1 is H.

[0062] In another preferred embodiment, L is -CH2.

[0063] In another preferred embodiment, Hy is a monocyclic heteroaryl, wherein the heteroatoms are represented by one or more N atoms.

[0064] In another preferred embodiment, the present invention provides a compound represented by the general formula (I), wherein Hy is 3-aminopyrazin-2-yl, pyrimidin-5-yl, 2-(methylcarbamoyl)pyridin-4-yl, -N-methyl-4-picolinamido, 4-methyl-3-oxopiperazin-1-yl)pyridin-3-yl, 2-aminopyrimidin-5-yl, 6-aminopyridin-3-yl, 4-aminopyrimidin-5-yl, 5-aminopyrazin-2-yl, 2-(methylamino)pyrimidin-5-yl, 6-acetamidopyridin-3-yl, The compound is selected from the group consisting of 2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl, 5-carbamoylpyridin-3-yl, 2-((1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl and (2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl).

[0065] In a further preferred embodiment, the present invention relates to compounds of general formula (I), in which X is selected from the group consisting of ((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phen-3-yl, 3-(trifluoromethyl)phenyl, 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl and (4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phen-3-yl.

[0066] According to a preferred embodiment, the present invention relates to at least one of the compounds listed in Table 1 below. These compounds are active on the receptors DDR1 and DDR2, as shown in Table 5. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5]

[0067] In another preferred embodiment, the present invention relates to compounds of general formula (I), wherein L is -CH2-.

[0068] In a further preferred embodiment, the present invention relates to a compound of general formula (I) in which L1 is -C(O)NH- and L is -CH2-, which has the formula (Ia): [ka] wherein Hy, R1 and X are as defined above.

[0069] In another particularly preferred embodiment, the present invention relates to a compound of formula (Ia), [ka] and a compound of formula (Ia1): [ka] wherein Hy, R1, R2 and R3 are as defined above.

[0070] In another preferred embodiment, the present invention provides a compound of formula (I), wherein L1 is -C(O)NH-, L is -CH2-, and X is X': [ka] and a compound of formula (Ia1′): [ka] wherein Hy, R1, R2 and R3 are as defined above.

[0071] In another particularly preferred embodiment, the present invention relates to compounds of formula (Ia1') [wherein R2 is -CF3 and R3 is selected from the group consisting of heteroaryl optionally substituted with one or more -(C1-C4)alkyl, and (C4-C7)heterocycloalkyl-(C1-C4)alkylene-, wherein said -(C4-C7)heterocycloalkyl is optionally substituted with one or more -(C1-C4)alkyl] and pharma- ceutically acceptable salts thereof.

[0072] In a further particularly preferred embodiment, the present invention relates to compounds of formula (Ia1') wherein R2 is -CF3 and R3 is selected from the group consisting of 4-methyl-1H-imidazol-1-yl and (4-methylpiperazin-1-yl)methyl.

[0073] In a further preferred embodiment, the present invention relates to compounds of the general formula (Ia1'), in which Hy is selected from the group consisting of 2-(methylcarbamoyl)pyridin-4-yl, 2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl, 2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl, 2-((1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl, 2-aminopyrimidin-5-yl and pyrimidin-5-yl-methyl.

[0074] According to a preferred embodiment, the present invention relates to at least one compound of formula (Ia1') and its pharma- ceutically acceptable salts as listed in Table 2 below. These compounds are active against the receptors DDR1 and DDR2, as shown in Table 5. [Table 2-1] [Table 2-2]

[0075] In another preferred embodiment, the present invention relates to a compound of formula (Ia) wherein X is X: [ka] and a compound of formula (Ia1″): [ka] [wherein Hy, R1, R2 and R3 are as defined above].

[0076] In another particularly preferred embodiment, the present invention relates to a compound of formula (Ia1″), wherein Hy is selected from the group consisting of 2-aminopyrimidin-5-yl, 6-aminopyridin-3-yl, 4-aminopyrimidin-5-yl, 2-(methylamino)pyrimidin-5-yl, 6-acetamidopyridin-3-yl, 6-(methylamino)pyridin-3-yl, 2-acetamidopyrimidin-5-yl and 5-aminopyrazin-2-yl, R2 is trifluoromethyl and R3 is (4-methylpiperazin-1-yl)methyl.

[0077] According to a preferred embodiment, the present invention relates to at least one compound of formula (Ia1″) listed in Table 7 below, and its pharma- ceutically acceptable salts. These compounds are active against the receptors DDR1 and DDR2, as shown in Table 5.

[0078] [Table 3-1] [Table 3-2]

[0079] In another particularly preferred embodiment, the present invention relates to a compound of formula (I) in which L is -NHC(O)- and L is -CH-, comprising the compound of formula (Ib) [ka] wherein Hy, R1 and X are as defined above.

[0080] In a further particularly preferred embodiment, the present invention relates to a compound of formula (Ib), wherein X is [ka] and a compound of formula (Ib1) [ka] wherein R1, Hy, R2 and R3 are as defined above.

[0081] In a further preferred embodiment, the present invention relates to a compound of formula (I) wherein L1 is -NHC(O)-, L is -CH2-, and X is X': [ka] and a compound of formula (Ib1′) [ka] wherein R1, Hy, R2 and R3 are as defined above.

[0082] In another further preferred embodiment, the present invention relates to a compound of formula (Ib1') wherein R2 is -CF3 and R3 is (C4-C7)heterocycloalkyl-(C1-C4)alkylene-, wherein said -(C4-C7)heterocycloalkyl may be optionally substituted by one or more -(C1-C4)alkyl.

[0083] In a preferred embodiment, the present invention relates to compounds of general formula (Ib1'), wherein R3 is selected from the group consisting of 4-methylpiperazin-1-yl)methyl and -(4-methyl-1H-imidazol-1-yl).

[0084] In a further preferred embodiment, the present invention relates to a compound of general formula (Ib1'), wherein Hy is selected from the group consisting of 3-aminopyrazin-2-yl, 2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl, 2-aminopyrimidin-5-yl and -N-methyl-4-picolinamide.

[0085] According to a preferred embodiment, the present invention relates to at least one compound of formula (Ib1') and its pharma- ceutically acceptable salts as listed in Table 3 below. These compounds are active against the receptors DDR1 and DDR2, as shown in Table 5.

[0086] [Table 4]

[0087] The compounds of the present invention (including all of the 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 skill in the art. Although specific embodiments of the present invention may be shown or described herein, those of skill in the art will recognize that all embodiments or aspects of the present invention may 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 skill in the art by routine optimization procedures.

[0088] 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. TW Greene, PGM Wuts).

[0089] Surprisingly, it has been found that the compounds of formula (I) of the present invention effectively inhibit both DDR1 and DDR2. Advantageously, inhibition of the receptors DDR1 and DDR2 can result in effective treatment of diseases or conditions in which the DDR receptors are involved.

[0090] In this regard, it has now been found that the compounds of formula (I) of the present invention have an inhibitory potency, expressed as a Ki constant, of less than 80 nM against DDR1 and DDR2, as shown in the experimental section. Preferably, the compounds of the present invention have a Ki of less than 50 nM against DDR1 and DDR2. More preferably, the compounds of the present invention have a Ki of less than 25 nM against DDR1 and DDR2.

[0091] Furthermore, the compounds of formula (I) of the present invention have both an affinity for either DDR1 and DD2 receptors and an inhibitory potency for either DDR1 and DDR2 receptors of less than about 80nM in binding (expressed as Ki) and cell-based assays (expressed as IC50) as shown in this experimental section.Preferably, the compounds of the present invention have a Ki and / or IC50 of less than 50nM for DDR1 and DDR2 receptors.More preferably, the compounds of the present invention have a Ki and / or IC50 of less than 25nM for DDR1 and DDR2 receptors.

[0092] 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.

[0093] In a preferred embodiment, the present invention relates to compounds of formula (I) and pharma- ceutically acceptable salts thereof for use in the treatment of a disease, disorder or condition associated with dysregulation of the DDR.

[0094] In another embodiment, 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.

[0095] In a preferred embodiment, the present invention relates to a compound of formula (I) or a pharma- ceutically acceptable salt thereof for use in the prophylaxis 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 prophylaxis and / or treatment of a disease, disorder or condition in which fibrosis is involved.

