Benzylamine derivatives as DDR inhibitors

Abstract

The present invention relates to compounds of 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 therapeutic uses thereof. The compounds of the present invention can be used to treat diseases or conditions associated with DDR dysregulation, in particular fibrosis.

Description

Field of the Invention

[0001] In general, the present invention relates to compounds that inhibit discoidin domain receptors (hereinafter DDR inhibitors); the present invention relates to compounds that are benzylamine derivatives, methods for preparing the compounds, pharmaceutical compositions comprising the compounds and therapeutic uses of the compounds.

[0002] The compounds of the invention can be used, for example, to treat a number of diseases associated with the DDR mechanism. Background of the Invention

[0004] The discoidin domain receptor (DDR) family includes two different members, DDR1 and DDR2. DDR is a type I transmembrane receptor tyrosine kinase (RTK) that exhibits an overall structural organization similar to many members of the RTK family. They were initially discovered in the early 1990s by homologous cloning based on their 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).

[0005] Subsequently, collagen was identified as a ligand for the DDR (see Vogel, W. (1997) Mol. Cell 1, 13-23; Shrivastava A. Mol Cell. 1997; 1: 25-34.), thus establishing a unique feature of these receptors among other members of the RTK superfamily, which are typically activated by soluble peptide-like growth factors.

[0006] 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 the N-terminal DS and DS-like domains is a defining feature of the DDR RTK subfamily.

[0007] The DS domain contains the collagen binding region and is responsible for mediating the 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).

[0008] The EJXM region of the human DDR that connects the DS domain to the TM fragment (49 residues in DDR1 and 31 residues in DDR2) has an unknown structure. The EJXM region contains several putative N-glycosylation and O-glycosylation sites that may regulate receptor trafficking, turnover and / or ligand-induced activation (see Curat, C. (2001) J. Biol. Chem. 276, 45952-45958).

[0009] A short TM helical segment (~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).

[0010] The unusually large (130-140 residues) IJXM region connects the TM segment to the KD. The IJXM region contains several tyrosine residues that serve as docking sites for cytoplasmic effectors and regulators necessary for signal transduction. The classical KD (~300 residues) follows the IJXM region in both DDR1 and DDR2.

[0011] The DDR1 subfamily consists of five membrane-anchored isoforms, and the DDR2 subfamily is represented by a single protein. Five DDR1 isoforms are produced by alternative splicing. They have extracellular and transmembrane domains in common, but differ in the cytoplasmic region. Of the five DDR1 isoforms, three (DDR1a, DDR1b, DDR1c) are functional receptors (see Valiathan, RR (2012) Cancer Metastasis Rev. 31, 295–321; Alves, F. (2001) FASEB J. 15, 1321–1323).

[0012] DDR is unique among RTKs in that they are activated by the extracellular matrix protein collagen. DDR binds collagen only in its native triple helical conformation 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).

[0013] Both DDRs show 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). The DDRs have different preferences for certain types of collagen. DDR1 but not DDR2 binds to basement membrane collagen IV, while DDR2 apparently preferentially binds to collagen II and collagen X (see Leitinger BJ Mol Biol. 2004; 344(4): 993–1003; Leitinger B. Matrix Biol. 2006; 25(6): 355–364). Similar to collagen binding to integrins, the DDRs recognize specific amino acid motifs in collagens. Detailed studies using a triple-helical peptide library revealed a six-amino acid motif, GVMGFO, as a binding motif for both DDRs (see Farndale RW et al. Biochem Soc Trans. 2008; 36(Pt 2): 241-250).

[0014] DDRs are unusual RTKs because they form non-covalently linked ligand-independent stable dimers (see Noordeen, NA (2006) J. Biol. Chem. 281, 22744–22751; Mihai CJ Mol Biol. 2009; 385: 432–445). DDR dimers may be formed during biosynthesis and exist on the cell surface before ligand binding. Upon collagen binding, DDR undergoes tyrosine autophosphorylation. Two distinguishing features of DDR phosphorylation kinetics are delayed and sustained responses. Although typical RTKs are activated within seconds to minutes, maximum DDR activation is usually only reached a few hours after stimulation with collagen and can remain 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 attractive features of DDR phosphorylation are poorly understood.

[0015] Phosphorylation of tyrosine residues within the intracellular domain of the 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; CG (2002) FASEB J. 16, 234–236; Koo, DH (2006) FEBS Lett. 580, 15–22; Yang, G., (2009) Proteomics 9, 4944–4961).

[0016] Evidence to date suggests that stimulation of DDR1 with 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).

[0017] 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).

[0018] The phenotype of DDR knockout mice demonstrates the importance of DDR as a collagen receptor. Although both DDR1 and DDR2 knockout mice are viable, they are small 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.). The fibula of DDR1 knockout mice is poorly mineralized. In DDR2 knockout mice, dwarfism is associated with shorter long bones due to reduced chondrocyte proliferation. In humans, DDR2 mutations are associated with a variety of skeletal defects, including short limbs and abnormal calcification. In addition to being smaller in size, DDR knockout / mutant mice exhibit reproductive defects. DDR1 knockout mice are unable to lactate due to abnormal mammary gland morphogenesis. In addition, DDR1 knockout mice exhibit altered renal 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 cannot control their ear movements and exhibit loss of hearing function, with significant 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, renal structure, or hearing function. These mice, however, exhibit impaired skin wound healing due to defects in proliferation, invasion, proteolytic activity, and ECM remodeling of skin fibroblasts (see Olaso E, J Biol Chem. 2002; 277(5): 3606–3613).

[0019] Although some developmental defects have been found in DDR-null mice, these mice have been valuable in underestimating the role of these receptors in a variety of diseases, including pulmonary fibrosis.

[0020] The first evidence for a protective role of DDR1 deficiency in pulmonary fibrosis was generated by Dr. Vogel's group in 2006 (see Avivi-Green C, Am J Respir Crit Care Med 2006;174:420–427). The authors demonstrated that DDR1-deficient mice were largely protected from bleomycin (BLM)-induced injury. Furthermore, myofibroblast expansion and apoptosis were much lower in these animals compared to their wild-type counterparts. The absence of inflammation in the knockout mice was confirmed by lavage cell counts and cytokine ELISA. These results suggest that DDR1 expression is a prerequisite for the development of pulmonary inflammation and fibrosis.

[0021] Wang Z. et al. confirmed the above results using pharmacological methods (and treatment regimens) (see Wang, Z., J. Med. Chem. 2016, 59, 5911-5916). After the onset of BLM-induced fibrotic damage, mice were treated with compound 6j (a tetrahydroisoquinoline derivative). Compound 6j prevented BLM-induced pathological changes (i.e., alveolar cavity reduction and ECM deposition) in a dose-dependent manner. The histological results were accompanied by reduced expression levels of fibrotic markers fibronectin, α-SMA, and collagen.

[0022] The role of DDR2 in organ fibrosis is poorly understood and controversial. DDR2-null mice have increased liver fibrosis after chronic liver injury (see Olaso E, Am J Pathol 2011;179:2894–2004). On the other hand, DDR2 deficiency or downregulation reduces bleomycin-induced lung 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 a key role in the induction of fibrosis and angiogenesis in the lung. The authors showed that DDR2 synergizes with transforming growth factor (TGF)-β to induce myofibroblast differentiation. In addition, they showed that treatment of injured mice with specific siRNA against DDR2 exhibited therapeutic efficacy against lung fibrosis. In a second publication, Jia et al. demonstrated that mice lacking DDR2 were protected from bleomycin-induced lung fibrosis (see Jia S, Am J Respir Cell Mol Biol 2018;59:295–305). The authors demonstrated that after bleomycin treatment, DDR2-null mice presented a remarkably preserved alveolar architecture without massive cellular infiltration of the air spaces. Furthermore, DDR2-null fibroblasts were significantly more prone to apoptosis than wild-type fibroblasts, supporting a paradigm in which fibroblast resistance to apoptosis is critical for the progression of fibrosis.

[0023] Various compounds have been described in the literature as DDR1 or DDR2 antagonists.

[0024] WO2015004481 (Astex) discloses bicyclic compounds as DDR1 and DDR2 inhibitors, which can be used to treat diseases such as cancer.

[0025] WO2017005583 (F. Hoffmann-La Roche) discloses triazaspiro derivatives as DDR1 inhibitors, which can be used to treat kidney disorders, liver disorders, inflammatory disorders, vascular disorders, cardiovascular disorders, fibrotic diseases, cancer, and acute and chronic organ transplant rejection.

[0026] WO2014032755 (Merck) discloses compounds useful for the treatment and / or prevention of physiological and / or pathophysiological states in the triggering of which DDR2 is involved, in particular for the treatment and / or prevention of osteoarthritis.

[0027] WO2013161851 (Chugai) discloses benzamide derivatives as DDR1 antagonists, which can be used to treat fibrosis and / or inflammation.

[0028] WO2015060373 (Chugai) discloses quinazolinone and isoquinolinone derivatives as DDR1 antagonists, which can be used to treat fibrosis and / or inflammation.

[0029] WO2016064970 (Guangzhou) discloses isoquinoline derivatives as DDR1 inhibitors, which can be used as therapeutic agents for preventing and treating inflammation, liver fibrosis, kidney fibrosis, lung fibrosis, skin scars, atherosclerosis and cancer.

[0030] WO2005092896 (Jeil Pharmaceutical) discloses furanopyrimidine derivatives as DDR2 inhibitors, which can be used to treat diseases caused by DDR2 tyrosine kinase activity, such as cirrhosis, rheumatoid arthritis or cancer.

[0031] WO2010062038 (Legochem) discloses compounds as DDR1 and DDR2 inhibitors, which can be used to treat diseases known to be mainly caused by overactivation of DDR1 and DDR2, such as cancer, cirrhosis, arteriosclerosis, rheumatoid arthritis, osteoarthritis.

[0032] WO2017038870 (Toray) discloses urea derivatives as DDR1 inhibitors, which can be used to treat diseases in which the DDR1 receptor is involved.

[0033] Daniel E. Jeffries et al., in “Discovery of VU6015929: A Selective DiscoidinDomain Receptor 1 / 2 (DDR1 / 2) Inhibitor to Explore the Role of DDR1 in Antifibrotic Therapy”, Med. Chem. Lett. 2020, 11, 29-33, disclosed the selective dual DDR1 / 2 inhibitor 7e (VU6015929) and suggested DDR1 inhibition as a stimulatory target for antifibrotic therapy.

[0034] Notably, antagonizing DDR receptors may be useful in treating fibrosis and diseases, disorders and conditions resulting from fibrosis, and even more so, antagonizing both receptors DDR1 and DDR2 may be particularly effective in treating such diseases, disorders and conditions.

[0035] Several efforts have been made in the past few years to develop novel DDR1 and DDR2 receptor antagonists that could be used to treat several diseases, and some of these compounds have also shown efficacy in humans.

[0036] Despite the prior art cited above, there is still potential to develop inhibitors of both receptors DDR1 and DDR2 that can be used to treat diseases or disorders associated with dysregulation of DDR receptors, in particular fibrosis.

[0037] In this respect, the prior art does not describe or suggest the benzylamine derivatives of the general formula (I) according to the invention having antagonist activity towards the receptor DDR, which represent a solution to the above-mentioned need. SUMMARY OF THE INVENTION

[0039] In a first aspect, the present invention relates to compounds of formula (I)

[0040]

[0041] in

[0042] L and L1 are different and independently selected from -C(O) and NH; L2 is absent or is NH, wherein when L and L2 are both NH, L1 is -C(O);

[0043] Z is absent or selected from -CH2 and -C(O);

[0044] R1 is H or selected from -O(C1-C4)alkyl,

[0045] n is an integer from 1 to 3,

[0046] R is selected from (C1-C4)alkyl, halogen, (C1-C4)haloalkyl and

[0047] (C3-C6)cycloalkyl;

[0048] R2 is selected from heteroaryl and heterocycloalkyl, wherein the heteroaryl and heterocycloalkyl are each optionally substituted with one or more -C(O)NHR6, -CN, (C1-C4)alkyl, halogen, -NHC(O)R6, heteroaryl and -NR7R8;

[0049] R3 is selected from (C1-C4)alkyl, (C1-C4)haloalkyl, (C3-C6)cycloalkyl and -O(C1-C4)haloalkyl;

[0050] R4 is H or selected from (C1-C4)alkyl, halogen and (C3-C6)cycloalkyl;

[0051] R5 is H or selected from (C1-C4)alkyl and heteroaryl (C1-C4)alkyl-;

[0052] R6 is H or (C1-C4) alkyl;

[0053] R7 and R8 are independently H at each occurrence or selected from (C1-C4)alkyl, (C3-C8)cycloalkyl, (C1-C6)haloalkyl and halogen;

[0054] and pharmaceutically acceptable salts thereof.

[0055] In a second aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) in admixture with one or more pharmaceutically acceptable carriers or excipients.

[0056] In a third aspect, the present invention relates to compounds of formula (I) for use as medicaments.

[0057] In another aspect, the invention relates to compounds of formula (I) for use in the treatment of a disease, disorder or condition associated with DDR dysregulation.

[0058] In another aspect, the invention relates to compounds of formula (I) for use in the prevention and / or treatment of fibrosis and / or diseases, disorders or conditions involving fibrosis.

[0059] In another aspect, the present invention relates to compounds of formula (I) for use in the prevention and / or treatment of idiopathic pulmonary fibrosis (IPF).

[0060] In another aspect, the present invention relates to a compound of formula VIII

[0061]

[0062] It is preferably used as an intermediate for the preparation of a series of compounds of formula (I), wherein R, R1, R3, R4, L, L1 and L2 are as shown above for formula (I).

[0063] In another aspect, the present invention relates to a compound of formula VII

[0064]

[0065] It is preferably used as an intermediate for preparing a series of compounds of formula (I) wherein Z is absent, is CH2 or -C(O), and R, R1, R2, R3, R4, L, L1 and L2 are as shown above for formula (I). DETAILED DESCRIPTION OF THE INVENTION

[0067] Unless otherwise specified, it is intended that the compounds of formula (I) of the present invention also include stereoisomers, tautomers or pharmaceutically acceptable salts or solvates thereof.

[0068] As used in this application, the term "pharmaceutically acceptable salts" refers to derivatives of compounds of formula (I) wherein the parent compound is appropriately modified by converting any free acid or basic groups (if present) into the corresponding addition salts with any base or acid conventionally expected to be pharmaceutically acceptable.

[0069] Suitable examples of the salt may thus include inorganic or organic acid addition salts of basic residues such as amino groups, and inorganic or organic base addition salts of acid residues such as carboxyl groups.

[0070] Suitable cations of inorganic bases for preparing salts include ions of alkali metals or alkaline earth metals, such as potassium, sodium, calcium or magnesium.

[0071] Salts obtained by reacting the main compound acting as a base with an inorganic or organic acid to form a salt include, for example, 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 salts.

[0072] The term "solvate" means a physical association of a compound of the invention with one or more solvent molecules, whether organic or inorganic. Such physical association includes hydrogen bonding. In certain cases, the solvate will be capable of separation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. The solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules.

[0073] The term "stereoisomer" refers to isomers of identical composition that differ in the arrangement of their atoms in space. Enantiomers and diastereomers are examples of stereoisomers.

[0074] The term "enantiomer" refers to one of a pair of molecular structures that are mirror images of each other and are non-superimposable.

[0075] The term "diastereoisomers" refers to stereoisomers that are not mirror images.

[0076] The term "racemate" or "racemic mixture" refers to a composition consisting of equimolar amounts of two enantiomeric structures, wherein the composition is devoid of optical activity.

[0077] The symbols "R" and "S" represent the configuration of substituents around a chiral carbon atom. The isomeric descriptors "R" and "S" are used as described in this application to represent the atomic configuration relative to the 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)).

[0078] The term "tautomer" refers to each of two or more isomers of a compound that exist together in equilibrium and are readily interchangeable by migration of atoms or groups within the molecule.

[0079] As used in this application, the term "halogen" or "halogen atom" or "halo" includes fluorine, chlorine, bromine and iodine atoms.

[0080] The term “(C x -C y )alkyl", wherein x and y are integers, refers to a straight or branched chain alkyl group having xy carbon atoms. Thus, for example, when x is 1 and y is 6, the term includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl.

[0081] The statement “(C x -C y ) haloalkyl", wherein x and y are integers, refers to the "C x -C y "alkyl", wherein one or more hydrogen atoms are replaced by one or more halogen atoms (which may be the same or different). x -C y Examples of "haloalkyl" groups may include halogenated, polyhalogenated and fully halogenated alkyl groups in which all hydrogen atoms are replaced by halogen atoms, such as trifluoromethyl.

[0082] 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.

[0083] 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, and includes groups having two such monocyclic rings, or one such monocyclic ring and a monocyclic aromatic ring, which are fused by a common bond. Examples of heteroaryl are pyridyl, pyrimidinyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazole, indazolyl, benzo[d][1,2,3]triazolyl, imidazo[1,5-a]pyridinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[4,3-b]pyridinyl and tetrazo[1,5-a]pyridinyl.

[0084] Specific examples of monocyclic heteroaryl groups are pyrimidinyl and pyridinyl.

