Benzylamine derivatives as DDR inhibitors

Abstract

Benzylamine 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 benzylamine derivatives, methods for preparing such compounds, pharmaceutical compositions containing them, and their pharmaceutical uses. The compounds of the present invention may be useful in treating diseases or conditions associated with dysregulation of DDRs, particularly fibrosis.

Description

[Technical Field]

[0001] The present invention relates generally to compounds that inhibit discoidin domain receptors (hereinafter DDR inhibitors); the present invention relates to compounds that are benzylamine derivatives, methods for preparing such compounds, pharmaceutical compositions containing them, and pharmaceutical uses thereof.

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

[0003] The discoidin domain receptor (DDR) family contains two distinct members, DDR1 and DDR2. DDRs are type I transmembrane receptor tyrosine kinases (RTKs) that display an overall structural organization similar to many members of the RTK family. They were first discovered in the early 1990s by homology cloning based on the catalytic kinase domain (KD) (see Johnson, JD (1993) Proc. Natl. Acad. Sci. USA 90, 5677-5681; Di Marco, E. (1993) J. Biol. Chem. 268, 24290-24295; Zerlin, M. (1993) Oncogene 8, 2731-2739; Perez, JL (1996) Oncogene 12, 1469-1477).

[0004] Collagen was subsequently identified as a ligand for DDR (see Vogel, W. (1997) Mol. Cell 1, 13-23; Shrivastava A. Mol. Cell. 1997; 1:25-34), thus establishing the unique characteristics of DDR receptors among other members of the RTK superfamily that are normally activated by soluble peptide-like growth factors.

[0005] All DDRs are single-pass type I transmembrane glycoproteins characterized by the presence of six distinct domains: a discoidin (DS) domain, a DS-like domain, an extracellular juxtamembrane (EJXM) region, a transmembrane (TM) segment, a long intracellular juxtamembrane (IJXM) region, and an intracellular kinase domain (KD). The presence of an N-terminal DS and DS-like domain is characteristic of the DDR RTK subfamily.

[0006] The DS domain contains the collagen-binding region and is involved in mediating DDR specificity for fibrillar and non-fibrillar collagens (see Curat, CA (2001) J. Biol. Chem. 276, 45952-45958; Leitinger, B. (2003) J. Biol. Chem. 278, 16761-16769; Abdulhussein, R. (2004) J. Biol. Chem. 279, 31462-31470; Xu, H. (2011) Matrix Biol. 30, 16-26). The function of the DS-like domain of the DDR is not fully understood, but published data suggest that it contributes to collagen-induced receptor activation (see Carafoli, F. (2012) Structure 20, 688-697).

[0007] The EJXM region of the human DDR (49 residues in DDR1 and 31 residues in DDR2) connects the DS domain and the TM segment, and its structure is unknown. The EJXM region contains several putative N- and O-glycosylation sites, which may regulate receptor trafficking, turnover, and ligand-induced activation (see Curat, C. (2001) J. Biol. Chem. 276, 45952-45958).

[0008] A short TM helical segment (approximately 20 residues) connects the extracellular and intracellular domains of the DDR. The TM segment plays a role in receptor dimerization (see Noordeen, NA (2006) J. Biol. Chem. 281, 22744-22751).

[0009] An unusually large (130-140 residues) IJXM domain connects the TM segment to the KD. The IJXM domain contains several tyrosine residues and functions as a docking site for cytoplasmic effectors and regulators essential for signal transduction. In both DDR1 and DDR2, the IJXM domain is followed by a traditional KD (approximately 300 residues).

[0010] The DDR1 subfamily consists of five membrane-anchored isoforms, while the DDR2 subfamily is expressed by a single protein. The five DDR1 isoforms are produced by alternative splicing. They all share the extracellular and transmembrane domains but differ in their cytoplasmic regions. Of the five DDR1 isoforms, three (DDR1a, DDR1b, and DDR1c) are functional receptors (see Valiathan, RR (2012) Cancer Metastasis Rev. 31, 295-321; Alves, F. (2001) FASEB J. 15, 1321-1323).

[0011] The DDR is unique among RTKs because it is activated by the extracellular matrix protein collagen: it binds only to collagen in its native triple-helical structure and does not recognize heat-denatured collagen (gelatin) (see Vogel, W. (1997) Mol. Cell 1, 13-23; Leitinger, B. (2003) J. Biol. Chem. 278, 16761-16769).

[0012] Both DDRs exhibit broad collagen specificity and are activated by many different collagen types, with fibrillar collagens (I-III and V) acting as ligands for both receptors (see Vogel, W. (1997) Mol. Cell 1, 13-23; Shrivastava A. Mol. Cell. 1997; 1:25-34). DDRs have distinct preferences for specific collagen types. DDR1 binds to basement membrane collagen IV, whereas DDR2 does not bind to basement membrane collagen IV, whereas DDR2 appears to bind preferentially to collagen II and collagen X (see Leitinger B. J Mol. Biol. 2004; 344(4):993-1003; Leitinger B. Matrix Biol. 2006; 25(6):355-364). Similar to collagen-binding integrins, DDRs recognize specific amino acid motifs in collagen. Detailed studies using a library of triple-helical peptides revealed a six-amino acid motif, GVMGFO, as the binding motif for both DDRs (see Farndale RWet al. Biochem Soc Trans. 2008; 36(Pt 2):241-250).

[0013] DDR is unusual in that it forms stable dimers that are noncovalently and ligand-independent (see Noordeen, N.A. (2006) J. Biol. Chem. 281, 22744-22751; Mihai C. J. Mol. Biol. 2009; 385:432-445). DDR dimers form during biosynthesis and appear to be present on the cell surface prior to ligand binding. Upon collagen binding, DDR undergoes tyrosine autophosphorylation. Two distinctive features of DDR phosphorylation dynamics are delayed and sustained responses. While typical RTKs are activated within seconds to minutes, maximal DDR activation is often achieved within hours of collagen stimulation and remains detectable for up to several days after stimulation (see Vogel, W. (1997) Mol. Cell 1, 13-23; Shrivastava A. Mol. Cell. 1997; 1:25-34). The molecular basis and biological effects of these two intriguing features of DDR phosphorylation remain poorly understood.

[0014] Phosphorylation of tyrosine residues within the intracellular domain of activated DDR generates docking sites for proteins containing SH2, SH3, and PTB domains (see Wang, CZ, (2006) Mol. Biol. Cell 17, 2839-2852; Lemeer, S., (2012) J. Proteomics 75, 3465-3477; L'hote, CG (2002) FASEB J. 16, 234-236; Koo, DH (2006) FEBS Lett. 580, 15-22; Yang, G., (2009) Proteomics 9, 4944-4961).

[0015] Previous evidence suggests that stimulation of DDR1 by collagen is coupled to activation of the PI3K / Akt and Ras / ERK MAPK cascades (see Lu, K. (2011) Cardiovasc. Pathol. 20, 71-76; Suh, HN, J. Cell. Phyisiol. 226, 3422-3432; Ongusaha, PP, EMBO J. 22, 1289-1301).

[0016] In the case of DDR2, evidence points to a role for Src as a downstream effector and regulator of DDR2 signaling (see Ikeda, K., (2002) J. Biol. Chem. 277, 19206-19212; Olaso, E. (2011) Fibrogenesis Tissue Repair 4, 5; Yang, K., J. Biol. Chem. 280, 39058-39066).

[0017] The importance of the DDR as a collagen receptor is evidenced by the phenotype of DDR knockout mice. Both DDR1 and DDR2 knockout mice are viable but are smaller in size compared to wild-type littermates (see Vogel WF, Mol Cell Biol. 2001; 21(8):2906-2917; Labrador JP, EMBO Rep. 2001; 2(5):446-452). In DDR1 knockout mice, fibula mineralization is insufficient. In DDR2 knockout mice, atrophy is associated with short long bones due to reduced chondrocyte proliferation. In humans, DDR2 mutations are associated with a variety of skeletal defects, including short limbs and abnormal mineralization. In addition to their small size, DDR knockout / mutant mice also exhibit reproductive defects. DDR1 knockout mice are unable to secrete lactate due to abnormal mammary gland morphogenesis. Furthermore, DDR1 knockout mice exhibit altered kidney structure and impaired adhesion of primary mesangial cells to the ECM (see Gross O, Kidney Int. 2004; 66(1):102-111; Curat CA, J Am Soc Nephrol. 2002; 13(11):2648-2656). These mice also lack ear movement control and exhibit loss of hearing function with profound structural changes throughout the cochlear duct (see Meyer zum Gottesberge AM, Lab Invest. 2008; 88(1):27-37). In contrast, DDR2 knockout mice show no defects in lactation, kidney structure, or hearing function. Instead, these mice exhibit impaired skin wound healing due to defects in proliferation, invasion, proteolytic activity, and ECM remodeling by dermal fibroblasts (see Olaso E, J Biol Chem. 2002; 277(5):3606-3613).

[0018] Despite some of the developmental defects found in DDR-null mice, these mice are valuable for understanding the role of these receptors in diverse diseases, including pulmonary fibrosis.

[0019] The first evidence for a protective role of DDR1 deficiency in pulmonary fibrosis was produced by Dr. Vogel's research group in 2006 (see Avivi-Green C, Am J Respir Crit Care Med 2006;174:420-427). The authors showed that DDR1-null mice were significantly protected from bleomycin (BLM)-induced injury. Furthermore, myofibroblast expansion and apoptosis were much less than in their wild-type counterparts. The absence of inflammation in the knockout mice was confirmed by lavage cell counts and cytokine ELISA. These results suggested that DDR1 expression is a prerequisite for the development of lung inflammation and fibrosis.

[0020] The above results were confirmed using a pharmacological approach (and therapeutic regimen) by Wang Z. et al. (See Wang, Z., J. Med. Chem. 2016, 59, 5911-5916). Mice were treated with compound 6j (a tetrahydroisoquinoline derivative) after the onset of BLM-induced fibrotic injury. Compound 6j dose-dependently prevented BLM-induced pathological changes (i.e., reduction of alveolar space and ECM deposition). This histological result was accompanied by a decrease in the expression levels of fibrotic markers fibronectin, α-SMA, and collagen.

[0021] The role of DDR2 in organ fibrosis is poorly understood and remains controversial. DDR2-null mice exhibit increased liver fibrosis after chronic liver injury (see Olaso E, Am J Pathol 2011;179:2894-2004). On the other hand, DDR2 deletion or downregulation attenuates bleomycin-induced pulmonary fibrosis (see Zhao H, Bian H, Bu X, Zhang S, Zhang P, Yu J, et al. Mol Ther 2016;24:1734-1744). Zhao et al. demonstrated that DDR2 plays an important role in the induction of pulmonary fibrosis and angiogenesis. The authors demonstrated that DDR2 synergizes with transforming growth factor (TGF)-β to induce myofibroblast differentiation. Furthermore, treatment of injured mice with DDR2-specific siRNA demonstrated therapeutic effects on 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). The authors showed that after bleomycin treatment, DDR2-null mice exhibited significantly preserved alveolar architecture and air spaces without heavy cellular infiltration. Furthermore, DDR2-null fibroblasts were significantly more prone to apoptosis than wild-type fibroblasts, supporting the paradigm that fibroblast resistance to apoptosis is important for the progression of fibrosis.

[0022] A variety of compounds have been described in the literature as DDR1 or DDR2 antagonists.

[0023] WO2015004481 (Astex) discloses bicyclic compounds as DDR1 and DDR2 inhibitors useful in the treatment of diseases such as cancer.

[0024] WO2017005583 (F. Hoffmann-La Roche) discloses triazaspiro derivatives as DDR1 inhibitors useful for the treatment of kidney diseases, liver diseases, inflammatory diseases, vascular diseases, cardiovascular diseases, fibrotic diseases, cancer, and acute and chronic organ transplant rejection.

[0025] WO2014032755 (Merck) discloses compounds useful for triggering physiological and / or pathophysiological conditions in which DDR2 is involved, in particular for use in the treatment and / or prevention of osteoarthritis.

[0026] WO2013161851 (Chugai) discloses benzamide derivatives as DDR1 antagonists useful for the treatment of fibrosis and / or inflammation.

[0027] WO2015060373 (Chugai) discloses quinazolinone and isoquinolinone derivatives as DDR1 antagonists useful for the treatment of fibrosis and / or inflammation.

[0028] WO2016064970 (Guangzhou) discloses isoquinoline derivatives as DDR1 inhibitors useful as therapeutic agents for the prevention and treatment of inflammation, liver fibrosis, kidney fibrosis, lung fibrosis, skin scars, atherosclerosis and cancer.

[0029] WO2005092896 (Jeil Pharmaceutical) discloses furopyrimidine derivatives as DDR2 inhibitors useful for treating diseases caused by DDR2 tyrosine kinase activity, such as liver cirrhosis, rheumatoid arthritis or cancer.

[0030] WO2010062038 (Legochem) discloses compounds as DDR1 and DDR2 inhibitors that are useful for treating diseases such as cancer, liver cirrhosis, arteriosclerosis, rheumatoid arthritis, and osteoarthritis, which are known to be primarily caused by excessive activation of DDR1 and DDR2.

[0031] WO2017038870 (Toray) discloses urea derivatives as DDR1 inhibitors, which are useful for treating diseases involving the DDR1 receptor.

[0032] In "Discovery of VU6015929: A Selective Discoidin Domain Receptor 1 / 2 (DDR1 / 2) Inhibitor to Explore the Role of DDR1 in Antifibrotic Therapy," Med. Chem. Lett. 2020, 11, 29-33, Daniel E. Jeffries et al. disclose a selective dual DDR1 / 2 inhibitor, 7e (VU6015929), suggesting that DDR1 inhibition is an exciting target for antifibrotic therapy.

[0033] It is noteworthy that antagonizing DDR receptors is useful in treating fibrosis and diseases, disorders and conditions caused by fibrosis, and further that antagonizing both DDR1 and DDR2 receptors may be particularly effective in treating the above-mentioned diseases, disorders and conditions.

[0034] Over the past few years, efforts have been made to develop novel DDR1 and DDR2 receptor antagonists useful in the treatment of several diseases, and some of these compounds have been shown to be effective in humans.

[0035] Notwithstanding the above prior art, there remains the possibility of developing inhibitors of both the DDR1 and DDR2 receptors that are useful in the treatment of diseases or conditions associated with dysregulation of DDR receptors, particularly fibrosis.

[0036] In this respect, the benzylamine derivatives of general formula (I) of the present invention having antagonist activity against the receptor DDR, which represent a solution to the aforementioned need, have not been described or suggested at present. Summary of the Invention

[0037] In a first embodiment of the present invention, a compound of formula (I): [ka] [In the formula, L and L1 are different and independently selected from -C(O) and NH; L2 is absent or NH, where when both L and L2 are NH, then L1 is -C(O); Z is absent or selected from -CH2 and -C(O); R1 is H or -O(C1-C4)alkyl; [ka] selected from the group consisting of: n is an integer from 1 to 3, R is selected from the group consisting of (C1-C4) alkyl, halo, (C1-C4) haloalkyl, and (C3-C6) cycloalkyl; R2 is selected from the group consisting of heteroaryl and heterocycloalkyl, wherein said heteroaryl and heterocycloalkyl are each optionally substituted by one or more of -C(O)NHR6, -CN, (C1-C4)alkyl, halo, -NHC(O)R6, heteroaryl, and -NR7R8; R3 is selected from the group consisting of (C1-C4) alkyl, (C1-C4) haloalkyl, (C3-C6) cycloalkyl, and —O(C1-C4) haloalkyl; R4 is H or selected from the group consisting of (C1-C4) alkyl, halo, and (C3-C6) cycloalkyl; R5 is H or selected from the group consisting of (C1-C4) alkyl and heteroaryl(C1-C4) alkyl-; R6 is H or (C1-C4) alkyl; R7 and R8, independently at each occurrence, are H or selected from the group consisting of (C1-C4) alkyl, (C3-C8) cycloalkyl, (C1-C6) haloalkyl, and halo. and pharmaceutically acceptable salts thereof.

[0038] In a second aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) admixed with one or more pharmaceutically acceptable carriers or excipients.

[0039] In a third aspect, the present invention relates to a compound of formula (I) for use as a medicament.

[0040] In a fourth aspect, the present invention relates to a compound of formula (I) for use in the treatment of a disease, disorder or condition associated with dysregulation of the DDR.

[0041] In a further aspect, the present invention relates to a compound of formula (I) for use in the prevention and / or treatment of fibrosis and / or diseases, disorders or conditions involving fibrosis.

[0042] In a further aspect, the present invention relates to compounds of formula (I) for use in the prevention and / or treatment of idiopathic pulmonary fibrosis (IPF).

[0043] In a further aspect, the present invention preferably provides a compound of formula VIII: [ka] wherein R, R, R, R, L, L, and L are as defined above for formula (I). The present invention relates to the compound

[0044] In a further aspect, the present invention preferably provides a compound of formula VII: for use as an intermediate in the preparation of a series of compounds of formula (I): [ka] wherein Z is absent, CH, or —C(O), and R, R, R, R, R, L, and L are as set forth above for formula (I). The present invention relates to the compound

[0045] Detailed Description of the Invention Unless otherwise specified, the compounds of formula (I) of the present invention are intended to include their stereoisomers, tautomers, or pharmaceutically acceptable salts or solvates.

[0046] As used herein, the term "pharmaceutically acceptable salts" refers to derivatives of compounds of formula (I) wherein the parent compound is suitably modified by converting any free acid or basic group, if any, into the corresponding addition salt with any base or acid that is conventionally considered to be pharmaceutically acceptable.

[0047] Thus, suitable examples of such salts include mineral acid addition salts or organic acid addition salts of basic residues such as amino groups, and mineral acid addition salts or organic base addition salts of acid residues such as carboxy groups.

[0048] Cations of inorganic bases suitable for use in preparing the salts include alkali metal or alkaline earth metal ions, for example potassium, sodium, calcium or magnesium.

[0049] Those obtained by reacting the main compound, which functions as a base, with an inorganic or organic acid to form a salt include, for example, salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, acetic acid, oxalic acid, maleic acid, fumaric acid, succinic acid, and citric acid.

[0050] The term "solvate" refers to a physical association of a compound of the present invention with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain instances, a solvate may be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. A solvate may contain either stoichiometric or non-stoichiometric amounts of solvent molecules.

[0051] The term "stereoisomers" refers to isomers of identical constitution but differing in the arrangement of their atoms in space. Enantiomers and diastereomers are examples of stereoisomers.

[0052] The term "enantiomer" refers to one of a pair of molecular species that are mirror images of each other and are not superimposable.

[0053] The term "diastereomers" means stereoisomers that are not mirror images.

[0054] The terms "racemate" or "racemic mixture" refer to a composition of equimolar amounts of two enantiomeric species, devoid of optical activity.

[0055] The symbols "R" and "S" indicate the arrangement of substituents around a chiral carbon atom(s). The isomeric descriptors "R" and "S" are used herein to indicate the atomic arrangement(s) relative to a core molecule and are intended to be used as defined in the literature (IUP AC Recommendations 1996, Pure and Applied Chemistry, 68:2193-2222 (1996)).

[0056] The term "tautomer" means each of two or more isomers of a compound that exist together in equilibrium and are readily interchangeable by shifting of atoms or groups within the molecule.

[0057] As used herein, the term "halogen" or "halogen atom" or "halo" includes fluorine, chlorine, bromine, and iodine atoms.

[0058] The term “(C x -C y ")alkyl" (where x and y are integers) means a straight or branched chain alkyl group having from x to y carbon atoms. Thus, for example, when x is 1 and y is 6, it includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, and n-hexyl.

[0059] The formula "(Cx-Cy)haloalkyl" (where x and y are integers) refers to a "C" group as defined above in which one or more hydrogen atoms have been replaced by one or more halogen atoms, which may be the same or different. x -C y Therefore, the above-mentioned "(C x -C y Examples of "haloalkyl" groups include halogenated alkyl groups, polyhalogenated alkyl groups, and fully halogenated alkyl groups in which all hydrogen atoms have been replaced by halogen atoms, such as trifluoromethyl.

[0060] The term "aryl" refers to a monocyclic carbocyclic ring system in which the ring is aromatic. Examples of suitable aryl monocyclic ring systems include, for example, phenyl.