[0096] As used herein, the term "fibrosis" or "fibrotic disorder" refers to conditions 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.

[0097] 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.

[0098] More preferably, the compounds of formula (I) above are for the treatment of idiopathic pulmonary fibrosis (IPF).

[0099] In one embodiment, 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 of such treatment a therapeutically effective amount of a compound of formula (I) as defined above.

[0100] In a further aspect, the present invention relates to the use of the compounds of formula (I) as defined above for treating disorders associated with DDR receptor mechanisms.

[0101] 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 a DDR receptor mechanism.

[0102] 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 of such treatment a therapeutically effective amount of a compound of formula (I) as defined above.

[0103] In a further aspect, the present invention relates to the use of the compounds of formula (I) as defined above for treating diseases, disorders or conditions associated with dysregulation of DDR receptors 1 and 2.

[0104] As used herein, a "safe effective amount" with respect to a compound of formula (I) or a pharma- ceutically acceptable salt thereof, or other pharma- ceutically active agent, means an amount of the compound that is sufficient to treat the patient's condition, yet low enough to avoid serious side effects, and may nevertheless be routinely determined by one of skill in the art.

[0105] The compound of formula (I) may be administered in a single dose or according to a dosing regimen in which multiple doses are administered at various time intervals over a given period of time. The typical daily dosage may vary depending on the selected route of administration.

[0106] 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 pharma- ceutically acceptable carriers or excipients.

[0107] In one embodiment, the present invention refers to a pharmaceutical composition of a compound of formula (I) in admixture with one or more pharma- ceutically acceptable carriers or excipients, such as those described in Remington's Pharmaceutical Sciences Handbook, XVII Ed., Mack Pub., NY, USA.

[0108] Administration of the compounds of the present invention and pharmaceutical compositions thereof can be accomplished, for example, orally, intranasally, parenterally (subcutaneously, intravenously, intramuscularly, intrasternally, and by injection) and by inhalation, depending on the needs of the patient.

[0109] Preferably, the compounds of the present invention are administered orally or by inhalation.

[0110] In one preferred embodiment, the pharmaceutical composition comprising a compound of formula (I) is a solid oral dosage form such as tablets, gelcaps, capsules, caplets, granules, lozenges and bulk powders.

[0111] In one embodiment, the pharmaceutical composition comprising a compound of Formula (I) is a tablet.

[0112] The compounds of the present invention can be administered alone or in combination with various pharma- ceutically acceptable carriers, diluents (such as sucrose, mannitol, lactose, starch, etc.), and other known excipients, including suspending agents, solubilizing agents, buffers, binders, disintegrating agents, preservatives, coloring agents, flavoring agents, lubricants, and the like.

[0113] In a further embodiment, the pharmaceutical composition comprising the compound of formula (I) is a liquid oral dosage form, 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 compound of the present invention.

[0114] 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.

[0115] 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.

[0116] Diluents or carriers which are chemically inert towards the compounds of the invention, such as lactose, or other additives suitable for improving the respirable fraction, can be added to the powdered compounds of the invention.

[0117] Inhalation aerosols containing a propellant gas such as hydrofluoroalkanes can contain the compounds of the invention either in solution or in dispersion form. Propellant-driven formulations may contain other ingredients such as cosolvents, stabilizers and optionally other excipients.

[0118] 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 nebulizers, or soft mist nebulizers known from the prior art.

[0119] The compounds of the present invention may be administered alone or in combination with other pharma- ceutical active ingredients.

[0120] 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.

[0121] The present invention is also directed to a device comprising a pharmaceutical composition comprising a compound of formula (I) according to the invention in the form of a single or multi-dose dry powder inhaler or a metered dose inhaler.

[0122] All preferred groups or embodiments mentioned above for the compounds of formula (I) can be combined with one another and apply mutatis mutandis.

[0123] The compounds of the present invention (including all of the 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 skill in the art. Although specific embodiments of the present invention may be shown or described herein, those of skill in the art will recognize that all embodiments or aspects of the present invention may 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 skill in the art by routine optimization procedures.

[0124] 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 the compounds of the present invention.

[0125] Any or at least one of the compounds listed herein of formula (I) may be prepared using generally known methods and according to the procedures outlined in detail in the schemes set out below.

[0126] Compounds of formula (I) [wherein R1, L, L1, Hy and X are as defined above] 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.

[0127] In a first embodiment of the present invention, compounds of formula (I) may be prepared as described in Scheme 1. [ka]

[0128] According to scheme 1, intermediate III can be prepared according to a one-step synthesis starting from intermediate II under suitable amide coupling reaction conditions. For example, intermediates II and IV can be reacted with 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 a temperature around RT for a period ranging from a few hours to overnight. Alternatively, intermediate III can be prepared starting from intermediate II via amidation in the presence of TCFH and 1-methylimidazole, which gives a transiently activated acylimidazolinium intermediate that reacts with the appropriate amine IV, in a solvent such as DMF, at a suitable temperature, for example room temperature.

[0129] In another approach, direct ester amidation (transamidation) can be carried out between intermediate IIb and intermediate IV using, for example, butyllithium as a promoter in a suitable organic solvent such as THF or dioxane at -78°C to give intermediate III.

[0130] Intermediate III can be converted to intermediate V by deprotection of 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. Reductive amination of intermediate V with a suitable aldehyde Hy-CHO X to give compounds of formula (I) can be carried out using a suitable reducing agent such as Na(OAc)3BH or NaCNBH3 in the presence of an acid such as acetic acid and optionally a coordinating agent such as titanium tetrahydroisopropoxide in a suitable solvent such as DCM or EtOH at room temperature.

[0131] Alternatively, intermediate V can be converted to intermediate VI by reductive amination using a suitable aldehyde such as 5-formylnicotinonitrile according to the conditions described above, followed by nitrile hydration conditions which can be applied to intermediate VI using a suitable hydrating agent such as Ghaffar-Parkins catalyst in a suitable solvent such as water at a suitable temperature, e.g. 100°C, to give compounds of formula (I).

[0132] Alternatively, intermediate IIa can be converted to intermediate VII by reductive amination with an appropriate aldehyde, such as 5-bromonicotinaraldehyde, using conditions described above, which can be hydrolyzed to intermediate VIII, using conditions described above, which can be converted to intermediate IX by amide coupling using conditions described above.

[0133] Finally, compounds of formula (I) can be prepared from intermediate IX by Pd-catalyzed cross-coupling with a suitable amine, such as 1-methylpiperazin-2-one, using a suitable Pd-ligand system, such as RuPhos Pd G3, in a suitable solvent, such as dioxane or DMF, in a suitable base, such as cesium carbonate or potassium carbonate, at a suitable temperature, for example 80° C.

[0134] Compounds of formula (I) can be prepared according to Scheme 2 set forth below, which provides at least one non-limiting synthetic route for the preparation of all examples.

[0135] In another embodiment, the compound of formula (I) (wherein R1, L, L1, Hy and X are as defined above) can be prepared as described in Scheme 2. [ka]

[0136] According to Scheme 2, intermediate XI can be prepared starting from intermediate IIc using an organic base such as DIPEA or TEA in the presence of BOC-anhydride and DMAP in a suitable organic solvent such as DCM at a temperature generally around room temperature for a period ranging from a few hours to overnight. The nitro group of intermediate XI can be reduced to the corresponding amine of intermediate XII under hydrogen atmosphere in the presence of a suitable catalyst such as Pd / C in a suitable solvent such as, but not limited to, ethyl acetate. Intermediate XIII can be prepared from intermediate XII under suitable amide coupling reaction conditions. For example, intermediates XII and IV can be reacted with 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 HATU or TBTU, in a suitable organic solvent such as DCM or DMF, for a time generally ranging from a few hours to overnight at a temperature around room temperature. Intermediate XIII can be converted to intermediate XIV by deprotecting the protected amine with BOC under acidic conditions such as trifluoroacetic acid in a suitable solvent such as, but not limited to, DCM, at room temperature for a few hours. Reductive amination of intermediate XIV with a suitable aldehyde Hy-CHO to give compounds of formula (I) can be carried out with a suitable reducing agent such as Na(OAc)3BH or NaCNBH3 in the presence of an acid, optionally such as acetic acid, and optionally a coordinating agent, such as titanium tetrahydroisopropoxide, in a suitable solvent, such as DCM or EtOH, at a suitable temperature, for example room temperature.