[0085] Specific examples of bicyclic heteroaryl are imidazo[1,2-a]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, 1H-indazolyl, indazolyl, benzo[d]thiazolyl.

[0086] The term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or bicyclic ring system of 3-10 ring atoms containing one or more heteroatoms selected from N, S or O. In a specific embodiment, heterocycloalkyl is a partially unsaturated bicyclic ring system of 7-9 ring atoms containing one or more heteroatoms selected from N, S or O. A specific example of a bicyclic partially unsaturated heterocycloalkyl is 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidinyl.

[0087] The term “(C x -C y )cycloalkyl", wherein x and y are integers, refers to a monovalent saturated monocyclic or bicyclic hydrocarbon radical having x to y ring carbon atoms. In a specific embodiment, cycloalkyl refers to a monovalent saturated monocyclic hydrocarbon radical of 3 to 8 ring carbon atoms. Bicyclic means consisting of two saturated carbon rings having one or more carbon atoms in common. Particular cycloalkyls are monocyclic. Examples of monocyclic cycloalkyls are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

[0088] The term "-O(C x -C y )cycloalkyl”, wherein x and y are integers, refers to the “(C x -C y )cycloalkyl" group wherein the carbon atom is attached to an oxygen atom. Examples include, for example, cyclopropyloxy.

[0089] The term “(C x -C y )aminoalkyl", wherein x and y are integers, refers to "(C1-C6)alkyl" as defined above, wherein one or more hydrogen atoms are replaced by one or more amino groups.

[0090] The bonds pointing to the wavy line or to the wavy line used in the structural formulae in this application, e.g. Describes the bond that is the point of attachment of a moiety or substituent to the core or backbone structure.

[0091] A dash ("-") that is not between two letters or symbols is intended to indicate a point of attachment for a substituent.

[0092] In the present application the carbonyl group is preferably represented as -C(O)-, as an alternative to other common representations such as -CO-, -(CO)- or -C(=O)-.

[0093] Generally, groups within brackets are pendant groups not included in the chain, and brackets are used to help disambiguate linear chemical formulas when deemed useful; for example, a sulfonyl group -SO2- can also be represented as -S(O)2- to disambiguate, for example, a sulfinyl group -S(O)O-.

[0094] Whenever a basic amino group or a quaternary ammonium group is present in a 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 naphthalene disulfonate. Likewise, in the presence of an acidic group such as a COOH group, a corresponding physiological cationic salt may also be present, for example comprising an alkali metal or alkaline earth metal ion.

[0095] The term "half maximal inhibitory concentration" (IC 50 ) represents the concentration of a specific compound or molecule required to obtain 50% inhibition of a biological process in vitro. IC 50 Values ​​can be logarithmically converted to pIC 50 Value (-log IC 50 ), where higher values ​​indicate exponentially greater potency. IC 50 The values ​​are not absolute but depend on the experimental conditions, such as the concentration used. The IC can be converted to 50 The values ​​were converted into absolute inhibition constants (Ki).

[0096] As mentioned above, the present invention relates to a series of compounds represented by formula (I) as described in detail below, which have inhibitory activity on receptors DDR1 and DDR2.

[0097] Advantageously, antagonizing both receptors DDRI and DDR2 may be particularly effective in treating those diseases in which DDR receptors play a relevant role in the pathogenesis, such as fibrosis and diseases, disorders and conditions resulting from fibrosis.

[0098] The compounds of formula (I) of the present invention are able to act as antagonists of both DDR1 and DDR2 receptors in a substantial and effective manner, which will be particularly appreciated by those skilled in the art when searching for suitable and effective compounds useful in the treatment of fibrosis, in particular idiopathic pulmonary fibrosis.

[0099] As shown in the experimental part, in fact, the compounds of formula (I) according to the invention are active both on the receptors DDR1 and DDR2, as shown in Table 3, where for each compound the potency expressed as inhibition constant (Ki) is reported.

[0100] It can be understood that the compounds of the present invention according to Table 3 show significant potency below about 1000 nM, and even below 300 nM for most of the compounds in terms of inhibitory activity against receptors DDR1 and DDR2, which confirms that they are able to antagonize the two isoforms of DDR receptors that are mainly involved in fibrosis and diseases caused by fibrosis.

[0101] In addition, some compounds of the present invention were characterized for their inhibitory activity against DDR1 and DDR2 receptors according to potency (IC 50 ) are classified in Table 4.

[0102] Therefore, the compounds of the present invention will be particularly appreciated by those skilled in the art in the search for suitable and effective compounds useful in the treatment of fibrosis, in particular idiopathic pulmonary fibrosis.

[0103] Thus, in one aspect, the present invention relates to compounds of formula (I) as DDR1 and DDR2 antagonists

[0104]

[0105] in

[0106] L and L1 are different and independently selected from -C(O) and NH; L2 is absent or NH, wherein when L and L2 are both NH, L1 is -C(O);

[0107] Z is absent or selected from -CH2 and -C(O);

[0108] R1 is H or selected from -O(C1-C4)alkyl,

[0109] n is an integer from 1 to 3,

[0110] R is selected from (C1-C4)alkyl, halogen, (C1-C4)haloalkyl and (C3-C6)cycloalkyl;

[0111] R2 is selected from heteroaryl and heterocycloalkyl, wherein the heteroaryl and heterocycloalkyl can be optionally substituted with one or more -C(O)NHR6, -CN, (C1-C4)alkyl, halogen, -NHC(O)R6, heteroaryl and -NR7R8;

[0112] R3 is selected from (C1-C4)alkyl, (C1-C4)haloalkyl, (C3-C6)cycloalkyl and -O(C1-C4)haloalkyl;

[0113] R4 is H or selected from (C1-C4)alkyl, halogen and (C3-C6)cycloalkyl;

[0114] R5 is H or selected from (C1-C4)alkyl and heteroaryl (C1-C4)alkyl-;

[0115] R6 is H or (C1-C4) alkyl;

[0116] R7 and R8 are independently H at each occurrence or selected from (C1-C4)alkyl, (C3-C8)cycloalkyl, (C1-C6)haloalkyl and halogen;

[0117] and pharmaceutically acceptable salts thereof.

[0118] In a preferred embodiment, the present invention relates to compounds of general formula (I)

[0119]

[0120] in

[0121] L and L1 are different and independently selected from -C(O) and NH; L2 is absent or NH;

[0122] Z is absent or selected from -CH2 and -C(O);

[0123] R1 is selected from -O(C1-C4)alkyl,

[0124] n is 1;

[0125] R is selected from (C1-C4) alkyl and halogen;

[0126] R2 is selected from heteroaryl and heterocycloalkyl, wherein the heteroaryl and heterocycloalkyl are each optionally substituted with one or more -C(O)NHR6 and CN;

[0127] R3 is selected from (C1-C4)haloalkyl and -O(C1-C4)haloalkyl;

[0128] R4 is H;

[0129] R5 is H or selected from (C1-C4)alkyl and heteroaryl (C1-C4)alkyl-;

[0130] R6 is H or (C1-C4) alkyl;

[0131] and pharmaceutically acceptable salts thereof.

[0132] In another preferred embodiment, the invention relates to compounds of general formula (I), wherein R1 is located in the meta position relative to the rest of the molecule, n is 1, L2 is absent, and R4 is H, said compound being represented by formula (Ia),

[0133]

[0134] in

[0135] L and L1 are different and independently selected from -C(O) and NH; Z is absent or selected from -CH2 and -C(O);

[0136] R1 is selected from -O(C1-C4)alkyl,

[0137] n is 1;

[0138] R is (C1-C4) alkyl;

[0139] R2 is selected from heteroaryl and heterocycloalkyl, wherein the heteroaryl and heterocycloalkyl are each optionally substituted with one or more -C(O)NHR6 and CN;

[0140] R3 is (C1-C4) haloalkyl;

[0141] R5 is H or selected from (C1-C4)alkyl and heteroaryl (C1-C4)alkyl-;

[0142] R6 is H or (C1-C4) alkyl;

[0143] and pharmaceutically acceptable salts thereof.

[0144] In another preferred embodiment, R2 is selected from 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.

[0145] In another preferred embodiment, the invention relates to compounds of formula (Ia), wherein L and L1 are different and independently selected from -C(O) and NH;

[0146] Z is absent or selected from -CH2 and -C(O);

[0147] R1 is selected from -OCH3,

[0148] n is 1;

[0149] R is selected from methyl, ethyl, propyl and isopropyl;

[0150] R2 is selected from 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 groups are each optionally substituted with one or more -C(O)NHR6 and CN;

[0151] R3 is trifluoromethyl;

[0152] R5 is H or selected from methyl, ethyl and 3-methylimidazo[1,2-a]pyridinyl;

[0153] R6 is H or methyl;

[0154] and pharmaceutically acceptable salts thereof.

[0155] According to a preferred embodiment, the present invention relates to at least one of the compounds listed in Table 1 below; as shown in Table 3, those compounds are active on DDR1 and DDR2 receptors.

[0156] Table 1 List of preferred compounds of formula (I)

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165] In another preferred embodiment, the present invention relates to compounds of general formula (Ia), wherein R1 is

[0166]

[0167] The compound is represented by the general formula (Ib),

[0168]

[0169] in

[0170] L and L1 are different and independently selected from -C(O) and NH;

[0171] Z is absent or selected from -CH2 and -C(O);

[0172] R is (C1-C4) alkyl;

[0173] R2 is selected from heteroaryl and heterocycloalkyl, wherein the heteroaryl and heterocycloalkyl are each optionally substituted with one or more -C(O)NHR6 and CN;

[0174] R3 is (C1-C4) haloalkyl;

[0175] R5 is H or selected from (C1-C4)alkyl and heteroaryl (C1-C4)alkyl-;

[0176] R6 is H or (C1-C4) alkyl;

[0177] and pharmaceutically acceptable salts thereof.

[0178] In another preferred embodiment, the invention relates to compounds of formula (Ib), wherein L and L1 are different and independently selected from -C(O) and NH;

[0179] Z does not exist or is C(O);

[0180] R is methyl or propyl;

[0181] R2 is selected from 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 groups are each optionally substituted with one or more -C(O)NHR6 and CN;

[0182] R3 is trifluoromethyl;

[0183] R5 is H or ethyl;

[0184] R6 is methyl.

[0185] In another preferred embodiment, the present invention relates to compounds of formula (Ia), wherein R1 is

[0186]

[0187] The compound is represented by the general formula (Ic),

[0188]

[0189] in

[0190] L and L1 are different and independently selected from -C(O) and NH;

[0191] Z is absent or selected from -CH2 and -C(O);

[0192] R is (C1-C4) alkyl;

[0193] R2 is selected from heteroaryl and heterocycloalkyl, wherein the heteroaryl and heterocycloalkyl are each optionally substituted with one or more -C(O)NHR6 and CN;

[0194] R3 is (C1-C4) haloalkyl;

[0195] R5 is H or selected from (C1-C4)alkyl and heteroaryl (C1-C4)alkyl-;

[0196] R6 is H or (C1-C4) alkyl;

[0197] and pharmaceutically acceptable salts thereof.

[0198] In another preferred embodiment, the invention relates to compounds of formula (Ic), wherein L and L1 are different and independently selected from -C(O) and NH;

[0199] Z is absent or selected from -CH2 and -C(O);

[0200] R is selected from methyl, propyl and isopropyl;

[0201] R2 is selected from imidazo[1,2-a]pyridinyl, pyrimidinyl, pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl and pyrazolo[1,5-a]pyrimidinyl, wherein the heteroaryl and heterocycloalkyl groups are each optionally substituted with one or more -C(O)NHR6;

[0202] R3 is trifluoromethyl;

[0203] R5 is H or 3-methylimidazo[1,2-a]pyridinyl;

[0204] R6 is a methyl group;

[0205] and pharmaceutically acceptable salts thereof.

[0206] In another embodiment, the present invention relates to a compound of formula (I), wherein L2 is absent, n is 1, R1 is -O(C1-C4)alkyl and is located in the para position relative to L1, and R4 is H, the compound is represented by formula (Id)

[0207]

[0208] in

[0209] L and L1 are different and independently selected from -C(O) and NH;

[0210] Z is absent or selected from -CH2 and -C(O);

[0211] R is (C1-C4) alkyl;

[0212] R2 is selected from heteroaryl and heterocycloalkyl, wherein the heteroaryl and heterocycloalkyl are each optionally substituted with one or more -C(O)NHR6 and CN;

[0213] R3 is (C1-C4) haloalkyl;

[0214] R5 is H or selected from (C1-C4)alkyl and heteroaryl (C1-C4)alkyl-;

[0215] R6 is H or (C1-C4) alkyl;

[0216] and pharmaceutically acceptable salts thereof.

[0217] In another embodiment, the invention relates to compounds of formula (Id), wherein L and L1 are different and independently selected from -C(O) and NH;

[0218] Z is absent or selected from -CH2 and -C(O);

[0219] R is selected from methyl, propyl and isopropyl;

[0220] R2 is selected from imidazo[1,2-a]pyridinyl, pyrimidinyl, pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl and pyrazolo[1,5-a]pyrimidinyl, wherein the heteroaryl and heterocycloalkyl groups are each optionally substituted with one or more -C(O)NHR6;

[0221] R3 is trifluoromethyl;

[0222] R5 is H or 3-methylimidazo[1,2-a]pyridinyl;

[0223] R6 is a methyl group;

[0224] and pharmaceutically acceptable salts thereof.

[0225] In another embodiment, the present invention relates to a compound of formula (Id), wherein L2 is absent, n is 1, R1 is -OCH3 and is located in the para position relative to L1, and R4 is H, the compound is represented by formula (Ie)

[0226]

[0227] in

[0228] L and L1 are different and independently selected from -C(O) and NH;

[0229] Z is absent or selected from -CH2 and -C(O);

[0230] R is (C1-C4) alkyl;

[0231] R2 is selected from heteroaryl and heterocycloalkyl, wherein the heteroaryl and heterocycloalkyl are each optionally substituted with one or more -C(O)NHR6 and CN;

[0232] R3 is (C1-C4) haloalkyl;

[0233] R5 is H or selected from (C1-C4)alkyl and heteroaryl (C1-C4)alkyl-;

[0234] R6 is H or (C1-C4) alkyl;

[0235] and pharmaceutically acceptable salts thereof.

[0236] In another preferred embodiment, the invention relates to compounds of formula (Ie), wherein L and L1 are different and independently selected from -C(O) and NH;

[0237] Z is absent or selected from -CH2 and -C(O);

[0238] R is selected from methyl, propyl and isopropyl;

[0239] R2 is selected from imidazo[1,2-a]pyridinyl, pyrimidinyl, pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl and pyrazolo[1,5-a]pyrimidinyl, wherein the heteroaryl and heterocycloalkyl groups are each optionally substituted with one or more -C(O)NHR6;

[0240] R3 is trifluoromethyl;

[0241] R5 is H or 3-methylimidazo[1,2-a]pyridinyl;

[0242] R6 is a methyl group;

[0243] and pharmaceutically acceptable salts thereof.

[0244] In another preferred embodiment, the present invention relates to compounds of general formula (I), wherein L2 is absent, R4 and R5 are -H, Z is absent, and the compound is represented by formula (If),

[0245]

[0246] in

[0247] L is -C(O); L1 is -NH;

[0248] R1 is H or selected from -O(C1-C4)alkyl and

[0249] R is selected from (C1-C4) alkyl and halogen;

[0250] R2 is selected from

[0251] R3 is selected from (C1-C4)haloalkyl and -O(C1-C4)haloalkyl;

[0252] and pharmaceutically acceptable salts thereof.

[0253] In another embodiment, the invention relates to compounds of formula (If), wherein L is -C(O); L1 is -NH;

[0254] R1 is H or selected from -OCH3 and

[0255] R is selected from methyl and fluorine;

[0256] R2 is selected from

[0257] R3 is selected from trifluoromethyl and trifluoromethoxy;

[0258] and pharmaceutically acceptable salts thereof.

[0259] In yet another preferred embodiment, the present invention relates to compounds of general formula (If), wherein L is -C(O), L1 is -NH, R1 is H or -OCH3, R is selected from methyl and fluorine, R2 is selected from

[0260] R3 is trifluoromethyl;

[0261] and pharmaceutically acceptable salts thereof.

[0262] In another preferred embodiment, the invention relates to at least one of the compounds listed in the following Table 2. As shown in Tables 3 and 4, those compounds are active on the receptors DDR1 and DDR2.

[0263] Table 2 List of preferred compounds of formula (If)

[0264]

[0265]

[0266] Compounds of the present invention, including all compounds listed above, can be prepared from readily available raw materials using the following general method and procedure or by using the slightly modified method that is easily available to those of ordinary skill in the art. Although specific embodiments of the present invention may be shown or described in the present application, it will be appreciated by those skilled in the art that all embodiments or aspects of the present invention can be obtained using the methods described in the present application or by using other known methods, reagents and raw materials. When typical or preferred process conditions (i.e. reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, other process conditions may also be used, except as otherwise specified. Although the optimal reaction conditions can vary depending on the specific reactants or solvents used, those skilled in the art can easily determine these conditions by conventional optimization methods.

[0267] Therefore, the methods described below and reported in the following schemes should not be construed as limiting the scope of synthetic methodologies that can be used to prepare the compounds of the present invention.