[0061] The term "heteroaryl" refers to a monocyclic or bicyclic aromatic ring system of 5 to 12 ring atoms containing one or more heteroatoms selected from S, N, and O, including groups having two such monocyclic rings or one such monocyclic ring fused to a monocyclic aryl ring through a common bond. Examples of heteroaryl include pyridinyl, pyrimidinyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazole, indazolyl, benzo[d][l,2,3]triazolyl, imidazo[l,5-a]pyridinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[4,3-b]pyridinyl, and tetrazolo[l,5-a]pyridinyl.

[0062] Particular examples of monocyclic heteroaryls are pyrimidinyl and pyridinyl.

[0063] Particular examples of bicyclic heteroaryls are imidazo[1,2-a]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, 1H-indazolyl, indazolyl, benzo[d]thiazolyl.

[0064] The term "heterocycloalkyl" means a saturated or partially unsaturated monocyclic or bicyclic ring system of 3 to 10 ring atoms containing one or more heteroatoms selected from N, S, or O. In certain embodiments, heterocycloalkyl means a partially unsaturated bicyclic ring system of 7 to 9 ring atoms containing one or more heteroatoms selected from N, S, or O. A particular example of a bicyclic partially unsaturated heterocycloalkyl is 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidinyl.

[0065] The term “(C x -C y")Cycloalkyl" (where x and y are integers) refers to a monovalent saturated monocyclic or bicyclic hydrocarbon radical of xy ring carbon atoms. In certain embodiments, cycloalkyl refers to a monovalent saturated monocyclic hydrocarbon radical of 3-8 ring carbon atoms. Bicyclic refers to two saturated carbocyclic rings which share one or more carbon atoms. Certain cycloalkyl groups are monocyclic. Examples of monocyclic cycloalkyl are cyclopropyl, cyclobutanyl, cyclopentyl, cyclohexyl, or cycloheptyl.

[0066] The term “-O(C x -C y (C )cycloalkyl" (where x and y are integers) means a "(C )cycloalkyl" as defined above, in which a carbon atom is bonded to an oxygen atom. x -C y )cycloalkyl" group. Examples include, for example, cyclopropyloxy.

[0067] The term “(C x -C y (C1-C6)aminoalkyl" (where x and y are integers) means a "(C1-C6)alkyl" group, as defined above, in which one or more hydrogen atoms are replaced by one or more amino groups.

[0068] As used in the structural formulas herein [ka] A bond that refers to a wavy or serpentine line, such as indicates a bond that is the point of attachment of a moiety or substituent to a core or backbone structure.

[0069] A dash (“-”) that is not between two letters or symbols denotes a point of attachment for a substituent.

[0070] Carbonyl groups are preferably depicted herein as -C(O)-, instead of other common representations such as -CO-, -(CO)- or -C(=O)-.

[0071] Generally, bracketed groups are side groups that are not included in a chain, and brackets are used to disambiguate linear chemical formulas where deemed useful; for example, the sulfonyl group -SO- may also be shown as -S(O)- to disambiguate, for example, the sulfinic group -S(O)O-.

[0072] Whenever a basic amino group or a quaternary ammonium group is present in the compound of formula (I), a physiologically acceptable anion may be present, selected from chloride, bromide, iodide, trifluoroacetate, formate, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate, p-toluenesulfonate, pamoate, and naphthalenedisulfonate. Similarly, in the presence of an acidic group, such as a COOH group, the corresponding physiological cationic salts may also be present, including, for example, alkali or alkaline earth metal ions.

[0073] "Half maximal inhibitory concentration" (IC50) refers to the concentration of a particular compound or molecule required to obtain 50% inhibition of a biological process in vitro. IC 50 Values ​​were log-transformed to give pIC 50 Value (-log IC 50 ), and the higher the value, the greater the exponential effect. 50 The IC values ​​are not absolute and depend on the experimental conditions, e.g., the concentrations used. 50 Values ​​can be converted to absolute inhibition constants (Ki) using the Cheng-Prusoff equation (Biochem. Pharmacol. (1973) 22:3099).

[0074] As described above, the present invention relates to a series of compounds represented by the general formula (I) detailed below, which have inhibitory activity against the receptors DDR1 and DDR2.

[0075] Advantageously, antagonizing both DDR1 and DDR2 receptors may be particularly effective in treating diseases in which DDR receptors play a relevant role in the pathogenesis, such as fibrosis and diseases, disorders and conditions resulting from fibrosis.

[0076] The compounds of formula (I) of the present invention can act as antagonists of both DDR1 and DDR2 receptors in a substantial and effective manner, and are particularly appreciated by those skilled in the art when looking for suitable and effective compounds useful in the treatment of fibrosis, particularly idiopathic pulmonary fibrosis.

[0077] As shown in the experimental section, the compounds of formula (I) of the present invention are indeed active against both receptors DDR1 and DDR2, as shown in Table 2, and for each compound the potency expressed as an inhibition constant (Ki) is reported.

[0078] As can be seen, the compounds of the invention according to Table 2 show remarkable potency in terms of their inhibitory activity against both receptors DDR1 and DDR2 at around 1000 nM or less, even 300 nM or less for most compounds, thereby confirming that they are able to antagonize the two isoforms of DDR receptors that are primarily involved in fibrosis and diseases resulting from fibrosis.

[0079] Additionally, some compounds of the present invention have potency (IC) in terms of inhibitory activity against DDR1 and DDR2 receptors in cell-based assays. 50 ) are classified in Table 4.

[0080] Therefore, the compounds of the present invention will be particularly appreciated by those skilled in the art when looking for suitable and effective compounds useful in the treatment of fibrosis, particularly idiopathic pulmonary fibrosis.

[0081] Thus, in one aspect of the present invention, compounds of the general formula (I): [ka] [In the formula, L and L1 are different and independently selected from -C(O) and NH; L2 is absent or is NH, where when both L and L2 are NH, then L1 is -C(O); Z is absent or -CH 2および -C(O); R1 is H or -O(C1-C4)alkyl; [ka] selected from the group consisting of: n is an integer from 1 to 3, R is selected from the group consisting of (C1-C4) alkyl, halo, (C1-C4) haloalkyl, and (C3-C6) cycloalkyl; R2 is selected from the group consisting of heteroaryl and heterocycloalkyl; wherein said heteroaryl and heterocycloalkyl are each optionally substituted by one or more of -C(O)NHR6, -CN, (C1-C4)alkyl, halo, -NHC(O)R6, heteroaryl, and -NR7R8; R3 is selected from the group consisting of (C1-C4) alkyl, (C1-C4) haloalkyl, (C3-C6) cycloalkyl, and —O(C1-C4) haloalkyl; R4 is H or selected from the group consisting of (C1-C4) alkyl, halo, and (C3-C6) cycloalkyl; R5 is H or selected from the group consisting of (C1-C4) alkyl and heteroaryl(C1-C4) alkyl-; R6 is H or (C1-C4) alkyl; R7 and R8, independently at each occurrence, are H or selected from the group consisting of (C1-C4) alkyl, (C3-C8) cycloalkyl, (C1-C6) haloalkyl, and halo. and pharmaceutically acceptable salts thereof.

[0082] In a preferred embodiment, the present invention provides a compound of general formula (I): [ka] [In the formula, L and L1 are different and independently selected from -C(O) and NH; L2 is absent or NH; Z is absent or selected from -CH2 and -C(O); R1 is -O(C1-C4)alkyl; [ka] selected from the group consisting of: n is 1; R is selected from the group consisting of (C1-C4) alkyl and halo; R2 is selected from the group consisting of heteroaryl and heterocycloalkyl, wherein said heteroaryl and heterocycloalkyl are each optionally substituted by one or more -C(O)NHR6 and CN; R3 is selected from the group consisting of (C1-C4)haloalkyl and —O(C1-C4)haloalkyl; R4 is H; R5 is H or selected from the group consisting of (C1-C4) alkyl and heteroaryl(C1-C4) alkyl-; R6 is H or (C1-C4) alkyl. and pharmaceutically acceptable salts thereof.

[0083] In a further preferred embodiment, the present invention provides compounds of the general formula (Ia): [ka] [In the formula, L and L1 are different and independently selected from -C(O) and NH; Z is absent or selected from -CH2 and -C(O); R1 is -O(C1-C4)alkyl; [ka] selected from the group consisting of: n is 1; R is (C1-C4) alkyl; R2 is selected from the group consisting of heteroaryl and heterocycloalkyl, wherein said heteroaryl and heterocycloalkyl are each optionally substituted by one or more -C(O)NHR6 and CN; R3 is (C1-C4)haloalkyl; R5 is H or selected from the group consisting of (C1-C4) alkyl and heteroaryl(C1-C4) alkyl-; R6 is H or (C1-C4) alkyl. Denoted by The present invention relates to compounds of the general formula (I): wherein R1 is meta to the rest of the molecule, n is 1, L2 is absent, and R4 is H, and pharmaceutically acceptable salts thereof.

[0084] In a further preferred embodiment, R2 is selected from the group consisting of pyrimidinyl, pyridinyl, imidazo[1,2-a]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, 1H-indazolyl, indazolyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidinyl and benzo[d]thiazolyl.

[0085] In a further preferred embodiment, the present invention provides compounds of the general formula (Ia): wherein L and L1 are different and independently selected from —C(O) and NH; Z is absent or selected from -CH2 and -C(O); R1 is -OCH3, [ka] selected from the group consisting of: n is 1; R is selected from the group consisting of methyl, ethyl, propyl, and isopropyl; R2 is selected from the group consisting of pyrimidinyl, pyridinyl, imidazo[1,2-a]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, 1H-indazolyl, indazolyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidinyl, and benzo[d]thiazolyl, wherein the heteroaryl and heterocycloalkyl are each optionally substituted by one or more -C(O)NHR6 and CN; R3 is trifluoromethyl; R5 is H or selected from the group consisting of methyl, ethyl, and 3-methylimidazo[1,2-a]pyridinyl; R6 is H or methyl. and pharmaceutically acceptable salts thereof.

[0086] According to a preferred embodiment, the present invention refers to at least one of the compounds shown in Table 1 below; which compounds have activity on the receptors DDR1 and DDR2, as shown in Table 2.

[0087] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7]

[0088] In a further preferred embodiment, the present invention provides compounds of the general formula (Ia): [Wherein R1 is [ka] is] and pharmaceutically acceptable salts thereof, which are represented by the general formula (Ib): [ka] [In the formula, L and L1 are different and independently selected from -C(O) and NH; Z is absent or selected from -CH2 and -C(O); R is (C1-C4) alkyl; R2 is selected from the group consisting of heteroaryl and heterocycloalkyl, wherein said heteroaryl and heterocycloalkyl are each optionally substituted by one or more -C(O)NHR6 and CN; R3 is (C1-C4)haloalkyl; R5 is H or selected from the group consisting of (C1-C4) alkyl and heteroaryl(C1-C4) alkyl-; R6 is H or (C1-C4) alkyl. and pharmaceutically acceptable salts thereof.

[0089] In a further preferred embodiment, the present invention provides a compound of formula (Ib): wherein L and L1 are different and independently selected from —C(O) and NH; Z is absent or is C(O); R is methyl or propyl; R2 is selected from the group consisting of imidazo[1,2-a]pyridinyl, pyrimidinyl, pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, 1H-indazolyl, benzo[d]thiazolyl, and 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidinyl, wherein the heteroaryl and heterocycloalkyl are each optionally substituted by one or more -C(O)NHR6 and CN; R3 is trifluoromethyl; R5 is H or ethyl; R6 is methyl] The present invention relates to the compound

[0090] In a further preferred embodiment, the present invention refers to a compound of general formula (Ia): [ka] is] and pharmaceutically acceptable salts thereof, which have the general formula (Ic): [ka] [In the formula, L and L1 are different and independently selected from -C(O) and NH; Z is absent or selected from -CH2 and -C(O); R is (C1-C4) alkyl; R2 is selected from the group consisting of heteroaryl and heterocycloalkyl, wherein said heteroaryl and heterocycloalkyl are each optionally substituted by one or more -C(O)NHR6 and CN; R3 is (C1-C4)haloalkyl; R5 is H or selected from the group consisting of (C1-C4) alkyl and heteroaryl(C1-C4) alkyl-; R6 is H or (C1-C4) alkyl. and pharmaceutically acceptable salts thereof.

[0091] In a further preferred embodiment, the present invention provides a compound of formula (Ic): wherein L and L1 are different and independently selected from —C(O) and NH; Z is absent or selected from -CH2 and -C(O); R is selected from the group consisting of methyl, propyl, and isopropyl; R2 is selected from the group consisting of imidazo[1,2-a]pyridinyl, pyrimidinyl, pyridinyl 1H-pyrrolo[2,3-b]pyridinyl and pyrazolo[1,5-a]pyrimidinyl, wherein said heteroaryl and heterocycloalkyl are each optionally substituted by one or more -C(O)NHR6; R3 is trifluoromethyl; R5 is H or 3-methylimidazo[1,2-a]pyridinyl; R6 is methyl] and pharmaceutically acceptable salts thereof.

[0092] In a further embodiment, the present invention provides compounds of general formula (I): wherein L2 is absent, n is 1, R1 is —O(C1-C4)alkyl and is para with respect to L1; and R4 is H. and pharmaceutically acceptable salts thereof, which have the general formula (Id): [ka] [In the formula, L and L1 are different and independently selected from -C(O) and NH; Z is absent or selected from -CH2 and -C(O); R is (C1-C4) alkyl; R2 is selected from the group consisting of heteroaryl and heterocycloalkyl, wherein said heteroaryl and heterocycloalkyl are each optionally substituted by one or more -C(O)NHR6 and CN; R3 is (C1-C4)haloalkyl; R5 is H or selected from the group consisting of (C1-C4) alkyl and heteroaryl(C1-C4) alkyl-; R6 is H or (C1-C4) alkyl. and pharmaceutically acceptable salts thereof.

[0093] In a further embodiment, the present invention provides a compound of formula (Id): wherein L and L1 are different and independently selected from —C(O) and NH; Z is absent or selected from -CH2 and -C(O); R is selected from the group consisting of methyl, propyl, and isopropyl; R2 is selected from the group consisting of imidazo[1,2-a]pyridinyl, pyrimidinyl, pyridinyl 1H-pyrrolo[2,3-b]pyridinyl, and pyrazolo[1,5-a]pyrimidinyl, wherein the heteroaryl and heterocycloalkyl are each optionally substituted by one or more -C(O)NHR6; R3 is trifluoromethyl; R5 is H or 3-methylimidazo[1,2-a]pyridinyl; R6 is methyl] and pharmaceutically acceptable salts thereof.

[0094] In a further embodiment, the present invention provides compounds of general formula (Id): wherein L2 is absent, n is 1, R1 is —OCH3 and is para with respect to L1; and R4 is H. and pharmaceutically acceptable salts thereof, which have the general formula (Ie): [ka] [In the formula, L and L1 are different and independently selected from -C(O) and NH; Z is absent or selected from -CH2 and -C(O); R is (C1-C4) alkyl; R2 is selected from the group consisting of heteroaryl and heterocycloalkyl, wherein said heteroaryl and heterocycloalkyl are each optionally substituted by one or more -C(O)NHR6 and CN; R3 is (C1-C4)haloalkyl; R5 is H or selected from the group consisting of (C1-C4) alkyl and heteroaryl(C1-C4) alkyl-; R6 is H or (C1-C4) alkyl. and pharmaceutically acceptable salts thereof.

[0095] In another preferred embodiment, the present invention provides a compound of formula (Ie): wherein L and L1 are different and independently selected from —C(O) and NH; Z is absent or selected from -CH2 and -C(O); R is selected from the group consisting of methyl, propyl, and isopropyl; R2 is selected from the group consisting of imidazo[1,2-a]pyridinyl, pyrimidinyl, pyridinyl 1H-pyrrolo[2,3-b]pyridinyl, and pyrazolo[1,5-a]pyrimidinyl, wherein the heteroaryl and heterocycloalkyl are each optionally substituted by one or more -C(O)NHR6; R3 is trifluoromethyl; R5 is H or 3-methylimidazo[1,2-a]pyridinyl; R6 is methyl] and pharmaceutically acceptable salts thereof.

[0096] In a further preferred embodiment, the present invention provides compounds of the general formula (I): wherein L2 is absent, R4 and R5 are -H, and Z is absent. and pharmaceutically acceptable salts thereof, having the general formula (If): [ka] [In the formula, L is -C(O); L is -NH; R1 is H or -O(C1-C4)alkyl and [ka] selected from the group consisting of: R is selected from the group consisting of (C1-C4) alkyl and halo; R2 is [ka] selected from the group consisting of: R3 is selected from the group consisting of (C1-C4)haloalkyl and -O(C1-C4)haloalkyl. and pharmaceutically acceptable salts thereof.

[0097] In a further embodiment, the present invention provides compounds of the general formula (If): wherein L is —C(O); L is —NH; R1 is H or -OCH3 and [ka] selected from the group consisting of: R is selected from the group consisting of methyl and fluorine; R2 is [ka] selected from the group consisting of: R3 is selected from the group consisting of trifluoromethyl and trifluoromethoxy. and pharmaceutically acceptable salts thereof.

[0098] In a further preferred embodiment, the present invention provides compounds of the general formula (If): wherein L is —C(O), L is —NH, R is H or —OCH, R is selected from the group consisting of methyl and fluorine, and R is [ka] selected from the group consisting of: R3 is trifluoromethyl. and pharmaceutically acceptable salts thereof.

[0099] In a further preferred embodiment, the present invention refers to at least one of the compounds shown in Table 3 below, which have activity on the receptors DDR1 and DDR2 as shown in Tables 2 and 4.

[0100] [Table 2-1] [Table 2-2]

[0101] The compounds of the present invention, including those listed herein above, can be prepared from readily available starting materials using the following general methods and procedures, or using slightly modified processes readily available to those of ordinary skill in the art. While specific embodiments of the present invention may be shown or described herein, those of ordinary skill in the art will recognize that all embodiments or aspects of the present invention can be obtained using the methods described herein or by 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, although such conditions can be readily determined by one of ordinary skill in the art by routine optimization procedures.

[0102] Accordingly, the processes described below and reported in the schemes below should not be construed as limiting the scope of synthetic methods available for the preparation of compounds of the present invention.

[0103] In some cases, commonly known protecting groups (PG) may be employed as needed to mask or protect sensitive or reactive moieties in accordance with general principles of chemistry (Protective groups in organic syntheses, 3rd ed. T.W. Greene, P.G.M. Wuts).

[0104] The preparative methods described below and reported in the following schemes should not be construed as limiting the scope of synthetic methods available for the preparation of compounds of the present invention.

[0105] Compounds of formula (I), including all compounds listed herein, can generally be prepared according to the procedures set forth in the following schemes: Where a particular synthetic step differs from that described in the general schemes, it is detailed in specific examples and / or described in additional schemes.

[0106] The compounds of formula (I) contain at least one asymmetric center, as indicated by an * in the photograph below. [ka]

[0107] Enantiomerically pure compounds can be prepared from the corresponding racemates by chiral chromatography. When two or more asymmetric centers are present in a compound of formula (I), the structure is characterized by different stereoisomers. Stereochemically pure compounds can be obtained stepwise by chiral separation from a diastereoisomeric mixture, or by chromatographic separation of diastereoisomers followed by further chiral separation into single stereoisomers.

[0108] Compounds of formula (I) can be prepared according to Scheme 1 set forth below, which provides at least one non-limiting synthetic route for the preparation of all examples.

[0109] [ka]

[0110] According to Scheme 1, intermediate III can be obtained from intermediate II via a palladium-catalyzed cross-coupling between X1 and X2 on the most reactive leaving group, where X1 and X2 can be, for example, chlorides, bromides, iodides, OMs, or OTs. For example, this reaction can be carried out according to the traditional Suzuki protocol by reacting bis(aryl halide) intermediate II with an alkylboronic acid or potassium alkyltrifluoroborate in the presence of an inorganic acid such as K2PO4 or cesium carbonate in a suitable organic solvent such as dioxane or THF at elevated temperature (about 100 °C) using a suitable palladium catalyst system such as Pd2(dppf)Cl2 or another palladium source / phosphine-based ligand for several hours.

[0111] Direct ester amidation (ammonolysis) can be carried out between intermediate III and intermediate IXa using, for example, potassium tert-butoxide or sodium methoxide as a promoter in a suitable organic solvent such as THF or dioxane at room temperature for several hours to give intermediate IV.