[0137] 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.

[0138] Preparation of Intermediates and Examples Chemical names of compounds were generated using Structure To Name Place IUPAC Name in PerkinElmer ChemDraw Professional 19.1.1.21. All reagents whose synthesis is not described in the experimental section are either commercially available, known compounds, or can be prepared from known compounds by known methods by one skilled in the art.

[0139] In the following procedures, some of the starting materials are identified with "Intermediate" or "Example" numbers and step numbers, which are provided solely for the assistance of the skilled chemist.

[0140] 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.

[0141] Abbreviation-Meaning t R= retention time; (CH3)3COK = potassium tert-butylate; Boc = tert-butoxycarbonyl; TEA = triethylamine; DMF = dimethylformamide; EtOAc = ethyl acetate; RT or rt = room temperature; THF = tetrahydrofuran; DCM = dichloromethane; MeOH = methyl alcohol; LCMS = liquid chromatography / mass spectrometry; HPLC = high performance liquid chromatography; d-DMSO = deuterated dimethyl sulfoxide. NMR = nuclear magnetic resonance; DIPEA = N,N-diisopropylethylamine; UPLC = ultra performance liquid chromatography; tBu XPhos = 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl; Pd(dba)2 = bis(dibenzylideneacetone)palladium(0); PdCl2(dppf) = [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); RuPhos = 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl; STAB = sodium triacetoxyborohydride; AcOH = acetic acid; prepHPLC = preparative high performance liquid chromatography; NaBH3CN = sodium cyanoborohydride; Na2SO4 = sodium sulfate; FCC = flash column chromatography; BuLi = n-butyllithium; NaHCO3 = 15% or saturated solution of sodium bicarbonate (sat.aq.sol.); SM = starting material; SCX = strong cation exchange; TFA = trifluoroacetic acid; T3P = propylphosphonic anhydride; sat.sol. = saturated solution.

[0142] 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 1H NMR spectra were recorded on a Bruker Fourier 300 MHz. Chemical shifts are reported in ppm relative to trimethylsilane (TMS) as an 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=to be determined).

[0143] The signal NH (exchangeable proton) from an amide or amine bond may not be visible.

[0144] The CH2 signal of the indoline ring may be hidden under the water signal or the DMSO signal.

[0145] LC / UV / MS analytical method

[0146] LC / MS retention times are estimated to be subject to experimental error of ±0.5 min.

[0147] Method 1: Kinetex® XB-C18 column, 4.6x50mm, 2.6μm, maintained at 25°C. Mobile phase: Water (0.1% formic acid) in MeCN (0.1% formic acid), 80% to 5% within 3.90 min; Flow rate: 1.0ml / min; Wavelength: 190-340nm DAD. Dionex UHPLC Ultimate 3000 / Thermo Scientific MSQ Plus with DAD detector.

[0148] Method 2: Acquity CSH C18 column 50mmx2.1mm 1.7μm, 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% within 1.5 min. Flow rate: 1mL / min. Wavelength: 210-400nm DAD. UPLC + Waters PDA + Waters QDA.

[0149] Method 3: 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% within 5.6 min. Flow rate: 0.4ml / min. Wavelength: 210-400nm DAD. UPLC + Waters DAD + Waters SQD2, single quadrupole UPLC-MS

[0150] Method 4: Kinetex® XB-C18 column, 4.6x50mm, 2.6μm, maintained at 25°C. Mobile phase: ACN (0.1% formic acid) in water (0.1% formic acid), 80% to 5% within 3.90 min; Flow rate: 1.0ml / min; Wavelength: 190-340nm DAD. Dionex UHPLC Ultimate 3000 / Thermo Scientific MSQ Plus with DAD detector.

[0151] Method 5: Acquity BEH UPLC column, 2.1x50mm, 1.7μm, maintained at 40°C. Mobile phase: MeCN (0.03% ammonia) in water (0.03% ammonia), 8% to 97% within 1.5 min; Flow rate: 0.8ml / min; Wavelength: 210-400nm DAD with PDA detector and QDa.

[0152] If the preparation of starting materials is not described, these are either commercially available, known in the literature, or readily available to one skilled in the art using standard procedures. All solvents were obtained from commercial sources and used without further purification.

[0153] Preparative HPLC was performed using reversed-phase (C18) preparative HPLC under basic (ACN+0.1% NH3, HO+0.1% NH3 or ACN, HO+0.05% NH3) or acidic (ACN+0.1% FA, HO+0.1% FA) conditions, in which case SCX(NH) was utilized to obtain the free base of the product unless otherwise noted.

[0154] Flash chromatography (FCC) was performed using prepacked silica gel cartridges or Isolera TM The flash purification was performed on Interchim PuriFlash 450 and 520Plus systems.

[0155] 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.

[0156] The starting material may not necessarily have been prepared from the reference batch.

[0157] As will be appreciated by those of skill in the art, reference to the use of "similar" or "analogous" procedures may involve slight variations in, for example, reaction temperatures, amounts of reagents / solvents, reaction times, work-up conditions, or chromatographic purification conditions. Unless otherwise noted, all final compounds were obtained as the free base.

[0158] Preparation of intermediates Preparation of 3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzoic acid - intermediate 1 [ka]

[0159] Step 1: Methyl 3-bromo-5-(trifluoromethyl)benzoate - Intermediate 2 [ka]

[0160] To a solution of 3-bromo-5-(trifluoromethyl)benzoic acid (75.0 g, 279 mmol) in MeOH (282 mL) at 0° C. was added SOCl2 (81.0 mL, 1115 mmol) dropwise. The reaction mixture was then stirred under reflux overnight, after which the volatiles were removed in vacuo. Water (200 mL) was added to the residue and the aqueous phase was extracted with EtOAc (2×250 mL). The organic phases were combined, washed with a saturated solution of NaHCO3, dried over Na2SO4 and concentrated in vacuo to give the title product (74.5 g, 94%).

[0161] 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).

[0162] Step 2: Methyl 3-[(4-methylpiperazin-1-yl)methyl]-5-(trifluoromethyl)benzoate - Intermediate 3 [ka]

[0163] Intermediate 2 (47.5 g, 168 mmol), Cs2CO3 (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, then Pd(OAc)2 (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 (2x150 mL). The organic phases were combined, concentrated and dried under vacuum to give the crude product, which was purified by column chromatography (DCM:MeOH, 9:1) to give the title compound (25.3 g, 48%).

[0164] 1H 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).

[0165] Step 3: 3-((4-Methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzoic acid - Intermediate 1

[0166] Intermediate 3 (25.3 g, 80.0 mmol) was dissolved in MeOH (700 mL). 1M LiOH solution (3.8 g, 160 mL) was added to the reaction mixture and stirred at RT overnight. The solvent was removed under vacuum 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%).

[0167] 1 H 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).

[0168] The salt was dissolved in 2M aqueous HCl until pH 4, then the solution was concentrated under reduced pressure. The residue was washed with water, filtered and dried under vacuum to give the title compound as the corresponding carboxylic acid in quantitative yield.

[0169] Preparation of 2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine-5-carbaldehyde - intermediate 4

[0170] Step 1: 2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine-5-carbaldehyde - Intermediate 4 [ka]

[0171] 2-Chloropyrimidine-5-carbaldehyde (50 mg, 0.351 mmol) was dissolved in THF (3.5 ml) and then 1-methyl-1H-pyrazol-4-amine (41 mg, 0.421 mmol), TEA (0.1 ml, 0.719 mmol) and THF (3.5 ml) were added. The reaction mixture was stirred at room temperature overnight. The mixture was quenched with DCM and brine. The phases were separated and the aqueous phase was washed with DCM (x2). The organic phases were combined, dried over Na2SO4, filtered and concentrated under vacuum. The crude material was purified by FCC eluting with hexane:ethyl acetate (1:1) to give the title product (35 mg, 39%).

[0172] 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).