[0268] In some cases, when it is necessary to mask or protect sensitive or reactive moieties, commonly known protecting groups (PG) may be used according to general principles of chemistry (Protective groups in organic syntheses, 3rd edition TW Greene, PGM Wuts).

[0269] The preparation methods described below and reported in the following schemes should not be construed as limiting the scope of synthetic methods that can be used to prepare the compounds of the present invention.

[0270] Compounds of formula (I), including all compounds listed above, can generally be prepared according to the methods shown in the following schemes. If a specific synthetic step differs from that described in the general schemes, it has been described in detail in the specific examples and / or additional schemes.

[0271] The compounds of formula (I) contain at least one stereogenic center, which is marked with an asterisk * in the following formula.

[0272]

[0273] Enantiomerically pure compounds can be prepared from the corresponding racemates by chiral chromatography. Whenever there are two or more stereocenters in a compound of formula (I), the structure is characterized by different stereoisomers. Stereochemically pure compounds can be obtained by chiral separation, or stepwise by chromatographic separation of diastereomers followed by further chiral separation into single stereoisomers.

[0274] Compounds of formula (I) can be prepared according to Scheme 1 described below, providing at least one non-limiting synthetic route for the preparation of all the Examples.

[0275] Solution 1

[0276]

[0277] According to Scheme 1, intermediate III can be obtained from intermediate II by palladium-catalyzed cross-coupling on the most reactive leaving group between X1 and X2, wherein X1 and X2 can be, for example, chlorine, bromine, iodine, OMs or OTs. For example, the reaction can be carried out by reacting the dihalogenated aryl intermediate II with alkylboronic acid or alkyltrifluoroborate potassium according to the classical Suzuki procedure in a suitable organic solvent such as dioxane or THF, in the presence of an inorganic base such as K2PO4 or cesium carbonate, with a suitable palladium catalytic system such as Pd2(dppf)Cl2 or another palladium source / phosphine-based ligand at high temperature (about 100°C) for several hours.

[0278] Direct amidation (aminolysis) of the ester between intermediate III and intermediate IXa to give intermediate IV can be carried out using, for example, potassium tert-butoxide or sodium methoxide as promoter in a suitable organic solvent such as THF or dioxane at room temperature for several hours.

[0279] In a different approach, intermediate IV can be prepared by 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 and generally at about room temperature for several hours to overnight.

[0280] When R4 = H, palladium-catalyzed reductive carbonylation of aryl halides can be carried out starting from intermediate IV to prepare intermediate V. For example, formic acid or formylsaccharin can be used as a CO source, silane or formic acid itself as a hydrogen donor, a suitable palladium catalytic system such as palladium acetate / Ph3P or palladium acetate / bis(diphenylphosphino)butane or another palladium source / phosphine-based ligand, TEA or Na2CO3 as a base, in a suitable solvent such as toluene or DMF, at a temperature of 60 to 100°C for several hours.

[0281] 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 the acid 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.

[0282] In a different approach, when R = CHF2, intermediate XX can be prepared from intermediate XXV by, for example, ester hydrolysis using LiOH in a suitable solvent such as THF or dioxane at room temperature.

[0283] Intermediate XXV can be obtained via ozonolysis using, for example, an ozone stream in a suitable solvent such as DCM and a suitable reductive work-up, for example using Ph3P or Me2S at a suitable temperature (eg, zero degrees).

[0284] Deoxyfluorination 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 reacting halide-aryl intermediate XXIII (wherein the halide is X3) with alkyl boronic acid or alkyl potassium trifluoroborate according to the classical Suzuki procedure in a suitable organic solvent such as dioxane or THF in the presence of an inorganic base such as K2PO4 or cesium carbonate with a suitable palladium catalytic system such as Pd2(dppf)Cl2 or another palladium source / phosphine-based ligand at elevated temperature (about 100°C) for several hours to give intermediate XXIV. Reductive amination of intermediate V with amine R2-NH2 (when R4=H) to give intermediate VII can be carried out in a solvent such as 1,2-dichloroethane or DCM in the presence of a reducing agent such as NaBH3CN or Na(OAc)3BH at room temperature.

[0285] Differently, intermediate VII can be prepared via a two-step synthesis, wherein intermediate V is first reacted with an amine R2-NH2 in a suitable solvent such as 1,2-dichloroethane, DCM or toluene at room temperature or under reflux (if necessary) to form the imine intermediate VI. 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.

[0286] When R4 = alkyl or cycloalkyl, intermediate VI can also be used to prepare intermediate VII by 1,2-addition of a suitable organometallic reagent such as a Grignard reagent or an organolithium reagent at a temperature between 78°C and room temperature.

[0287] In another approach, intermediate VII (when R4 = alkyl or cycloalkyl) can be prepared by converting intermediate V to amine intermediate VIII by reductive amination with 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 a temperature between room temperature and 50° C. Intermediate VIII can then be subjected to a Buchwald-Hartwig cross-coupling reaction with a halide or triflate R2-X (when R2 = heteroaryl) in a suitable organic solvent such as dioxane or toluene in the presence of an inorganic base such as K2PO4 or cesium carbonate using a suitable palladium catalytic system such as Pd(dba)2 / RuPhos or another palladium source / phosphine-based ligand at elevated temperature (about 100° C.) for a period of several hours to overnight.

[0288] Alternatively, the leaving group of R2-X (when R2 = heteroaryl) is Ipso-substituted by the amine group of intermediate VIII to give intermediate VII, which can be carried out in a high boiling point organic solvent such as DMSO or DMA, at a temperature equal to or higher than 100°C, and in the presence of an inorganic base such as tBuOK or K2CO3.

[0289] When R5 = H, intermediate VII is converted to compound I without further reaction.

[0290] When R5 is not H and Z is absent or is CH2, intermediate VII can be converted to a compound of formula (I) by reductive amination with an alkanal R5-CHO in a manner analogous to that described for the preparation of intermediate VII from intermediate V.

[0291] Alternatively, compounds of formula (I) may be prepared according to Scheme 2 described below, which provides at least one non-limiting synthetic route for the preparation of all of the Examples.

[0292] Solution 2

[0293]

[0294] According to Scheme 2, intermediate XVIII can be converted to intermediate XV by Pd-catalyzed alkylation of the aryl bromide via Negishi, Stille or Suzuki cross-coupling by reacting XVIII with an alkyl zinc halide or alkyl stannane in the presence of a suitable organic solvent such as THF or toluene with a suitable palladium catalytic system such as Pd(OAc)2 / CPhos or another palladium source / phosphine-based ligand at elevated temperature (about 100°C) for a period of several hours to overnight.

[0295] Alternatively, intermediate XV can be prepared via intermediate XVII, which is obtained starting from intermediate XVIII according to the Suzuki protocol using, for example, alkenyl boronic acids or vinyl trifluoroborate with a suitable palladium catalytic system such as PdCl2 ( dppf), in the presence of an inorganic base such as TEA or cesium carbonate, in a suitable solvent such as dioxane or iPrOH, at elevated temperature (about 100°C) for a period of several hours to overnight. Intermediate XVII can then be converted to intermediate XV by reduction under a hydrogen atmosphere in the presence of a suitable catalyst (e.g. Pd / C) in a suitable solvent (e.g., but not limited to EtOH) at room temperature for several hours.

[0296] In a different approach, intermediates XV can be obtained from intermediates XVI by Pd-catalyzed cyanation of aryl halides using, for example, zinc cyanide in a suitable solvent such as DMF or DMA and a suitable Pd catalyst such as Pd(PPh3)4 or Xantphos-PdCl2 at elevated temperatures (about 100°C).

[0297] Catalytic hydrogenation of intermediate XV to give intermediate XIV can be carried out under a hydrogen atmosphere using, for example, Raney nickel or platinum dioxide and ammonia or KOH in a suitable solvent such as MeOH or iPrOH at room temperature.

[0298] Intermediate XIV can be converted to intermediate XIII by a Buchwald-Hartwig cross-coupling reaction using a halide or triflate R2-X (when R2 = heteroaryl) in a suitable organic solvent such as dioxane or toluene in the presence of an inorganic base such as K2PO4 or cesium carbonate with a suitable palladium catalytic system such as Pd(dba)2 / RuPhos or another palladium source / phosphine-based ligand at elevated temperature (about 100°C) for a period of several hours to overnight. When Z = CO, the amide coupling can be carried out using an activator such as COMU or HATU with an organic base such as DIPEA or TEA in a suitable organic solvent such as DCM or DMF and generally at about room temperature for a period of several hours to overnight.

[0299] Ester hydrolysis of intermediate XIII using an inorganic base such as LiOH or Ba(OH)2 in an organic solvent such as THF and / or a mixture of methanol and water, generally at room temperature, for a period of 1 hour to overnight can provide intermediate XII. Intermediate XII can be converted to intermediate VII by amide coupling reaction with amine IXa, using an activating agent such as BTFFH or T3P, with an organic base such as DIPEA or TEA, in a suitable organic solvent such as DCM or DMF, and generally at a temperature of about room temperature, for a period of several hours to overnight.

[0300] Direct amidation (aminolysis) of the ester between intermediate XIII and intermediate IXa can be carried out 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.

[0301] When R5 = H, intermediate VII requires no further reaction to be converted into the compound of formula (I).

[0302] Intermediate VII can be converted to compounds of formula (I) by alkylation of the amide nitrogen using, for example, an alkyl halide or alkyl triflate R5-X with a suitable base such as KOH or NaH in a suitable solvent such as DMSO or DMF when R5 is not H and Z is CO.

[0303] In various methods, compounds of formula (I) may be prepared according to Scheme 3 described below, which provides at least one non-limiting synthetic route for the preparation of all of the Examples.

[0304] Solution 3

[0305]

[0306] According to Scheme 3, intermediate VIII can be converted to intermediate VII by reductive amination in a manner similar to that described for the preparation of intermediate VII from intermediate V using a heteroaryl aldehyde R2-CHO.

[0307] Buchwald-Hartwig amination can be carried out starting from intermediate VIII in a similar manner as described above for the preparation of intermediate XIII to afford intermediate VII (when Z is absent).

[0308] Alternatively, intermediate VII can be prepared by reacting intermediate VIII with a fluoroaryl R2-X, using for example LiOH as a base, in a suitable high boiling point solvent such as DMF, at a temperature between room temperature and 100°C for ipso-substitution.

[0309] Catalytic hydrogenation of the cyano group on intermediate XI in a manner similar to that described above for intermediate XIV can provide intermediate VIII. When L=NH and L2 is absent, intermediate XI can be obtained by amide coupling using intermediate X and carboxylic acid Xa in a manner similar to that described above for intermediate XIII.

[0310] When L2 = NH, intermediate XI can be prepared in a two-step process using a p-nitrochloroformate with a suitable base such as pyridine or TEA in a suitable solvent such as DCM at room temperature to form the p-nitrocarbamate, followed by the formation of the urea using an amine IXa, a suitable solvent such as DCM or DMF and a base such as DIPEA or TEA at room temperature.

[0311] In a different approach, when L2 = CO, intermediate XI can be obtained directly from intermediate XIX via amide coupling with intermediate IXa in a manner similar to the preparation of intermediate XIII described above.

[0312] In another alternative method, intermediate XI can be prepared from intermediate IV via Pd-catalyzed cyanation in a manner similar to the preparation of intermediate XV described above.

[0313] When R5 = H, intermediate VII requires no further reaction to be converted to the compound of formula (I).

[0314] When R5 is not H and Z is CO, intermediate VII can be converted to compounds of formula (I) by alkylation of the amide nitrogen using, for example, an alkyl halide or alkyl triflate R5-X with a suitable base such as KOH or NaH in a suitable solvent such as DMSO or DMF.

[0315] Alternatively, when R5 is not H and Z is absent or is CH2, intermediate VII can be converted to compounds of formula (I) via reductive amination with an alkyl aldehyde R5-CHO in a manner similar to that described for the preparation of intermediate VII from intermediate V.

[0316] As mentioned above, the compounds of formula (I) of the present invention can be conveniently prepared by using common intermediates represented by compounds of formula VII and VIII.

[0317] In another aspect, the present invention relates to a compound of formula VIII

[0318]

[0319] wherein R, R1, R3 and R4 are as shown above.

[0320] In another aspect, the present invention relates to a compound of formula VII

[0321]

[0322] wherein Z is absent, is CH2 or -C(O), and R, R1, R2, R3 and R4 are as shown above.

[0323] In another aspect, the present invention relates to the use of compound VII as an intermediate for preparing a compound of formula (I), wherein Z is absent, is CH2 or -C(O), and R, R1, R2, R3 and R4 are as shown above.

[0324] In another aspect, the present invention relates to the use of compound VIII as an intermediate for the preparation of compounds of formula (I).

[0325] It has surprisingly been found that the compounds of formula (I) of the present invention effectively inhibit both receptors DDR1 and DDR2. Advantageously, the inhibition of receptors DDR1 and DDR2 may lead to effective treatment of diseases or disorders in which DDR receptors are involved.

[0326] In particular in this regard, it has now been found that the compounds of formula (I) according to the present invention have antagonist drug potency expressed as inhibition constants (Ki) for DDR1 and DDR2, which, as shown in the experimental part of the present application, show Ki values ​​below 1000 nM, and for the vast majority of the compounds according to the present invention, Ki is even below 300 nM. Preferably, the compounds according to the present invention have a Ki of less than or equal to 30 nM for DDR1 and DDR2.

[0327] Furthermore, it has been found that some compounds of formula (I) of the present invention have an activity expressed as IC 50 The inhibitory drug potency, its IC 50 Below 15 nM and even more preferably below 10 nM.

[0328] In one aspect, the invention relates to compounds of formula (I) for use as medicaments.

[0329] In a preferred embodiment, the invention relates to compounds of formula (I) for use in the treatment of disorders associated with the DDR receptor mechanism.

[0330] In another embodiment, the invention relates to compounds of formula (I) for use in the treatment of a disease, disorder or condition associated with a DDR receptor.

[0331] In one embodiment, the invention relates to compounds of formula (I) which are useful for preventing and / or treating fibrosis and / or diseases, disorders or conditions involving fibrosis.

[0332] As used in this application, the term "fibrosis" or "fibrotic disorder" refers to a disorder associated with abnormal accumulation of cells and / or fibronectin and / or collagen and / or increased recruitment of fibroblasts, and includes, but is not limited to, fibrosis of an individual organ or tissue such as the heart, kidney, liver, joints, lung, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal, and digestive tract.

[0333] Preferably, the compounds of formula (I) of the present invention can be used to treat and / or prevent fibrosis, such as pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), liver fibrosis, kidney fibrosis, eye fibrosis, cardiac fibrosis, arterial fibrosis and systemic sclerosis. More preferably, the compounds of formula (I) of the present invention can be used to treat IPF.

[0334] In one aspect, the present invention also relates to a method for preventing and / or treating a disorder associated with the DDR receptor mechanism, said method comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I).

[0335] In another aspect, the present invention relates to the use of compounds of formula (I) according to the present invention for treating disorders associated with the DDR receptor mechanism.

[0336] In one aspect, the present invention relates to the use of a compound of formula (I) for the preparation of a medicament for the treatment of a disorder associated with the DDR receptor mechanism.

[0337] In another aspect, the invention relates to a method for preventing and / or treating disorders or conditions associated with DDR receptor 1 and receptor 2 dysregulation by administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I).

[0338] In another aspect, the invention relates to the use of a compound of formula (I) for treating a disease, disorder or condition associated with DDR receptor 1 and receptor 2 dysregulation.

[0339] As used in this application, "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 sufficient to treat the patient's condition but low enough to avoid serious side effects, and it can still be determined by conventional methods by those skilled in the art.

[0340] The compounds of formula (I) may be administered once or according to a dosing regimen in which multiple doses are administered at varying intervals over a given period of time. The typical daily dose may vary depending on the route of administration chosen.

[0341] The present invention also relates to pharmaceutical compositions comprising a compound of formula (I) in admixture with at least one or more pharmaceutically acceptable carriers or excipients.

[0342] In one embodiment, the invention relates to pharmaceutical compositions of compounds of formula (I) in admixture with one or more pharmaceutically acceptable carriers or excipients, such as those described in Remington's Pharmaceutical Sciences Handbook, XVII Ed., Mack Pub., NY, USA.

[0343] Administration of the compounds of the invention and pharmaceutical compositions thereof can be accomplished according to the patient's needs, for example, orally, intranasally, parenterally (subcutaneously, intravenously, intramuscularly, intrasternal and by infusion) and by inhalation.

[0344] Preferably, the compounds of the invention are administered orally or by inhalation.

[0345] In a preferred embodiment, the pharmaceutical composition comprising the compound of formula (I) is a solid oral dosage form, such as tablets, gelcaps, capsules, caplets, granules, lozenges and bulk powders.

[0346] In one embodiment, the pharmaceutical composition comprising a compound of formula (I) is a tablet.

[0347] The compounds of the present invention can be administered alone or in combination with various pharmaceutically acceptable carriers, diluents (e.g., sucrose, mannitol, lactose, starch) and known excipients, including suspending agents, solubilizers, buffers, binders, disintegrants, preservatives, colorants, flavoring agents, lubricants, etc.