[0112] In another approach, intermediate IV can be prepared in a one-step synthesis starting from intermediate IX under suitable amide coupling reaction conditions. For example, intermediates IX and IXa can be reacted with an organic base such as DIPEA or TEA in the presence of an activating agent such as COMU or HATU in a suitable organic solvent such as DCM or DMF, typically at around RT, for a period ranging from several hours to overnight.

[0113] Palladium-catalyzed reductive carbonylation of aryl halides, where R4 = H, can be carried out starting from intermediate IV to prepare intermediate V. For example, in a suitable solvent such as toluene or DMF at a temperature range of 60-100 °C for several hours, formic acid or formylsaccharin can be used as the CO source, a silane or formic acid itself as the hydrogen donor, a suitable palladium catalyst system such as palladium acetate / Ph3P or palladium acetate / bis(diphenylphosphino)butane or another palladium source / phosphine-based ligand, and TEA or Na2CO3 as the base can be used.

[0114] Alternatively, intermediate V can be prepared from intermediate XX under suitable amide coupling reaction conditions as described for the preparation of intermediate IV. Intermediate V can also be prepared from intermediate XX by conversion to acyl chloride XXI using, for example, thionyl chloride or oxalyl chloride in a suitable solvent such as DCM, followed by amide coupling using a suitable base such as DIPEA or TEA in a suitable solvent such as DCM or DMF at room temperature.

[0115] In another approach, when R = CHF2, intermediate XX can be prepared from intermediate XXV via, for example, ester hydrolysis using LiOH in a suitable solvent such as THF or dioxane at room temperature.

[0116] Intermediate XXV can be obtained via ozonolysis, for example by applying a stream of ozone in a suitable solvent such as DCM at a suitable temperature such as 0° C. followed by a suitable reductive workup, such as with Ph3P or Me2S.

[0117] Deoxofluorination of intermediate XXII to give intermediate XXIII can be carried out in a solvent such as DCM or DMF in the presence of a fluorinating agent such as DAST or Deoxo-Fluor reagent at a suitable temperature such as room temperature. Pd-catalyzed cross-coupling can be carried out by According to the classic Suzuki protocol, intermediate XXIV can be obtained by reacting aryl halide intermediate XXIII (where the halide is X3) with an alkylboronic acid or potassium alkyltrifluoroborate using a suitable palladium catalyst system such as Pd2(dppf)Cl2 or another palladium source / phosphine-based ligand in the presence of an inorganic base such as K2PO4 or cesium carbonate at elevated temperature (ca. 100 °C) in a suitable organic solvent such as dioxane or THF for several hours. Reductive amination of intermediate V with an amine R2-NH2 (when R4 = H) to give intermediate VII can be carried out at room temperature in the presence of a reducing agent such as NaBH3CN or Na(OAc)3BH in a solvent such as 1,2-dichloroethane or DCM.

[0118] Alternatively, intermediate VII can be prepared via a two-step synthesis in which the imine intermediate VI is first formed by reacting intermediate V with an amine R2-NH2 in a suitable solvent such as 1,2-dichloroethane, DCM, or toluene at room temperature or reflux as appropriate. The presence of a dehydrating agent can aid in the formation of the imine, which is then converted to VII by the addition of a reducing agent as described above.

[0119] Intermediate VI may also be useful in preparing intermediate VII when R4 = alkyl or cycloalkyl by 1,2-addition of suitable organometallic reagents such as Grignard or organolithium reagents at temperatures ranging from 78°C to room temperature.

[0120] In a further method, intermediate VII, when R4 = alkyl or cycloalkyl, can also be prepared by converting intermediate V to the amine intermediate VIII, which undergoes reductive amination using an ammonia source such as ammonium acetate or ammonia solution and a reducing agent such as NaBH3CN or NaBH4 in a suitable solvent such as MeOH or EtOH at temperatures ranging from room temperature to 50 °C. Intermediate VIII can then undergo a Buchwald-Hartwig cross-coupling reaction with a halide or triflate R2-X (when R2 = heteroaryl) using an appropriate palladium catalyst system such as Pd(dba)2 / RuPhos or another palladium source / phosphine-based ligand in a suitable organic solvent such as dioxane or toluene at elevated temperatures (approximately 100 °C) in the presence of an inorganic base such as K2PO4 or cesium carbonate for several hours to overnight.

[0121] Alternatively, ipso displacement of the leaving group of R2-X (when R2=heteroaryl) by the amine group of intermediate VIII to give intermediate VII can be carried out in a high boiling organic solvent such as DMSO or DMA at a temperature equal to or greater than 100° C. in the presence of an inorganic base such as tBuOK or K2CO3.

[0122] Intermediate VII requires no further reaction to be converted to compound I when R5 = H.

[0123] Intermediate VII can be converted to compounds of formula (I) via reductive amination with an alkyl aldehyde R5-CHO, carried out in a similar manner as described for the preparation of intermediate VII from intermediate V, when R5 is different from H and Z is absent or is CH2.

[0124] Alternatively, 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.

[0125] [ka]

[0126] According to Scheme 2, intermediate XVIII can be converted to intermediate XV by Pd-catalyzed alkylation of an aryl bromide via Negishi, Stille, or Suzuki cross-coupling by reacting it with an alkylzinc halide or alkylstannane using a suitable palladium catalyst system such as Pd(OAc)2 / CPhos or another palladium source / phosphine-based ligand at elevated temperature (ca. 100°C) in the presence of a suitable organic solvent such as THF or toluene.

[0127] Alternatively, intermediate XV can be prepared by the reaction of, for example, an alkenylboronic acid or vinyltrifluoroborate with PdCl 2 in a suitable solvent such as dioxane or iPrOH under an inorganic base such as TEA or cesium carbonate at elevated temperature (ca. 100°C). 2( dppf)。 Intermediate XVII can be prepared by following the Suzuki protocol starting from intermediate XVIII using a suitable palladium catalyst system such as, but not limited to, Pd / C in a suitable solvent such as EtOH under a hydrogen atmosphere at room temperature for several hours to give intermediate XV.

[0128] In another approach, intermediate XV can be obtained from intermediate XVI by Pd-catalyzed cyanation reaction of aryl halides using, for example, zinc cyanide at elevated temperature (ca. 100 °C), in a suitable solvent such as DMF or DMA, and a suitable Pd catalyst such as Pd(PPh3)4 or XantPhos-PdCl2.

[0129] Catalytic hydrogenation of intermediate XV to give intermediate XIV can be carried out using, for example, Raney nickel or platinum dioxide and ammonia or KOH under a hydrogen atmosphere in a suitable solvent such as MeOH or iPrOH at room temperature.

[0130] Intermediate XIV, when Z is absent, can be converted to intermediate XIII by a Buchwald-Hartwig cross-coupling reaction using a halide or triflate R2-X (when R2 = heteroaryl) with a suitable palladium catalyst system in the presence of an inorganic base such as K2PO4 or cesium carbonate in a suitable organic solvent such as dioxane or toluene at elevated temperature (ca. 100 °C) for a period ranging from several hours to overnight. When Z = CO, the amide coupling can be carried out using an activating agent such as COMU or HATU and an organic base such as DIPEA or TEA in a suitable organic solvent such as DCM or DMF at a temperature around RT for a period ranging from several hours to overnight.

[0131] Ester hydrolysis of intermediate XIII can lead to intermediate XII using an inorganic base such as LiOH or Ba(OH) in a mixture of water and an organic solvent such as THF and / or methanol, typically at RT, for times ranging from 1 hour to overnight. Intermediate XII can be converted to intermediate VII by an amide coupling reaction using an activating agent such as BTFFH or T3P and an organic base such as DIPEA or TEA in a suitable organic solvent such as DCM or DMF, typically at a temperature around RT, for times ranging from several hours to overnight.

[0132] Direct ester amidation (ammonolysis) can be carried out between intermediate XIII and intermediate IXa using, for example, potassium tert-butoxide or sodium methoxide as a promoter in a suitable organic solvent such as THF or dioxane at room temperature for several hours to give intermediate VII.

[0133] Intermediate VII, when R5 = H, requires no further reaction to be converted to a compound of formula (I).

[0134] Intermediate VII, when R5 is different from H and Z is CO, may be converted to compounds of formula (I) by alkylation on the amide nitrogen using, for example, an alkyl halide or alkyl triflate R5-X and a suitable base such as KOH or NaH in a suitable solvent such as DMSO or DMF.

[0135] In another approach, compounds of formula (I) can be prepared according to Scheme 3 set forth below, which provides at least one non-limiting synthetic route for the preparation of all examples.

[0136] [ka]

[0137] According to Scheme 3, intermediate VIII can be converted to intermediate VII via reductive amination with a heteroaryl aldehyde R2-CHO in a manner similar to that described for the preparation of intermediate VII from intermediate V.

[0138] Intermediate VII (when Z is absent) can be obtained by Buchwald-Hartwig amination starting from intermediate VIII in a similar manner as described above for the preparation of intermediate XIII.

[0139] Alternatively, intermediate VII can be prepared by reacting intermediate VIII and a fluoroaryl R2-X, which undergoes ipso substitution using, for example, LiOH as a base, in a suitable high boiling solvent such as DMF at temperatures ranging from room temperature to 100°C.

[0140] Catalytic hydrogenation of the cyano group on intermediate XI, carried out in a manner similar to that described above for the preparation of intermediate XIV, can provide intermediate VIII, which, when L=NH and L2 are absent, can be obtained by amide coupling using intermediate X and carboxylic acid Xa, carried out in a manner similar to that described above for the preparation of intermediate XIII.

[0141] Intermediate XI, when L2 = NH, can be prepared in a two-step process involving p-nitrocarbamate formation using p-nitrochloroformate and a suitable base such as pyridine or TEA in a suitable solvent such as DCM at room temperature, followed by urea formation using amine IXa, a suitable solvent such as DCM or DMF and a base such as DIPEA or TEA at room temperature.

[0142] In another approach, intermediate XI, when L2 = CO, can be obtained directly from intermediate XIX via amide coupling with intermediate IXa in a manner similar to that described above for the preparation of intermediate XIII.

[0143] In a further alternative approach, intermediate XI can be prepared from intermediate IV via Pd-catalyzed cyanation in a manner similar to that described above for the preparation of intermediate XV.

[0144] Intermediate VII, when R5 = H, requires no further reaction to be converted to a compound of formula (I).

[0145] Intermediate VII, when R5 is different from H and Z is CO, can be converted to compounds of formula (I) by alkylation on the amide nitrogen using, for example, an alkyl halide or alkyl triflate R5-X and a suitable base such as KOH or NaH in a suitable solvent such as DMSO or DMF.

[0146] Alternatively, intermediate VII can be converted to compounds of formula (I) via reductive amination with an alkyl aldehyde R5-CHO, carried out in a similar manner as described for the preparation of intermediate VII from intermediate V, when R5 is different from H and Z is absent or is CH2.

[0147] As noted above, the compounds of formula (I) of the present invention can be conveniently prepared by using common intermediates represented by compounds of formulas VII and VIII.

[0148] In a further aspect, the present invention provides a compound of formula VIII: [ka] wherein R, R, R, and R are as defined above. The present invention relates to the compound

[0149] In a further aspect, the present invention provides a compound of formula VII: [ka] wherein Z is absent or is CH or —C(O), and R, R, R, R, and R are as defined above. The present invention relates to the compound

[0150] In a further aspect, the present invention relates to the use of compound VII as an intermediate for the preparation of compounds of formula (I), wherein Z is absent, CH or —C(O), and R, R, R, R and R are as defined above.

[0151] In a further aspect, the present invention relates to compound VIII as an intermediate for the preparation of compounds of formula (I).

[0152] The compounds of formula (I) of the present invention have surprisingly been found to effectively inhibit both the receptors DDR1 and DDR2. Advantageously, the inhibition of the receptors DDR1 and DDR2 can result in the effective treatment of diseases or conditions in which the DDR receptors are involved.

[0153] In particular in this regard, the compounds of formula (I) of the present invention exhibit antagonist potency, expressed as inhibition constant (Ki), on DDR1 and DDR2, with Ki values ​​lower than 1000 nM, and for most of the compounds of the present invention, the Ki is now found to be even lower than 300 nM as shown in the experimental section. Preferably, the compounds of the present invention have a Ki on DDR1 and DDR2 lower than or equal to 30 nM.

[0154] Furthermore, among the compounds of formula (I) of the present invention, IC 50 It has been found that some of the compounds have inhibitory potencies against DDR1 and DDR2, as indicated by the formula (I), of less than 15 nM, and more preferably less than 10 nM.

[0155] In one aspect, the present invention relates to a compound of formula (I) for use as a medicament.

[0156] In a preferred embodiment, the present invention relates to compounds of formula (I) for use in the treatment of disorders associated with DDR receptor mechanisms.

[0157] In a further embodiment, the present invention relates to a compound of formula (I) for use in the treatment of a disease, disorder or condition associated with a DDR receptor.

[0158] In one embodiment, the present invention relates to compounds of formula (I) useful for the prevention and / or treatment of fibrosis and / or diseases, disorders, or conditions involving fibrosis.

[0159] As used herein, the term "fibrosis" or "fibrotic disorder" refers to a condition involving abnormal accumulation of cells and / or fibronectin and / or collagen and / or increased recruitment of fibroblasts, 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.

[0160] Preferably, the compound of formula (I) of the present invention is 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. More preferably, the compound of formula (I) of the present invention is useful for the treatment of IPF.

[0161] 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).

[0162] In a further aspect, the present invention relates to the use of compounds of formula (I) according to the invention for the treatment of disorders associated with DDR receptor mechanisms.

[0163] In one aspect, the present invention relates to the use of a compound of formula (I) in the preparation of a medicament for the treatment of a disorder associated with a DDR receptor mechanism.

[0164] In a further aspect, the present invention relates to a method for the prevention and / or treatment of 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).

[0165] In a further aspect, the present invention relates to the use of compounds of formula (I) for the treatment of diseases, disorders or conditions associated with dysregulation of DDR receptors 1 and 2.

[0166] As used herein, a "safe and effective amount" with respect to a compound of formula (I) or a pharmaceutically acceptable salt thereof or other pharmaceutically active agent means an amount of the compound that is sufficient to treat the patient's condition, yet low enough to avoid significant side effects, which can nevertheless be routinely determined by one of ordinary skill in the art.

[0167] The compound of formula (I) may be administered once or according to a dosing regimen in which multiple doses are administered at varying time intervals over a predetermined period of time. The typical daily dose may vary depending on the selected route of administration.

[0168] The present invention also relates to pharmaceutical compositions comprising a compound of formula (I) admixed with at least one or more pharmaceutically acceptable carriers or excipients.

[0169] In one embodiment, the present invention relates to pharmaceutical compositions of compounds of formula (I) in admixture with one or more pharmaceutically acceptable carriers or excipients, e.g., as described in Remington's Pharmaceutical Sciences Handbook, XVII Ed., Mack Pub., NY, USA.

[0170] Administration of the compounds of the present invention, and pharmaceutical compositions thereof, can be accomplished, for example, orally, nasally, parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally and by infusion) and by inhalation, as needed by the patient.

[0171] Preferably, the compounds of the present invention are administered orally or by inhalation.

[0172] In a preferred embodiment, the pharmaceutical composition comprising a compound of Formula (I) is a solid oral dosage form such as a tablet, gelcap, capsule, caplet, granule, lozenge, bulk powder, or the like.

[0173] In one embodiment, the pharmaceutical composition comprising a compound of Formula (I) is a tablet.

[0174] The compounds of the present invention can be administered alone or in combination with various pharmaceutically acceptable carriers, diluents (sucrose, mannitol, lactose, starch, etc.), and known excipients including suspending agents, solubilizing agents, buffers, binders, disintegrating agents, preservatives, coloring agents, flavoring agents, and lubricants.

[0175] In further embodiments, pharmaceutical compositions comprising compounds of formula (I) are liquid oral dosage forms such as aqueous and non-aqueous solutions, emulsions, suspensions, syrups, and elixirs. Such liquid dosage forms may also contain suitable known inert diluents such as water, and suitable known excipients such as preservatives, wetting agents, sweeteners, flavoring agents, and agents for emulsifying and / or suspending the compounds of the present invention.

[0176] 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.

[0177] For administration as a dry powder, single or multi-dose inhalers known from the prior art can be used, in which case the powder may be filled into gelatin, plastic or other capsules, cartridges or blister packs, or into a reservoir.

[0178] Diluents or carriers which are chemically inert to the compounds of the invention, such as lactose or other additives suitable for improving the respirable fraction, may be added to the powdered compounds of the invention.

[0179] Inhalation aerosols containing a propellant gas such as a hydrofluoroalkane can contain the compounds of the invention in solution or dispersed form. Propellant-driven formulations can also contain other ingredients such as cosolvents, stabilizers, and optionally other excipients.

[0180] Propellant-free inhalable formulations comprising the compounds of the invention may be in the form of solutions or suspensions in aqueous, alcoholic or hydroalcoholic media, and they may be delivered by jet or ultrasonic nebulizers known from the prior art, or by soft mist nebulizers.

[0181] The compounds of the invention can be administered as the sole active substance or in combination with other pharmaceutically active ingredients.

[0182] The dosage of the compounds of the present invention will depend on a variety of factors, including the particular disease being treated, the severity of the condition, the route of administration, and the like.

[0183] The present invention also relates to a device in the form of a single or multi-dose dry powder inhaler or a metered dose inhaler, which contains a pharmaceutical composition comprising a compound of formula (I) according to the invention.

[0184] All preferred groups or embodiments mentioned above for compounds of formula (I) may be combined with one another and are equally applicable mutatis mutandis.

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

[0186] Preparation of Intermediates and Examples Chemical names of compounds were generated with Structure To Name Place IUPAC Name in PerkinElmer ChemDraw Professional 18.1.

[0187] The compounds of the present invention can be prepared from readily available starting materials using the following general methods and procedures, or using other information readily available to those of ordinary skill in the art. While specific embodiments of the present invention may be shown or described herein, those of ordinary skill in the art will recognize that all embodiments or aspects of the present invention can be prepared using the methods described herein or other methods, reagents, and starting materials known to those of ordinary skill in the art. It will also be understood that where typical or preferred process conditions (i.e., reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise specified. Optimum reaction conditions may vary depending on the particular reactants or solvents used, but such conditions can be readily determined by one of ordinary skill in the art through route optimization procedures.

[0188] Abbreviation EtN = triethylamine; TEA = triethylamine; HATU = (dimethylamino)-N,N-dimethyl(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methaniminium hexafluorophosphate; DAST = diethylaminosulfur trifluoride; DMAP = 4-dimethylaminopyridine; DMF = dimethylformamide; MeS, or (CH)S = methyl sulfide; MnO = manganese(IV) oxide; EtOAc = ethyl acetate; RT = room temperature; THF = tetrahydrofuran; DCM = dichloromethane; MeOH = methyl alcohol; LCMS = liquid chromatography / mass spectrometry; HPLC = high-pressure liquid chromatography; TLC = thin-layer chromatography; d-DMSO = deuterated dimethyl sulfoxide. CDCl3 = deuterated chloroform; NMR = nuclear magnetic resonance; DIPEA = N,N-diisopropylethylamine; UPLC = ultra-performance liquid chromatography; tBu XPhos = 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl; Pd2(dba)3 = tris(dibenzylideneacetone)dipalladium(0); iPrOH = isopropanol; PdCl 2(dppf) = [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); atm = atmosphere; RuPhos = 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl; Pd(dba)2 = bis(dibenzylideneacetone)palladium(0); BINAP = (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene; STAB = sodium triacetoxyborohydride; CPhos = 2-dicyclohexylphosphino-2',6'-bis(N,N-dimethylamino)biphenyl; Pd(OAc)2 = palladium(II) acetate; AcOH = acetic acid; Py = pyridine; T3P = propanephosphonic anhydride; prepHPLC = preparative high-pressure liquid chromatography; NaBH4 = sodium borohydride; Na2SO4 = sodium sulfate; BTFFH = fluoro-dipyrrolidinocarbenium hexafluorophosphate; pTLC = preparative thin-layer chromatography; FCC = flash column chromatography; amu = atomic mass unit; t R = retention time; FA = formic acid

[0189] General experiment content NMR characterization 1 H NMR spectra were recorded on a Bruker Avance III HD 400 MHz or a Bruker Fourier 300 MHz. Chemical shifts are reported as δ values ​​in ppm relative to tetramethylsilane (TMS) as the internal standard. Coupling constants (J values) are given in Hertz (Hz), and multiplicities are reported using the following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, and nd = undetermined.