[0173] Preparation of 2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidine-5-carbaldehyde (Intermediate 17) [ka]

[0174] Step 1: 2-Chloro-5-(diethoxymethyl)pyrimidine (Intermediate 18) [ka]

[0175] 2-Chloropyrimidine-5-carbaldehyde (2.07 g, 14.52 mmol), triethyl orthoformate (7.24 ml, 43.5 mmol) and p-toluenesulfonic acid monohydrate (276 mg, 1.451 mmol) were added to Dissolved in absolute EtOH (41 ml) in a dry round bottom flask under Ar. The mixture was stirred at reflux for 1 hr. The solution was cooled in an ice bath. 40 mL of saturated NaHCO3 was added. The mixture was allowed to warm to RT. EtOH was evaporated and the resulting suspension was extracted with AcOEt. The organic phases were combined, dried over Na2SO4, filtered and evaporated to dryness. The crude material was purified by FCC (100 / 0 -> 80 / 20 hexane / AcOEt) to give the title compound (2.68 g, 12.37, 85%).

[0176] NMR: 1 H NMR (300 MHz, DMSO-d6) δ 8.75 (s, 2H), 5.68 (s, 1H), 3.67 - 3.50 (m, 4H), 1.17 (t, J = 7.0 Hz, 6H).

[0177] Step 2: 5-(diethoxymethyl)-N-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrimidin-2-amine (Intermediate 19) [ka]

[0178] The previous intermediate 18 (435 mg, 2.008 mmol) was dissolved in toluene (7 ml) and dioxane (7.0 ml) in a reaction tube under Ar. 1-(2-Methoxyethyl)-1H-pyrazol-4-amine (0.3 ml, 2.53 mmol) and potassium phosphate tribasic (1.32 g, 6.22 mmol) was added to the solution. The solution was purged with Ar for 15 min. 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (98 mg, 0.206 mmol) and Pd2(dba)3 (94 mg, 0.103 mmol) were added to the solution. The tube was sealed and the mixture was heated at 100 °C for 48 hr. The crude mixture was filtered through Celite, washed with MeOH and evaporated. After purification by FCC (DCM / MeOH / NH3 (100 / 0 to 90 / 10)), the title compound (458 mg, 1.42 mmol, 71%) was obtained.

[0179] The compounds reported in the following table were prepared as described for intermediate 19, applying the corresponding commercially available amines. [Table 5]

[0180] Step 3: 2-((1-(2-Methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidine-5-carbaldehyde (Intermediate 17)

[0181] Intermediate 19 (458 mg, 1.425 mmol) was placed in a round bottom flask. Hydrochloric acid, 1N hydrochloric acid in water (45 ml, 45.0 mmol) was added and the mixture was stirred at RT overnight. The mixture was cooled in an ice bath and saturated NaOH solution was added slowly until pH=13. The aqueous phase was extracted with AcOEt. The organic phase was dried over Na2SO4 and evaporated to give the title compound (312 mg, 1.62 mmol, 89%).

[0182] 1 H NMR (300 MHz, DMSO-d6) δ 10.44 (s, 1H), 9.80 (s, 1H), 8.92 - 8.80 (m, 2H), 8.01 (s, 1H), 7.60 (s, 1H), 4.24 (t, J = 5.3 Hz, 2H), 3.66 (t, J = 5.3 Hz, 2H), 3.23 (s, 3H).

[0183] The compounds reported in the following table were prepared as described for intermediate 17, applying the corresponding commercially available amines.

[0184] [Table 6]

[0185] Preparation of N-(5-formylpyrimidin-2-yl)acetamide (Intermediate 22) [ka]

[0186] Step 1: N-(5-formylpyrimidin-2-yl)acetamide (Intermediate 22)

[0187] 2-Aminopyrimidine-5-carbaldehyde (100 mg, 0.812 mmol) was dissolved in acetic anhydride (2.0 mL, 22.8 mmol) and the reaction mixture was heated at 140° C. for 90 min. The reaction mixture was allowed to cool to RT and the solid was precipitated by addition of 2:1 cyclohexane / diethyl ether, filtered, washed with cyclohexane, and dried under reduced pressure to give the title compound (84 mg, 0.5086 mmol, 62.6% yield). 1 H NMR (400 MHz, CDCl3) d 10.03 (s, 1H), 9.04 (s, 2H), 8.76 (s, 1H), 2.58 (s, 3H).

[0188] Preparation of Examples

[0189] Example 1: Preparation of N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-1-(pyrimidin-5-ylmethyl)indoline-6-carboxamide) [ka]

[0190] Step 1: tert-Butyl 6-((3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)carbamoyl)indoline-1-carboxylate - Intermediate 5 [ka]

[0191] 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). Then DIPEA (1.990 ml, 11.39 mmol) and 50% T3P in ethyl acetate (4.48 ml, 7.60 mmol) were added. The reaction mixture was stirred at 20° C. for 20 hr. 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 (100% DCM to 5% MeOH in DCM). Only 200 mg of the pure desired product was obtained, giving 1.4 g of a mixture of the desired product and starting material (acid). This material was dissolved in DCM (100 ml) and washed with Na2CO3 (3x50 ml) and brine (100 ml) to remove residual acid. The organic phase was dried over Na2SO4, filtered and evaporated to dryness on a rotary evaporator to give the title compound (1.01 g, 55%).

[0192] 1 H 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).

[0193] Step 2: N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide - Intermediate 6 [ka]

[0194] Intermediate 5 (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 allowed to stir at room temperature for 30 min (bubbles were observed). Then the phases were separated. The organic phase was washed with NaHCO3, dried over Na2SO4 and evaporated under vacuum. The material was used without further purification. The title compound was obtained as the free base (900 mg, 100%).

[0195] 1 H 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).

[0196] Step 3: N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-1-(pyrimidin-5-ylmethyl)indoline-6-carboxamide (Example 1)

[0197] Intermediate 6 (0.1 g, 0.259 mmol) was dissolved in DCM (2 ml) and then pyrimidine-5-carbaldehyde (0.028 g, 0.259 mmol), NaCNBH3 (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 hr. The reaction mixture was evaporated and 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 K2CO3 (aq.sat.sol.), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified via preparative HPLC eluting with ACN+0.1% NH3, H2O+0.1% NH3, and the residue was then purified via preparative TLC eluting with DCM / MeOH (9:1) to give the title compound (14 mg, 11%).

[0198] [Table 7]

[0199] Example 2 was prepared via reductive amination as described for steps 1-3 of Example 1, applying the corresponding commercially available carbaldehyde in step 3:

[0200] [Table 8]

[0201] Example 3: Preparation of N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-1-(pyrimidin-5-ylmethyl)indoline-6-carboxamide [ka]

[0202] Step 1: tert-Butyl 6-((3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)carbamoyl)indoline-1-carboxylate - Intermediate 7 [ka]

[0203] In a dried (heat gun / vacuum / N2 cycles) 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, then butyllithium (0.793 mL, 1.983 mmol) was added dropwise. The solution was stirred for 15 min, then a solution of 1-(tert-butyl) 6-methylindoline-1,6-dicarboxylate (0.275 g, 0.992 mmol) in anhydrous THF (1 mL) was added dropwise. The mixture was stirred while the temperature was raised from -78 °C to room temperature. Water (50 mL) was added, then extraction was performed with EtOAc (3x10 mL). The organic phase was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated to dryness. The crude was purified with FCC(NH) elution system DCM / MeOH (100:0 to 90:10) to give the title compound (518 mg, 100%).

[0204] 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

[0205] Step 2: N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide - Intermediate 8 [ka]

[0206] Intermediate 7 (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. After evaporation of the solvent, the crude was diluted with water (20 mL) and then the pH was adjusted to about 7-8. The product was extracted with DCM (2x20 mL) via a phase separator. The organic phase was then concentrated to dryness to give the title compound (415 mg, 100%).

[0207] 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

[0208] Step 3: N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-1-(pyrimidin-5-ylmethyl)inoline-6-carboxamide (Example 3)

[0209] In a 40 mL vial equipped with a magnetic stir bar, a solution of intermediate 8 (0.05 g, 0.119 mmol) and pyrimidine-5-carbaldehyde (0.013 g, 0.119 mmol) in anhydrous methanol (5 ml) and AcOH (0.500 ml) was stirred at room temperature for 10 min, then NaCNBH3 (7.51 mg, 0.119 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with DCM (5 ml) and washed with water (5 ml). The organic phase was washed with saturated K2CO3 solution (2x10 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by column chromatography eluting with H2O / MeCN / HCO2H (95:5:0.1 to 5:95:0.1) to give the title compound (22 mg, 33%). Deblocking of the formate salt was achieved by SCX and the pure product was recovered as the free base (13 mg, 100%).