[0348] In another embodiment, the pharmaceutical composition comprising the compound of formula (I) is a liquid oral dosage form, such as aqueous and non-aqueous solutions, emulsions, suspensions, syrups and elixirs. Such liquid dosage forms may also include suitable known inert diluents (e.g., water) and suitable known excipients (e.g., preservatives, wetting agents, sweeteners, flavoring agents) and agents for emulsifying and / or suspending the compounds of the invention.

[0349] In another embodiment, the pharmaceutical composition comprising a compound of formula (I) is an inhalable formulation, such as an inhalable powder, a propellant-containing metered aerosol or a propellant-free inhalable formulation.

[0350] For administration as dry powder, single-dose or multi-dose inhalers known in the prior art can be used. In this case, the powder can be filled in gelatin, plastic or other capsules, cartridges or blister packs or in a reservoir.

[0351] A diluent or carrier which is chemically inert to the compounds of the invention, for example lactose or any other additive suitable for improving the respirable fraction may be added to the powdered compounds of the invention.

[0352] Inhalation aerosols containing propellant gases such as hydrofluoroalkanes may contain the compounds of the invention in solution or dispersed form. Propellant-driven formulations may also contain other ingredients such as co-solvents, stabilizers and optionally other excipients.

[0353] Propellant-free inhalable preparations containing the compounds of the invention may be in the form of solutions or suspensions in water, alcohol or hydroalcoholic media, and they may be delivered by means of jet or ultrasonic nebulizers or by soft mist nebulizers known in the art.

[0354] The compounds of the present invention may be administered as the sole active agent or in combination with other pharmaceutically active ingredients.

[0355] The dosage of the compounds of the invention will depend on a variety of factors, including the specific disease to be treated, the severity of the symptoms, the route of administration, and the like.

[0356] The present invention also relates to a device comprising a pharmaceutical composition comprising a compound of formula (I) according to the invention, in the form of a single-dose or multi-dose dry powder inhaler or a metered dose inhaler.

[0357] All preferred groups or embodiments described above for the compounds of the formula (I) can be combined with one another and, mutatis mutandis, can also be applied to one another.

[0358]

[00136] Various aspects of the invention described in this application are illustrated by the following examples, which are not meant to limit the invention in any way.

[0359] Preparation of Intermediates and Examples

[0360] The chemical names of the compounds were generated using Structure To Name Place IUPAC Name of PerkinElmer ChemDraw Professional 18.1.

[0361] The compounds of the present invention can be prepared from readily available raw materials using the following general methods and procedures or by using other information that is readily available to those of ordinary skill in the art. Although a specific embodiment of the present invention may be shown or described in the present application, it will be appreciated by those skilled in the art that all embodiments or aspects of the present invention can be prepared using the methods described in the present application or by using other methods, reagents and raw materials known to those skilled in the art. It should also be understood that, in the case of giving typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.), unless otherwise indicated, other process conditions may also be used. Although the optimum reaction conditions may vary according to the specific reactants or solvents used, those skilled in the art can easily determine these conditions by conventional optimization methods.

[0362] abbreviation

[0363] Et3N = triethylamine; TEA = triethylamine; HATU = (dimethylamino)-N,N-dimethyl(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methanamineium hexafluorophosphate; DAST = diethylaminosulfur trifluoride; DMAP = 4-dimethylaminopyridine; DMF = dimethylformamide; Me2S or (CH3)2S = methylsulfide; MnO2 = manganese(IV) dioxide; EtOAc = ethyl acetate; RT = room temperature; THF = tetrahydrofuran; DCM = dichloromethane; MeOH = methanol; 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; PdCl2(dppf) = [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II); atm = atmospheric pressure; RuPhos = 2-dicyclohexylphosphino-2′,6′-diisopropylbiphenyl; Pd(dba)2 = bis(dibenzylideneacetone)palladium(0); BINAP = (±)-2,2′-bis(diphenylphosphino)-1,1′- Binaphthyl; 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-dipyrrolidinium hexafluorophosphate; pTLC = preparative thin layer chromatography; FCC = flash column chromatography; amu = atomic mass unit; t R = retention time; FA = formic acid

[0364] General experimental details

[0365] NMR characterization

[0366] Recorded on a Bruker Avance III HD 400MHz or Bruker Fourier 300MHz 1 H NMR spectra. Chemical shifts are reported as δ values ​​in ppm relative to tetramethylsilane (TMS) as an internal standard. Coupling constants (J values) are given in Hertz (Hz) and multiplicities are reported using the following abbreviations (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, nd = not determined).

[0367] LC / UV / MS analysis method

[0368] The LC / MS retention times were estimated to be subject to an experimental error of ±0.5 min.

[0369] Method 1 (LCMS-019-20-80-95-6-1-25-UV-BCM)

[0370] Instrument: Dionex UHPLC Ultimate3000 with DAD detector / Thermo Scientific MSQ Plus

[0371] column: 2.6μm XB-C18 (4.6x50mm), 110A, column number 00B-4496-E0, inner column number 019

[0372] Reagents:

[0373] Formic acid ≥98%, Sigma-Aldrich

[0374] HPLC UV / gradient grade acetonitrile, Baker

[0375] μQ-Water for LCMS

[0376] HPLC conditions:

[0377] Wavelength range: (190–340)nm±4nm

[0378] Flow rate: 1.0ml / min

[0379] Column temperature: 25°C

[0380] Automatic sampler temperature: 20℃

[0381] Injection volume: 2.0 μl

[0382] Analysis time: 6 minutes

[0383] Elution: Gradient

[0384]

[0385]

[0386] Mobile phase A: 0.1% v / v formic acid in water

[0387] Mobile phase B: 0.1% v / v formic acid in acetonitrile

[0388] Syringe wash solution: 20% MeOH

[0389] MS conditions:

[0390] Mass range: 100–1000 m / z

[0391] Ionization: Alternating

[0392] Scanning speed: 12000amu / sec

[0393] Method 2 (LCMS-019-10-60-95-6-1-25-UV)

[0394] Instrument: Dionex UHPLC Ultimate3000 with DAD detector / Thermo Scientific MSQ Plus

[0395] column: 2.6μm XB-C18 (4.6x50mm), 110A, column number 00B-4496-E0, inner column number 019

[0396] Reagents:

[0397] Formic acid ≥98%, Sigma-Aldrich

[0398] HPLC UV / gradient grade acetonitrile, Baker

[0399] μQ-Water for LCMS

[0400] HPLC conditions:

[0401] Wavelength range: (190–340)nm±4nm

[0402] Flow rate: 1.0ml / min

[0403] Column temperature: 25°C

[0404] Automatic sampler temperature: 20℃

[0405] Injection volume: 2.0 μl

[0406] Analysis time: 6 minutes

[0407] Elution: Gradient

[0408] Time [min] Mobile phase A[%] Mobile phase B[%] Flow rate [ml / min] 0.0 90 10 1.0 3.35 40 60 1.0 3.75 40 60 1.0 3.9 5 95 1.0 4.75 5 95 1.0 5.0 90 10 1.0 6.0 90 10 1.0

[0409] Mobile phase A: 0.1% v / v formic acid in water

[0410] Mobile phase B: 0.1% v / v formic acid in acetonitrile

[0411] Syringe wash solution: 20% MeOH

[0412] MS conditions:

[0413] Mass range: 100–1000 m / z

[0414] Ionization: Alternating

[0415] Scanning speed: 12000amu / sec

[0416] Method 3 (LCMS-019-5-80-80-7-1-25-UV-Rot)

[0417] Instrument: Dionex UHPLC Ultimate3000 with DAD detector / Thermo Scientific MSQ Plus

[0418] column: 2.6μm XB-C18 (4.6x50mm), 110A, column number OOB-4496-E0, inner column number 019

[0419] Reagents:

[0420] Formic acid ≥98%, Sigma-Aldrich

[0421] HPLC UV / gradient grade acetonitrile, Baker

[0422] μQ-Water for LCMS

[0423] HPLC conditions:

[0424] Wavelength range: (190–340)nm±4nm

[0425] Flow rate: 1.0ml / min

[0426] Column temperature: 25°C

[0427] Automatic sampler temperature: 20℃

[0428] Analysis time: 7 minutes

[0429] Elution: Gradient

[0430] Time [min] Mobile phase A[%] Mobile phase B[%] Flow rate [ml / min] 0.0 95 5 1.0 1.0 95 5 1.0 4.75 20 80 1.0 5.25 20 80 1.0 6.0 95 5 1.0 7.0 95 5 1.0

[0431] Mobile phase A: 0.1% v / v formic acid in water

[0432] Mobile phase B: 0.1% v / v formic acid in acetonitrile

[0433] Syringe wash solution: 20% MeOH

[0434] MS conditions:

[0435] Mass range: 100–1000 m / z

[0436] Ionization: Alternating

[0437] Scanning speed: 12000amu / sec

[0438] Method 4 (LCMS-019-10-70-95-6-1-25-UV)

[0439] Instrument: Dionex UHPLC Ultimate3000 with DAD detector / Thermo Scientific MSQ Plus

[0440] column: 2.6μm XB-C18 (4.6x50mm), 110A, column number 00B-4496-E0, inner column number 019

[0441] Reagents:

[0442] Formic acid ≥98%, Sigma-Aldrich

[0443] HPLC UV / gradient grade acetonitrile, Baker

[0444] μQ-Water for LCMS

[0445] HPLC conditions:

[0446] Wavelength range: (190–340)nm±4nm

[0447] Flow rate: 1.0ml / min

[0448] Column temperature: 25°C

[0449] Automatic sampler temperature: 20℃

[0450] Injection volume: 2.0 μl

[0451] Analysis time: 6 minutes

[0452] Elution: Gradient

[0453] Time [min] Mobile phase A[%] Mobile phase B[%] Flow rate [ml / min] 0.0 90 10 1.0 3.35 30 70 1.0 3.75 30 70 1.0 3.9 5 95 1.0 4.75 5 95 1.0 5.0 90 10 1.0 6.0 90 10 1.0

[0454] Mobile phase A: 0.1% v / v formic acid in water

[0455] Mobile phase B: 0.1% v / v formic acid in acetonitrile

[0456] Syringe wash solution: 20% MeOH

[0457] MS conditions:

[0458] Mass range: 100–1000 m / z

[0459] Ionization: Alternating

[0460] Scanning speed: 12000amu / sec

[0461] Method 5 (LCMS-005-1-30-50-10-05-55-UV)

[0462] Instrument: Dionex UHPLC Ultimate3000 with DAD detector / Thermo Scientific MSQ Plus

[0463] Column: ACQUITY UPLC BEH C8 1.7 μm (2.1 x 150 mm), 130A, column number 186003377, inner column number 005

[0464] Reagents:

[0465] Formic acid ≥98%, Sigma-Aldrich

[0466] HPLC UV / gradient grade acetonitrile, Baker

[0467] μQ-Water for LCMS

[0468] HPLC conditions:

[0469] Wavelength range: (190–340)nm±4nm

[0470] Flow rate: 0.5ml / min

[0471] Column temperature: 55°C

[0472] Automatic sampler temperature: 20℃

[0473] Analysis time: 10 minutes

[0474] Elution: Gradient

[0475] Time [min] Mobile phase A[%] Mobile phase B[%] Flow rate [ml / min] 0.0 99 1 0.5 0.5 99 1 0.5 3.0 70 30 0.5 6.5 50 50 0.5 7.5 20 80 0.5 8.0 20 80 0.5 8.1 99 1 0.5 10.0 99 1 0.5

[0476] Mobile phase A: 0.1% v / v formic acid in water

[0477] Mobile phase B: 0.1% v / v formic acid in acetonitrile

[0478] Syringe washing solution: 20% MeOH

[0479] MS conditions:

[0480] Mass range: 100–1000 m / s

[0481] Ionization: Alternating

[0482] Scanning speed: 12000amu / sec

[0483] Method 6: (LCMS-019-30-80-95-6-1-25-UV)

[0484] Instrument: Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific MSQ Plus

[0485] column: 2.6μm XB-C18 (4.6x50mm), 110A, column number 00B-4496-E0, inner column number 019

[0486] Reagents:

[0487] Formic acid ≥98%, Sigma-Aldrich

[0488] HPLC UV / gradient grade acetonitrile, Baker

[0489] μQ-Water for LCMS

[0490] HPLC conditions:

[0491] Wavelength range: (190–340)nm±4nm

[0492] Flow rate: 1.0ml / min

[0493] Column temperature: 25°C

[0494] Automatic sampler temperature: 20℃

[0495] Analysis time: 6 minutes

[0496] Elution: Gradient

[0497] Time [min] Mobile phase A[%] Mobile phase B[%] Flow rate [ml / min] 0.0 70 30 1.0 3.35 20 80 1.0 3.75 20 80 1.0 3.90 5 95 1.0 4.75 5 95 1.0 5.00 70 30 1.0 6.00 70 30 1.0

[0498] Mobile phase A: 0.1% v / v formic acid in water

[0499] Mobile phase B: 0.1% v / v formic acid in acetonitrile

[0500] Syringe wash solution: 20% MeOH

[0501] MS conditions:

[0502] Mass range: 100–1000 m / z

[0503] Ionization: Alternating

[0504] Scanning speed: 12000amu / sec

[0505] If the preparation of starting materials is not described, these are either commercially available, known in the literature or readily available to those skilled in the art using standard methods. All solvents were purchased from commercial sources and used without further purification.

[0506] Thin layer chromatography was performed on Merck silica gel 60 F254 TLC plates.

[0507] Preparative thin layer chromatography (pTLC) was performed using single plate 1000 micron or 500 micron silica gel plates. Flash chromatography was performed on the Interchim PuriFlash 450 and 520 Plus systems using pre-packed silica gel columns.

[0508] When referring to the use of "similar" or "analogous" methods, such methods may involve minor changes, such as reaction temperature, reagent / solvent amounts, reaction time, workup conditions or chromatographic purification conditions, as will be understood by those skilled in the art. Unless otherwise stated, all final compounds are obtained in free base form.

[0509] General Method A for Amide Coupling

[0510] Carboxylic acid or carboxylate (1.0 eq), amine (1.0 eq.) and DIPEA (6.0 eq.) were dissolved in anhydrous DCM in an argon atmosphere. T3P (50% EtOAc solution, 1.5 eq.) was then added and the reaction system was stirred overnight at RT. 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 a crude product which was purified by the method shown.

[0511] General Procedure B for Amide Couplings

[0512] Carboxylic acid or carboxylate (1.0 eq) was dissolved in anhydrous DMF under argon atmosphere, and BTFFH (3.0 eq) and DIPEA (4.5 eq) were then added. Next, amine (1.5 eq) was added and the reaction was stirred at 80 ° C overnight. The reaction mixture was then concentrated to dryness in vacuo and the residue was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (3x), the combined organic phases were washed with brine, and concentrated to give a crude product, which was purified by the method shown.

[0513] General Method C for Amide Couplings:

[0514] 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 overnight at RT, then the reaction mixture was partitioned between DCM and saturated NaHCO. The aqueous phase was extracted with DCM (3x), the combined organic layers were dried over NaSO, and concentrated in vacuo to give a crude product, which was purified by the method shown.

[0515] Scheme for the preparation of the intermediate 3-[(4-methylpiperazin-1-yl)methyl]-5-(trifluoromethyl)benzoate lithium

[0516]

[0517] Step 1: Preparation of methyl 3-bromo-5-(trifluoromethyl)benzoate

[0518]

[0519] To a solution of 3-bromo-5-(trifluoromethyl)benzoic acid (75.0 g, 279 mmol) in MeOH (282 mL) was added dropwise SOCl2 (81.0 mL, 1115 mmol) at 0°C. The reaction mixture was then stirred overnight under reflux, and the volatiles were removed in vacuo. Water (200 mL) was added to the residue, and the aqueous layer was extracted with EtOAc (2x250 mL). The combined organic layers were washed with a saturated solution of NaHCO3 (2x200 mL), dried over Na2SO4, and concentrated in vacuo to give the product (74.5 g, 94%) as a light brown solid.

[0520] 1 H NMR (300MHz, DMSO-d6) δ 8.30 (dt, J=1.8, 0.8Hz, 2H), 8.13 (td, J=1.6, 0.8Hz, 1H), 3.90 (s, 3H).

[0521] Step 2: Preparation of methyl 3-[(4-methylpiperazin-1-yl)methyl]-5-(trifluoromethyl)benzoate

[0522]

[0523] 3-Bromo-5-(trifluoromethyl)benzoate (47.5 g, 168 mmol), Cs2CO3 (164 g, 503 mmol), 1-methyl-4-trifluoroboric acid methylpiperazine (40.6 g, 184.6 mmol) were suspended in a mixture of THF (100 mL) and water (11 mL). The suspension was degassed, then Pd(OAc)2 (3.76 g, 16.8 mmol) and XPhos (16.0 g, 33.5 mmol) were added and the reaction was allowed to proceed at 80°C for 24 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 150 mL). The combined organic phases were concentrated and dried in vacuo 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%).

[0524] 1H NMR (300MHz, DMSO-d6) δ8.16 (d, J=1.7Hz, 1H), 8.07 (t, J=1.8Hz, 1H), 7.97–7.86 (m, 1H), 3.90 (s, 3H), 3.62 (s, 2H), 2.38 (s, 8H), 2.15 (s, 3H).