[0190] LC / UV / MS analysis method LC / MS retention times are estimated to be subject to experimental error of ±0.5 min.

[0191] Method 1 (LCMS-019-20-80-95-6-1-25-UV-BCM) Instrument: Dionex UHPLC Ultimate 3000 (with DAD detector) / Thermo Scientific MSQ Plus Column: Kinetex® 2.6 μm XB-C18 (4.6 x 50 mm), 110A, column number 00B-4496-E0, internal column number 019 reagent: Formic acid ≥98%, Sigma-Aldrich HPLC UV / Gradient Grade Acetonitrile, Baker μQ-water for LCMS HPLC conditions: Wavelength range: (190~340)nm±4nm Flow rate: 1.0ml / min Column temperature: 25℃ Autosampler temperature: 20℃ Injection volume: 2.0μl Analysis time: 6 minutes Elution: Gradient

[0192] [Table 3]

[0193] Mobile phase A: 0.1% v / v formic acid in water Mobile phase B: 0.1% v / v formic acid in acetonitrile Syringe cleaning solution: 20% MeOH MS conditions: Mass range: 100 to 1000 m / z Ionization: Alternating Scanning speed: 12000 amu / sec

[0194] Method 2 (LCMS-019-10-60-95-6-1-25-UV) Instrument: Dionex UHPLC Ultimate 3000 (with DAD detector) / Thermo Scientific MSQ Plus Column: Kinetex® 2.6 μm XB-C18 (4.6 x 50 mm), 110A, column number 00B-4496-E0, internal column number 019 reagent: Formic acid ≥98%, Sigma-Aldrich HPLC UV / Gradient Grade Acetonitrile, Baker μQ-water for LCMS HPLC conditions: Wavelength range: (190~340)nm±4nm Flow rate: 1.0ml / min Column temperature: 25℃ Autosampler temperature: 20℃ Injection volume: 2.0μl Analysis time: 6 minutes Elution: Gradient

[0195] [Table 4]

[0196] Mobile phase A: 0.1% v / v formic acid in water Mobile phase B: 0.1% v / v formic acid in acetonitrile Syringe cleaning solution: 20% MeOH MS conditions: Mass range: 100 to 1000 m / z Ionization: Alternating Scanning speed: 12000 amu / sec

[0197] Method 3 (LCMS-019-5-80-80-7-1-25-UV-Rot) Instrument: Dionex UHPLC Ultimate 3000 (with DAD detector) / Thermo Scientific MSQ Plus Column: Kinetex® 2.6 μm XB-C18 (4.6 x 50 mm), 110A, column number OOB-4496-E0, internal column number 019 reagent: Formic acid ≥98%, Sigma-Aldrich HPLC UV / Gradient Grade Acetonitrile, Baker μQ-water for LCMS HPLC conditions: Wavelength range: (190~340)nm±4nm Flow rate: 1.0ml / min Column temperature: 25℃ Autosampler temperature: 20℃ Analysis time: 7 minutes Elution: Gradient

[0198] [Table 5]

[0199] Mobile phase A: 0.1% v / v formic acid in water Mobile phase B: 0.1% v / v formic acid in acetonitrile Syringe cleaning solution: 20% MeOH MS conditions: Mass range: 100 to 1000 m / z Ionization: Alternating Scanning speed: 12000 amu / sec

[0200] Method 4 (LCMS-019-10-70-95-6-1-25-UV) Instrument: Dionex UHPLC Ultimate 3000 (with DAD detector) / Thermo Scientific MSQ Plus Column: Kinetex® 2.6 μm XB-C18 (4.6 x 50 mm), 110A, column number 00B-4496-E0, internal column number 019 reagent: Formic acid ≥98%, Sigma-Aldrich HPLC UV / Gradient Grade Acetonitrile, Baker μQ-water for LCMS HPLC conditions: Wavelength range: (190~340)nm±4nm Flow rate 1.0ml / min Column temperature: 25℃ Autosampler temperature: 20℃ Injection volume: 2.0μl Analysis time: 6 minutes Elution: Gradient

[0201] [Table 6]

[0202] Mobile phase A: 0.1% v / v formic acid in water Mobile phase B: 0.1% v / v formic acid in acetonitrile Syringe cleaning solution: 20% MeOH MS conditions: Mass range: 100 to 1000 m / z Ionization: Alternating Scanning speed: 12000 amu / sec

[0203] Method 5 (LCMS-005-1-30-50-10-05-55-UV) Instrument: Dionex UHPLC Ultimate 3000 (with DAD detector) / Thermo Scientific MSQ Plus Column: ACQUITY UPLC BEH C8 1.7 μm (2.1 x 150 mm), 130A, column number 186003377, internal column number 005 reagent: Formic acid ≥98%, Sigma-Aldrich HPLC UV / Gradient Grade Acetonitrile, Baker μQ-water for LCMS HPLC conditions: Wavelength range: (190~340)nm±4nm Flow rate: 0.5ml / min Column temperature: 55℃ Autosampler temperature: 20℃ Analysis time: 10 minutes Elution: Gradient

[0204] [Table 7]

[0205] Mobile phase A: 0.1% v / v formic acid in water Mobile phase B: 0.1% v / v formic acid in acetonitrile Syringe cleaning solution: 20% MeOH MS conditions: Mass range: 100-1000m / Ionization: Alternating Scanning speed: 12 000 amu / sec

[0206] Method 6: (LCMS-019-30-80-95-6-1-25-UV) Instrument: Dionex UHPLC Ultimate 3000 (with DAD detector) / Thermo Scientific MSQ Plus Column: Kinetex® 2.6 μm XB-C18 (4.6 × 50 mm), 110A, column number 00B-4496-E0, internal column number 019 reagent: Formic acid ≥98%, Sigma-Aldrich HPLC UV / Gradient Grade Acetonitrile, Baker μQ-water for LCMS HPLC conditions: Wavelength range: (190~340)nm±4nm Flow rate: 1.0ml / min Column temperature: 25℃ Autosampler temperature: 20℃ Analysis time: 6 minutes Elution: Gradient

[0207] [Table 8]

[0208] Mobile phase A: 0.1% v / v formic acid in water Mobile phase B: 0.1% v / v formic acid in acetonitrile Syringe cleaning solution: 20% MeOH MS conditions: Mass range: 100 to 1000 m / z Ionization: Alternating Scanning speed: 12000 amu / sec

[0209] Where the preparation of starting materials is not described, these are commercially available, known in the literature, or readily available to those skilled in the art using standard procedures. All solvents were purchased commercially and used without further purification.

[0210] Thin layer chromatography was performed on Merck silica gel 60 F254 TLC plates.

[0211] Preparative thin-layer chromatography (pTLC) was performed on Uniplate 1000 micron or 500 micron silica gel plates. Flash chromatography was performed on Interchim PuriFlash 450 and 520Plus systems using prepacked silica gel cartridges.

[0212] As will be understood by those skilled in the art, when reference is made to the use of "similar" or "analogous" procedures, such procedures may involve slight variations, for example, in reaction temperatures, amounts of reagents / solvents, reaction times, work-up conditions or chromatographic purification conditions, etc. Unless otherwise noted, all final compounds were obtained as the free base.

[0213] General Method A for Amide Coupling Carboxylic acid or carboxylate (1.0 eq), amine (1.0 eq), and DIPEA (6.0 eq) were dissolved in anhydrous DCM under argon. T3P (50% in EtOAc, 1.5 eq.) was then added, and the reaction was stirred at RT overnight. The reaction mixture was partitioned between DCM and water. The aqueous phase was extracted with DCM (3x), and the combined organic phases were concentrated to give the crude product, which was purified as indicated.

[0214] General Method B for Amide Coupling The carboxylic acid or carboxylate salt (1.0 eq) was dissolved in anhydrous DMF under argon, followed by the addition of BTFFH (3.0 eq) and DIPEA (4.5 eq). The amine (1.5 eq) was then added, and the reaction was stirred at 80 °C overnight. The reaction mixture was then concentrated to dryness under reduced pressure, and the residue was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (3x), and the organic phases were combined, washed with brine, and concentrated to give the crude product, which was purified as indicated.

[0215] General Method C for Amide Coupling: The carboxylate (1.0 eq) and amine (1.0 eq.) were dissolved in a mixture of DMF:DCM (1:3), then DIPEA (8.0 eq.) and HATU (2.0 eq.) were added. The reaction was stirred at RT overnight, and then the reaction mixture was partitioned between DCM and saturated NaHCO. The aqueous phase was extracted with DCM (3x), and the organic layers were combined, dried over NaSO, and concentrated under reduced pressure to give the crude product, which was purified as indicated.

[0216] Scheme for the preparation of the intermediate lithio 3-[(4-methylpiperazin-1-yl)methyl]-5-(trifluoromethyl)benzoate

[0217] [ka]

[0218] Step 1: Preparation of methyl 3-bromo-5-(trifluoromethyl)benzoate [ka]

[0219] To a solution of 3-bromo-5-(trifluoromethyl)benzoic acid (75.0 g, 279 mmol) in MeOH (282 mL) was added SOCl (81.0 mL, 1115 mmol) dropwise at 0 °C. The reaction mixture was then stirred under reflux overnight, whereupon the volatiles were removed under reduced pressure. Water (200 mL) was added to the residue, and the aqueous phase was extracted with EtOAc (2 x 250 mL). The organic phases were combined, washed with a saturated solution of NaHCO (2 x 200 mL), dried over NaSO, and concentrated under reduced pressure to give the product (74.5 g, 94%) as a beige solid. 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).

[0220] Step 2: Preparation of methyl 3-[(4-methylpiperazin-1-yl)methyl]-5-(trifluoromethyl)benzoate [ka]

[0221] 3-Bromo-5-(trifluoromethyl)benzoate (47.5 g, 168 mmol), CsCO (164 g, 503 mmol), and potassium 1-methyl-4-trifluoroborate methylpiperazine (40.6 g, 184.6 mmol) were suspended in a mixture of THF (100 mL) and water (11 mL). The suspension was degassed, and then Pd(OAc) (3.76 g, 16.8 mmol) and XPhos (16.0 g, 33.5 mmol) were added. The reaction was carried out at 80 °C for 24 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 × 150 mL). The organic phases were combined, concentrated, and dried under reduced pressure to give the crude product, which was purified by column chromatography (DCM:MeOH, 9:1) to give the title compound as a brown oil (25.3 g, 48%). 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).

[0222] Step 3: Preparation of lithio 3-[(4-methylpiperazin-1-yl)methyl]-5-(trifluoromethyl)benzoate [ka]

[0223] Methyl 3-[(4-methylpiperazin-1-yl)methyl]-5-(trifluoromethyl)benzoate (25.3 g, 80.0 mmol) was dissolved in MeOH (700 mL). 1 M LiOH solution (3.8 g, 160 mL) was added to the reaction mixture and stirred at RT overnight. The solvent was removed under reduced pressure, and the crude material was triturated with diethyl ether (2x) and filtered. The solid was collected to give the title product as a solid (26.0 g, 100%). 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).

[0224] Scheme for the preparation of intermediate 5-(1-methyl-1H-pyrazol-3-yl)pyridin-3-amine [ka]

[0225] Step 1: Preparation of 5-(1-methyl-1H-pyrazol-3-yl)pyridin-3-amine 5-Bromopyridin-3-amine (0.5 g, 2.89 mmol), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.782 g, 3.76 mmol), and CsCO (2.82 g, 8.67 mmol) were suspended in dioxane (11.42 mL) and water (1.142 mL). The mixture was purged with Ar for 15 minutes, and then Pd(dppf)Cl (0.211 g, 0.289 mmol) was added. The reaction mixture was stirred at 90 °C for 3 hours, then cooled to RT and concentrated. The crude material was purified via FCC (eluent: 100% to 10% MeOH in DCM). The compound was triturated with EtO to give the desired product (468 mg, 93%). 1 H NMR (300 MHz, DMSO-d6) δ 8.20 - 8.10 (m, 1H), 7.84 (d, J = 2.6 Hz, 1H), 7.73 (d, J = 2.2 Hz, 1H), 7.31 (dd, J = 2.6, 1.8 Hz, 1H), 6.62 (d, J = 2.3 Hz, 1H), 5.33 (s, 2H), 3.87 (s, 3H).

[0226] 4-Methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((pyrazolo[1,5-a]pyrimidin-6-ylamino)methyl)benzamide

[0227] [ka]

[0228] Step 1: 3-iodo-4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]benzamide [ka]

[0229] A solution of 3-iodo-4-methylbenzoic acid (7.00 g, 26.7 mmol) in SOCl2 (47 mL) was refluxed for 2 h and then evaporated under reduced pressure to remove residual SOCl2. The residue was dissolved in anhydrous THF (25 mL), and a solution of DIPEA (4.14 g, 32.0 mmol), 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (6.44 g, 26.7 mmol), and DMAP (130 mg, 1.06 mmol) in anhydrous THF (48 mL) was added dropwise. The reaction mixture was stirred at RT for 17 h and evaporated under reduced pressure. The residue was dissolved in EtOAc (200 mL). Water (180 mL) was added, and the pH was adjusted to 8 with 1 M NaOH. The phases were separated and the aqueous phase was extracted with dilute DCM / MeOH 100:5 (100 mL x 5). The organic extracts were combined and evaporated under reduced pressure to give the final product as an off-white solid (13.05 g, 100%). 1 H NMR (300 MHz, DMSO-d6) δ 10.67 (s, 1H), 8.46 (d, J = 1.9 Hz, 1H), 8.27 (t, J = 1.9 Hz, 1H), 8.21 (d, J = 1.4 Hz, 1H), 8.13 (d, J = 1.8 Hz, 1H), 7.94 (dd, J = 7.9, 1.9 Hz, 1H), 7.74 (d, J = 1.8 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 1.6 Hz, 1H), 2.46 (s, 3H), 2.18 (d, J = 1.0 Hz, 3H).

[0230] Step 2: 3-Formyl-4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]benzamide [ka]

[0231] PPh (1.62 g, 6.2 mmol), I (1.57 g, 6.2 mmol), and toluene (20 mL) were added to a 100 mL sealed tube equipped with a stir bar and stirred at RT for 10 minutes. Next, 3-iodo-4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]benzamide (2.50 g, 5.15 mmol), Pd(OAc) (34.7 mg, 3 mol%), and EtN (3.13 g, 30.9 mmol) were added to the solution. Next, HCOOH (0.95 g, 20.6 mmol) was added, the tube was immediately sealed, and the mixture was stirred at 80 °C for 4 hours. The reaction mixture was cooled to RT, diluted with EtOAc (150 mL), and washed with 0.01 M NaOH. The aqueous phase was extracted with EtOAc (150 mL × 2), and the combined extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (DCM / MeOH 100:1 to 100:4) to give the product as a yellow solid (1.055 g, 53%). 1 H NMR (300 MHz, DMSO-d6) δ 10.83 (s, 1H), 10.35 (s, 1H), 8.48 (d, J = 2.1 Hz, 1H), 8.30 (d, J = 2.0 Hz, 1H), 8.22 (d, J = 1.4 Hz, 1H), 8.18 (dd, J = 8.0, 1.8 Hz, 1H), 8.16 - 8.14 (m, 1H), 7.75 (s, 1H), 7.59 (s, 1H), 7.50 (t, J = 1.3 Hz, 1H), 2.73 (s, 3H), 2.18 (d, J = 1.0 Hz, 3H).

[0232] Step 3: Preparation of 4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((pyrazolo[1,5-a]pyrimidin-6-ylamino)methyl)benzamide [ka]

[0233] 3-Formyl-4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5(trifluoromethyl)phenyl]benzamide (190 mg, 0.49 mmol) and pyrazolo[1,5-a]pyrimidin-6-amine (65.8 mg, 0.49 mmol) were dissolved in glacial AcOH (2.0 mL). The brown solution was stirred at RT for 3 h. STAB (208 mg, 0.98 mmol) was then added, and the reaction mixture was stirred at RT overnight. The AcOH was evaporated under reduced pressure, the residue was dissolved in 1 M NaOH (25 mL), and the product was extracted with EtOAc (50 mL) and DCM:MeOH 100:5 (50 mL x 2). The extracts were combined and evaporated under reduced pressure and the solid residue was purified by column chromatography (DCM:MeOH, 100:4 to 100:8) to give the product as a yellow solid (215 mg, 86%).

[0234] [Table 9]

[0235] Example 2 3-((ethyl(pyrazolo[1,5-a]pyrimidin-6-yl)amino)methyl)-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide [ka]

[0236] 4-Methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((pyrazolo[1,5-a]pyrimidin-6-ylamino)methyl)benzamide (Example 1) (30.0 mg, 0.059 mmol) was dissolved in glacial AcOH (0.4 mL), and acetaldehyde (0.10 mL, 1.78 mmol) was added at RT. Then, STAB (25.2 mg, 0.12 mmol) was added, and the reaction mixture was stirred at RT overnight. The reaction mixture was treated with 0.1 M NaOH (10 mL), and the product was extracted with DCM (30 mL x 3). The extracts were combined, dried over Na2SO4, filtered, and evaporated under reduced pressure. The solid residue was purified by prep HPLC to give the product as a pale yellow solid (5 mg, 16%).

[0237] [Table 10]

[0238] In a manner similar to steps 1 to 3 of Example 1, the following compounds were prepared via reductive amination, applying the corresponding commercially available amine in step 3.

[0239] [Table 11-1] [Table 11-2]

[0240] Example 6 4-Methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(((4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)amino)methyl)benzamide [ka]

[0241] 4-Methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((pyrazolo[1,5-a]pyrimidin-6-ylamino)methyl)benzamide (Example 1) (30.0 mg, 0.059 mmol) was dissolved in glacial AcOH (0.4 mL), and NaBH (9 mg, 0.24 mmol) was added at RT. The reaction mixture was stirred at RT overnight. AcOH was evaporated under reduced pressure, the residue was dissolved in 0.4 M NaOH (7 mL), and the product was extracted with DCM (20 mL × 3). The extracts were combined and evaporated under reduced pressure, and the solid residue was purified by pTLC (DCM:MeOH, 100:4) to give the product as a colorless solid (16 mg, 53%).

[0242] [Table 12]

[0243] Example 7 3-(((2-cyanopyridin-4-yl)amino)methyl)-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide

[0244] [ka]

[0245] Step 1: Preparation of 3-cyano-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide [ka]

[0246] 3-Iodo-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide (7 g, 14.43 mmol), prepared as described in Step 1 of Example 1, zinc cyanide (2.028 g, 17.31 mmol), and Pd(PPh3)4 (0.834 g, 0.721 mmol) were dissolved in DMF (48.1 ml). The reaction mixture was stirred at 80 °C for 4 h. The mixture was diluted with EtOAc and washed with water. The organic solvent was then removed under reduced pressure. The crude material was purified via dry flash chromatography (hexane:EtOAc, 9:1) to give the product as a beige powder (6.7 g, quant.). 1 H NMR (300 MHz, DMSO-d6) δ 10.78 (s, 1H), 8.42 (d, J = 1.9 Hz, 1H), 8.27 (t, J = 1.9 Hz, 1H), 8.22 (d, J = 1.4 Hz, 1H), 8.19 (dd, J = 8.1, 2.0 Hz, 1H), 8.13 (d, J = 1.9 Hz, 1H), 7.77 (d, J = 2.2 Hz, 1H), 7.69 (d, J = 8.2 Hz, 1H), 7.51 (t, J = 1.3 Hz, 1H), 2.59 (s, 3H), 2.19 (d, J = 1.0 Hz, 3H).

[0247] Step 2: Preparation of 3-(aminomethyl)-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide [ka]

[0248] 3-Cyano-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide (2.2 g, 5.72 mmol) was dissolved in MeOH (45.8 ml) and ammonia (11.45 ml), then Raney nickel (2 ml, 5.72 mmol) was added. The reaction mixture was stirred under a hydrogen atmosphere (balloon) for 3 d. The reaction mixture was filtered through a pad of Celite, concentrated under reduced pressure, and dried to give the crude product (1.62 g, 67.6%), which was used in the next step without further purification. 1 H NMR (300 MHz, DMSO-d6) δ 10.59 (s, 1H), 8.31 (s, 1H), 8.19 (d, J = 14.4 Hz, 2H), 8.03 (s, 1H), 7.78 (d, J = 7.4 Hz, 1H), 7.72 (s, 1H), 7.50 (s, 1H), 7.33 (d, J = 7.9 Hz, 1H), 3.80 (s, 2H), 2.36 (s, 3H), 2.18 (s, 3H).