[0210] [Table 9]

[0211] The compounds reported in the following tables were prepared by reductive amination as described for steps 1-3 of Example 3, applying the corresponding commercially available or previously synthesized aldehydes in step 3. Any changes in reducing agent, solvent or chromatographic purification conditions are reported in the tables.

[0212] [Table 10-1] [Table 10-2] [Table 10-3]

[0213] Example 4Preparation of N-(1-((2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)methyl)indolin-6-yl)-3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamide [ka]

[0214] Step 1: tert-Butyl 6-nitroindoline-1-carboxylate - Intermediate 9 [ka]

[0215] 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), DCM (244 ml) were added to a flask. The reaction mixture was stirred at rt 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 using eluent (hexane / ethyl acetate (9:1)) to give the title compound (29 g, 90%).

[0216] H 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).

[0217] Step 2: tert-Butyl 6-aminoindoline-1-carboxylate - Intermediate 10 [ka]

[0218] A three-necked round-bottom flask was charged with intermediate 9 (29.13 g, 110 mmol). Air was removed using a water pump and purged with argon, this process was repeated three times. Palladium on carbon 10 wt.% (2.91 g, 27.3 mmol) and ethyl acetate (551 ml) were then added. The reaction mixture was purged with argon, removed using a water pump, and then purged with hydrogen. The mixture was stirred under hydrogen atmosphere at rt overnight. The reaction mixture was filtered through a celite pad and concentrated to give the title compound (27 g, 100%).

[0219] 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).

[0220] Step 3: tert-Butyl 6-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamido)indoline-1-carboxylate - Intermediate 11 [ka]

[0221] Intermediate 10 (6.45 g, 21.34 mmol) was placed in a flask, then HATU (16.23 g, 42.7 mmol), DIPEA (14.91 ml, 85 mmol), DMF (53.4 ml) and dichloromethane (160 ml) were added. The reaction mixture was stirred at rt for 30 min. Then tert-butyl 6-aminoindoline-1-carboxylate (5 g, 21.34 mmol) was added. Stirring was continued overnight. Extraction was performed with water and DCM. 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%).

[0222] 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).

[0223] Step 4: N-(indolin-6-yl)-3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamide - Intermediate 12 [ka]

[0224] Intermediate 11 (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 NaHCO3 and brine (10 mL). The organic phase was separated, dried over Na2SO4, filtered and concentrated to dryness. The crude material was purified via column chromatography and elution system 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%).

[0225] 1H 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).

[0226] Step 5: N-(1-((2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)methyl)indolin-6-yl)-3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamide (Example 4)

[0227] Intermediate 12 (0.065 g, 0.155 mmol) was dissolved in anhydrous DCM (2.4 ml), then 2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine-5-carbaldehyde (0.032 g, 0.155 mmol) was added, followed by AcOH (17.78 μl, 0.311 mmol) and magnesium sulfate (37.4 mg, 0.311 mmol). The reaction mixture was stirred at rt for 30 min. Then STAB (65.8 mg, 0.311 mmol) was added and the reaction mixture was stirred at rt overnight. The mixture was quenched with sat.NaHCO3. The phases were separated and the aqueous phase was washed with DCM (x2). The organic phase was collected, dried over Na2SO4 and the solvent was removed under vacuum. The crude material was purified by FCC eluting with DCM / MeOH (4:1) and ACN, preparative HPLC eluting with H2O+0.05% NH3 to give the title compound (56 mg, 21%).

[0228] [Table 11]

[0229] The following compounds were prepared by reductive amination as described for step 1 of Example 4, applying the corresponding commercially available aldehyde in step 1.

[0230] [Table 12]

[0231] Example 6 Preparation of N-methyl-4-((6-(2-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-2-oxoethyl)indolin-1-yl)methyl)picolinamide [ka]

[0232] Step 1: tert-Butyl 6-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl) benzamido)indoline-1-carboxylate - Intermediate 13 [ka]

[0233] 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), DIPEA (4.47 ml, 25.6 mmol) were placed in a flask and DMF (0.907 ml) and DCM (2.721 ml) were added. The reaction mixture was stirred at rt overnight. 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 remove the title compound (2.2 g, 90%).

[0234] 1H 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).

[0235] Step 2: N-(indolin-6-yl)-3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl) benzamide - Intermediate 14 [ka]

[0236] Intermediate 13 (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. It was washed with NaHCO3, DCM and then dried over Na2SO4. 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%).

[0237] 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).

[0238] Step 3: N-Methyl-4-((6-(2-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-2-oxoethyl)indolin-1-yl)methyl)picolinamide (Example 6)

[0239] A flask was charged with intermediate 14 (100 mg, 0.259 mmol), 4-formyl-N-methylpicolinamide (42 mg, 0.259 mmol), followed by acetic acid (30 μl, 0.518 mmol) and DCM (2.4 ml). The reaction mixture was stirred at rt for ½ h. Then NaBH3CN (62.8 mg, 0.388 mmol) was added and the mixture was stirred overnight. The mixture was quenched by adding sat.NaHCO3. The phases were separated and the aqueous phase was washed with DCM (x2). All the 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) and preparative HPLC eluting with ACN, H2O+0.05% NH3 to give the title compound (40 mg, 28%).

[0240] [Table 13]

[0241] Example 7: Preparation of 1-((5-(4-methyl-3-oxopiperazin-1-yl)pyridin-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)indoline-6-carboxamide [ka]

[0242] Step 1: Methyl 1-((5-bromopyridin-3-yl)methyl)indoline-6-carboxylate (Intermediate 23) [ka]

[0243] Starting from methylindoline-1-ium-6-carboxylate hydrochloride (1 g, 4.68 mmol) and 5-bromo-3-pyridinecarbaldehyde (871 mg, 4.68 mmol), the title compound was obtained in a similar manner to step 5 of example 4 (1.54 g, 87%).

[0244] 1 H NMR (400 MHz, DMSO) δ 8.88 - 8.79 (m, 2H), 8.68 - 8.68 (m, 1H), 8.36 - 8.35 (m, 1H), 7.76 - 7.70 (m, 1H), 7.46 - 7.42 (m, 1H), 4.09 (t, J=8.2 Hz, 2H), 3.88 - 3.84 (m, 3H), 3.18 (t, J=8.3 Hz, 2H)

[0245] Step 2: 1-((5-bromopyridin-3-yl)methyl)indoline-6-carboxylic acid (Intermediate 24) [ka]

[0246] To a solution of intermediate 23 (1 g, 2.88 mmol) in MeOH (15 mL) was added lithium hydroxide monohydrate (363 mg, 8.64 mmol) in water (15 mL) and the resulting mixture was stirred at rt for 3 days and then at 40° C. for 2 h. The reaction mixture was cooled to room temperature, concentrated and acidified with 1M HCl(aq). The resulting precipitate was filtered, washed with water and dried to give the title compound (890 mg, 93%).

[0247] 1H NMR (400 MHz, DMSO) δ 12.62 (s, 1H), 8.63 (d, J=2.0 Hz, 1H), 8.57 (s, 1H), 8.03 (s, 1H), 7.27 (d, J=7.5 Hz, 1H), 7.15 (d, J=7.5 Hz, 1H), 7.08 (s, 1H), 4.38 (s, 2H), 3.38 (t, J=8.2 Hz, 2H), 2.98 (t, J=8.3 Hz, 2H).

[0248] Step 3: 1-((5-bromopyridin-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)indoline-6-carboxamide (Intermediate 25) [ka]

[0249] Starting from intermediate 24 (500 mg, 1.50 mmol) and 3-(trifluoromethyl)aniline (0.20 mL, 1.58 mmol), the title compound was obtained (373 mg, 52%) in a similar manner to intermediate 11.