[0525] Step 3: Preparation of lithium 3-[(4-methylpiperazin-1-yl)methyl]-5-(trifluoromethyl)benzoate

[0526]

[0527] 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 overnight at RT. The solvent was removed in vacuo and the crude material was triturated with ether (2x) and filtered. The solid was collected to give the title product as a solid (26.0 g, 100%).

[0528] 1 H NMR (300MHz, DMSO-d6) δ 8.02 (s, 2H), 7.49 (s, 1H), 3.51 (s, 2H), 2.32 (s, 8H), 2.14 (s, 3H).

[0529] Scheme for the preparation of intermediate 5-(1-methyl-1H-pyrazol-3-yl)pyridin-3-amine

[0530]

[0531] Step 1: Preparation of 5-(1-methyl-1H-pyrazol-3-yl)pyridin-3-amine

[0532] 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 min, and then Pd(dppf)Cl (0.211 g, 0.289 mmol) was added. The reaction mixture was stirred at 90 ° C for 3 h, then cooled to RT and concentrated. The crude material was purified by FCC (elution system: 100% to 10% MeOH in DCM). The compound was ground with EtO to obtain the desired product (468 mg, 93%).

[0533] 1 H NMR (300MHz, DMSO-d6) δ8.20–8.10 (m, 1H), 7.84 (d, J = 2.6Hz, 1H), 7.73 (d, J = 2.2Hz , 1H), 7.31 (dd, J=2.6, 1.8Hz, 1H), 6.62 (d, J=2.3Hz, 1H), 5.33 (s, 2H), 3.87 (s, 3H).

[0534] Example 1

[0535] 4-Methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((pyrazolo[1,5-a]pyrimidin-6-ylamino)methyl)benzamide

[0536]

[0537] Step 1: Preparation of 3-iodo-4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]benzamide

[0538]

[0539] The solution of 3-iodo-4-methylbenzoic acid (7.00g, 26.7mmol) in SOCl2 (47mL) was refluxed for 2h, then evaporated in vacuo to remove residual SOCl2. The residue was dissolved in anhydrous THF (25mL), added dropwise to a solution of DIPEA (4.14g, 32.0mmol), 3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)aniline (6.44g, 26.7mmol) and DMAP (130mg, 1.06mmol) in anhydrous THF (48mL). The reaction mixture was stirred at RT for 17h, evaporated in vacuo. The residue was dissolved in EtOAc (200mL). Water (180mL) was added, and pH was adjusted to 8 with 1M NaOH. The layers were then separated, and the aqueous layer was extracted with DCM / MeOH 100:5 (100mL x5). The combined organic extracts were evaporated in vacuo to give the final product as an off-white solid (13.05 g, 100%).

[0540] 1H NMR (300MHz, DMSO-d6) δ10.67 (s, 1H), 8.46 (d, J = 1.9Hz, 1H), 8.27 (t, J = 1.9Hz, 1H), 8.21 (d, J = 1.4Hz, 1H), 8.13 (d, J = 1.8Hz, 1H), 7 .94 (dd, J=7.9, 1.9Hz, 1H), 7.74 (d, J=1.8Hz, 1H), 7.53 (d, J=8.0Hz, 1H), 7.49 (d, J=1.6Hz, 1H), 2.46 (s, 3H), 2.18 (d, J=1.0Hz, 3H).

[0541] Step 2: Preparation of 3-formyl-4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]benzamide

[0542]

[0543] PPh3 (1.62 g, 6.2 mmol), I2 (1.57 g, 6.2 mmol) and toluene (20 mL) were added to a 100 mL sealed test tube equipped with a stirring bar and stirred at RT for 10 min. 3-iodo-4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]benzamide (2.50 g, 5.15 mmol), Pd(OAc)2 (34.7 mg, 3 mol%) and Et3N (3.13 g, 30.9 mmol) were then added to the solution. HCOOH (0.95 g, 20.6 mmol) was then added, the test tube was immediately sealed, and the mixture was stirred at 80°C for 4 h. The reaction mixture was cooled to RT, diluted with EtOAc (150 mL) and washed with 0.01 M NaOH. The aqueous layer was extracted with EtOAc (150 mL x 2) and the combined extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (DCM / MeOH 100:1 to 100:4) to give the product as a yellow solid (1.055 g, 53%).

[0544] 1H NMR (300MHz, DMSO-d6) δ10.83 (s, 1H), 10.35 (s, 1H), 8.48 (d, J = 2.1Hz, 1H), 8.30 (d, J = 2.0Hz, 1H), 8.22 (d, J = 1.4Hz, 1H), 8.18 ( dd, J=8.0, 1.8Hz, 1H), 8.16–8.14 (m, 1H), 7.75 (s, 1H), 7.59 (s, 1H), 7.50 (t, J=1.3Hz, 1H), 2.73 (s, 3H), 2.18 (d, J=1.0Hz, 3H).

[0545] 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

[0546]

[0547] 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. Next, STAB (208 mg, 0.98 mmol) was added and the reaction mixture was stirred at RT overnight. 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 x2). The combined extracts were 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%).

[0548]

[0549] Example 2

[0550] 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

[0551]

[0552] 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. STAB (25.2 mg, 0.12 mmol) was then added and the reaction mixture was stirred overnight at RT. The reaction mixture was treated with 0.1 M NaOH (10 mL) and the product was extracted with DCM (30 mL x 3). The combined extracts were dried over Na2SO4, filtered and evaporated under reduced pressure. The solid residue was purified by preparative HPLC to give the product as a light yellow solid (5 mg, 16%).

[0553]

[0554] The following compounds were prepared by reductive amination as described in Example 1, Steps 1-3, using the corresponding commercially available amine in Step 3.

[0555]

[0556]

[0557] Example 6

[0558] 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

[0559]

[0560] 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 NaBH4 (9 mg, 0.24 mmol) was added at RT. The reaction mixture was stirred at RT overnight. AcOH was evaporated under reduced pressure and the residue was dissolved in 0.4 M NaOH (7 mL) and the product was extracted with DCM (20 mL x 3). The combined extracts were 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%).

[0561]

[0562] Example 7

[0563] 3-(((2-cyanopyridin-4-yl)amino)methyl)-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide

[0564]

[0565] Step 1: Preparation of 3-cyano-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide

[0566]

[0567] 3-Iodo-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide (7 g, 14.43 mmol), zinc cyanide (2.028 g, 17.31 mmol) and Pd(PPh3)4 (0.834 g, 0.721 mmol) prepared as described in Example 1, Step 1 were dissolved in DMF (48.1 ml). The reaction mixture was stirred at 80°C for 4 hr. The mixture was diluted with EtOAc and washed with water. The organic solvent was then removed under reduced pressure. The crude material was purified by dry flash chromatography (hexane:EtOAc, 9:1) to give the product as a light brown powder (6.7 g, quantitative)

[0568] 1 H NMR (300MHz, DMSO-d6) δ10.78 (s, 1H), 8.42 (d, J = 1.9Hz, 1H), 8.27 (t, J = 1.9Hz, 1H), 8.22 (d, J = 1.4Hz, 1H), 8.19 (dd, J = 8.1, 2.0Hz, 1H), 8.13 (d, J=1.9Hz, 1H), 7.77 (d, J=2.2Hz, 1H), 7.69 (d, J=8.2Hz, 1H), 7.51 (t, J=1.3Hz, 1H), 2.59 (s, 3H), 2.19 (d, J=1.0Hz, 3H).

[0569] Step 2: Preparation of 3-(aminomethyl)-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide

[0570]

[0571] 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,) and 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 celite pad, concentrated and dried in vacuo to give a crude product (1.62 g, 67.6%), which was used in the next step without further purification.

[0572] 1 H NMR (300MHz, DMSO-d6) δ10.59 (s, 1H), 8.31 (s, 1H), 8.19 (d, J=14.4Hz, 2H), 8.03 (s, 1H), 7.78 (d, J= 7.4Hz, 1H), 7.72 (s, 1H), 7.50 (s, 1H), 7.33 (d, J=7.9Hz, 1H), 3.80 (s, 2H), 2.36 (s, 3H), 2.18 (s, 3H).

[0573] 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 (Example 7)

[0574]

[0575] 3-(aminomethyl)-4-methyl-N-(3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)phenyl)benzamide (0.1g, 0.257mmol) and 4-fluoropyridine-2-carbonitrile (0.038g, 0.309mmol) are dissolved in DMF (0.52ml). Then LiOH (0.013g, 0.548mmol) is added, and the reaction mixture is stirred overnight at RT. The reaction mixture is diluted with water and extracted with AcOEt (x3). The organic layers are combined and Na is used SO Drying, filtered, and concentrated. By FCC purification of crude material (100% DCM to 10% MeOH in DCM solution), the desired product is obtained as a white solid (67mg, 53%).

[0576]

[0577] Example 8 was prepared according to the above scheme using the appropriate fluoro-arylamine.

[0578]

[0579]

[0580] Example 9

[0581] N-(4-methyl-3-((pyrimidin-5-ylamino)methyl)phenyl)-3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamide

[0582]

[0583] Step 1: Preparation of N-(3-cyano-4-methylphenyl)-3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamide

[0584]

[0585] 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 (3x50 mL). The aqueous phase was then extracted with DCM (3x50 mL). The combined organic layers were washed with brine (100 mL) and concentrated in vacuo. The crude material was purified by column chromatography (DCM:MeOH, 100:0 to 90:10) to give the title compound (0.342 g, 22% yield) as a pink-white solid.

[0586] 1 H NMR (300MHz, DMSO-d6) δ10.67 (s, 1H), 8.26-8.13 (m, 3H), 7.97-7.87 (m, 2H), 7.49 (d, J=8.5Hz, 1H), 3.65 (s, 2H), 2.47 (s, 3H), 2.38 (d, J=21.9Hz, 8H), 2.16 (s, 3H).

[0587] Step 2: Preparation of N-(3-(aminomethyl)-4-methylphenyl)-3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamide

[0588]

[0589] 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 added to Raney Nickel (1.6 ml, 0.828 mmol) and stirred at RT under a hydrogen atmosphere (balloon) for 16 h. The reaction mixture was filtered through a pad of celite, concentrated, and dried in vacuo to give the crude product (334 mg, 96% yield) as a yellow solid which was used in the subsequent step without additional purification.

[0590] 1 H NMR (300MHz, DMSO-d6) δ10.41 (d, J=10.1Hz, 1H), 8.19 (d, J=9.4Hz, 2H), 7.84 (s, 1H), 7.70 (d, J=2.2Hz, 1H), 7.59 (dd, J =8.1, 2.3Hz, 1H), 7.11 (d, J = 8.3Hz, 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).

[0591] Step 3: Preparation of N-(4-methyl-3-((pyrimidin-5-ylamino)methyl)phenyl)-3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamide (Example 9)

[0592]

[0593] N-(3-(Aminomethyl)-4-methylphenyl)-3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamide (110 mg, 0.262 mmol), 5-bromopyrimidine (49.9 mg, 0.314 mmol) and Cs2(CO)3 (256 mg, 0.785 mmol) were suspended in toluene (2 mL). The mixture was degassed with argon, then RuPhos (24.42 mg, 0.052 mmol) and Pd(dba)2 (15.04 mg, 0.026 mmol) were added, and the reaction system was stirred at 110°C for 16 h. The reaction was partitioned between water and DCM, the product was extracted with DCM (x3), the combined organic layers were washed with brine and concentrated in vacuo 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.

[0594]

[0595] Example 10

[0596] N-methyl-4-((2-methyl-5-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamido)benzyl)amino)picolinamide

[0597]

[0598] N-(3-(Aminomethyl)-4-methylphenyl)-3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamide (110 mg, 0.262 mmol), 4-bromo-N-methylpicolinamide (67.5 mg, 0.314 mmol) and Cs2(CO)3 (256 mg, 0.785 mmol), prepared as described in Step 1-2 of Example 9, were suspended in toluene (2 mL). The mixture was degassed with argon, then BINAP (32.6 mg, 0.052 mmol) and Pd(dba)2 (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 compound was extracted with DCM (x3), the combined organic layers were washed with brine and concentrated in vacuo 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 light brown solid.

[0599]

[0600]

[0601] Embodiment 11

[0602] N-(4-methyl-3-(((pyrimidin-5-ylmethyl)amino)methyl)phenyl)-3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamide

[0603]

[0604] N-(3-(Aminomethyl)-4-methylphenyl)-3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamide (0.07 g, 0.166 mmol) prepared as described in Example 9, Step 1-2 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)4 (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. 1 M NaOH solution was added to the reaction mixture. The desired product was then extracted with EtOAc (3x10 mL) and the combined organic layers were washed with brine (1x10 mL) and concentrated in vacuo to give the crude material which was purified by column chromatography (DCM:MeOH, 100:0-90:10) to afford the title compound (22.98 mg, 27% yield) as a yellow solid.

[0605]

[0606]

[0607] The following compounds were prepared by reacting the corresponding commercially available aldehydes via reductive amination as described in Example 11.

[0608]

[0609]

[0610]

[0611] Example 16

[0612] 4-Isopropyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5(trifluoromethyl)phenyl)-3-((pyrazolo[1,5-a]pyrimidin-6-ylamino)methyl)benzamide

[0613]

[0614] Step 1: Preparation of 3-cyano-4-(propan-2-yl)benzoate; 3-cyano-4-propylbenzoic acid methyl ester

[0615]

[0616] To a mixture of 4-bromo-3-cyanobenzoic acid methyl ester (4.00 g, 16.67 mmol), CPhos (0.146 g, 0.333 mmol) and Pd(OAc)2 (0.037 g, 0.167 mmol) in THF (67 mL) was added dropwise a 0.5 M solution of isopropylzinc (II) bromide in THF (40 ml, 20.00 mmol) at 0 °C. The reaction was allowed to proceed for 3 h at RT and then the reaction mixture was concentrated in vacuo. The residue was partitioned between EtOAc and water, the desired compound was extracted with EtOAc (2x30 mL), the combined organic phases were washed with water (30 mL) and then with brine (30 mL), then dried over Na2SO4 and concentrated in vacuo. The resulting crude product was purified by column chromatography (hexanes:EtOAc, 98:2 to 96:4) to give a mixture of isomers (1:1 ratio) as a light yellow oil (2.76 g, 81%).

[0617] 1 H NMR (300MHz, DMSO-d6) δ8.26 (dd, J=3.7, 1.8Hz, 2H), 8.18 (ddd, J=9.9, 8.2, 1.9Hz, 2H), 7.73 (d, J=8.3Hz, 1H), 7.65 (d, J=8.2Hz, 1H), 3 .88 (s, 6H), 3.30 (dd, J=14.1, 7.2Hz, 1H), 2.84 (dd, J=8.4, 6.8Hz, 2H), 1.75–1.60 (m, 2H), 1.30 (d, J=6.9Hz, 6H), 0.93 (t, J=7.3Hz, 3H).

[0618] Step 2: Preparation of 3-cyano-4-(propan-2-yl)benzoic acid; 3-cyano-4-propylbenzoic acid

[0619]

[0620] 1M LiOH (8.61 mL) was added 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 and the reaction was allowed to proceed for 16 h at RT. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was washed with EtOAc (2x30 mL) and the organic phase was discarded. The aqueous layer was then acidified with 1M HCl and the product was extracted with EtOAc (3x50 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give the title isomeric mixture as a white solid (1:1 ratio, 1.25 g, 77%).

[0621] 1H NMR (300MHz, DMSO-d6) δiPr 13.40 (s, 1H, OH), 8.26-8.12 (m, 2H, CH), 7.70 (d, J = 8.2Hz, 1H, CH), 3.32-3.21 (m, 1H, CHMe2), 1.30 (d, J = 6.9Hz, 6H, CH3) δnPr 13.40 (s, 1H, OH), 8.26-8.12 (m, 2H, CH), 7.62 (d, J=8.1Hz, 1H, CH), 2.84 (dd, J=8.5, 6.7Hz, 2H, CH2), 1.77-1.60 (m, 2H, CH2), 0.93 (t, J=7.3Hz, 3H, CH3).

[0622] 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

[0623]

[0624] DMF (8.18 μl, 0.106 mmol) and oxalyl chloride (0.370 ml, 4.23 mmol) were added 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) under argon atmosphere and the mixture was stirred at RT for 4 h. Next, the solvent was 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) at 0°C and stirred at RT for 16 h. The reaction was diluted with DCM, washed with water (25 mL) and the aqueous phase was extracted with DCM (3x25 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4 and concentrated in vacuo to give the crude product, which was purified by column chromatography (DCM:MeOH, 100:0-90:10) to give a mixture of isomers as a white solid (1:1 ratio, 0.672 g, 72%).

[0625] 1H NMR(300MHz, 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=8.4Hz), 7.38 (s, 1H), 3.56 (s, 2H), 3.29 (m, 1H), 2.38 (m, 8H), 2.16 (s, 3H), 1.33 (d, J=6.9Hz, 6H). δnPr 10.63 (s, 1H), 8.41 (m, 1H), 8.28-8.15 (m, 2H), 8.00 (s, 1H), 7.68 (d, J=8.1Hz, 1H), 7.38 (s, 1H), 3.56 ( s, 2H), 2.86 (t, J=7.6Hz, 2H), 2.38 (m, 8H), 2.16 (s, 3H), 1.69 (p, J=7.4Hz, 2H), 0.95 (t, J=7.3Hz, 3H).