[0249] Step 3: Preparation of 3-(((2-cyanopyridin-4-yl)amino)methyl)-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide [ka]

[0250] 3-(Aminomethyl)-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide (0.1 g, 0.257 mmol) and 4-fluoropicolinonitrile (0.038 g, 0.309 mmol) were dissolved in DMF (0.52 ml). LiOH (0.013 g, 0.548 mmol) was then added, and the reaction mixture was stirred at rt overnight. The reaction mixture was diluted with water and extracted with AcOEt (x3). The organic phases were combined, dried over Na2SO4, filtered, and concentrated. The crude material was purified via FCC (100% DCM to 10% MeOH in DCM) to give the desired product as a white solid (67 mg, 53%).

[0251] [Table 13]

[0252] Example 8 was prepared according to the protocol above using the appropriate fluoroarylamine.

[0253] [Table 14]

[0254] Example 9 N-(4-methyl-3-((pyrimidin-5-ylamino)methyl)phenyl)-3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamide

[0255] [ka]

[0256] Step 1: Preparation of N-(3-cyano-4-methylphenyl)-3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamide [ka]

[0257] 5-Amino-2-methylbenzonitrile (0.500 g, 3.78 mmol) and lithium 3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzoate (1.166 g, 3.78 mmol) were dissolved in DCM (38 mL), followed by the addition of DIPEA (3.96 mL, 22.70 mmol) and 50% T3P in EtOAc (3.34 mL, 5.67 mmol). The reaction mixture was stirred at 40 °C for 24 h, after which it was diluted with DCM and washed with water (3 × 50 mL). The aqueous phase was then extracted with DCM (3 × 50 mL). The organic phases were combined, washed with brine (100 mL), and concentrated under reduced pressure. The crude material was purified via column chromatography (DCM:MeOH, 100:0 to 90:10) to afford the title compound (0.342 g, 22% yield) as a reddish-white solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.67 (s, 1H), 8.26 - 8.13 (m, 3H), 7.97 - 7.87 (m, 2H), 7.49 (d, J = 8.5 Hz, 1H), 3.65 (s, 2H), 2.47 (s, 3H), 2.38 (d, J = 21.9 Hz, 8H), 2.16 (s, 3H).

[0258] Step 2: Preparation of N-(3-(aminomethyl)-4-methylphenyl)-3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamide [ka]

[0259] A solution of N-(3-cyano-4-methylphenyl)-3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamide (0.345 g, 0.828 mmol) in MeOH (8.28 mL) was charged with Raney nickel (1.6 mL, 0.828 mmol) and stirred at RT for 16 h under a hydrogen atmosphere (balloon). The reaction mixture was filtered through a pad of Celite, concentrated, and dried under reduced pressure to give the crude product (334 mg, 96% yield) as a yellow solid, which was used in the next step without further purification. 1 H NMR (300 MHz, DMSO-d6) δ 10.41 (d, J = 10.1 Hz, 1H), 8.19 (d, J = 9.4 Hz, 2H), 7.84 (s, 1H), 7.70 (d, J = 2.2 Hz, 1H), 7.59 (dd, J = 8.1, 2.3 Hz, 1H), 7.11 (d, J = 8.3 Hz, 1H), 3.71 (s, 2H), 3.63 (s, 2H), 2.37 (m, 8H), 2.24 (s, 3H), 2.24 (m, 2H), 2.15 (s, 3H).

[0260] Step 3: Preparation of N-(4-methyl-3-((pyrimidin-5-ylamino)methyl)phenyl)-3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamide (Example 9) [ka]

[0261] N-(3-(aminomethyl)-4-methylphenyl)-3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamide (110 mg, 0.262 mmol) was suspended in toluene (2 mL) with 5-bromopyrimidine (49.9 mg, 0.314 mmol) and Cs(CO) (256 mg, 0.785 mmol). The mixture was degassed with argon, then RuPhos (24.42 mg, 0.052 mmol) and Pd(dba) (15.04 mg, 0.026 mmol) were added, and the reaction was stirred at 110 °C for 16 h. The reaction was partitioned between water and DCM, the product was extracted with DCM (x3), the organic phases were combined, washed with brine and concentrated under reduced pressure to give the crude material, which was purified by FCC (DCM:MeOH, 100:0 to 90:10) to give the title compound (18.00 mg, 14% yield) as a yellow solid.

[0262] [Table 15]

[0263] Example 10 N-methyl-4-((2-methyl-5-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamido)benzyl)amino)picolinamide [ka]

[0264] N-(3-(aminomethyl)-4-methylphenyl)-3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamide (110 mg, 0.262 mmol), prepared as described in step 1-2 of Example 9, 4-bromo-N-methylpicolinamide (67.5 mg, 0.314 mmol), and Cs(CO) (256 mg, 0.785 mmol) were suspended in toluene (2 mL). The mixture was degassed with argon, then BINAP (32.6 mg, 0.052 mmol) and Pd(dba) (15.04 mg, 0.026 mmol) were added, and the reaction was stirred at 110 °C for 16 h. The reaction was partitioned between water and DCM, and the compound was extracted with DCM (x3). The combined organic phases were washed with brine and concentrated under reduced pressure to give the crude material, which was purified by FCC (DCM:MeOH, 100:0 to 90:10) and then triturated with pentane to give the title compound (0.04 g, 28% yield) as a beige solid.

[0265] [Table 16]

[0266] Example 11 N-(4-methyl-3-(((pyrimidin-5-ylmethyl)amino)methyl)phenyl)-3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamide [ka]

[0267] N-(3-(aminomethyl)-4-methylphenyl)-3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamide (0.07 g, 0.166 mmol), prepared as described in step 1-2 of Example 9, and pyrimidine-5-carbaldehyde (0.018 g, 0.166 mmol) were mixed, and the tube was backfilled with argon (x3). THF (1.7 mL) was added to the mixture, followed by Ti(OEt) (0.070 mL, 0.333 mmol). The reaction mixture was cooled to 0 °C, and STAB (0.141 g, 0.666 mmol) was added. The reaction mixture was warmed to RT and stirred for 16 h. The reaction mixture was added to 1 M NaOH solution. The desired product was then extracted with EtOAc (3 x 10 mL), and the combined organic phases were washed with brine (1 x 10 mL) and concentrated under reduced pressure to give the crude material, which was purified by column chromatography (DCM:MeOH, 100:0 to 90:10) to afford the title compound (22.98 mg, 27% yield) as a yellow solid.

[0268] [Table 17]

[0269] The following compounds were prepared by reacting the corresponding commercially available aldehydes via reductive amination as described in Example 11.

[0270] [Table 18]

[0271] [Table 19]

[0272] Example 16 4-Isopropyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5(trifluoromethyl)phenyl)-3-((pyrazolo[1,5-a]pyrimidin-6-ylamino)methyl)benzamide

[0273] [ka]

[0274] Step 1: Preparation of methyl 3-cyano-4-(propan-2-yl)benzoate; methyl 3-cyano-4-propylbenzoate [ka]

[0275] To a mixture of methyl 4-bromo-3-cyanobenzoate (4.00 g, 16.67 mmol), CPhos (0.146 g, 0.333 mmol), and Pd(OAc) (0.037 g, 0.167 mmol) in THF (67 mL) was added 0.5 M isopropylzinc(II) bromide in THF (40 mL, 20.00 mmol) dropwise at 0 °C. The reaction was allowed to proceed at RT for 3 h, and then the reaction mixture was concentrated under reduced pressure. The residue was partitioned between EtOAc and water, and the desired compound was extracted with EtOAc (2 × 30 mL). The combined organic phases were washed with water (30 mL), then brine (30 mL), then dried over NaSO, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (hexane: EtOAc, 98:2 to 96:4) to give a mixture of isomers (ratio 1:1) as a pale yellow oil (2.76 g, 81%). 1H NMR (300 MHz, DMSO-d6) δ 8.26 (dd, J = 3.7, 1.8 Hz, 2H), 8.18 (ddd, J = 9.9, 8.2, 1.9 Hz, 2H), 7.73 (d, J = 8.3 Hz, 1H), 7.65 (d, J = 8.2 Hz, 1H), 3.88 (s, 6H), 3.30 (dd, J = 14.1, 7.2 Hz, 1H), 2.84 (dd, J = 8.4, 6.8 Hz, 2H), 1.75 - 1.60 (m, 2H), 1.30 (d, J = 6.9 Hz, 6H), 0.93 (t, J = 7.3 Hz, 3H).

[0276] Step 2: Preparation of 3-cyano-4-(propan-2-yl)benzoic acid; 3-cyano-4-propylbenzoic acid [ka]

[0277] To a mixture of methyl 3-cyano-4-propylbenzoate and methyl 3-cyano-4-isopropylbenzoate (1.75 g, 8.62 mmol, 1:1 ratio) in THF (17.5 mL) at 0 °C, a solution of 1 M LiOH (8.61 mL) was added, and the reaction was allowed to proceed at RT for 16 h. The reaction mixture was partitioned between EtOAc and water, the aqueous phase was washed with EtOAc (2 × 30 mL), and the organic phase was discarded. The aqueous phase was then acidified with 1 M HCl, and the product was extracted with EtOAc (3 × 50 mL). The organic phases were combined, dried over Na SO , and concentrated under reduced pressure to give the title isomeric mixture as a white solid (1:1 ratio, 1.25 g, 77%). 1H NMR (300 MHz, DMSO-d6) δiPr 13.40 (s, 1H, OH), 8.26 - 8.12 (m, 2H, CH), 7.70 (d, J = 8.2 Hz, 1H, CH), 3.32 - 3.21 (m, 1H, CHMe2), 1.30 (d, J = 6.9 Hz, 6H, CH3) δnPr 13.40 (s, 1H, OH), 8.26 - 8.12 (m, 2H, CH), 7.62 (d, J = 8.1 Hz, 1H, CH), 2.84 (dd, J = 8.5, 6.7 Hz, 2H, CH2), 1.77 - 1.60 (m, 2H, CH2), 0.93 (t, J = 7.3 Hz, 3H, CH3).

[0278] Step 3: Preparation of 3-cyano-N-{3-[(4-methylpiperazin-1-yl)methyl]-5-(trifluoromethyl)phenyl}-4-(propan-2-yl)benzamide; 3-cyano-N-{3-[(4-methylpiperazin-1-yl)methyl]-5-(trifluoromethyl)phenyl}-4-propylbenzamide [ka]

[0279] Under an argon atmosphere, to a solution of 3-cyano-4-propylbenzoic acid and 3-cyano-4-isopropylbenzoic acid (0.40 g, 2.12 mmol, 1:1 ratio) in DCM (4 mL) was added DMF (8.18 μL, 0.106 mmol) and oxalyl chloride (0.370 mL, 4.23 mmol), and the mixture was stirred at RT for 4 h. The solvent was then removed under reduced pressure, and the residue was dissolved in anhydrous DCM (2 mL). The resulting solution was added dropwise to a solution of 3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)aniline (0.636 g, 2.325 mmol) and triethylamine (0.589 mL, 4.23 mmol) in anhydrous DCM (2 mL) and stirred at RT for 16 h. The reaction was diluted with DCM and washed with water (25 mL), then the aqueous phase was extracted with DCM (3 x 25 mL). The organic phases were combined, washed with brine (50 mL), dried over NaSO, and concentrated under reduced pressure to give the crude material, which was purified via column chromatography (DCM:MeOH, 100:0 to 90:10) to give the isomeric mixture as a white solid (1:1 ratio, 0.672 g, 72%). 1 H NMR (300 MHz, DMSO-d6) δiPr 10.63 (s, 1H), 8.41 (m, 1H), 8.28 - 8.15 (m, 2H), 8.00 (s, 1H), 7.75 (d, J = 8.4 Hz), 7.38 (s, 1H), 3.56 (s, 2H), 3.29 (m, 1H), 2.38 (m, 8H), 2.16 (s, 3H), 1.33 (d, J = 6.9 Hz, 6H). δnPr 10.63 (s, 1H), 8.41 (m, 1H), 8.28 - 8.15 (m, 2H), 8.00 (s, 1H), 7.68 (d, J = 8.1 Hz, 1H), 7.38 (s, 1H), 3.56 (s, 2H), 2.86 (t, J = 7.6 Hz, 2H), 2.38 (m, 8H), 2.16 (s, 3H), 1.69 (p, J = 7.4 Hz, 2H), 0.95 (t, J = 7.3 Hz, 3H).

[0280] Step 4: Preparation of 3-(aminomethyl)-N-{3-[(4-methylpiperazin-1-yl)methyl]-5-(trifluoromethyl)phenyl}-4-(propan-2-yl)benzamide; 3-(aminomethyl)-N-{3-[(4-methylpiperazin-1-yl)methyl]-5-(trifluoromethyl)phenyl}-4-propylbenzamide [ka]

[0281] A solution of 3-cyano-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4-propylbenzamide and 3-cyano-4-isopropyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)benzamide (0.672 g, 1.51 mmol, 1:1 ratio) in MeOH (30 mL) was charged with Raney nickel (3 mL, 3.02 mmol) and stirred under a hydrogen atmosphere (balloon) at RT for 3 d. The reaction mixture was filtered through a pad of Celite and concentrated to dryness under reduced pressure to afford the isomeric mixture as a greenish-yellow solid (iPr:nPr ratio 3:1, 0.589 g, 87%), which was used in the next step without further purification. 1H NMR (300 MHz, Methanol-d4) δiPr 8.10 (s, 1H), 7.95 (d, J = 2.2 Hz, 2H), 7.85 (dd, J = 8.1, 2.1 Hz, 1H), 7.50 (d, J = 8.2 Hz, 1H), 7.45 (s, CH iPr masked by solvent peak. δnPr 8.10 (s, 1H), 7.95 (d, J = 2.2 Hz, 1H), 7.80 (dd, J = 8.1, 2.1 Hz, 1H), 7.45 (s, 1H), 7.37 (d, J = 8.0 Hz, 2H), 4.05 - 3.93 (m, 2H), 3.63 (d, J = 9.8 Hz, 2H), 2.83 - 2.68 (m, 2H), 2.55 (m, 8H) 2.30 (s, 3H), 1.69 (m, 2H), 1.04 (t, J = 7.3 Hz, 3H).

[0282] Step 5: Preparation of 4-isopropyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-3-((pyrazolo[1,5-a]pyrimidin-6-ylamino)methyl)benzamide (Example 16) and N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4-propyl-3-((pyrazolo[1,5-a]pyrimidin-6-ylamino)methyl)benzamide (Example 17). [ka]

[0283] A mixture of 3-(aminomethyl)-4-isopropyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)benzamide and 3-(aminomethyl)-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4-propylbenzamide (200 mg, 0.446 mmol, iPr:nPr ratio 3:1) was dissolved in anhydrous toluene (5 mL). 6-Bromopyrazolo[1,5-a]pyrimidine (161 mg, 0.813 mmol) and sodium t-butoxide (65.1 mg, 0.678 mmol) were added, followed by Pd(dba) (62.1 mg, 0.068 mmol) and tBuXPhos (57.6 mg, 0.136 mmol). The reaction was stirred at 80° C. for 17 hr, then the reaction mixture was filtered through Celite, the filtrate was then washed with water and the organic phase was concentrated. The crude material was purified via FCC (DCM:MeOH 1:0 to 0:1) followed by prep HPLC (ACN, HO+0.1% NH) to afford 4-isopropyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-3-((pyrazolo[1,5-a]pyrimidin-6-ylamino)methyl)benzamide (Example 16) (0.029 g, 15%) and N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4-propyl-3-((pyrazolo[1,5-a]pyrimidin-6-ylamino)methyl)benzamide (Example 17) (0.009 g, 14%) as a white solid.

[0284] [Table 20]

[0285] Example 18 4-Methyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5(trifluoromethyl)phenyl)-3-((pyrazolo[1,5-a]pyrimidin-6ylamino)methyl)benzamide

[0286] [ka]

[0287] Step 1: Preparation of methyl 3-cyano-4-methylbenzoate [ka]

[0288] In a three-neck flask, methyl 3-bromo-4-methylbenzoate (10.0 g, 48.7 mmol) and zinc cyanide (6.9 g, 58.5 mmol) were dissolved in anhydrous DMF (150 mL). The solution was degassed under argon. Pd(PPh3)4 (2.8 g, 2.4 mmol) was added, and the reaction was stirred at 100 °C overnight. After this time, the reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. The crude material was purified via FCC (hexane:EtOAc, 98:2 to 95:5) to give the title compound as a white solid (7.47 g, 86%).

[0289] Step 2: Preparation of methyl 3-(aminomethyl)-4-methylbenzoate [ka]

[0290] Methyl 3-cyano-4-methylbenzoate (6.99 g, 39.9 mmol) in MeOH (399 mL) was charged with Raney nickel (80 mL, 50% dispersion in water) and stirred overnight at RT under a hydrogen atmosphere (balloon). The reaction mixture was filtered through a pad of Celite and concentrated to dryness under reduced pressure to give the crude material, which was purified via FCC (hexanes:EtOAc, 50:50 MeOH:EtOAc:NH3 10:89:1) to give the title compound as a yellow oil (3.63 g, 47%). 1H NMR (300 MHz, DMSO-d6) δ 8.03 (s, 1H), 7.72 (dd, J = 1.9, 7.7 Hz, 1H), 7.27 (d, J = 7.7 Hz, 1H), 3.84 (s, 3H), 3.74 (s, 2H), 2.32 (s, 3H), 2.01 (br s, 2H)

[0291] Step 3: Preparation of 4-methyl-3-((pyrazolo[1,5-a]pyrimidin-6-ylamino)methyl)benzoic acid [ka]

[0292] To a mixture of 6-bromopyrazolo[1,5-a]pyrimidine (0.398 g, 2.01 mmol) and sodium tert-butoxide (0.483 g, 5.02 mmol) was added a solution of methyl 3-(aminomethyl)-4-methylbenzoate (0.300 g, 1.67 mmol) in anhydrous toluene (6 mL). The mixture was degassed under argon, and then tBuXphos (0.142 g, 0.335 mmol) and Pd2(dba)3 (0.153 g, 0.167 mmol) were added. The reaction was carried out at 110 °C overnight, then filtered through a pad of Celite and concentrated to dryness under reduced pressure to give the crude material, which was purified by FCC (MeOH:DCM, 5:95 to 20:80) to give the title material as a red solid (0.059 g, 11%). 1 H NMR (300 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.41 (s, 1H), 7.96 - 7.84 (m, 2H), 7.78 (d, J = 8.1 Hz, 1H), 7.35 (d, J = 7.8 Hz, 2H), 6.54 (s, 1H), 6.41 (t, J = 5.6 Hz, 1H), 4.30 (d, J = 5.4 Hz, 2H), 2.43 (s, 3H).

[0293] Step 4: Preparation of 4-methyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-3-((pyrazolo[1,5-a]pyrimidin-6-ylamino)methyl)benzamide (Example 8) [ka]

[0294] Example 18 was prepared according to general procedure A for amide coupling by reacting 4-methyl-3-((pyrazolo[1,5-a]pyrimidin-6-ylamino)methyl)benzoic acid (0.03 g) with the required amine to give a yellow solid (0.006 g; 11%).

[0295] [Table 21]

[0296] Example 19 4-Methyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-3-((pyrimidin-5-ylamino)methyl)benzamide

[0297] [ka]

[0298] Step 1: Preparation of 4-methyl-3-((pyrimidin-5-ylamino)methyl)benzoic acid [ka]

[0299] Methyl 3-(aminomethyl)-4-methylbenzoate (0.500 g, 2.79 mmol), prepared as described in step 1-3 of Example 18, CsCO (2.73 g, 8.37 mmol), and 5-bromopyrimidine (1.06 g, 6.67 mmol) were suspended in anhydrous toluene (9.0 mL). The suspension was degassed, and then RuPhos (0.520 g, 1.11 mmol) and Pd(dba) (0.320 g, 0.557 mmol) were added, and the reaction was heated at 100 °C for 24 h. The reaction mixture was filtered through a pad of Celite and concentrated to dryness under reduced pressure to give the crude material, which was purified via column chromatography (DCM:3.5 M NH in MeOH, 80:20 to 50:50) to give the title compound as a yellow oil (0.755 g, 100%). 1 H NMR (300 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.39 (s, 1H), 8.13 (s, 2H), 7.76 - 7.67 (m, 2H), 7.25 (dd, J = 7.7, 5.1 Hz, 2H), 4.33 (d, J = 5.7 Hz, 2H), 2.37 (d, J = 2.3 Hz, 3H).