[0250] 1 H NMR (400 MHz, DMSO) δ 10.33 (s, 1H), 8.65 (d, J=2.3 Hz, 1H), 8.60 (d, J=1.8 Hz, 1H), 8.22 (s, 1H), 8.06 (t, J=2.1 Hz, 1H), 8.03 (d, J=9.3 Hz, 1H), 7.58 (t, J=8.0 Hz, 1H), 7.44 - 7.41 (m, 1H), 7.29 (q, J=3.0 Hz, 1H), 7.21 (d, J=7.6 Hz, 1H), 7.16 (d, J=1.2 Hz, 1H), 4.43 (s, 2H), 3.38 (t, J=8.2 Hz, 2H), 3.01 (t, J=8.3 Hz, 2H)

[0251] Step 4: 1-((5-(4-methyl-3-oxopiperazin-1-yl)pyridin-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)indoline-6-carboxamide (Example 7)

[0252] A mixture of intermediate 25 (70 mg, 0.147 mmol), 1-methylpiperazin-2-one (18 mg, 0.162 mmol) and cesium carbonate (96 mg, 0.294 mmol) in anhydrous 1,4-dioxane (2.00 mL) was degassed and RuPhos Pd G3 (12 mg, 0.0147 mmol) was added. The reaction mixture was heated and stirred at 80 °C under argon for 18 h. The reaction mixture was cooled, filtered through a pad of celite and concentrated. The crude compound was purified by preparative HPLC (Sunfire C18 19x150 mm, 10 um 20-80% ACN / H2O (10 mM NH4CO3), 20 ml / min, RT) to give the title compound (44 mg, 57%) as an off-white solid.

[0253] LC-MS (ESI): (Method 3) R = 3.58 min; m / z [M+H] + = 510.5 1 H NMR (400 MHz, DMSO) δ 10.34 (s, 1H), 8.26 - 8.24 (m, 2H), 8.06 (d, J=1.6 Hz, 1H), 8.04 (s, 1H), 7.60 (t, J=8.0 Hz, 1H), 7.45 (d, J=7.8 Hz, 1H), 7.36 (t, J=2.2 Hz, 1H), 7.29 (q, J=3.0 Hz, 1H), 7.23 - 7.20 (m, 2H), 4.36 (s, 2H), 3.85 (s, 2H), 3.57 (dd, J=4.5, 6.3 Hz, 2H), 3.44 (dd, J=4.3, 6.4 Hz, 2H), 3.38 (t, J=8.5 Hz, 2H), 3.00 (t, J=8.3 Hz, 2H), 2.91 (s, 3H).

[0254] Example 8: Preparation of 1-((2-aminopyrimidin-5-yl)methyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)indoline-6-carboxamide [ka]

[0255] Step 1: tert-Butyl 6-((4-((4-methylpiperazin-1-yl)methyl)-3-trifluoromethyl)phenyl)carbamoyl)indoline-1-carboxamide (Intermediate 26) [ka]

[0256] 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 chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (1.60 g, 5.70 mmol). The reaction mixture was stirred at RT for 24 h. The mixture was partitioned between brine and ethyl acetate. The organic phase was dried (Na2SO4) and concentrated. The residue was purified by FCC (0-10% 2M NH3 / MeOH in DCM) to give the title compound (2.22 g, 100%).

[0257] LCMS (Method 5) R = 1.72 min, m / z [M+H] = 519

[0258] Step 2: N-((4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)indoline-6-carboxamide (Intermediate 27) [ka]

[0259] Following a similar procedure to intermediate 12, starting from intermediate 26 (2.22 g, 4.28 mmol) in DCM (15 mL), the title compound was obtained (1.47 g, 82%).

[0260] 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)

[0261] Step 3: 1-((2-aminopyrimidin-5-yl)methy)lN-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)indoline-6-carboxamide (Example 8)

[0262] Starting from 2-aminopyrimidine-5-carbaldehyde (18 mg, 0.149 mmol) and intermediate 27 (50 mg, 0.119 mmol), the procedure was followed similar to step 3 of example 4 to give the title compound (50 mg, 79%) after purification by HPLC (Xbridge Phenyl 19x150 mm, 10 um 40-100% MeOH / H2O (10 mM NH4CO3), 20 ml / min, RT).

[0263] LC-MS (ESI): (Method 3) R = 3.07 min; m / z [M+H] + = 526.2 1H NMR (400 MHz, DMSO) δ 10.30 (s, 1H), 8.26 (s, 2H), 8.21 (d, J=2.4 Hz, 1H), 8.04 (dd, J=2.1, 8.6 Hz, 1H), 7.70 (d, J=8.7 Hz, 1H), 7.29 - 7.17 (m, 3H), 6.61 (s, 2H), 4.18 (s, 2H), 3.58 (s, 2H), 3.29 (t, J=7.6 Hz, 2H), 2.99 - 2.93 (m, 2H), 2.40 - 2.34 (m, 8H), 2.18 - 2.17 (m, 3H)

[0264] The compounds reported in the following table were prepared as described for step 3 of Example 8, applying the corresponding commercially available aldehyde in step 3.

[0265] [Table 14-1] [Table 14-2] [Table 14-3] [Table 14-4] [Table 14-5] [Table 14-6] [Table 14-7]

[0266] Example 16: Preparation of 1-((2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)methyl)-N-(3-(trifluoromethyl)phenyl)indoline-6-carboxamide [ka]

[0267] Step 1: tert-Butyl 3-methyl-6-((3-(trifluoromethyl)phenyl)carbamoyl)indoline-1-carboxylate (Intermediate 28) [ka]

[0268] 3-(Trifluoromethyl)aniline (2.027 ml, 16.23 mmol) was dissolved in dry THF (27.0 ml) and the solution was cooled to -78°C. Then, n-BuLi (5.41 ml, 13.52 mmol) was added, the mixture was stirred for 30 min, and then 1-(tert-butyl) 6-methyl indoline-1,6-dicarboxylate (1.5 g, 5.41 mmol) in anh.THF (27.0 ml) was added. The mixture was stirred overnight in a dry ice bath. The reaction mixture was quenched by adding water and the solution was extracted with AcOEt. All the organic phases were combined, dried over Na2SO4, filtered and concentrated.

[0269] The crude material was purified by FCC (elution system: Hex 100% to Hex / AcOEt (1 / 1)), then dissolved in AcOEt and extracted with 0.5 M HCl to give the title compound (1.70 g, 4.2 mmol, 77%).

[0270] 1 H NMR (300 MHz, DMSO-d6) δ 10.52 (s, 1H), 8.23 ​​(d, J = 2.0 Hz, 2H), 8.09 - 8.00 (m, 1H), 7.63 - 7.52 (m, 2H), 7.44 (ddd, J = 7.8, 2.0, 1.0 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 3.97 (t, J = 8.7 Hz, 2H), 3.14 (t, J = 8.6 Hz, 2H), 1.53 (s, 9H).

[0271] Step 2: 3-Methyl-N-(3-(trifluoromethyl)phenyl)indoline-6-carboxamide (Intermediate 29) [ka]

[0272] Starting from intermediate 28 (560 mg, 1.332 mmol) and following a similar procedure as for intermediate 12, the title compound was obtained (375 mg, 86%).

[0273] 1 H NMR (300 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.25 (d, J = 2.0 Hz, 1H), 8.03 (dt, J = 8.0, 1.3 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.41 (ddt, J = 7.8, 1.9, 0.9 Hz, 1H), 7.20 - 7.12 (m, 2H), 7.04 (t, J = 1.0 Hz, 1H), 5.76 (d, J = 2.1 Hz, 1H), 3.48 (td, J = 8.6, 1.9 Hz, 2H), 2.97 (t, J = 8.5 Hz, 2H).

[0274] Step 3: 1-((2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)methyl)-N-(3-(trifluoromethyl)phenyl)indoline-6-carboxamide (Example 16)

[0275] Starting from intermediate 29 (148 mg, 0.483 mmol) and 2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidine-5-carbaldehyde (107 mg, 0.433 mmol), the title compound was obtained (20.4 mg, 0.04 mmol, 8%) according to a procedure similar to that of step 5 of example 4.