[0626] 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

[0627]

[0628] To 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 added Raney Nickel (3 mL, 3.02 mmol) and stirred at RT under hydrogen atmosphere (balloon) for 3 d. The reaction mixture was filtered through a pad of celite, concentrated and dried in vacuo to give a mixture of isomers as a green-yellow solid (iPr:nPr ratio 3:1, 0.589 g, 87%) which was used in the next step without further purification.

[0629] 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, 1H), 4.05-3.93 (m, 2H), 3.63 (s, 2H), 2.55 (m, 8H), 2.30 (s, 3H) 1.30 (d, J = 6.8 Hz, 6H). CHiPr was obscured by the solvent peak. ΔnPr 8.10 (s, 1H), 7.95 (d, J=2.2Hz, 1H), 7.80 (dd, J=8.1, 2.1Hz, 1H), 7.45 (s, 1H), 7.37 (d, J=8.0Hz, 2H), 4.05-3.93 (m, 2H), 3.63 (d, J=9.8Hz, 2H), 2.83-2.68 (m, 2H), 2.55 (m, 8H) 2.30 (s, 3H), 1.69 (m, 2H), 1.04 (t, J=7.3Hz, 3H).

[0630] 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).

[0631]

[0632]

[0633] 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 tert-butoxide (65.1 mg, 0.678 mmol) were added, followed by Pd2(dba)3 (62.1 mg, 0.068 mmol) and tBuXPhos (57.6 mg, 0.136 mmol). The reaction system was stirred at 80°C for 17 hr, and 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 by FCC (DCM:MeOH 1:0 to 0:1) and then by preparative HPLC (ACN, H2O + 0.1% NH3) to give 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 white solids.

[0634]

[0635]

[0636] Embodiment 18

[0637] 4-Methyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5(trifluoromethyl)phenyl)-3-((pyrazolo[1,5-a]pyrimidin-6-ylamino)methyl)benzamide

[0638]

[0639] Step 1: Preparation of methyl 3-cyano-4-methylbenzoate

[0640]

[0641] In a 3-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 in an argon atmosphere. Pd(PPh3)4 (2.8 g, 2.4 mmol) was added and the reaction system was stirred at 100°C overnight. Thereafter, the reaction mixture was filtered through a celite pad and the filtrate was concentrated in vacuo. The crude product was purified by FCC (hexane: EtOAc, 98:2-95:5) to give the title compound as a white solid (7.47 g, 86%).

[0642] 1 H NMR (300MHz, CDCl3) δ 8.30 (d, J=1.7Hz, 1H), 8.16 (dd, J=1.8, 8.3Hz, 1H), 7.44 (d, J=8.1Hz, 1H), 3.97 (s, 3H), 2.64 (s, 3H).

[0643] Step 2: Preparation of methyl 3-(aminomethyl)-4-methylbenzoate

[0644]

[0645] To a solution of methyl 3-cyano-4-methylbenzoate (6.99 g, 39.9 mmol) in MeOH (399 mL) was added 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, concentrated, and dried in vacuo to give a crude material which was purified by FCC (hexanes:EtOAc, 50:50 to MeOH:EtOAc:NH3 10:89:1) to give the title compound as a yellow oil (3.63 g, 47%).

[0646] 1 H NMR (300MHz, DMSO-d6) δ8.03 (s, 1H), 7.72 (dd, J=

[0647] 1.9, 7.7Hz, 1H), 7.27 (d, J=7.7Hz, 1H), 3.84 (s, 3H), 3.74 (s, 2H), 2.32 (s, 3H), 2.01 (br s, 2H)

[0648] Step 3: Preparation of 4-methyl-3-((pyrazolo[1,5-a]pyrimidin-6-ylamino)methyl)benzoic acid

[0649]

[0650] 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 an argon atmosphere and tBuXPhos (0.142 g, 0.335 mmol) and Pd2(dba)3 (0.153 g, 0.167 mmol) were added. The reaction was allowed to proceed at 110 °C overnight and then filtered through a pad of celite, concentrated and dried in vacuo to give a 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%)

[0651] 1 H NMR (300MHz, DMSO-d6) δ12.43 (s, 1H), 8.41 (s, 1H), 7.96–7.84 (m, 2H), 7.78 (d, J = 8.1Hz, 1H), 7.35 (d, J=7.8Hz, 2H), 6.54 (s, 1H), 6.41 (t, J=5.6Hz, 1H), 4.30 (d, J=5.4Hz, 2H), 2.43 (s, 3H).

[0652] 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 18)

[0653]

[0654] Example 18 was prepared following the general procedure A for amide coupling by reaction of 4-methyl-3-((pyrazolo[1,5-a]pyrimidin-6-ylamino)methyl)benzoic acid (0.03 g) with the desired amine to give a yellow solid (0.006 g; 11%).

[0655]

[0656] Embodiment 19

[0657] 4-Methyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-3-((pyrimidin-5-ylamino)methyl)benzamide

[0658]

[0659] Step 1: Preparation of 4-methyl-3-((pyrimidin-5-ylamino)methyl)benzoic acid

[0660]

[0661] Methyl 3-(aminomethyl)-4-methylbenzoate (0.500 g, 2.79 mmol), prepared as described in steps 1-3 of Example 18, Cs2CO3 (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, then RuPhos (0.520 g, 1.11 mmol) and Pd(dba)2 (0.320 g, 0.557 mmol) were added and the reaction was allowed to proceed at 100°C for 24 h. The reaction mixture was filtered through a pad of celite, concentrated and dried in vacuo to give the crude material, which was purified by column chromatography (DCM: 3.5 M NH3 in MeOH, 80:20 to 50:50) to give the title compound as a yellow oil (0.755 g, 100%).

[0662] 1 H NMR (300MHz, DMSO-d6) δ8.64(s, 1H), 8.39(s, 1H), 8.13(s, 2H), 7.76–7.67(m, 2H), 7.25 (dd, J=7.7, 5.1Hz, 2H), 4.33 (d, J=5.7Hz, 2H), 2.37 (d, J=2.3Hz, 3H).

[0663] 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).

[0664] Reaction of 4-methyl-3-((pyrimidin-5-ylamino)methyl)benzoic acid with the desired amine afforded the following compounds, Examples 19 and 20 were prepared according to General Method A, while Examples 31 and 32 were prepared according to General Method C:

[0665]

[0666]

[0667] Embodiment 21

[0668] N-(2-methyl-5-((3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)carbamoyl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide

[0669]

[0670] Step 1: Preparation of methyl 3-((imidazo[1,2-a]pyridine-3-carboxamido)methyl)-4-methylbenzoate

[0671]

[0672] 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 Example 18, steps 1-2, was added anhydrous DCM (13 mL) followed by DIPEA (1.4 mL, 7.81 mmol). The reaction was stirred overnight at RT, then the reaction mixture was partitioned between DCM (15 mL) and water (15 mL), and the desired compound was extracted with DCM (2 x 15 mL). The combined organic phases were washed with water (15 mL), brine (15 mL), then dried over Na2SO4, filtered, and concentrated. The crude material was purified by FCC (MeOH:DCM, 1:99 to 5:95) to give the title compound (1.26 g, 66%) as an off-white solid.

[0673] 1 H NMR (300MHz, CDCl3) δ9.69 (d, J=6.7Hz, 1H, CH), 8.26 (br s, 1H, CH), 8.03 (s, 1H, CH), 7.90 (dd, J=7.9, 1.6Hz, 1H, CH), 7.76 (d, J=8.9Hz, 1H, CH), 7.46 (t, J=7.6Hz, 1H, CH), 7.31 (s, 1H, CH), 7.07 (t, J=6.9Hz, 1H, CH), 6.93 (br s, 1H, NH), 4.72 (d, J=5.5Hz, 2H, CH2), 3.90 (s, 3H, CH3), 2.48 (s, 3H, CH3).

[0674] Step 2: Preparation of lithium 3-((imidazo[1,2-a]pyridine-3-carboxamido)methyl)-4-methylbenzoate

[0675]

[0676] 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 in vacuo and the crude material was triturated with ether (30 mL) and filtered. The solid was collected to give the title product as an off-white solid (0.348 g, 86%).

[0677] 1 H NMR (300MHz, DMSO-d6) δ9.54 (d, J=7.0Hz, 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, 1.3Hz, 1H), 7.10 (m, 1H), 7.10 (m, 1H), 4.49 (s, 2H), 2.32 (s, 3H).

[0678] 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).

[0679] Example 21 and Example 22 were prepared according to General Procedure A for Amide Coupling by reacting lithium 4-3-((imidazo[1,2-a]pyridine-3-carboxamido)methyl)-4-methylbenzoate with the desired amine to give the following compounds:

[0680]

[0681]

[0682] Embodiment 23

[0683] N-methyl-4-((2-methyl-5-((3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)carbamoyl)benzyl)amino)picolinamide

[0684]

[0685] Step 1: Preparation of 4-methyl-3-(((2-(methylcarbamoyl)pyridin-4-yl)amino)methyl)benzoic acid

[0686]

[0687] To 4-bromo-N-methylpyridine-2-carboxamide (0.720 g, 3.35 mmol) and Cs2CO3 (2.73 g, 8.37 mmol), prepared as described in step 1-2 of Example 18, was added a solution of methyl-3-(aminomethyl)-4-methyl-benzoate (0.500 g, 2.79 mmol) in anhydrous toluene (9 mL). The reaction mixture was degassed, BINAP (0.347 g, 0.558 mmol) and Pd(dba)2 (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, concentrated, and dried in vacuo to give a crude material, which was purified by FCC (MeOH:DCM, 10:90-50:50) to give the title product (0.650 g, 78%) as a yellow solid.

[0688] 1 H NMR (300MHz, DMSO-d6) δ8.56 (q, J=4.6Hz, 1H), 8.06 (d, J=5.7Hz, 1H), 7.82-7.78 (m, 2H), 7.78-7.72 (m, 1H), 7.39 (t, J=5.6H z, 1H), 7.33 (d, J=7.9Hz, 1H), 7.24 (s, 1H), 6.63 (d, J=5.4Hz, 1H), 4.38 (d, J=5.5Hz, 2H), 2.76 (d, J=4.9Hz, 3H), 2.40 (s, 3H).

[0689] 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)

[0690] Example 23 and Example 24 were prepared following General Procedure A for Amide Couplings by reacting 4-methyl-3-(((2-(methylcarbamoyl)pyridin-4-yl)amino)methyl)benzoic acid with the desired amine to provide the following compounds.

[0691]

[0692]

[0693] Embodiment 25

[0694] N-(2-methyl-5-((3-(4-methyl-1H-imidazol-1-yl)-5(trifluoromethyl)phenyl)carbamoyl)benzyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide

[0695]

[0696] Step 1: Preparation of methyl 4-methyl-3-(((1H-pyrrolo[2,3-b]pyridin-5-yl)formamido)methyl)benzoate

[0697]

[0698] To a solution of methyl 3-(aminomethyl)-4-methylbenzoate (0.300 g, 1.67 mmol), 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (0.324 g, 2.01 mmol) and HATU (0.636 g, 1.67 mmol) prepared as described in Step 1-2 of Example 18 in anhydrous DCM (5 mL) was added DIPEA (0.6 mL, 3.35 mmol) 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 layer was dried over Na2SO4 and evaporated to dryness. The crude product was purified by column chromatography (DCM:MeOH, 98:2-96:4) to give the title amide as an off-white solid (0.323 g. 60%).

[0699] NMR (d-DMSO, 300MHz): δ11.93 (s, 1H), 9.04 (t, J=5.7Hz, 1H), 8.78 (d, J=2.1Hz, 1H), 8.50 (d, J=2.0Hz, 1H), 7.91 (d, J=1.5Hz, 1H), 7.77 (dd, J=7.8, 1.8Hz, 1H), 7.58 (dd, J=3.5, 2.3Hz, 1H), 7.34 (d, J=7.9Hz, 1H), 6.63–6.55 (m, 1H), 4.54 (d, J=5.7Hz, 2H), 3.80 (s, 3H), 2.43 (s, 3H).

[0700] Step 2: Preparation of lithium 3-((1H-pyrrolo[2,3-b]pyridine-5-carboxamido)methyl)-4-methylbenzoate

[0701]

[0702] 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) and then 1 M aqueous LiOH solution (3.0 mL) was added and the reaction mixture was stirred at RT for 3 days. The reaction mixture was then concentrated in vacuo and the residue was triturated with diethyl ether to give the title compound as a bright yellow solid (238 mg, 76%).

[0703] NMR (d-DMSO, 300MHz): δ8.58 (d, J=5.7Hz, 1H), 8.55 (d, J=2.3Hz, 1H), 8.25 (d, J=2.3Hz, 1H), 7.86 (d, J=1.6Hz, 1H), 7.66 (dd , J=7.6, 1.7Hz, 1H), 7.47 (d, J=2.6Hz, 1H), 7.05 (d, J=7.7Hz, 1H), 6.25 (d, J=2.6Hz, 1H), 4.45 (d, J=5.3Hz, 2H), 2.32 (s, 3H).

[0704] 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)

[0705] Reaction of lithium 3-((1H-pyrrolo[2,3-b]pyridine-5-carboxamido)methyl)-4-methylbenzoate with the desired amine gave the following compounds, Example 25 and Example 26 were prepared according to General Method A for amide coupling:

[0706]

[0707] Embodiment 27

[0708] N-(2-isopropyl-5-((3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)carbamoyl)benzyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide

[0709]

[0710] Step 1: Preparation of methyl 3-(aminomethyl)-4-isopropylbenzoate

[0711]

[0712] To a mixture of methyl 3-cyano-4-isopropylbenzoate and methyl 3-cyano-4-propylbenzoate (2.76 g, 13.6 mmol, 1:1 ratio) prepared as described in Step 1-2 of Example 16 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 allowed to proceed for 60 h at RT and then filtered through a pad of celite, concentrated, and dried in vacuo to give a crude product which was purified by column chromatography (DCM: 5.5 M NH3 in MeOH, 99:1 to 90:10)) to give a mixture of isomers (1:1 ratio of isomers, 1.33 g, 94%) as a bright yellow oil.

[0713] 1 H 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 (septet, 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, 1.9Hz, 2H), 7.27 (d, J=7.9Hz, 1H), 3.83 (s, 3H), 3.78 (s, 2H), 2 .71-2.59 (m, 2H), 2.07 (s, 2H), 1.57 (sextet, J=7.3Hz, 2H), 0.94 (t, J=7.3Hz, 3H).

[0714] Step 2: Preparation of methyl 3-((1H-pyrrolo[2,3-b]pyridine-5-carboxamido)methyl)-4-isopropylbenzoate

[0715]

[0716] 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) was added 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), followed by DIPEA (448 μl, 2.57 mmol). The reaction was allowed to proceed for 16 h at RT, then diluted with DCM, washed with water, and the desired compound was extracted with DCM. The combined organic phases were concentrated and dried in vacuo to give a crude product, which was purified by FCC (hexane: EtOAc, 100: 0-50: 50) to give a mixture of isomers. The isomers were then subjected to preparative HPLC separation to give the desired isomer (105 mg, 47%) as a white crystalline solid.

[0717] 1H NMR (300MHz, DMSO-d6) δ11.95 (s, 1H), 9.06 (t, J=5.7Hz, 1H), 8.77 (d, J=2.1Hz, 1H), 8.49 (d, J=2.1Hz, 1H), 7.95 (d, J=1.9Hz, 1H), 7.85 (dd, J=8.1, 1. 9Hz, 1H), 7.58 (d, J=3.4Hz, 1H), 7.49 (d, J=8.1Hz, 1H), 6.58 (d, J=3.5Hz, 1 H), 4.62 (d, J=5.6Hz, 2H), 3.82 (s, 3H), 3.38 (s, 1H), 1.24 (d, J=6.8Hz, 6H).

[0718] Step 3: Preparation of 3-((1H-pyrrolo[2,3-b]pyridine-5-carboxamido)methyl)-4-isopropylbenzoic acid

[0719]

[0720] 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), 1M LiOH solution (0.65 ml, 0.448 mmol) was added to the solution and stirred at 35° C. for 60 h. The reaction system was concentrated in vacuo, and the obtained residue was dissolved in water and acidified to pH=4 with 10% KHSO4 solution. The product was extracted with EtOAc, and the combined organic layers were dried over Na2SO4 and concentrated in vacuo to give the title compound (0.043 g, 43%), which was used in the next step without additional purification.

[0721] 1H NMR (300MHz, methanol-d4) δ8.76 (d, J=2.1Hz, 1H), 8.52 (d, J=2.1Hz, 1H), 8.06 (d, J=1.9Hz, 1H), 7.95 (dd, J=8.1, 1. 9Hz, 1H), 7.51-7.46 (m, 2H), 6.62 (d, J=3.5Hz, 1H), 4.76 (s, 2H), 3.41 (p, J=7.0Hz, 1H), 1.32 (d, J=6.8Hz, 6H).