[0300] Step 2: Preparation of 4-methyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-3-((pyrimidin-5-ylamino)methyl)benzamide (Example 19), 4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((pyrimidin-5-ylamino)methyl)benzamide (Example 20), N-(4-methoxy-3-(trifluoromethyl)phenyl)-4-methyl-3-((pyrimidin-5-ylamino)methyl)benzamide (Example 31), and 4-methyl-3-((pyrimidin-5-ylamino)methyl)-N-(3-(trifluoromethyl)phenyl)benzamide (Example 32).

[0301] Examples 19 and 20 were prepared according to general procedure A, and Examples 31 and 32 were prepared according to general procedure C, where 4-methyl-3-((pyrimidin-5-ylamino)methyl)benzoic acid was reacted with the required amine to give the following compounds:

[0302] [Table 22-1] [Table 22-2]

[0303] Example 21 N-(2-methyl-5-((3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)carbamoyl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide

[0304] [ka]

[0305] Step 1: Preparation of methyl 3-((imidazo[1,2-a]pyridine-3-carboxamido)methyl)-4-methylbenzoate [ka]

[0306] To a mixture of methyl 3-(aminomethyl)-4-methylbenzoate (0.7 g, 3.91 mmol), imidazo[1,2-a]pyridine-3-carboxylic acid (0.760 g, 4.69 mmol), and HATU (1.49 g, 3.91 mmol, 1 eq), prepared as described in Step 1-2 of Example 18, was added anhydrous DCM (13 mL), followed by DIPEA (1.4 mL, 7.81 mmol). The reaction was stirred overnight at RT, and then the reaction mixture was partitioned between DCM (15 mL) and water (15 mL), and the desired compound was extracted with 2×15 mL. The organic phases were combined, washed with water (15 mL), brine (15 mL), and then dried over NaSO, filtered, and concentrated. The crude material was purified via FCC (MeOH:DCM, 1:99 to 5:95) to afford the title compound (1.26 g, 66%) as an off-white solid. 1 H NMR (300 MHz, CDCl3) δ 9.69 (d, J = 6.7 Hz, 1H, CH), 8.26 (br s, 1H, CH), 8.03 (s, 1H, CH), 7.90 (dd, J = 7.9, 1.6 Hz, 1H, CH), 7.76 (d, J = 8.9 Hz, 1H, CH), 7.46 (t, J = 7.6 Hz, 1H, CH), 7.31 (s, 1H, CH), 7.07 (t, J = 6.9 Hz, 1H, CH), 6.93 (br s, 1H, NH), 4.72 (d, J = 5.5 Hz, 2H, CH2), 3.90 (s, 3H, CH3), 2.48 (s, 3H, CH3).

[0307] Step 2: Preparation of lithium 3-((imidazo[1,2-a]pyridine-3-carboxamido)methyl)-4-methylbenzoate [ka]

[0308] Methyl 3-((imidazo[1,2-a]pyridine-3-carboxamido)methyl)-4-methylbenzoate (0.416 g, 1.29 mmol) was dissolved in THF (13 mL) and 1 M LiOH solution (2 mL, 1.93 mmol) was added. The reaction was stirred at 60 °C for 16 h. The solvent was removed under reduced pressure and the crude material was triturated with diethyl ether (30 mL) and filtered. The solid was collected to give the title product as an off-white solid (0.348 g, 86%). 1 H NMR (300 MHz, DMSO-d6) δ9.54 (d, J = 7.0 Hz, 1H), 9.02 (br s, 1H), 8.45 (s, 1H), 7.80 (s, 1H), 7.69 (m, 1H), 7.69 (m, 1H), 7.45 (ddd J = 8.7, 6.8, 1.3 Hz, 1H), 7.10 (m, 1H), 7.10 (m, 1H), 4.49 (s, 2H), 2.32 (s, 3H).

[0309] Step 3: Preparation of N-(2-methyl-5-((3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)carbamoyl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide (Example 21) and N-(2-methyl-5-((3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)carbamoyl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide (Example 22).

[0310] The preparation of Examples 21 and 22 followed General Procedure A for Amide Coupling, reacting lithium 3-((imidazo[1,2-a]pyridine-3-carboxamido)methyl)-4-methylbenzoate with the required amine to give the following compounds:

[0311] [Table 23]

[0312] Example 23 N-methyl-4-((2-methyl-5-((3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)carbamoyl)benzyl)amino)picolinamide

[0313] [ka]

[0314] Step 1: Preparation of 4-methyl-3-(((2-(methylcarbamoyl)pyridin-4-yl)amino)methyl)benzoic acid [ka]

[0315] To 4-bromo-N-methylpyridine-2-carboxamide (0.720 g, 3.35 mmol), prepared as described in step 1-2 of Example 18, and CsCO (2.73 g, 8.37 mmol), was added a solution of methyl-3-(aminomethyl)-4-methylbenzoate (0.500 g, 2.79 mmol) in anhydrous toluene (9 mL). The reaction mixture was degassed, and BINAP (0.347 g, 0.558 mmol) and Pd(dba) (0.160 g, 0.279 mmol) were added, and the reaction was stirred at 100 °C overnight. The reaction mixture was filtered through a pad of Celite and concentrated to dryness under reduced pressure to give the crude material, which was purified via FCC (MeOH:DCM, 10:90 to 50:50) to give the title product as a yellow solid (0.650 g, 78%). 1H NMR (300 MHz, DMSO-d6) δ8.56 (q, J = 4.6 Hz, 1H), 8.06 (d, J = 5.7 Hz, 1H), 7.82-7.78 (m, 2H), 7.78-7.72 (m, 1H), 7.39 (t, J = 5.6 Hz, 1H), 7.33 (d, J = 7.9 Hz, 1H), 7.24 (s, 1H), 6.63 (d, J = 5.4 Hz, 1H), 4.38 (d, J = 5.5 Hz, 2H), 2.76 (d, J = 4.9 Hz, 3H), 2.40 (s, 3H).

[0316] Step 2: Preparation of N-methyl-4-((2-methyl-5-((3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)carbamoyl)benzyl)amino)picolinamide (Example 23) and N-methyl-4-((2-methyl-5-((3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)carbamoyl)benzyl)amino)picolinamide (Example 24)

[0317] Examples 23 and 24 were prepared according to general procedure A for amide coupling, where 4-methyl-3-(((2-(methylcarbamoyl)pyridin-4-yl)amino)methyl)benzoic acid was reacted with the required amine to give the following compounds:

[0318] [Table 24]

[0319] Example 25 N-(2-methyl-5-((3-(4-methyl-1H-imidazol-1-yl)-5(trifluoromethyl)phenyl)carbamoyl)benzyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide

[0320] [ka]

[0321] Step 1: Preparation of methyl 4-methyl-3-(((1H-pyrrolo[2,3-b]pyridin-5-yl)formamido)methyl)benzoate [ka]

[0322] To a solution of methyl 3-(aminomethyl)-4-methylbenzoate (0.300 g, 1.67 mmol) prepared as described in step 1-2 of Example 18, 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (0.324 g, 2.01 mmol), HATU (0.636 g, 1.67 mmol), and DIPEA (0.6 mL, 3.35 mmol) in anhydrous DCM (5 mL) were added, and the mixture was stirred at RT for 16 h. The reaction was quenched by the addition of saturated NaHCO3 and then extracted with DCM (x3). The organic phase was dried over Na2SO4 and evaporated to dryness. The crude product was purified by column chromatography (DCM:MeOH, 98:2 to 96:4) to afford the title amide as an off-white solid (0.323 g, 60%). NMR (d-DMSO, 300 MHz): δ 11.93 (s, 1H), 9.04 (t, J = 5.7 Hz, 1H), 8.78 (d, J = 2.1 Hz, 1H), 8.50 (d, J = 2.0 Hz, 1H), 7.91 (d, J = 1.5 Hz, 1H), 7.77 (dd, J = 7.8, 1.8 Hz, 1H), 7.58 (dd, J = 3.5, 2.3 Hz, 1H), 7.34 (d, J = 7.9 Hz, 1H), 6.63 - 6.55 (m, 1H), 4.54 (d, J = 5.7 Hz, 2H), 3.80 (s, 3H), 2.43 (s, 3H).

[0323] Step 2: Preparation of lithium 3-((1H-pyrrolo[2,3-b]pyridine-5-carboxamido)methyl)-4-methylbenzoate [ka] Methyl 4-methyl-3-(((1H-pyrrolo[2,3-b]pyridin-5-yl)formamido)methyl)benzoate (323 mg, 0.999 mmol) was dissolved in THF (10 mL), then 1 M aqueous LiOH (3.0 mL) was added, and the reaction mixture was stirred at RT for 3 days. The reaction mixture was then concentrated under reduced pressure, and the residue was triturated with diethyl ether to give the title compound as a bright yellow solid (238 mg, 76%). NMR (d-DMSO, 300 MHz): δ 8.58 (d, J = 5.7 Hz, 1H), 8.55 (d, J = 2.3 Hz, 1H), 8.25 (d, J = 2.3 Hz, 1H), 7.86 (d, J = 1.6 Hz, 1H), 7.66 (dd, J = 7.6, 1.7 Hz, 1H), 7.47 (d, J = 2.6 Hz, 1H), 7.05 (d, J = 7.7 Hz, 1H), 6.25 (d, J = 2.6 Hz, 1H), 4.45 (d, J = 5.3 Hz, 2H), 2.32 (s, 3H).

[0324] Step 3: Preparation of N-(2-methyl-5-((3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)carbamoyl)benzyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (Example 25) and N-(2-methyl-5-((3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)carbamoyl)benzyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (Example 26)

[0325] The preparation of Examples 25 and 26 followed general procedure A for amide coupling, reacting lithium 3-((1H-pyrrolo[2,3-b]pyridine-5-carboxamido)methyl)-4-methylbenzoate with the required amine to give the following compounds:

[0326] [Table 25]

[0327] Example 27 N-(2-isopropyl-5-((3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)carbamoyl)benzyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide

[0328] [ka]

[0329] Step 1: Preparation of methyl 3-(aminomethyl)-4-isopropylbenzoate [ka]

[0330] To a mixture of methyl 3-cyano-4-isopropylbenzoate (2.76 g, 13.6 mmol, 1:1 ratio) prepared as described in Step 1-2 of Example 16 and methyl 3-cyano-4-propylbenzoate in MeOH (200 mL) was added Raney nickel (4 mL, 6.80 mmol). The reaction mixture was placed in a Parr apparatus under a hydrogen atmosphere (7 atm.). The reaction was carried out at RT for 60 h, then filtered through a pad of Celite and concentrated to dryness under reduced pressure to give the crude material, which was purified by column chromatography (DCM:5.5 M NH in MeOH, 99:1 to 90:10)) to give the isomeric mixture (1:1 isomer ratio, 1.33 g, 94%) as a pale yellow oil. 1H NMR (d-DMSO, 300 MHz): iPr δ 7.77 (ddd, J = 15.1, 8.0, 2.0 Hz, 2H), 3.83 (s, 3H), 3.82 (s, 2H), 3.25 (sept, J = 6.8 Hz, 1H), 2.07 (br, 2H), 1.20 (d, J = 6.8 Hz, 6H) nPr δ 8.04 (dd, J = 11.3, 1.9 Hz, 2H), 7.27 (d, J = 7.9 Hz, 1H), 3.83 (s, 3H), 3.78 (s, 2H), 2.71 - 2.59 (m, 2H), 2.07 (s, 2H), 1.57 (sext, J = 7.3 Hz, 2H), 0.94 (t, J = 7.3 Hz, 3H).

[0331] Step 2: Preparation of methyl 3-((1H-pyrrolo[2,3-b]pyridine-5-carboxamido)methyl)-4-isopropylbenzoate [ka]

[0332] To a mixture of 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (250 mg, 1.54 mmol) and HATU (488 mg, 1.283 mmol), a solution of methyl 3-(aminomethyl)-4-isopropylbenzoate and methyl 3-(aminomethyl)-4-propylbenzoate (266 mg, 1.28 mmol, 1:1 ratio) in DCM (4.3 mL) was added, followed by DIPEA (448 μL, 2.57 mmol). The reaction was stirred at RT for 16 h, then diluted with DCM, washed with water, and the desired compound was re-extracted with DCM. The organic phases were combined and concentrated to dryness under reduced pressure to give the crude material, which was purified via FCC (hexane:EtOAc, 100:0 to 50:50) to give an isomeric mixture. The isomers were then subjected to preparative HPLC separation to give the desired isomer (105 mg, 47%) as a white crystalline solid. 1H NMR (300 MHz, DMSO-d6) δ 11.95 (s, 1H), 9.06 (t, J = 5.7 Hz, 1H), 8.77 (d, J = 2.1 Hz, 1H), 8.49 (d, J = 2.1 Hz, 1H), 7.95 (d, J = 1.9 Hz, 1H), 7.85 (dd, J = 8.1, 1.9 Hz, 1H), 7.58 (d, J = 3.4 Hz, 1H), 7.49 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 3.5 Hz, 1H), 4.62 (d, J = 5.6 Hz, 2H), 3.82 (s, 3H), 3.38 (s, 1H), 1.24 (d, J = 6.8 Hz, 6H).

[0333] Step 3: Preparation of 3-((1H-pyrrolo[2,3-b]pyridine-5-carboxamido)methyl)-4-isopropylbenzoic acid [ka]

[0334] Methyl 3-((1H-pyrrolo[2,3-b]pyridine-5-carboxamido)methyl)-4-isopropylbenzoate (0.105 g, 0.299 mmol) was dissolved in THF (3 ml), and 1 M LiOH solution (0.65 ml, 0.448 mmol) was added to the solution and stirred at 35° C. for 60 h. The reaction was concentrated under reduced pressure, and the resulting residue was dissolved in water and acidified to pH=4 with 10% KHSO solution. The product was extracted with EtOAc, and the organic phases were combined and dried over NaSO. 、 Concentration under reduced pressure gave the title compound (0.043 g, 43%), which was used in the next step without further purification. 1H NMR (300 MHz, Methanol-d4) δ 8.76 (d, J = 2.1 Hz, 1H), 8.52 (d, J = 2.1 Hz, 1H), 8.06 (d, J = 1.9 Hz, 1H), 7.95 (dd, J = 8.1, 1.9 Hz, 1H), 7.51 - 7.46 (m, 2H), 6.62 (d, J = 3.5 Hz, 1H), 4.76 (s, 2H), 3.41 (p, J = 7.0 Hz, 1H), 1.32 (d, J = 6.8 Hz, 6H).

[0335] Step 4: Preparation of N-(2-isopropyl-5-((3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)carbamoyl)benzyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (Example 27) [ka]

[0336] To a solution of 3-((1H-pyrrolo[2,3-b]pyridine-5-carboxamido)methyl)-4-isopropylbenzoic acid (0.043 g, 0.127 mmol) in DMF (0.1 mL) was added BTFFH (0.121 g, 0.382 mmol) and DIPEA (0.100 mL, 0.574 mmol). The mixture was stirred for 15 min, then 3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)aniline (0.052 g, 0.191 mmol) was added, and the reaction mixture was stirred at 80 °C for 18 h. The mixture was then diluted with EtOAc and washed with water. The organic phase was then washed with brine and concentrated under reduced pressure. The crude material was purified by prep HPLC (ACN + 0.1% FA, HO + 0.1% FA) and then by preparative TLC (DCM:MeOH, 90:10) to give the formate salt of the title compound. The resulting material was dissolved in MeOH and stirred over Amberlite IRN-78 for 2 h, filtered, and concentrated under reduced pressure to give the title compound (0.003 g, 4% yield) as a white solid.

[0337] [Table 26]

[0338] Example 28 N-(5-((3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)carbamoyl)-2-propylbenzyl)imidazo[1,2-a]pyridine-3-carboxamide formate

[0339] [ka]

[0340] Step 1: Preparation of methyl 3-cyano-4-(prop-1-salt-2-yl)benzoate; methyl 3-cyano-4-[(1E)-prop-1-salt-1-yl]benzoate [ka]

[0341] To a solution of methyl 4-bromo-3-cyanobenzoate (2.00 g, 8.33 mmol) and potassium isopropenyltrifluoroborate (2.47 g, 16.7 mmol) in iPrOH (21 mL) was added TEA (4.7 mL, 33.3 mmol), followed by PdCl 2( dppf) (0.305 g, 0.417 mmol) was added. The mixture was degassed with argon and stirred at 110 °C overnight. The reaction mixture was then concentrated to dryness and partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (3 × 20 mL) and washed with water (3 × 20 mL) and brine (20 mL). The organic phases were combined, dried over Na2SO4, and concentrated under reduced pressure to give the crude material, which was purified via FCC (hexane:EtOAc, 99:1 to 90:10) to give the product as an isomeric mixture (1:1 ratio, 1.68 g, 56%). 1H NMR (d-DMSO, 300 MHz): δiPr 8.23 ​​(m, 2H), 7.96 (d, J = 8.4 Hz, 1H), 5.52 (t, J = 1.5 Hz, 1H), 5.33 (s, 1H, CH), 3.90 (s, 3H), 2.17 (s, 3H) δnPr 8.23 ​​(m, 2H), 7.70 (m, 1H), 6.76 (m, 2H), 3.90 (s, 3H), 1.98 (dd, J = 6.2, 1.1 Hz, 3H).

[0342] Step 2: Preparation of methyl 3-cyano-4-(propan-2-yl)benzoate; methyl 3-cyano-4-propylbenzoate [ka]

[0343] A mixture of methyl 3-cyano-4-(prop-1-salt-2-yl)benzoate and methyl 3-cyano-4-[(1E)-prop-1-salt-1-yl]benzoate (500 mg, 2.49 mmol, 1:1 ratio) was dissolved in ethanol (100 mL) in a Parr apparatus. 10% palladium on carbon (5.89 mg, 0.05 mmol) was added to the reaction mixture, which was then stirred under a hydrogen atmosphere (7 atm) for 16 h. The reaction mixture was filtered through Celite, concentrated under reduced pressure, and the mixture of methyl 3-cyano-4-(propan-2-yl)benzoate and methyl 3-cyano-4-propylbenzoate (1:1 ratio, 506 mg, 100%) was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δiPr 8.26 (dd, J = 4.8, 1.8 Hz, 2H), 7.72 (d, J = 8.3 Hz, 1H), 3.88 (s, 3H), 3.29 (m, 1H), 1.29 (d, J = 6.9 Hz, 6H). δnPr 8.18 (ddd, J = 13.0, 8.2, 1.9 Hz, 2H), 7.64 (d, J = 8.1 Hz, 1H), 3.88 (s, 3H), 2.84 (dd, J = 8.4, 6.8 Hz, 2H), 1.67 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H).