[0276] LC-MS (ESI): (Method 1) R = 3.077 min; m / z [M+H] + = 538.2 1H NMR (300 MHz, Methanol-d4) δ 8.43 (s, 2H), 8.15 (s, 1H), 7.99 (d, J = 0.8 Hz, 1H), 7.93 (d, J = 8.3 Hz, 1H), 7.59 (d, J = 0.8 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.42 (d, J = 7.8 Hz, 1H), 7.29 (dd, J = 7.5, 1.6 Hz, 1H), 7.23 - 7.18 (m, 2H), 4.28 - 4.23 (m, 4H), 3.72 (t, J = 5.2 Hz, 2H), 3.37 (t, J = 8.3 Hz, 2H), 3.01 (t, J = 8.3 Hz, 2H). Note: The OMe signal is not visible due to overlap with the solvent signal.

[0277] Example 17: Preparation of 1-[(5-carbamoyl-3-pyridyl)methyl]-N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]indoline-6-carboxamide [ka]

[0278] Step 1: 1-[(5-cyano-3-pyridyl)methyl]-N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]indoline-6-carboxamide (Intermediate 30) [ka]

[0279] Starting from intermediate 27 (100 mg, 0.23 mmol) and 5-formylpyridine-3-carbonitrile (39 mg, 0.3 mmol), the title compound was obtained (128 mg, 100%) according to a procedure similar to that of step 5 of example 4.

[0280] 1H NMR (300 MHz, DMSO) δ 10.30 (s, 1H), 8.99 (d, J=2.0 Hz, 1H), 8.91 (d, J=2.1 Hz, 1H), 8.34 (dd, J=2.1, 2.1 Hz, 1H), 8.20 (d, J=2.3 Hz, 1H), 8.03 (dd, J=2.0, 8.4 Hz, 1H), 7.70 (d, J=8.5 Hz, 1H), 7.30 (dd, J=1.4, 7.5 Hz, 1H), 7.23 (d, J=7.5 Hz, 1H), 7.17 (s, 1H), 4.49 (s, 2H), 3.57 (s, 2H), 3.44 - 3.37 (m, 2H), 3.03 (dd, J=8.3, 8.3 Hz, 2H), 2.50 - 2.34 (m, 8H), 2.18 (s, 3H)

[0281] Step 2: 1-[(5-carbamoyl-3-pyridyl)methyl]-N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]indoline-6-carboxamide (Example 17)

[0282] To a solution of intermediate 30 (110 mg, 0.206 mmol) in water (0.5 mL) was added hydrido(dimethylphosphinate-kP)[hydrogen bis(dimethylphosphinite-kP)]platinum(II) (8.8 mg, 0.021 mmol) and the mixture was stirred at 100° C. for 2 hours. The reaction mixture was concentrated and the residue was purified by preparative HPLC (Sunfire C18 19x150 mm, 10 um 20-80% ACN / H2O (10 mM NH4CO3), 20 ml / min, RT) to give the title compound (41 mg, 34%).

[0283] LC-MS (ESI): (Method 3) R = 3.02 min; m / z [M+H] + = 553.5 1H NMR (400 MHz, DMSO) d 10.30 (s, 1H), 8.98 (d, J=2.1 Hz, 1H), 8.74 (d, J=2.0 Hz, 1H), 8.24 - 8.19 (m, 3H), 8.03 (dd, J=1.9, 8.5 Hz, 1H), 7.70 (d, J=8.5 Hz, 1H), 7.62 (s, 1H), 7.30 (dd, J=1.3, 7.6 Hz, 1H), 7.24 - 7.19 (m, 2H), 4.47 (s, 2H), 3.57 (s, 2H), 3.44 - 3.35 (m, 2H), 3.02 (dd, J=8.3, 8.3 Hz, 2H), 2.39 - 2.34 (m, 6H), 2.17 (s, 3H). There are two piperazine protons below the solvent peak.

[0284] For comparison, newly synthesized compounds lack a linker between the indoline ring and the Hy group, whereas the compounds of the invention exhibit the linkers -CH2- or -C(O)- in that position.

[0285] Example C1 Preparation of N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-1-(pyrimidin-5-yl)indoline-6-carboxamide [ka]

[0286] A 10 mL vial equipped with a magnetic stir bar and fitted with a screw cap was charged with intermediate 8 (0.030 g, 0.072 mmol), obtained as in steps 1-4 of Example 4, cesium carbonate (0.070 g, 0.215 mmol), bis(dibenzylideneacetone)palladium (4.12 mg, 7.17 μmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (6.69 mg, 0.014 mmol) and 5-bromopyrimidine (0.015 g, 0.093 mmol). The vial was filled with toluene (4 ml) and purged with argon for 5 min. The solution was heated at 105 °C for 3 h. After cooling to room temperature, the solution was filtered through a pad of Celite and then concentrated to dryness. The crude material was purified by column chromatography eluting with DCM / MeOH (100:0 to 90:10) to give the title compound (11 mg, 30%).

[0287] [Table 15]

[0288] Example C2: Preparation of N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-1-(pyrimidin-5-yl)indoline-6-carboxamide [ka]

[0289] Step 1: Methyl indoline-6-carboxylate - intermediate 15 [ka]

[0290] 1-(tert-Butyl) 6-methylindoline-1,6-dicarboxylate (0.1 g, 0.361 mmol) was dissolved in a 3:1 mixture of DCM (6 ml) and 2,2,2-trifluoroacetic acid (2.1 ml). The solution was stirred at room temperature for 3 h. The solvent was evaporated and the residue was used as is (65 mg, 100%).

[0291] 1 H NMR (DMSO-d6, 400MHz): δ = 7.15 (d, 1H, J = 7.7 Hz), 7.11 (d, 1H, J = 7.7 Hz), 7.01 (s, 1H), 5.74 (s, 1H), 3.78 (s, 3H), 3.46 (t, 2H, J = 8.6 Hz), 2.96 (t, 2H, J = 8.6 Hz) ppm

[0292] Step 2: Methyl 1-(pyrimidin-5-yl)indoline-6-carboxylate - Intermediate 16 [ka]

[0293] A 50 mL flask equipped with a magnetic stir bar and fitted with a rubber septum was charged with intermediate 15 (0.065 g, 0.367 mmol), 5-bromopyrimidine (0.076 g, 0.477 mmol), cesium carbonate (0.359 g, 1.100 mmol), bis(dibenzylideneacetone)palladium (0.021 g, 0.037 mmol) and 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (0.034 g, 0.073 mmol). The vessel was evacuated and backfilled with argon and toluene (5 ml) was added via syringe. The solution was heated at 100 °C and stirred for 16 h. After cooling to room temperature, the solution was filtered through a pad of Celite and then concentrated to dryness. The crude material was purified by column chromatography eluting with Hept / EtOAc (100:0 to 0:100) to afford the title compound (87 mg, 93%).

[0294] 1H NMR (DMSO-d6, 400MHz): δ = 8.81 (s, 3H), 7.62 (s, 1H), 7.48 (d, 1H, J = 7.5 Hz), 7.37 (d, 1H, J = 7.5 Hz), 4.09 (t, 2H, J = 8.5 Hz), 3.83 (s, 3H), 3.23 (t, 2H, J = 8.5 Hz) ppm

[0295] Step 3: N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-1-(pyrimidin-5-yl)indoline-6-carboxamide (Example C2)

[0296] In a 10 mL vial, intermediate 16 (0.03 g, 0.118 mmol) and 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (0.028 g, 0.118 mmol) were dissolved in anhydrous THF (5 ml). The solution was cooled to 0° C. (ice bath) and then potassium tert-butylate (0.040 g, 0.353 mmol) was added in one portion. The solution was stirred at room temperature for 5 h. Additional potassium tert-butylate (0.040 g, 0.353 mmol) and anhydrous DMF (2.0 ml) were added to the solution and stirring was maintained overnight. The reaction mixture was quenched with ice water (5 mL) and then extracted with EtOAc (10 mL). The organic phase was dried over Na2SO4, filtered and concentrated to dryness. The crude material was purified by column chromatography eluting with DCM / MeOH (100:0 to 90:10) to give the title compound (4.6 mg, 8%).