[0722] 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)

[0723]

[0724] 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 minutes, 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 layer was then washed with brine and concentrated in vacuo. The crude material was purified by preparative HPLC (ACN + 0.1% FA, H2O + 0.1% FA) followed by preparative TLC (DCM: MeOH, 90: 10) to give the formate salt of the title compound. The resulting material was dissolved in MeOH, stirred with Amberlite IRN-78 for 2 h, filtered, and concentrated in vacuo to give the title compound (0.003 g, 4% yield) as a white solid.

[0725]

[0726] Embodiment 28

[0727] N-(5-((3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)carbamoyl)-2-propylbenzyl)imidazo[1,2-a]pyridine-3-carboxamide formate

[0728]

[0729] Step 1: Preparation of methyl 3-cyano-4-(prop-1-en-2-yl)benzoate; methyl 3-cyano-4-[(1E)-prop-1-en-1-yl]benzoate

[0730]

[0731] To a solution of methyl 4-bromo-3-cyanobenzoate (2.00 g, 8.33 mmol) and potassium isopropylene trifluoroborate (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). 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 (3x20 mL), washed with water (3x20 mL) and brine (20 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give the crude product which was purified by FCC (hexane:EtOAc, 99:1-90:10) to give the product as a mixture of isomers (1:1 ratio, 1.68 g, 56%)

[0732] 1 H NMR (d-DMSO, 300MHz): δiPr 8.23 ​​(m, 2H), 7.96 (d, J=8.4Hz, 1H), 5.52 (t, J=1.5Hz, 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, 1.1Hz, 3H).

[0733] Step 2: Preparation of methyl 3-cyano-4-(propan-2-yl)benzoate; methyl 3-cyano-4-propylbenzoate

[0734]

[0735] A mixture of methyl 3-cyano-4-(prop-1-en-2-yl)benzoate and methyl 3-cyano-4-[(1E)-prop-1-en-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 and stirred under hydrogen atmosphere (7 atm) for 16 h. The reaction mixture was filtered through celite, concentrated in vacuo, and the mixture of methyl 3-cyano-4-(prop-2-yl)benzoate and methyl 3-cyano-4-propylbenzoate (1:1 ratio, 506 mg, 100%) was used in the next step without further purification.

[0736] 1 H NMR (400MHz, DMSO-d6) δiPr 8.26 (dd, J=4.8, 1.8Hz, 2H), 7.72 (d, J=8.3Hz, 1H), 3.88 (s, 3H), 3.29 (m, 1H), 1.29 (d, J=6.9Hz, 6H). δnPr 8.18 (ddd, J=13.0, 8.2, 1.9Hz, 2H), 7.64 (d, J=8.1Hz, 1H), 3.88 (s, 3H), 2.84 (dd, J=8.4, 6.8Hz, 2H), 1.67 (m, 2H), 0.93 (t, J=7.4Hz, 3H).

[0737] Step 3: Preparation of methyl 3-(aminomethyl)-4-(propan-2-yl)benzoate; methyl 3-(aminomethyl)-4-propylbenzoate

[0738]

[0739] 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 reaction mixture and stirred for 16 h under a hydrogen atmosphere (7 atm). The reaction mixture was filtered through celite and concentrated in vacuo to give a crude material which was purified by column chromatography (DCM: 5.5 M NH3 in MeOH, 99:1-98:2) to give a mixture of methyl 3-(aminomethyl)-4-(propan-2-yl)benzoate and methyl 3-(aminomethyl)-4-propylbenzoate (ratio: 1:1, 118 mg, 23%).

[0740] 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, 2H), 3.26 (septet, J = 6.9 Hz, 1H), 1.84 (m, 2H), 1.20 (d, J = 6.8 Hz, 6H). nPr: δ8.06 (d, J=2.0Hz, 1H), 7.74 (dd, J=7.9, 2.0Hz, 1H), 7.27 (d, J=7.9Hz , 1H), 3.84 (s, 3H), 3.83 (s, 2H) 2.64 (m, 2H), 1.57 (m, 2H), 0.94 (t, J=7.3Hz)

[0741] 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

[0742]

[0743] To a solution of 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 and then extracted with DCM (3x25 mL). The combined organic layers were washed with water (25 mL), brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by column chromatography (DCM:MeOH, 98:2) followed by preparative HPLC to afford isopropyl (93 mg, 71%) and n-propyl (108 mg, 82%) isomers.

[0744] 1H 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, 1.9Hz, 1H), 7.73 (dt, J=9.0, 1.2Hz, 1H), 7.54-7.43 (m, 2H), 7.13 (td, J=6.9, 1.3Hz, 1 H), 4.62 (d, J=5.6Hz, 2H), 3.82 (s, 3H,), 3.40 (d, J=6.7Hz, 1H), 1.23 (d, J=6.8Hz, 6H).

[0745] 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, 1.4Hz, 1H, CH), 7.36 (d, J=8.0Hz, 1H, CH), 7.13 (td, J=6.9, 1.3Hz, 1H, CH), 4.59 ( d, J=5.7Hz, 2H, CH2), 3.81 (s, 3H, OCH3), 2.79-2.70 (m, 2H, CH2), 1.68-1.53 ​​(m, 2H), 0.94 (t, J=7.3Hz, 3H).

[0746] Step 5: Preparation of lithium 3-((imidazo[1,2-a]pyridine-3-carboxamido)methyl)-4-propylbenzoate

[0747]

[0748] Methyl 3-((imidazo[1,2-a]pyridine-3-carboxamido)methyl)-4-isopropylbenzoate (108 mg, 0.293 mmol) was dissolved in THF (3 mL), 1 M LiOH H2O solution (0.70 mL, 0.700 mmol) was added, and the reaction mixture was stirred at RT for 3 d. The reaction mixture was concentrated in vacuo and triturated with ether to give the title product as an off-white solid (114 mg, 100%).

[0749] 1H NMR (300MHz, DMSO-d6) δ9.54 (d, J=7.0Hz, 1H), 8.96 (s, 1H), 8.42 (s, 1H), 7.85 (d, J=1.5Hz, 1H), 7.71 (d, J=9.0Hz, 1H), 7.66 (dd, J=7.8, 1.6Hz, 1H), 7.49-7.41 (m, 1H), 7.11 (t, J=7.0Hz, 1H), 7.05 (d, J=7.7Hz, 1H), 4. 53 (s, 2H), 2.68-2.59 (m, 2H), 1.64-1.50 (m, 2H), 0.92 (t, J=7.3Hz, 3H).

[0750] 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)

[0751] Example 28 was prepared following General Procedure B for Amide Couplings by reacting lithium 3-((imidazo[1,2-a]pyridine-3-carboxamido)methyl)-4-propylbenzoate with the desired amine to give the following compound:

[0752]

[0753] Embodiment 29

[0754] N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4-propyl-3-((pyrimidin-5-ylamino)methyl)benzamide

[0755]

[0756] Step 1: Preparation of 4-propyl-3-((pyrimidin-5-ylamino)methyl)benzoic acid and 4-isopropyl-3-((pyrimidin-5-ylamino)methyl)benzoic acid

[0757] 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 described in Step 1-2 of Example 16 was added 5-bromopyrimidine (184 mg, 1.158 mmol) and Cs2(CO)3 (943 mg, 2.89 mmol) followed by toluene (2 mL). The mixture was degassed, RuPhos (90 mg, 0.193 mmol) and Pd(dba)2 (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 in vacuo to give the crude product, which was purified by column chromatography (DCM:MeOH, 99:1-0:100) followed by preparative HPLC to give isopropyl (69 mg, 53%) and n-propyl (87 mg, 67%) isomers.

[0758] 1 H NMR iPr (300MHz, DMSO-d6) δ 8.40 (s, 1H), 8.14 (s, 2H), 7.86 (d, J = 1.7Hz, 1H), 7.84-7.77 (m, 1H), 7.38 (d, J = 8. 0Hz, 1H), 6.56 (t, J=5.5Hz, 1H), 4.36 (d, J=5.2Hz, 2H), 3.23 (sept., J=6.8Hz, 1H), 1.22 (d, J=6.8Hz, 6H). 1 H NMR nPr (300MHz, DMSO-d6) δ9.32 (s, 1H), 8.38 (s, 1H), 8.12 (s, 2H), 7.82 (d, J = 1.7Hz, 1H), 7.69 (dd, J = 7.8, 1.7Hz, 1H), 7.12 (d, J = 7 .8Hz, 1H), 6.58 (t, J=5.5Hz, 1H), 4.29 (d, J=5.4Hz, 2H), 2.63 (dd, J=8.9, 6.5Hz, 2H), 1.68-1.49 (m, 2H), 0.93 (t, J=7.3Hz, 3H).

[0759] 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).

[0760] Example 29 and Example 30 were prepared following 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 desired amine to give the following compounds:

[0761]

[0762]

[0763] Embodiment 33

[0764] 3-(((1H-pyrrolo[2,3-b]pyridin-5-yl)amino)methyl)-4-fluoro-N-(3-(trifluoromethyl)phenyl)benzamide

[0765]

[0766] Step 1: Preparation of 4-fluoro-3-formyl-N-(3-(trifluoromethyl)phenyl)benzamide

[0767] The solution of 4-fluoro-3-formylbenzoic acid (200mg, 1.190mmol) in SOCl2 (2.386ml, 32.7mmol) was refluxed for 2h, then evaporated in vacuo to remove residual SOCl2. The brown solid residue was dissolved in anhydrous THF (4.0ml) and added dropwise to a solution of DIPEA (0.249ml, 1.428mmol), 3-(trifluoromethyl)aniline (192mg, 1.190mmol) and DMAP (5.81mg, 0.048mmol) in anhydrous THF (2.0ml). The reaction mixture was stirred at RT for 18h. The reaction mixture was quenched by addition to water (20mL). 1M NaOH (4mL) was added to adjust pH to 10. The product was extracted with AcOEt (3×25mL), and the combined organic extracts were evaporated in vacuo to obtain a crude product (548mg). The crude product was purified by column chromatography (hexane / DCM, 1:3-0:1) to give the title product (265 mg, 72%).

[0768] 1 H NMR (300MHz, DMSO-d6) δ10.76 (s, 1H), 10.30 (s, 1H), 8.51 (dd, J=6.7, 2.5Hz, 1H), 8.35 (ddd, J=8.7, 5.0, 2.5Hz, 1H), 8.23 ​​(d, J=2.2Hz, 1H), 8.07 (d, J=8.3Hz, 1H), 7.67–7.58 (m, 2H), 7.52–7.46 (m, 1H).

[0769] Step 2: Preparation of 3-(((1H-pyrrolo[2,3-b]pyridin-5-yl)amino)methyl)-4-fluoro-N-(3-(trifluoromethyl)phenyl)benzamide

[0770] 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 atmosphere. Glacial AcOH (1.0 ml) was added and the reaction mixture was stirred at RT for 3 h. The reaction mixture was cooled with ice water and STAB (163 mg, 0.771 mmol) was added as a suspension in glacial acetic acid (1.0 ml) and the reaction mixture was stirred at RT for 72 h. The reaction mixture was added to 1 M NaOH (50 mL), the aqueous layer was extracted with AcOEt (3×25 mL), the organic layers were combined, dried (Na2SO4), filtered and evaporated to give the crude product (126 mg). The crude product was purified by preparative TLC (SiO2, DCM / MeOH 100:5) to afford the title compound (35.26 mg. 32%).

[0771]

[0772] Embodiment 34

[0773] 4-Methyl-3-((pyridin-3-ylamino)methyl)-N-(3-(trifluoromethyl)phenyl)benzamide

[0774]

[0775] Step 1: Preparation of 3-formyl-4-methylbenzoyl chloride

[0776] 3-Formyl-4-methylbenzoic acid (1g, 6.09mmol) was dissolved in DCM (20.31ml). The solution was cooled to 0°C, then oxalyl chloride (1.569ml, 18.27mmol) and DMF (catalytic amount) were added. The reaction mixture was stirred for 3h in an ice bath. The formation of acyl chloride was confirmed by quenching the reaction with MeOH (methyl esters). The mixture was concentrated to obtain the desired product (1.1g, 99%), which was used in the next step without further purification.

[0777] Step 2: Preparation of 3-formyl-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide

[0778] 3-formyl-4-methylbenzoyl chloride (1g, 5.48mmol) is dissolved in THF (5.37ml), this solution is added to 3-(trifluoromethyl) aniline (0.684ml, 5.48mmol), DIPEA (1.145ml, 6.57mmol) and DMAP (0.027g, 0.219mmol) in THF (10.74ml).This mixture is stirred overnight at RT.Concentrate the reaction mixture.The thick material is dissolved in saturated NaHCO , extract with DCM (x3).Wash all the organic layers merging with 5% citric acid, use Na SO Drying, filter, concentrate.By FCC (100% hexane to 30%AcOEt in hexane solution) purification of thick material, obtain desired product (1.13g, 67%).

[0779] 1 H NMR (300MHz, DMSO-d6) δ10.68 (s, 1H), 10.33 (s, 1H), 8.46 (d, J = 2.1Hz, 1H), 8.25 (d, J = 2.0Hz, 1H), 8.16 (dd, J = 8.0, 2 .1Hz, 1H), 8.07 (dt, J=7.9, 2.3Hz, 1H), 7.62 (t, J=8.0Hz, 1H), 7.54 (d, J=8.0Hz, 1H), 7.51–7.44 (m, 1H), 2.71 (s, 3H).

[0780] Step 3: Preparation of 4-methyl-3-((pyridin-3-ylamino)methyl)-N-(3-(trifluoromethyl)phenyl)benzamide

[0781] 3-Formyl-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide (0.1 g, 0.325 mmol) and pyridine-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 NaBH3CN (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, quenched with 1M NaOH aqueous solution, and the product was extracted with AcOEt (x3). All the combined organic layers were dried over Na2SO4, filtered and concentrated. The crude material was purified by FCC (DCM 100%-10% MeOH in DCM) and then purified again by preparative HPLC (ACN+0.1% FA, H2O+0.1% FA). The obtained product was washed with saturated NaHCO3 to remove formic acid to obtain the desired product (48 mg. 38%).

[0782]

[0783] Embodiment 35

[0784] 4-Fluoro-3-(((5-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)amino)methyl)-N-(3-(trifluoromethoxy)phenyl)benzamide

[0785]

[0786] Step 1: Preparation of 4-fluoro-3-formylbenzoyl chloride

[0787] 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 acyl 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.

[0788] Step 2: Preparation of 4-fluoro-3-formyl-N-(3-(trifluoromethoxy)phenyl)benzamide

[0789] 4-fluoro-3-formylbenzoyl chloride (0.2g, 1.072mmol) is dissolved in THF (1.083ml), in this solution, add 3-(trifluoromethoxy)aniline (0.172ml, 1.286mmol), DIPEA (0.224ml, 1.286mmol) and DMAP (5.24mg, 0.043mmol) solution in THF (2.166ml).This mixture is stirred overnight at RT.Use saturated NaHCO dilute the reaction mixture, extract with AcOEt (x3).Wash all the organic layers merging with 5% citric acid, use Na SO Drying, filter, concentrate.By FCC (hexane solution of 100% hexane-50% AcOEt) purification of crude material, obtain expected product (227mg, 65%).

[0790] 1H NMR (300MHz, DMSO-d6) δ10.71 (s, 1H), 10.29 (s, 1H), 8.48 (dd, J=6.7, 2.4Hz, 1H), 8.33 (ddd, J=8.7, 5.0, 2.5Hz, 1H), 7.92 (dq, J=2.3, 1.1Hz, 1H), 7.78 (ddd, J=8.3, 2.0, 0.9Hz, 1H), 7.61 (dd, J=10.3, 8.7Hz, 1H), 7.51 (t, J=8.2Hz, 1H), 7.12 (ddt, J=8.2, 2.4, 1.1Hz, 1H).

[0791] Step 3: Preparation of 4-fluoro-3-(((5-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)amino)methyl)-N-(3-(trifluoromethoxy)phenyl)benzamide

[0792] 4-Fluoro-3-formyl-N-(3-(trifluoromethoxy)phenyl)benzamide (0.1 g, 0.306 mmol) and 5-(1-methyl-1H-pyrazol-3-yl)pyridine-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 then 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 the combined organic layers were dried over NaSO, filtered, and concentrated. The crude material was purified by FCC (100% DCM to 10% MeOH in DCM) followed by preparative HPLC (ACN+0.1% NH3, H2O+0.1% NH3) to give the desired product (47 mg, 32%).

[0793]

[0794]

[0795] The following compounds were prepared by reductive amination as described for Example 35, Steps 1-3, employing commercially available amines in Step 3 and using STAB as the reducing agent.

[0796]

[0797] Embodiment 36

[0798] 4-(Difluoromethyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((pyrimidin-5-ylamino)methyl)benzamide

[0799]

[0800] Step 1: Preparation of methyl 3-bromo-4-(difluoromethyl)benzoate

[0801] 3-bromo-4-formylbenzoic acid methyl ester (5g, 20.57mmol) is dissolved in anhydrous DCM (103ml), cooled to 0 ℃.Next add DAST (4.08ml, 30.9mmol), the reaction mixture is stirred at RT overnight. Use saturated NaHCO Make the mixture quench, extract with DCM (x3). Use Na SO Dry all organic layers, filter, vacuum concentration, obtain the desired product, it is used for next step (5.37g, 98%) without further purification.