[0344] Step 3: Preparation of methyl 3-(aminomethyl)-4-(propan-2-yl)benzoate; methyl 3-(aminomethyl)-4-propylbenzoate [ka]

[0345] A mixture of methyl 3-cyano-4-(propan-2-yl)benzoate and methyl 3-cyano-4-propylbenzoate (1:1 ratio, 505 mg, 2.485 mmol) was dissolved in ethanol (300 mL) in a Parr apparatus. Raney nickel (5 mL) was added to the mixture and stirred under a hydrogen atmosphere (7 atm) for 16 h. The reaction was filtered through Celite and concentrated under reduced pressure to give the crude material, which was purified by column chromatography (DCM: 5.5 M NH3 in MeOH, 99:1 to 98:2) to give a mixture of methyl 3-(aminomethyl)-4-(propan-2-yl)benzoate and methyl 3-(aminomethyl)-4-propylbenzoate (1:1 ratio, 118 mg, 23%). 1H NMR (d-DMSO, 400 MHz): iPr: δ 8.02 (d, J = 1.9 Hz, 1H), 7.79 (dd, J = 8.1, 2.0 Hz, 1H), 7.41 (d, J = 8.1 Hz, 1H), 3.84 (s, 3H), 3.79 (s, nPr: δ 8.06 (d, J = 2.0 Hz, 1H), 7.74 (dd, J = 7.9, 2.0 Hz, 1H), 7.27 (d, J = 7.9 Hz, 1H), 3.84 (s, 3H), 3.83 (s, 2H) 2.64 (m, 2H), 1.57 (m, 2H), 0.94 (t, J = 7.3 Hz)

[0346] Step 4: Preparation of methyl 3-[({imidazo[1,2-a]pyridin-3-yl}formamido)methyl]-4-(propan-2-yl)benzoate; methyl 3-[({imidazo[1,2-a]pyridin-3-yl}formamido)methyl]-4-propylbenzoate [ka]

[0347] To methyl 3-(aminomethyl)-4-isopropylbenzoate and methyl 3-(aminomethyl)-4-propylbenzoate (1:1 ratio, 0.156 g, 0.748 mmol), imidazo[1,2-a]pyridine-3-carboxylic acid (0.146 g, 0.897 mmol), and HATU (0.284 g, 0.748 mmol) in DCM (7.5 mL) was added DIPEA (0.26 mL, 1.50 mmol), and the mixture was stirred at RT for 16 h. The reaction was quenched by the addition of water, which was then extracted with DCM (3 x 25 mL). The organic phases were combined, washed with water (25 mL), brine (20 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The crude material was purified via column chromatography (DCM:MeOH, 98:2) and then by prepHPLC to give the isopropyl (93 mg, 71%) and n-propyl (108 mg, 82%) isomers. 1 H NMR (300 MHz, d-DMSO): δ (methyl 3-((imidazo[1,2-a]pyridine-3-carboxamido)methyl)-4-isopropylbenzoate) 9.48 (d, J = 6.9 Hz, 1H), 9.03 (t, J = 5.7 Hz, 1H), 8.41 (s, 1H), 7.95 (d, J = 1.9 Hz, 1H), 7.86 (dd, J = 8.1, 1.9 Hz, 1H), 7.73 (dt, J = 9.0, 1.2 Hz, 1H), 7.54 - 7.43 (m, 2H), 7.13 (td, J = 6.9, 1.3 Hz, 1H), 4.62 (d, J = 5.6 Hz, 2H), 3.82 (s, 3H,), 3.40 (d, J = 6.7 Hz, 1H), 1.23 (d, J = 6.8 Hz, 6H). δ (methyl 3-((imidazo[1,2-a]pyridine-3-carboxamido)methyl)-4-propylbenzoate) 9.48 (dt, J = 7.0, 1.2 Hz, 1H, CH), 9.05 (t, J = 5.8 Hz, 1H, NH), 8.42 (s, 1H, CH), 7.95 (d, J = 1.9 Hz, 1H, CH), 7.80 (dd, J = 7.9, 1.9 Hz, 1H, CH), 7.73 (dt, J = 9.1, 1.2 Hz, 1H, CH), 7.47 (ddd, J = 9.1, 6.8, 1.4 Hz, 1H, CH), 7.36 (d, J = 8.0 Hz, 1H, CH), 7.13 (td, J = 6.9, 1.3 Hz, 1H, CH), 4.59 (d, J = 5.7 Hz, 2H, CH2), 3.81 (s, 3H, OCH3), 2.79 - 2.70 (m, 2H, CH2), 1.68 - 1.53 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H).

[0348] Step 5: Preparation of lithium 3-((imidazo[1,2-a]pyridine-3-carboxamido)methyl)-4-propylbenzoate [ka]

[0349] Methyl 3-((imidazo[1,2-a]pyridine-3-carboxamido)methyl)-4-isopropylbenzoate (108 mg, 0.293 mmol) was dissolved in THF (3 mL), a 1 M solution of LiOH in HO (0.70 mL, 0.700 mmol) was added, and the reaction mixture was stirred at RT for 3 d. The reaction mixture was concentrated under reduced pressure and triturated with diethyl ether to give the title product as an off-white solid (114 mg, 100%). 1H NMR (300 MHz, DMSO-d6) δ 9.54 (d, J = 7.0 Hz, 1H), 8.96 (s, 1H), 8.42 (s, 1H), 7.85 (d, J = 1.5 Hz, 1H), 7.71 (d, J = 9.0 Hz, 1H), 7.66 (dd, J = 7.8, 1.6 Hz, 1H), 7.49 - 7.41 (m, 1H), 7.11 (t, J = 7.0 Hz, 1H), 7.05 (d, J = 7.7 Hz, 1H), 4.53 (s, 2H), 2.68 - 2.59 (m, 2H), 1.64 - 1.50 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H).

[0350] Step 6: Preparation of N-(5-((3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)carbamoyl)-2-propylbenzyl)imidazo[1,2-a]pyridine-3-carboxamide formate (Example 28)

[0351] Preparation of Example 28 Following general procedure B for amide coupling, lithium 3-((imidazo[1,2-a]pyridine-3-carboxamido)methyl)-4-propylbenzoate was reacted with the required amine to give the following compound:

[0352] [Table 27]

[0353] Example 29 N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4-propyl-3-((pyrimidin-5-ylamino)methyl)benzamide

[0354] [ka]

[0355] Step 1: Preparation of 4-propyl-3-((pyrimidin-5-ylamino)methyl)benzoic acid and 4-isopropyl-3-((pyrimidin-5-ylamino)methyl)benzoic acid

[0356] To a mixture of methyl 3-(aminomethyl)-4-isopropylbenzoate and methyl 3-(aminomethyl)-4-propylbenzoate (1:1 ratio, 200 mg, 0.964 mmol) prepared as in Step 1-2 of Example 16, 5-bromopyrimidine (184 mg, 1.158 mmol) and Cs(CO) (943 mg, 2.89 mmol) were added, followed by toluene (2 mL). The mixture was degassed, and RuPhos (90 mg, 0.193 mmol) and Pd(dba) (55.5 mg, 0.096 mmol) were added, and the reaction mixture was stirred at 110 °C overnight. The reaction mixture was filtered through Celite and concentrated under reduced pressure to give the crude material, which was purified by column chromatography (DCM:MeOH, 99:1 to 0:100) and then by prepHPLC to give the iso-propyl (69 mg, 53%) and n-propyl (87 mg, 67%) isomers. 1 H NMR iPr (300 MHz, DMSO-d6) δ 8.40 (s, 1H), 8.14 (s, 2H), 7.86 (d, J = 1.7 Hz, 1H), 7.84 - 7.77 (m, 1H), 7.38 (d, J = 8.0 Hz, 1H), 6.56 (t, J = 5.5 Hz, 1H), 4.36 (d, J = 5.2 Hz, 2H), 3.23 (sept., J = 6.8 Hz, 1H), 1.22 (d, J = 6.8 Hz, 6H). 1H NMR nPr (300 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.38 (s, 1H), 8.12 (s, 2H), 7.82 (d, J = 1.7 Hz, 1H), 7.69 (dd, J = 7.8, 1.7 Hz, 1H), 7.12 (d, J = 7.8 Hz, 1H), 6.58 (t, J = 5.5 Hz, 1H), 4.29 (d, J = 5.4 Hz, 2H), 2.63 (dd, J = 8.9, 6.5 Hz, 2H), 1.68 - 1.49 (m, 2H), 0.93 (t, J = 7.3Hz, 3H).

[0357] Step 2: Preparation of N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4-propyl-3-((pyrimidin-5-ylamino)methyl)benzamide (Example 29) and 4-isopropyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-3-((pyrimidin-5-ylamino)methyl)benzamide (Example 30).

[0358] Examples 29 and 30 were prepared according to general procedure B for amide coupling by reacting 4-propyl-3-((pyrimidin-5-ylamino)methyl)benzoic acid and 4-isopropyl-3-((pyrimidin-5-ylamino)methyl)benzoic acid with the required amine to give the following compounds:

[0359] [Table 28]

[0360] Example 33 3-(((1H-pyrrolo[2,3-b]pyridin-5-yl)amino)methyl)-4-fluoro-N-(3-(trifluoromethyl)phenyl)benzamide

[0361] [ka]

[0362] Step 1: Preparation of 4-fluoro-3-formyl-N-(3-(trifluoromethyl)phenyl)benzamide A solution of 4-fluoro-3-formylbenzoic acid (200 mg, 1.190 mmol) in SOCl2 (2.386 mL, 32.7 mmol) was refluxed for 2 h and then evaporated under reduced pressure to remove residual SOCl2. The brown solid residue was dissolved in anhydrous THF (4.0 mL), and a solution of DIPEA (0.249 mL, 1.428 mmol), 3-(trifluoromethyl)aniline (192 mg, 1.190 mmol), and DMAP (5.81 mg, 0.048 mmol) in anhydrous THF (2.0 mL) was added dropwise. The reaction mixture was stirred at RT for 18 h. The reaction mixture was quenched by the addition of water (20 mL). The pH was adjusted to 10 by the addition of 1 M NaOH (4 mL). The product was extracted with AcOEt (3 × 25 mL), and the organic extracts were combined and evaporated under reduced pressure to give the product (548 mg). The crude material was purified by column chromatography (hexane / DCM, 1:3 to 0:1) to give the title product (265 mg, 72%). 1 H NMR (300 MHz, DMSO-d6) δ 10.76 (s, 1H), 10.30 (s, 1H), 8.51 (dd, J = 6.7, 2.5 Hz, 1H), 8.35 (ddd, J = 8.7, 5.0, 2.5 Hz, 1H), 8.23 ​​(d, J = 2.2 Hz, 1H), 8.07 (d, J = 8.3 Hz, 1H), 7.67 - 7.58 (m, 2H), 7.52 - 7.46 (m, 1H).

[0363] Step 2: Preparation of 3-(((1H-pyrrolo[2,3-b]pyridin-5-yl)amino)methyl)-4-fluoro-N-(3-(trifluoromethyl)phenyl)benzamide

[0364] 4-Fluoro-3-formyl-N-(3-(trifluoromethyl)phenyl)benzamide (80 mg, 0.257 mmol) and 1H-pyrrolo[2,3-b]pyridin-5-amine (34.2 mg, 0.257 mmol) were placed in a round-bottom flask under argon. Glacial AcOH (1.0 mL) was added, and the reaction mixture was stirred at RT for 3 h. The reaction mixture was cooled in ice water, and then STAB (163 mg, 0.771 mmol) as a suspension in glacial acetic acid (1.0 mL) was added, and the reaction mixture was stirred at RT for 72 h. The reaction mixture was added to 1 M NaOH (50 mL), the aqueous phase was extracted with AcOEt (3 × 25 mL), and the organic phases were combined, dried (NaSO), filtered, and evaporated to give the crude product (126 mg). The crude product was purified by preparative TLC (SiO 2 , DCM / MeOH 100:5) to give the title compound (35.26 mg, 32%).

[0365] [Table 29]

[0366] Example 34 4-Methyl-3-((pyridin-3-ylamino)methyl)-N-(3-(trifluoromethyl)phenyl)benzamide

[0367] [ka]

[0368] Step 1: Preparation of 3-formyl-4-methylbenzoyl chloride 3-Formyl-4-methylbenzoic acid (1 g, 6.09 mmol) was dissolved in DCM (20.31 mL). The solution was cooled to 0 °C, and then oxalyl chloride (1.569 mL, 18.27 mmol) and DMF (catalytic amount) were added. The reaction mixture was stirred in an ice bath for 3 h. The formation of the acid chloride was confirmed by quenching the reaction with MeOH (methyl ester). The mixture was concentrated to give the desired product (1.1 g, 99%), which was used in the next step without further purification.

[0369] Step 2: Preparation of 3-formyl-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide 3-Formyl-4-methylbenzoyl chloride (1 g, 5.48 mmol) was dissolved in THF (5.37 mL), and this solution was added to a solution of 3-(trifluoromethyl)aniline (0.684 mL, 5.48 mmol), DIPEA (1.145 mL, 6.57 mmol), and DMAP (0.027 g, 0.219 mmol) in THF (10.74 mL). The mixture was stirred at RT overnight. The reaction mixture was concentrated. The crude material was dissolved in saturated NaHCO and extracted with DCM (x3). All organic phases were combined, washed with 5% citric acid, dried over NaSO, filtered, and concentrated. The crude material was purified via FCC (100% hexane to 30% AcOEt in hexane) to give the desired product (1.13 g, 67%). 1 H NMR (300 MHz, DMSO-d6) δ 10.68 (s, 1H), 10.33 (s, 1H), 8.46 (d, J = 2.1 Hz, 1H), 8.25 (d, J = 2.0 Hz, 1H), 8.16 (dd, J = 8.0, 2.1 Hz, 1H), 8.07 (dt, J = 7.9, 2.3 Hz, 1H), 7.62 (t, J = 8.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.51 - 7.44 (m, 1H), 2.71 (s, 3H).

[0370] Step 3: Preparation of 4-methyl-3-((pyridin-3-ylamino)methyl)-N-(3-(trifluoromethyl)phenyl)benzamide

[0371] 3-Formyl-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide (0.1 g, 0.325 mmol) and pyridin-3-amine (0.031 g, 0.325 mmol) were dissolved in MeOH (1.63 ml) and AcOH (0.06 ml). The mixture was stirred at 50 °C for 1 h. Then the reaction mixture was cooled to RT and NaBHCN (0.092 g, 1.464 mmol) was added. The solution was stirred at 50 °C for 1 h. The reaction mixture was cooled to RT and quenched with 1 M NaOH aq. solution, and the product was extracted with AcOEt (x3). All organic phases were combined, dried over Na2SO4, filtered, and concentrated. The crude material was purified via FCC (DCM 100% to 10% MeOH in DCM) and then repurified via preparative HPLC (ACN + 0.1% FA, HO + 0.1% FA). The resulting product was washed with saturated NaHCO to remove formic acid to give the desired product (48 mg, 38%).

[0372] [Table 30]

[0373] Example 35 4-Fluoro-3-(((5-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)amino)methyl)-N-(3-(trifluoromethoxy)phenyl)benzamide

[0374] [ka]

[0375] Step 1: Preparation of 4-fluoro-3-formylbenzoyl chloride 4-Fluoro-3-formylbenzoic acid (0.2 g, 1.190 mmol) was dissolved in DCM (5.95 mL). The solution was cooled to 0 °C, and then oxalyl chloride (0.306 mL, 3.57 mmol) and DMF (catalytic amount) were added. The mixture was stirred in an ice bath for 3 h. The formation of the acid chloride was confirmed by quenching the reaction with MeOH (methyl ester). The reaction mixture was concentrated (222 mg, 100%), and the material was used in the next step without further purification.

[0376] Step 2: Preparation of 4-fluoro-3-formyl-N-(3-(trifluoromethoxy)phenyl)benzamide

[0377] 4-Fluoro-3-formylbenzoyl chloride (0.2 g, 1.072 mmol) was dissolved in THF (1.083 mL), and this solution was added to a solution of 3-(trifluoromethoxy)aniline (0.172 mL, 1.286 mmol), DIPEA (0.224 mL, 1.286 mmol), and DMAP (5.24 mg, 0.043 mmol) in THF (2.166 mL). The mixture was stirred overnight at RT. The reaction mixture was diluted with saturated NaHCO and extracted with AcOEt (x3). All organic phases were combined, washed with 5% citric acid, dried over NaSO, filtered, and concentrated. The crude material was purified via FCC (100% hexane to 50% AcOEt in hexane) to give the desired product (227 mg, 65%). 1 H NMR (300 MHz, DMSO-d6) δ 10.71 (s, 1H), 10.29 (s, 1H), 8.48 (dd, J = 6.7, 2.4 Hz, 1H), 8.33 (ddd, J = 8.7, 5.0, 2.5 Hz, 1H), 7.92 (dq, J = 2.3, 1.1 Hz, 1H), 7.78 (ddd, J = 8.3, 2.0, 0.9 Hz, 1H), 7.61 (dd, J = 10.3, 8.7 Hz, 1H), 7.51 (t, J = 8.2 Hz, 1H), 7.12 (ddt, J = 8.2, 2.4, 1.1 Hz, 1H).

[0378] Step 3: Preparation of 4-fluoro-3-(((5-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)amino)methyl)-N-(3-(trifluoromethoxy)phenyl)benzamide

[0379] 4-Fluoro-3-formyl-N-(3-(trifluoromethoxy)phenyl)benzamide (0.1 g, 0.306 mmol) and 5-(1-methyl-1H-pyrazol-3-yl)pyridin-3-amine (0.053 g, 0.306 mmol) were dissolved in MeOH (1.528 ml) and AcOH (0.053 ml, 0.917 mmol). The mixture was stirred at 50 °C for 1 h, then cooled to RT, and NaBHCN (0.086 g, 1.375 mmol) was added. The solution was stirred at 50 °C for 1 h. The reaction mixture was cooled to RT, quenched with saturated NaHCO, and the product was extracted with AcOEt (x3). All organic phases were combined, dried over NaSO, filtered, and concentrated. The crude material was purified via FCC (100% DCM to 10% MeOH in DCM) and then re-purified via preparative HPLC (ACN+0.1% NH3, H2O+0.1% NH3) to give the desired product (47 mg, 32%).

[0380] [Table 31]

[0381] The following compounds were prepared via reductive amination as described in steps 1-3 of Example 35, applying the corresponding commercially available amine in step 3 and using STAB as the reducing agent.

[0382] [Table 32]

[0383] Example 36 4-(Difluoromethyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((pyrimidin-5-ylamino)methyl)benzamide

[0384] [ka]

[0385] Step 1: Preparation of methyl 3-bromo-4-(difluoromethyl)benzoate Methyl 3-bromo-4-formylbenzoate (5 g, 20.57 mmol) was dissolved in anhydrous DCM (103 mL) and the solution was cooled to 0 °C. DAST (4.08 mL, 30.9 mmol) was then added, and the reaction mixture was stirred at RT overnight. The mixture was quenched with saturated NaHCO and extracted with DCM (x3). The combined organic phases were dried over NaSO, filtered, and concentrated in vacuo to give the desired product, which was used in the next step without purification (5.37 g, 98%). 1 H NMR (300 MHz, Chloroform-d) δ 8.28 (q, J = 1.4 Hz, 1H), 8.07 (dt, J = 8.1, 1.0 Hz, 1H), 7.73 (d, J = 8.1 Hz, 1H), 6.92 (t, J = 54.5 Hz, 1H), 3.95 (s, 3H).

[0386] Step 2: Preparation of methyl 4-(difluoromethyl)-3-vinylbenzoate Methyl 3-bromo-4-(difluoromethyl)benzoate (5.37 g, 20.26 mmol), potassium trifluoro(vinyl)borate (5.43 g, 40.5 mmol), and K2CO3 (7.00 g, 50.7 mmol) were placed in an oven-dried pressure reactor. Under an argon atmosphere, dioxane (57.9 ml) was added via syringe. The solution was backfilled with argon (10 min), and then Pd(dppf)Cl2 (1.482 g, 2.026 mmol) was added. The tube was sealed and heated at 110 °C overnight. The reaction mixture was filtered through a pad of Celite and washed with AcOEt. The filtrate was concentrated, and the crude material was purified via automated FCC (elution system: 100% hexane to 10% AcOEt in hexane) to give the desired product (2.49 g, 58%). 1 H NMR (300 MHz, Chloroform-d) δ 8.23 ​​(t, J = 1.2 Hz, 1H), 8.01 (dt, J = 8.1, 1.1 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.07 (d, J = 1.6 Hz, 1H), 6.84 (t, J = 54.9 Hz, 2H), 5.82 (dd, J = 17.4, 0.9 Hz, 1H), 5.52 (dd, J = 11.1, 0.9 Hz, 1H), 3.95 (s, 3H).

[0387] Step 3: Preparation of methyl 4-(difluoromethyl)-3-formylbenzoate Methyl 4-(difluoromethyl)-3-vinylbenzoate (2.37 g, 11.17 mmol) was dissolved in anhydrous DCM (55.8 ml) and the solution was cooled to -78 °C. Ozone was then bubbled through the reaction for 20 min. The ozone stream was then replaced with a stream of argon. Me2S (1.230 ml, 16.75 mmol) was then added, and the mixture was stirred at -78 °C for 30 min, then at RT for an additional 30 min. The solvent was evaporated, and the crude material was purified via FCC (100% hexane to 30% AcOEt in hexane) to give the desired product (1.73, 72%). 1H NMR (300 MHz, Chloroform-d) δ 10.21 (s, 1H), 8.58 (s, 1H), 8.36 (dd, J = 8.1, 1.8 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.47 (t, J = 54.6 Hz, 1H), 4.00 (s, 3H).