[0297] [Table 16]

[0298] Example C3 Preparation of 3-((4-methylpiperazin-1-yl)methyl)-N-(1-(pyrimidin-5-yl)indolin-6-yl)-5-(trifluoromethyl)benzamide [ka]

[0299] Step 1: 3-((4-methylpiperazin-1-yl)methyl)-N-(1-(pyrimidin-5-yl)indolin-6-yl)-5-(trifluoromethyl)benzamide

[0300] A 40 mL vial equipped with a magnetic stir bar and fitted with a rubber septum was charged with intermediate 12 (0.095 g, 0.227 mmol), 5-bromopyrimidine (0.047 g, 0.295 mmol), cesium carbonate (0.222 g, 0.681 mmol), bis(dibenzylideneacetone)palladium (0.013 g, 0.023 mmol) and 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (0.021 g, 0.045 mmol) dissolved in toluene (5 ml). The vessel was purged with argon for 10 min, then the solution was heated at °C for 16 h. After cooling to room temperature, the solution was filtered through a pad of Celite and then concentrated to dryness. The crude material was purified by FCC eluting with H2O / MeCN / HCO2H (95:5:0.1 to 5:95:0.1) to give the title compound as a formate salt (123 mg, 100%).

[0301] [Table 17]

[0302] Pharmacological activity of the compounds of the invention

[0303] In vitro assays Binding assays DDR1 and DDR2 binding assays were performed using LanthaScreen from Life Technologies. TMThe europium kinase binding assay was used. Compounds were incubated with 5 nM DDR1 (Carna Biosciences) or 5 nM DDR2 (Life Technologies) 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) in assay buffer (50 mM HEPES pH 7.5, 10 mM MgCI2, 1 mM EGTA, 0.01% BRIJ35) for 1 h at room temperature. The ratio of fluorescence emission 665 nm / 615 nm after excitation at 340 nm was determined using a Tecan Spark 20M plate reader. IC50 values ​​were determined using a four-parameter model of log(inhibitor) vs response in GraphPad Prism 8.0 software. IC50 values ​​were converted to Ki using the Cheng-Prusoff equation (Ki=IC50 / (1+[tracer] / Kd)).

[0304] 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 in white 384-well plates at a density of 5000 cells / well and incubated for 2 hours at 37°C and 5% CO2. Cells were then treated with various concentrations of compounds and incubated for 30 minutes, 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 DiscoverX protocol, 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 on 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.

[0305] DDR2 cell-based assay Inhibition of DDR2 phosphorylation by compounds was evaluated by phospho-ELISA assay using HEK293T-DDR2 recombinant cells. Briefly, HEK293T-DDR2 cells were seeded at a density of 250.000 cells / well in poly-D-lysine coated 24-well plates and incubated in DMEM+10% FBS at 37°C and 5% CO2 for 1.5 h. Afterwards, the medium was changed to serum-free DMEM and cells were incubated for 3 h. Test compounds were then added at various concentrations 30 min before stimulation with 50 μg / ml bovine type II collagen for another 3 h. 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 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% normalized) and positive control (100% normalized; 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.

[0306] The results for individual compounds are shown in Table 5, categorized in terms of binding affinity (Ki) for the DDR1 and DDR2 receptors, and potency (IC50) for inhibitory activity against the DDR1 and DDR2 receptors.

[0307] [Table 18]

[0308] As can be seen, the compounds in Table 5, 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 for treating diseases, disorders or conditions related to 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.

[0309] Comparative Example The compounds of Examples C1-C3 were tested in the same binding assay as above.

[0310] [Table 19]

[0311] As shown in Table 5, the compounds of the present invention have both binding affinity, expressed as Ki, to DDR1 and DDR2 receptors, and inhibitory potency, expressed as IC50, to DDR1 and DDR2 receptors, lower than 80 nM, and most of the compounds have lower than 50 nM, or even lower than 25 nM. Conversely, as shown in Table 6, comparative examples C1-C3 have binding affinity (Ki) to DDR1 receptors higher than 30000 nM, even 58000 for C2 and C3, and binding affinity (Ki) to DDR2 receptors higher than 4000 nM, even equal to or higher than 50000 for C1 and C3, respectively.

[0312] These data show that, relative to the compounds of Examples C1 to C3, which are characterized by the lack of a 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 significantly determines the appropriate increase in inhibitory activity against the DDR1 and DDR2 receptors.

Claims

1. Formula (I): 【Chemistry 1】 [In the formula, R 1 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 and oxo, optionally substituted with one or more groups selected from -(CH 2 ) n NR 4 R 5 , -C(O)NR 4 R 5 , -(C 1 -C 4 ) alkyl, -NR 4 (CO)R 5 , -(C 1 -C 4 )Alkylene-O-(C 1 -C 4 ) alkyl and -(C 4 -C 7 ) heterocycloalkyl; n is 0, 1 or 2; R 4 is H or -(C 1 -C 4 ) alkyl; R 5 is H or -(C 1 -C 4 ) alkyl, -(C 1 -C 4 ) Alkylene-NR 1 R 4 and -(C 1 -C 4 )Alkylene-O-(C 1 -C 4 ) alkyl, optionally substituted by one or more groups selected from 3 -C 7 )cycloalkyl, -(C 1 -C 4 ) selected from the group consisting of alkyl and heteroaryl; X is 【Chemistry 2】 (In the formula, R 2 is -(C 1 -C 4 ) alkyl, -O(C 1 -C 4 ) haloalkyl, halogen atom, -(C 1 -C 4 ) haloalkyl, -(C 3 -C 7 )cycloalkyl and -O(C 3 -C 7 ) cycloalkyl; R 3 is H or -O(C 1 -C 4 ) alkyl, one or more -(C 1 -C 4 ) heteroaryl optionally substituted with alkyl, and (C 4 -C 7 )Heterocycloalkyl-(C 1 -C 4 ) alkylene-, wherein said -(C 4 -C 7 )Heterocycloalkyl is -(C 1 -C 4 ) alkyl and -O(C 1 -C 4 ) alkyl, is] or a pharma- ceutically acceptable salt thereof.

2. L is -CH 2 or a pharma- ceutically acceptable salt thereof. 。

3. L 1 is -C(O)NH- and X is X': 【Chemistry 3】 Formula (Ia1′), 【Chemistry 4】 3. The compound of formula (I) according to claim 2, wherein:

4. N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-1-(pyrimidin-5-ylmethyl)indoline-6-carboxamide; N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-1-((2-(methylcarbamoyl)pyridin-4-yl)methyl)indoline-6-carboxamide; N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-1-(pyrimidin-5-ylmethyl)indoline-6-carboxamide; 1-((2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)methyl)-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide; 1-((2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)methyl)-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide; and 1-((2-((1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)methyl)-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide, or a pharma- ceutically acceptable salt thereof.

5. L 1 is -C(O)NH- and X is X'': 【Chemistry 5】 Formula (Ia1″): 【Chemistry 6】 3. The compound of formula (I) according to claim 2, wherein:

6. 1-((2-aminopyrimidin-5-yl)methyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)indoline-6-carboxamide; 1-((6-aminopyridin-3-yl)methyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)indoline-6-carboxamide; 1-((4-aminopyrimidin-5-yl)methyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)indoline-6-carboxamide; 1-((5-aminopyrazin-2-yl)methyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)indoline-6-carboxamide; 1-((2-(methylamino)pyrimidin-5-yl)methyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)indoline-6-carboxamide; 1-((6-acetamidopyridin-3-yl)methyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)indoline-6-carboxamide; 1-((6-(methylamino)pyridin-3-yl)methyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)indoline-6-carboxamide; 1-((2-acetamidopyrimidin-5-yl)methyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)indoline-6-carboxamide; and 1-((5-carbamoylpyridin-3-yl)methyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)indoline-6-carboxamide, or a pharma- ceutically acceptable salt thereof.

7. L 1 is -NHC(O)- and X is X': 【Chemistry 7】 Formula (Ib1′), 【Chemistry 8】 3. The compound of formula (I) according to claim 2, wherein:

8. N-(1-((2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)methyl)indolin-6-yl)-3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamide; N-(1-((3-aminopyrazin-2-yl)methyl)indolin-6-yl)-3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamide; N-methyl-4-((6-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzamido)indolin-1-yl)methyl)picolinamide; and N-(1-((2-aminopyrimidin-5-yl)methyl)indolin-6-yl)-3-((4-methylpiperazin-1-yl)methyl)-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 a discoidin domain receptor.

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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