[0802] 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).

[0803] Step 2: Preparation of methyl 4-(difluoromethyl)-3-vinylbenzoate

[0804] In a drying pressure reactor, methyl 3-bromo-4-(difluoromethyl)benzoate (5.37 g, 20.26 mmol), potassium trifluoro(vinyl)borate (5.43 g, 40.5 mmol), K2CO3 (7.00 g, 50.7 mmol) were placed and dioxane (57.9 ml) was added via a syringe in an argon atmosphere. The solution was filled with argon (10 minutes) and then Pd(dppf)Cl2 (1.482 g, 2.026 mmol) was added. The test tube was sealed and heated at 110°C overnight. The reaction mixture was passed through a diatomaceous earth pad and washed with AcOEt. The filtrate was concentrated and the crude material was purified by automated FCC (elution system: 100% hexane to 10% AcOEt in hexane) to obtain the desired product (2.49 g, 58%).

[0805] 1H NMR (300MHz, chloroform-d) δ8.23 (t, J=1.2Hz, 1H), 8.01 (dt, J=8.1, 1.1Hz, 1H), 7.64 (d, J=8.1Hz, 1H), 7.07 (d, J=1 .6Hz, 1H), 6.84 (t, J=54.9Hz, 2H), 5.82 (dd, J=17.4, 0.9Hz, 1H), 5.52 (dd, J=11.1, 0.9Hz, 1H), 3.95 (s, 3H).

[0806] Step 3: Preparation of methyl 4-(difluoromethyl)-3-formylbenzoate

[0807] Methyl 4-(difluoromethyl)-3-vinylbenzoate (2.37 g, 11.17 mmol) was dissolved in anhydrous DCM (55.8 ml) and cooled to -78 °C. The reaction system was then bubbled with ozone for 20 min. After this, the ozone gas flow was replaced with an argon gas flow. Me2S (1.230 ml, 16.75 mmol) was then added and the mixture was stirred at -78 °C for 30 min and then stirred at RT for another 30 min. The solvent was evaporated and the crude material was purified by FCC (100% hexane to 30% AcOEt in hexane) to give the desired product (1.73, 72%).

[0808] 1 H 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).

[0809] Step 4: Preparation of a mixture of 4-(difluoromethyl)-3-(hydroxymethyl)benzoic acid and 4-(difluoromethyl)isophthalic acid

[0810] Methyl 4-(difluoromethyl)-3-formylbenzoate (1.73 g, 8.08 mmol) was dissolved in MeOH (40.4 ml) and to this solution was added 1 M LiOH (32.3 ml, 32.3 mmol). The mixture was stirred at RT for 1 h. A mixture of alcohol and carboxylic acid was obtained because Cannizzaro disproportionation occurred. The crude product was extracted with AcOEt: 1 M HCl. The mixture of alcohol (0.76 g, 46%) and acid (0.76 g, 44%) was concentrated and used as is in the next step.

[0811] Step 5: Preparation of 4-(difluoromethyl)-3-formylbenzoic acid

[0812] 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 celite pad. The filtrate was concentrated and the crude material was purified by FCC (100% DCM to 10% MeOH in DCM) to obtain the desired product (197 mg, 14%).

[0813] 1 H NMR (300MHz, DMSO-d6) δ 13.65 (s, 1H), 10.24 (s, 1H), 8.58 (d, J=1.5Hz, 1H), 8.34 (dd, J=8.0, 1.8Hz, 1H), 7.96 (d, J=8.1Hz, 1H), 7.65 (t, J=54.5Hz, 1H).

[0814] Step 6: Preparation of 4-(difluoromethyl)-3-formylbenzoyl chloride

[0815] 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 and then concentrated and the material was used in the next step without further purification.

[0816] Step 7: Preparation of 4-(difluoromethyl)-3-formyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide

[0817] 4-(difluoromethyl)-3-formylbenzoyl chloride (0.19g, 0.869mmol) is dissolved in THF (0.852ml), this solution is added to 3-(4-methyl isophthalic acid H-imidazoles-1-yl)-5-(trifluoromethyl) aniline (0.210g, 0.869mmol), DIPEA (0.182ml, 1.043mmol) and DMAP (4.25mg, 0.035mmol) in THF (1.704ml).Reaction mixture is stirred overnight at RT.Concentrate the reaction mixture, thick material is dissolved in 1M NaOH, extract with AcOEt (x3).Use Na SO Dry the organic layer merged, filter, concentrate, by FCC (100%DCM to 10% MeOH DCM solution) purification of thick material, obtain desired compound (146mg, 40%).

[0818] 1H NMR (300MHz, DMSO-d6) δ11.02 (s, 1H), 10.30 (d, J = 1.2Hz, 1H), 8.66 (d, J = 1.7Hz, 1H), 8.41 (dd, J = 8.1, 1.9Hz, 1H), 8.29 (d, J = 2.0Hz, 1H), 8.23 (d, J=1.4Hz, 1H), 8.14 (d, J=1.8Hz, 1H), 8.04 (d, J=8.1Hz, 1H), 7.79 (d, J=1.9Hz, 1H), 7.51 (t, J=1.2Hz, 1H), 2.19 (d, J=1.0Hz, 3H).

[0819] Step 8: Preparation of 4-(difluoromethyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((pyrimidin-5-ylamino)methyl)benzamide

[0820] 4-(Difluoromethyl)-3-formyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide (0.06 g, 0.142 mmol) and pyrimidine-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. Thereafter, the reaction mixture was cooled to RT and NaBH3CN (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 NaOH aqueous solution, the product was extracted with AcOEt (x3), and all the combined organic layers were dried over Na2SO4, filtered and concentrated. The crude material was purified by FCC (100% DCM to 10% MeOH in DCM) and then repurified by preparative HPLC (ACN+0.1% NH3, H2O+0.1% NH3) to give the desired product as a white solid (30 mg, 42%).

[0821]

[0822] Embodiment 37

[0823] 4-Methyl-3-((pyrimidin-5-ylamino)methyl)-N-(3-(trifluoromethoxy)phenyl)benzamide

[0824]

[0825] Step 1: Preparation of 3-formyl-4-methyl-N-(3-(trifluoromethoxy)phenyl)benzamide

[0826] 3-Formyl-4-methylbenzoyl chloride (0.6 g, 3.29 mmol) prepared as in Example 34, Step 1 was dissolved in THF (3.22 ml) and the 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 combined organic layers were washed with 5% citric acid, dried over NaSO, filtered and concentrated. The crude material was purified by FCC (100% hexanes to 30% AcOEt in hexanes) to give the desired product (450 mg, 42%).

[0827] 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).

[0828] Step 2: Preparation of 4-methyl-3-((pyrimidin-5-ylamino)methyl)-N-(3-(trifluoromethoxy)phenyl)benzamide

[0829] 3-Formyl-4-methyl-N-(3-(trifluoromethoxy)phenyl)benzamide (0.1g, 0.309mmol) and pyrimidine-5-amine (0.029g, 0.309mmol) are dissolved in MeOH (1.547ml) and AcOH (0.053ml, 0.928mmol). The mixture is stirred for 1h at 50°C, the reaction mixture is cooled to RT, then NaBHCN (0.087g, 1.392mmol) is added. The solution is stirred for 1h at 50°C. The reaction mixture is cooled to RT and diluted with DCM. The solution is extracted with saturated NaHCO and the aqueous layer is washed with DCM (x2). All organic phases are combined, NaSO is dried, filtered, and concentrated. The crude material is purified by FCC (100% DCM to 5% MeOH in DCM solution) to obtain the desired product (63mg, 51%).

[0830]

[0831] Pharmacological activities of the compounds of the present invention

[0832] In vitro assay

[0833] Binding assay

[0834] Using Life Technologies LanthaScreen TM Europium Kinase Binding Assays DDR1 and DDR2 binding assays were performed. Compounds were incubated with 5 nM DDR1 (Carna Biosciences) or 5 nM DDR2 (Life Technologies) for 1 hour at room temperature in a white 384-well Optiplate (PerkinElmer) containing 20 nM or 10 nM kinase tracer 178 and 2 nM europium-labeled anti-GST antibody (Life Technologies), respectively, in assay buffer (50 mM HEPES pH 7.5, 10 mM MgCl2, 1 mM EGTA, and 0.01% BRIJ35).

[0835] The ratio of fluorescence emission at 665 nm / 615 nm after excitation at 340 nm was obtained using a Tecan Spark 20M plate reader. IC was determined in GraphPad Prism 7.0 software using a 4-parameter model: log(inhibitor) vs. response. 50 The Cheng-Prusoff equation (Ki = IC 50 / (1+[Tracer] / Kd), IC 50 The value is converted to Ki.

[0836] DDR1 cell-based assay

[0837] According to the manufacturer's instructions, The U2OSDDR1 assay (EurofinsDiscoverX) evaluated the inhibition of DDR1 receptor activation by compounds. 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. The cells were then treated with different concentrations of compounds and incubated for 30 minutes, then stimulated with 20 μg / ml bovine type II collagen and incubated overnight at 37°C and 5% CO2. PathHunter detection reagents were prepared according to the protocol provided by DiscoverX, and 20 μL / well of this mixture was added to each well. After incubating the plate in the dark for 1 hour at room temperature, the luminescent signal was acquired with a plate reader. The raw data were calibrated relative to the medium control (0% for calibration) and the positive control (100% for calibration; cells treated with 20 μg / ml collagen II), and the IC was calculated in GraphPad Prism 8.0 software using a sigmoidal dose-response curve fit with a variable slope. 50 parameter.

[0838] DDR2 cell-based assay

[0839] The inhibition of DDR2 phosphorylation by the compound was evaluated in HEK293T-DDR2 recombinant cells by phospho-ELISA assay. In brief, HEK293T-DDR2 cells were seeded in poly-D-lysine coated 24-well plates at a density of 250.000 cells / well and incubated in DMEM+10% FBS for 1.5 hours at 37°C and 5% CO2. Thereafter, the culture medium was replaced with serum-free DMEM, and the cells were incubated for 3 hours. Then different concentrations of test compounds were added 30 minutes before restimulation for 3 hours with 50 μg / ml bovine type II collagen. For 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. The protein concentration in the sample was determined by BCA assay, and the level of phospho-DDR2 was determined according to R&D Systems instructions. The raw data were normalized to the maximal inhibition control (calibrated 0%) and the positive control (calibrated 100%; cells treated with 20 μg / ml collagen II), and the IC was calculated in GraphPad Prism 8.0 software using a sigmoidal dose-response curve fit with a variable slope. 50 parameter.

[0840] The results of the binding assays for individual compounds are provided in Table 3 below, where the compounds are categorized according to their potency with respect to their inhibitory activity expressed as Ki against DDR1 and DDR2:

[0841] Table 3

[0842]

[0843]

[0844] DDR1

[0845] +: Ki contains 1000 to 300nM

[0846] ++: Ki ranges from 300 to 30 nM

[0847] +++: Ki below 30nM

[0848] DDR2

[0849] +: Ki contains 1000 to 300nM

[0850] ++: Ki ranges from 300 to 30 nM

[0851] +++: Ki below 30nM

[0852] In Table 4 below, the inhibitory activities of the DDR1 and DDR2 receptors are shown according to their potency (IC 50 ) classified some compounds of the present invention.

[0853] Table 4

[0854] Example No. <![CDATA[IC 50 DDR1]]> <![CDATA[IC 50 DDR2]]> Embodiment 20 ++ + Embodiment 31 ++ ++ Embodiment 32 ++ ++ Embodiment 34 ++ ++ Embodiment 37 ++ + Embodiment 38 ++ + Embodiment 35 ++ ++

[0855] DDR1

[0856] +:IC 50 Contains 15 to 10nM

[0857] ++:IC 50 Less than 10nM

[0858] DDR2

[0859] +:IC 50 Contains 15 to 10nM

[0860] ++:IC 50 Less than 10nM

[0861] As can be appreciated, the compounds of Table 3 and Table 4 show good activity as DDR1 and DDR2 receptor antagonists. Therefore, the compounds of the present invention can be effectively used to treat diseases, disorders or conditions associated with DDR receptors, such as fibrosis, such as pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), liver fibrosis, kidney fibrosis, eye fibrosis, cardiac fibrosis, arterial fibrosis and systemic sclerosis.

Claims

1. A compound of formula (I), in L and L1 are different and independently selected from -C(O) and NH; L2 does not exist; Z is absent or selected from -CH2 and -C(O); R1 is selected from -O(C1-C4)alkyl, and and it is in the meta position relative to the rest of the molecule; n is 1; R is (C1-C4)alkyl; R2 is selected from heteroaryl and heterocycloalkyl, wherein the heteroaryl and heterocycloalkyl are each optionally substituted with one or more -C(O)NHR6 and CN; R3 is (C1-C4) haloalkyl; R4 is H; R5 is H or selected from (C1-C4)alkyl and heteroaryl (C1-C4)alkyl-; R6 is H or (C1-C4) alkyl; wherein the heteroaryl is a monocyclic or bicyclic aromatic ring system of 5 to 12 ring atoms containing one or more heteroatoms selected from S, N and O, and includes groups having two such monocyclic rings, or one such monocyclic ring and a monocyclic aromatic ring, which are fused via a common bond; wherein the heterocycloalkyl is a saturated or partially unsaturated monocyclic or bicyclic ring system of 3-10 ring atoms containing one or more heteroatoms selected from N, S or O; and pharmaceutically acceptable salts thereof.

2. The compound according to claim 1, 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 selected from -OCH3, and ; R is selected from methyl, ethyl, propyl and isopropyl; R2 is selected from pyrimidinyl, pyridinyl, imidazo[1,2-a]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, indazolyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidinyl and benzo[d]thiazolyl, wherein the heteroaryl and heterocycloalkyl are each optionally substituted with one or more -C(O)NHR6 and CN; R3 is trifluoromethyl; R5 is H or selected from methyl, ethyl and 3-methylimidazo[1,2-a]pyridinyl; R6 is H or methyl; and pharmaceutically acceptable salts thereof.

3. The compound according to claim 1, wherein R1 is , The compound is represented by formula (Ib) in 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 heteroaryl and heterocycloalkyl, wherein the heteroaryl and heterocycloalkyl are each optionally substituted with one or more -C(O)NHR6 and CN; R3 is (C1-C4) haloalkyl; R5 is H or selected from (C1-C4)alkyl and heteroaryl (C1-C4)alkyl-; R6 is H or (C1-C4) alkyl; wherein the heteroaryl and heterocycloalkyl have the meanings defined in claim 1; and pharmaceutically acceptable salts thereof.

4. The compound according to claim 1, wherein R1 is , The compound is represented by formula (Ic) in 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 heteroaryl and heterocycloalkyl, wherein the heteroaryl and heterocycloalkyl are each optionally substituted with one or more -C(O)NHR6 and CN; R3 is (C1-C4) haloalkyl; R5 is H or selected from (C1-C4)alkyl and heteroaryl (C1-C4)alkyl-; R6 is H or (C1-C4) alkyl; wherein the heteroaryl and heterocycloalkyl have the meanings defined in claim 1; and pharmaceutically acceptable salts thereof.

5. The compound according to claim 1, wherein L2 does not exist, R4 and R5 are -H, Z does not exist, and the compound is represented by formula (If) in L is -C(O); L1 is -NH; R1 is selected from -O(C1-C4)alkyl and and it is in the meta position relative to the rest of the molecule; R is (C1-C4) alkyl; R2 is selected from ; R3 is (C1-C4) haloalkyl; and pharmaceutically acceptable salts thereof.

6. The compound according to claim 5, wherein L is -C(O); L1 is -NH; R1 is selected from -OCH3 and ; R is a methyl group; R2 is selected from ; R3 is trifluoromethyl; and pharmaceutically acceptable salts thereof.

7. The compound according to claim 6, wherein L is -C(O); L1 is -NH; R1 is -OCH3; R is a methyl group; R2 is selected from ; R3 is trifluoromethyl; and pharmaceutically acceptable salts thereof.

8. A compound selected from at least one of the following compounds: 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-6-ylamino)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; N-(4-methoxy-3-(trifluoromethyl)phenyl)-4-methyl-3-((pyrimidin-5-ylamino)methyl)benzamide; and pharmaceutically acceptable salts thereof.

9. A compound selected from at least one of the following compounds: 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; and pharmaceutically acceptable salts thereof.

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 in admixture with one or more pharmaceutically acceptable carriers or excipients.

11. The pharmaceutical composition according to claim 10, which is for oral administration or administration by inhalation.

12. Use of a compound according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 10 or 11 for the preparation of a medicament for treating a disease, disorder or condition associated with DDR1 and DDR2 dysregulation.

13. Use of a compound according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 10 or 11 for the preparation of a medicament for preventing and / or treating fibrosis and / or a disease, disorder or condition involving fibrosis.

14. The use according to claim 13, wherein the fibrosis is selected from the group consisting of pulmonary fibrosis, liver fibrosis, kidney fibrosis, eye fibrosis, cardiac fibrosis, arterial fibrosis and systemic sclerosis.

15. The use according to claim 14, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis.

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