[0388] Step 4: Preparation of a mixture of 4-(difluoromethyl)-3-(hydroxymethyl)benzoic acid and 4-(difluoromethyl)isophthalic acid

[0389] Methyl 4-(difluoromethyl)-3-formylbenzoate (1.73 g, 8.08 mmol) was dissolved in MeOH (40.4 ml), and then 1 M LiOH (32.3 ml, 32.3 mmol) was added to the solution. The mixture was stirred at RT for 1 h. Cannizzaro disproportionation occurred, resulting in a mixture of alcohol and carboxylic acid. The crude material was extracted with AcOEt:1 M HCl. The mixture of alcohol (0.76 g, 46%) and acid (0.76 g, 44%) was concentrated and then used directly in the next step.

[0390] Step 5: Preparation of 4-(difluoromethyl)-3-formylbenzoic acid 4-(Difluoromethyl)-3-(hydroxymethyl)benzoic acid (1.42 g, 7.02 mmol) was dissolved in acetonitrile (46.8 mL), and then MnO (1.832 g, 21.07 mmol) was added. The mixture was stirred at 80 °C overnight, and then the reaction mixture was cooled to RT and filtered through a pad of Celite. The filtrate was concentrated, and the crude material was purified via FCC (100% DCM to 10% MeOH in DCM) to give the desired product (197 mg, 14%). 1H NMR (300 MHz, DMSO-d6) δ 13.65 (s, 1H), 10.24 (s, 1H), 8.58 (d, J = 1.5 Hz, 1H), 8.34 (dd, J = 8.0, 1.8 Hz, 1H), 7.96 (d, J = 8.1 Hz, 1H), 7.65 (t, J = 54.5 Hz, 1H).

[0391] Step 6: Preparation of 4-(difluoromethyl)-3-formylbenzoyl chloride 4-(Difluoromethyl)-3-formylbenzoic acid (0.19 g, 0.949 mmol) was dissolved in DCM (4.75 mL). The solution was cooled to 0 °C, and then oxalyl chloride (0.245 mL, 2.85 mmol) and DMF (catalytic amount) were added. The reaction mixture was stirred in an ice bath for 3 h, then it was concentrated, and the material was used in the next step without purification.

[0392] Step 7: Preparation of 4-(difluoromethyl)-3-formyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide 4-(Difluoromethyl)-3-formylbenzoyl chloride (0.19 g, 0.869 mmol) was dissolved in THF (0.852 mL), and this solution was added to a solution of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (0.210 g, 0.869 mmol), DIPEA (0.182 mL, 1.043 mmol), and DMAP (4.25 mg, 0.035 mmol) in THF (1.704 mL). The reaction mixture was stirred overnight at RT. The reaction mixture was concentrated, and the crude material was dissolved in 1 M NaOH and extracted with AcOEt (x3). The organic phases were combined, dried over Na2SO4, filtered, concentrated and the crude material was purified via FCC (100% DCM to 0% MeOH in DCM) to give the desired compound (146 mg, 40%). 1H NMR (300 MHz, DMSO-d6) δ 11.02 (s, 1H), 10.30 (d, J = 1.2 Hz, 1H), 8.66 (d, J = 1.7 Hz, 1H), 8.41 (dd, J = 8.1, 1.9 Hz, 1H), 8.29 (d, J = 2.0 Hz, 1H), 8.23 ​​(d, J = 1.4 Hz, 1H), 8.14 (d, J = 1.8 Hz, 1H), 8.04 (d, J = 8.1 Hz, 1H), 7.79 (d, J = 1.9 Hz, 1H), 7.51 (t, J = 1.2 Hz, 1H), 2.19 (d, J = 1.0 Hz, 3H).

[0393] Step 8: Preparation of 4-(difluoromethyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((pyrimidin-5-ylamino)methyl)benzamide 4-(Difluoromethyl)-3-formyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide (0.06 g, 0.142 mmol) and pyrimidin-5-amine (0.013 g, 0.142 mmol) were dissolved in MeOH (0.71 mL) and AcOH (0.024 mL). Molecular sieves were added, and the mixture was stirred at 50 °C overnight. After that, the reaction mixture was cooled to RT, and NaBHCN (0.040 g, 0.638 mmol) was added. The solution was stirred at 50 °C for 1 h. The reaction mixture was cooled to RT, quenched with 1 M aqueous NaOH, and the product was extracted with AcOEt (x3). All organic phases were combined, dried over NaSO, filtered, and concentrated. The crude material was purified via FCC (100% DCM to 10% MeOH in DCM), which was then repurified via preparative HPLC (ACN+0.1% NH, H0+0.1% NH) to give the desired product as a white solid (30 mg, 42%).

[0394] [Table 33]

[0395] Example 37 4-Methyl-3-((pyrimidin-5-ylamino)methyl)-N-(3-(trifluoromethoxy)phenyl)benzamide

[0396] [ka]

[0397] Step 1: Preparation of 3-formyl-4-methyl-N-(3-(trifluoromethoxy)phenyl)benzamide

[0398] 3-Formyl-4-methylbenzoyl chloride (0.6 g, 3.29 mmol), purified as in Step 13 of Example 34, was dissolved in THF (3.22 mL), and this solution was added to a solution of 3-(trifluoromethoxy)aniline (0.582 g, 3.29 mmol), DIPEA (0.687 mL, 3.94 mmol), and DMAP (0.016 g, 0.131 mmol) in THF (6.44 mL). The reaction mixture was stirred overnight at RT. The reaction mixture was concentrated, and the crude material was dissolved in saturated NaHCO and extracted with DCM (x3). All organic phases were combined, washed with 5% citric acid, dried over NaSO, filtered, and concentrated. The crude material was purified via FCC (100% hexane to 30% in hexane) to give the desired product (450 mg, 42%). 1 H NMR (300 MHz, Chloroform-d) δ 10.37 (s, 1H), 8.29 (d, J = 2.0 Hz, 1H), 8.06 (dd, J = 8.0, 2.0 Hz, 1H), 8.01 (s, 1H), 7.73 (s, 1H), 7.56 - 7.50 (m, 1H), 7.46 - 7.35 (m, 2H), 7.07 - 7.00 (m, 1H), 2.76 (s, 3H).

[0399] Step 2: Preparation of 4-methyl-3-((pyrimidin-5-ylamino)methyl)-N-(3-(trifluoromethoxy)phenyl)benzamide

[0400] 3-Formyl-4-methyl-N-(3-(trifluoromethoxy)phenyl)benzamide (0.1 g, 0.309 mmol) and pyrimidin-5-amine (0.029 g, 0.309 mmol) were dissolved in MeOH (1.547 ml) and AcOH (0.053 ml, 0.928 mmol). The mixture was stirred at 50 °C for 1 h. Then, the reaction mixture was cooled to RT, and NaBHCN (0.087 g, 1.392 mmol) was added. The solution was stirred at 50 °C for 1 h. The reaction mixture was cooled to RT and diluted with DCM. The solution was extracted with saturated NaHCO and the aqueous phase was washed with DCM (x2). All organic phases were combined, dried over NaSO, filtered, and concentrated. The crude material was purified via FCC (100% DCM to 5% MeOH in DCM) to give the desired product (63 mg, 51%).

[0401] [Table 34]

[0402] Pharmacological activity of the compounds of the present invention

[0403] In vitro assays Binding assay DDR1 and DDR2 binding assays were performed using LanthaScreen from Life Technologies. TMThe Europium Kinase Binding assay was performed in a white 384-well OptiPlate (PerkinElmer). Compounds were incubated with 5 nM DDR1 (Carna Biosciences) or 5 nM DDR2 (Life Technologies) in assay buffer (50 mM HEPES pH 7.5, 10 mM MgCl2, 1 mM EGTA, and 0.01% BRIJ35) at room temperature for 1 hour with 20 nM or 10 nM kinase tracer 178 and 2 nM Europium-labeled anti-GST antibody (Life Technologies).

[0404] The fluorescence emission 665 nm / 615 nm ratio was obtained after excitation at 340 nm using a Tecan Spark 20M plate reader. IC 50 IC values ​​were determined using GraphPad Prism 7.0 software using a four-parameter model: log(inhibitor) vs. response. 50 The value is calculated using the Cheng-Prusoff equation (Ki=IC 50 was converted to Ki using the formula: / (1 + [tracer] / Kd).

[0405] 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 at a density of 5000 cells / well in white 384-well plates and incubated for 2 hours at 37°C and 5% CO2. Cells were then treated with various concentrations of compounds, incubated for 30 minutes, and then stimulated with 20 μg / ml bovine type II collagen and incubated overnight at 37°C and 5% CO2. PathHunter detection reagent was prepared according to the protocol provided by DiscoverX, and 20 μl / well of this mixture was added to each well. After incubating the plate at room temperature in the dark for 1 hour, luminescence signals were acquired using a plate reader. Raw data were normalized to the vehicle control (0% for normalization) and the positive control (100% for normalization; cells treated with 20 μg / ml collagen II) to determine the IC. 50 Parameters were calculated in GraphPad Prism 8.0 software using sigmoidal dose-response curve fitting with variable slope.

[0406] DDR2 cell-based assay Inhibition of DDR2 phosphorylation by compounds was assessed by phospho-ELISA assay using HEK293T-DDR2 recombinant cells. Briefly, HEK293T-DDR2 cells were seeded at a density of 250,000 cells / well on poly-D-lysine-coated 24-well plates and incubated in DMEM + 10% FBS at 37°C and 5% CO2 for 1.5 hours. The medium was then changed to serum-free DMEM, and the cells were incubated for 3 hours. Different concentrations of test compounds were then added 30 minutes before stimulation with 50 μg / ml bovine type II collagen for an additional 3 hours. For the DDR2 phospho-ELISA assay (DuoSet IC human phospho-DDR2; R&D Systems), protein extracts were obtained by adding 60 μl / well of lysis buffer prepared according to the manufacturer's instructions. Protein concentrations in the samples were determined by BCA assay, and phospho-DDR2 levels were measured according to the R&D Systems label. Raw data were normalized to the maximum inhibition control (0% for normalization) and positive control (100% for normalization; cells treated with 20 μg / ml collagen II) and IC 50 Parameters were calculated in GraphPad Prism 8.0 software using variable slope sigmoidal dose-response curve fitting.

[0407] The results of the binding assays for individual compounds are shown below in Table 2, where the compounds are classified in terms of potency with respect to inhibitory activity, expressed as Ki, against DDR1 and DDR2.

[0408] [Table 35-1] [Table 35-2]

[0409] In Table 4 below, some compounds of the present invention are listed in terms of potency (IC) for inhibitory activity against DDR1 and DDR2 receptors in cell-based assays. 50) are classified from the perspective of

[0410] [Table 36]

[0411] As can be seen, the compounds in Tables 2 and 4 show good activity as antagonists of DDR1 and DDR2 receptors. Therefore, the compounds of the present invention can be effectively used in the treatment of diseases, disorders or conditions associated with DDR receptors, such as fibrosis, for example, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), liver fibrosis, renal fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis and systemic sclerosis. Furthermore, the present invention includes the following aspects. [Aspect 1] Formula (I): [ka] [In the formula, L and L 1 are different and independently selected from —C(O) and NH; L 2 is absent or is NH; Z is absent or -CH 2 and —C(O); R 1 is -O(C 1 -C 4 ) alkyl, [ka] selected from the group consisting of: n is 1; R is (C 1 -C 4 ) selected from the group consisting of alkyl and halo; R 2 is selected from the group consisting of heteroaryl and heterocycloalkyl, wherein said heteroaryl and heterocycloalkyl each optionally contain one or more —C(O)NHR 6 and optionally substituted by CN; R 3 is (C 1 -C 4 ) haloalkyl and -O(C 1 -C 4 ) haloalkyl; R 4 is H; R 5 is H or (C 1 -C 4 ) alkyl and heteroaryl (C 1 -C 4 ) alkyl-; R 6 is H or (C 1 -C 4 ) alkyl] and pharmaceutically acceptable salts thereof. [Aspect 2] R 1 is meta to the rest of the molecule, n is 1, and L 2 is absent, and R 4 is H, general formula (Ia):

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Claims

1. Formula (I): 【Chemistry 1】 [In the formula, L and L 1 are different and independently selected from —C(O) and NH; L 2 is absent; Z is absent or -CH 2 and —C(O); R 1 is -O(C 1 -C 4 ) alkyl, 【Chemistry 2】 and is meta to the rest of the molecule; n is 1; R is (C 1 -C 4 ) alkyl; R2 is selected from the group consisting of pyrimidinyl, pyridinyl, imidazo[1,2-a]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, 1H-indazolyl, indazolyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidinyl, and benzo[d]thiazolyl, wherein said heteroaryl and heterocycloalkyl are each optionally substituted by one or more of -C(O)NHR6 and CN; R 3 is (C 1 -C 4 ) haloalkyl; R 4 is H; R 5 is H or (C 1 -C 4 ) alkyl and heteroaryl (C 1 -C 4 ) alkyl-; R 6 is H or (C 1 -C 4 ) alkyl] or a pharmaceutically acceptable salt thereof.

2. L and L 1 are different and independently selected from —C(O) and NH; Z is absent or -CH 2 and —C(O); R 1 Yes, -AND 3 、 【Transformation 3】 selected from the group consisting of: n is 1; R is selected from the group consisting of methyl, ethyl, propyl, and isopropyl; R 2 is selected from the group consisting of pyrimidinyl, pyridinyl, imidazo[1,2-a]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, 1H-indazolyl, indazolyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidinyl, and benzo[d]thiazolyl, wherein said heteroaryl and heterocycloalkyl are each optionally selected from one or more —C(O)NHR 6 and optionally substituted by CN; R 3 is trifluoromethyl; R 5 is H or is selected from the group consisting of methyl, ethyl, and 3-methylimidazo[1,2-a]pyridinyl; R 6 is H or methyl, or a pharmaceutically acceptable salt thereof.

3. R 1 but, 【Chemistry 4】 General formula (Ib) which is: 【Transformation 5】 [In the formula, L and L 1 are different and independently selected from —C(O) and NH; Z is absent or -CH 2 and —C(O); R is (C 1 -C 4 ) alkyl; R2 is selected from the group consisting of pyrimidinyl, pyridinyl, imidazo[1,2-a]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, 1H-indazolyl, indazolyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidinyl, and benzo[d]thiazolyl, wherein said heteroaryl and heterocycloalkyl are each optionally substituted by one or more of -C(O)NHR6 and CN; R 3 is (C 1 -C 4 ) haloalkyl; R 5 is H or (C 1 -C 4 ) alkyl and heteroaryl (C 1 -C 4 ) alkyl-; R 6 is H or (C 1 -C 4 ) alkyl] 2. The compound of claim 1, wherein:

4. R 1 but, 【Transformation 6】 General formula (Ic) which is: 【Transformation 7】 [In the formula, L and L 1 are different and independently selected from —C(O) and NH; Z is absent or -CH 2 and —C(O); R is (C 1 -C 4 ) alkyl; R2 is selected from the group consisting of pyrimidinyl, pyridinyl, imidazo[1,2-a]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, 1H-indazolyl, indazolyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidinyl, and benzo[d]thiazolyl, wherein said heteroaryl and heterocycloalkyl are each optionally substituted by one or more of -C(O)NHR6 and CN; R 3 is (C 1 -C 4 ) haloalkyl; R 5 is H or (C 1 -C 4 ) alkyl and heteroaryl (C 1 -C4) alkyl-; R 6 is H or (C 1 -C 4 ) alkyl] 2. The compound of claim 1, wherein:

5. L 2 is absent and R 4 and R 5 is -H and Z is absent, 【Transformation 8】 [In the formula, L is —C(O); L 1 is —NH; R 1 is -O(C 1 -C 4 ) alkyl and 【Chemistry 9】 and is meta to the rest of the molecule; R is (C 1 -C 4 ) alkyl; R 2 teeth, 【Chemistry 10】 selected from the group consisting of: R 3 is (C 1 -C 4 ) haloalkyl] 2. The compound of claim 1, wherein:

6. L is —C(O); L 1 is -NH; R 1 But, -OCH 3 and 【Chemistry 11】 selected from the group consisting of: R is methyl; R 2 but, 【Chemistry 12】 selected from the group consisting of: R 3 6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein is trifluoromethyl.

7. L is -C(O), and L 1 is -NH and R 1 Ga-OCH 3 where R is methyl and R 2 but, 【Chemistry 13】 selected from the group consisting of: R 3 7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein is trifluoromethyl.

8. N-(2-methyl-5-((3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)carbamoyl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide; 4-methyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-3-((pyrimidin-5-ylamino)methyl)benzamide; N-methyl-4-((2-methyl-5-((3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)carbamoyl)benzyl)amino)picolinamide; N-methyl-4-((2-methyl-5-((3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)carbamoyl)benzyl)amino)picolinamide; N-(2-methyl-5-((3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)carbamoyl)benzyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide; N-(2-methyl-5-((3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)carbamoyl)benzyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide; N-(2-methyl-5-((3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)carbamoyl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide 4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((pyrimidin-5-ylamino)methyl)benzamide; 4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((pyrazolo[1,5-a]pyrimidin-6-ylamino)methyl)benzamide; 4-methyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-3-((pyrazolo[1,5-a]pyrimidin-6-ylamino)methyl)benzamide; N-(5-((3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)carbamoyl)-2-propylbenzyl)imidazo[1,2-a]pyridine-3-carboxamide formate; 4-Isopropyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-3-((pyrimidin-5-ylamino)methyl)benzamide; N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4-propyl-3-((pyrimidin-5-ylamino)methyl)benzamide; N-methyl-4-((2-methyl-5-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamido)benzyl)amino)picolinamide; N-(2-isopropyl-5-((3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)carbamoyl)benzyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide; N-(4-methyl-3-((pyrimidin-5-ylamino)methyl)phenyl)-3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamide; 4-Isopropyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5(trifluoromethyl)phenyl)-3-((pyrazolo[1,5-a]pyrimidin-6ylamino)methyl)benzamide; N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4-propyl-3-((pyrazolo[1,5-a]pyrimidin-6-ylamino)methyl)benzamide; N-(4-methyl-3-(((pyrimidin-5-ylmethyl)amino)methyl)phenyl)-3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamide; N-(3-((bis(imidazo[1,2-a]pyridin-3-ylmethyl)amino)methyl)-4-methylphenyl)-3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamide; N-methyl-4-(((2-methyl-5-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamido)benzyl)amino)methyl)picolinamide; N-(3-((((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)amino)methyl)-4-methylphenyl)-3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamide; 3-((ethyl(pyrazolo[1,5-a]pyrimidin-6-yl)amino)methyl)-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide; 4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(((4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)amino)methyl)benzamide; 3-(((1H-pyrrolo[2,3-b]pyridin-5-yl)amino)methyl)-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide; 3-(((1H-indazol-5-yl)amino)methyl)-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide; 3-(((5-cyanopyridin-2-yl)amino)methyl)-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide; 3-(((2-cyanopyridin-4-yl)amino)methyl)-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide; 3-((benzo[d]thiazol-6-ylamino)methyl)-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide; N-(3-(((imidazo[1,2-a]pyridin-3-ylmethyl)amino)methyl)-4-methylphenyl)-3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamide; 2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, selected from at least one of:

9. 4-methyl-3-((pyrimidin-5-ylamino)methyl)-N-(3-(trifluoromethyl)phenyl)benzamide; 3-(((1H-pyrrolo[2,3-b]pyridin-5-yl)amino)methyl)-4-fluoro-N-(3-(trifluoromethyl)phenyl)benzamide; 4-methyl-3-((pyridin-3-ylamino)methyl)-N-(3-(trifluoromethyl)phenyl)benzamide; 4-fluoro-3-(((5-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)amino)methyl)-N-(3-(trifluoromethoxy)phenyl)benzamide; 4-(difluoromethyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((pyrimidin-5-ylamino)methyl)benzamide; 4-methyl-3-((pyrimidin-5-ylamino)methyl)-N-(3-(trifluoromethoxy)phenyl)benzamide; and 3-(((1H-pyrrolo[2,3-b]pyridin-5-yl)amino)methyl)-4-fluoro-N-(3-(trifluoromethoxy)phenyl)benzamide, or a pharmaceutically acceptable salt thereof.

10. 10. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 9, in admixture with one or more pharmaceutically acceptable carriers or excipients.

11. 11. The pharmaceutical composition of claim 10 for oral administration or inhalation.

12. A medicament comprising a compound of formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10 or 11.

13. The pharmaceutical of claim 12 for treating a disease, disorder or condition associated with dysregulation of DDR1 and DDR2.

14. 14. A medicament according to claim 12 or 13 for the prevention and / or treatment of fibrosis and / or diseases, disorders or conditions involving fibrosis.

15. 15. The medicament according to claim 14, 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.

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

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