Heteroaryl derivatives as DDR inhibitors

Abstract

The present invention relates to compounds of formula (I) that inhibit discoidin domain receptors (DDR inhibitors), to methods for preparing such compounds, to intermediate compounds useful in such preparations, to pharmaceutical compositions containing them, and to their therapeutic uses. The compounds of the present invention may be useful, for example, in the treatment of a number of disorders associated with DDR mechanisms. JPEG2025525571000100.jpg46107

Description

[Technical Field]

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

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

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

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

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

[0006] The DDR receptor family has been found to be involved in a range of diseases, including pulmonary fibrosis, and in particular idiopathic pulmonary fibrosis (IDF). The first evidence for a protective role of DDR1 deficiency in pulmonary fibrosis was provided by Dr. Vogel's research group in 2006 (see Avivi-Green C, Am J Respir Crit Care Med 2006;174:420-427). The authors showed that DDR1-null mice were significantly protected against bleomycin (BLM)-induced injury. Furthermore, these animals exhibited significantly reduced myofibroblast proliferation and apoptosis compared with wild-type mice. Bronchoalveolar lavage cell counts and cytokine ELISA confirmed that the knockout mice lacked inflammation. These results indicated that DDR1 expression is required for the development of pulmonary inflammation and fibrosis.

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

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

[0009] In particular, antagonism of DDR receptors may be useful in treating fibrosis and diseases, disorders, and conditions resulting from fibrosis. Furthermore, antagonism of both DDR1 and DDR2 receptors may be particularly effective in treating the above diseases, disorders, and conditions.

[0010] Several efforts have been made in the past few years to develop novel DDR1 and DDR2 receptor antagonists useful for the treatment of several diseases, and some of these compounds have also shown efficacy in humans. However, there is potential to develop selective inhibitors of both the DDR1 and DDR2 receptors, which are administered via the inhalation route and feature a favorable inhalation profile corresponding to good activity in the lungs, good lung retention, and low metabolic stability, which are useful for the treatment of diseases, disorders, or conditions associated with DDR receptor dysregulation in the respiratory field, particularly idiopathic pulmonary fibrosis (IPF), in order to minimize systemic exposure and associated safety issues.

[0011] To this end, it has been surprisingly found that a novel series of compounds of general formula (I) shown below solves the problem of providing DDR1 and DDR2 receptor inhibitors for inhaled administration that act as selective inhibitors of the DDR1 and DDR2 receptors with respect to other human protein kinases. Such compounds exhibit high efficacy, a good inhalation profile, low metabolic stability, low systemic exposure, improved safety and tolerability. Summary of the Invention

[0012] In a first aspect, the present invention provides a compound of formula (I): [ka] [During the ceremony, A is, [ka] and phenyl, wherein [ka] indicates a direct bond to NH; W1 and W2 are substituents of Ring A selected from the group consisting of hydrogen, halogen, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, R1R2N-(C1-C4) alkyl and (C3-C6) cycloalkyl, preferably selected from H, F, CH3, OCH3, OCF3, CF3, C(CH3)3, CH2CH3, C(CH3)2CF3, OCF2H, CHF2, CH2CF3, CH2N(CH3)2 and cyclopropyl; Z is selected from the group consisting of (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, (C1-C4) hydroxyalkyl and (C3-C6) cycloalkyl, preferably CH3, CF2H, OCH3, CH2OH and cyclopropyl; L is [ka] (In the formula, [ka] indicates a direct bond to the phenyl, [ka] indicates a direct bond to B) selected from the group consisting of: B is a monocyclic or bicyclic heteroaryl ring, preferably selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyrazolo[1,5-a]pyrazinyl, 1H-pyrazolo[3,4-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, imidazo[1,2-a]pyridinyl, thieno[3,2-d]pyrimidinyl, 1H-pyrrolo[2,3-b]pyridinyl and pyrazolyl; Y1 and Y2 are hydrogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)alkoxy-(C1-C4)alkoxy, hydroxy-(C1-C4)alkoxy, hydroxy-(C1-C4)alkyl, (C1-C4)alkyl-heterocycloalkyl-(C0-C4)alkoxy, (C1-C4)haloalkoxy, halogen, cyano, cyano-(C1-C4)alkyl, cyano-(C1-C4)alkyl-heterocycloalkyl, CONR1R2, NHCOR1, NR1R2, R1R2N-(C1-C4)alkyl, heterocycloalkyl, (C1-C4)alkyl-heterocycloalkyl substituents on Ring B independently selected from the group consisting of cycloalkyl, heterocycloalkyl-(C1-C4)alkyl, (C1-C4)alkyl-heterocycloalkyl-carbonyl, (C0-C4)alkyl-heterocycloalkyl-carbonyl, (C1-C4)alkyl-phenyl, and monocyclic (C1-C4)alkyl-heteroaryl, where Y1 is preferably selected from CONH2, CF2H, OCH3, cyano, Br, NHCOCH3, NH2, 4-methylpiperazine-1-carbonyl, 4-methylpiperazin-1-yl, and 1-methyl-1H-pyrazol-4-yl, and Y2 is preferably hydrogen; R1 and R2 are independently selected from the group consisting of hydrogen, (C1-C4) alkyl, (C1-C4) hydroxyalkyl, (C1-C4) alkoxy(C1-C4) alkyl, (C1-C4) alkylamino-(C1-C4) alkyl, di(C1-C4) alkylamino-(C1-C4) alkyl, optionally substituted (C3-C6) cycloalkyl, optionally substituted heterocycloalkyl, and optionally substituted heterocycloalkyl-(C1-C4) alkoxy, wherein the optional substituents are one or more and are selected from (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl, and (C1-C4) haloalkoxy; wherein R1 and R2 are preferably independently selected from the group consisting of CH2CH2N(CH3)2, CH2CHOCH3, CH3, CH2CH2OH, oxetan-3-yl, and 3-hydroxycyclobutyl; R3 is selected from hydrogen and (C1-C4) alkyl, preferably hydrogen and methyl. or stereoisomers, tautomers, solvates and pharmaceutically acceptable salts thereof.

[0013] In a second aspect, the present invention refers to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in admixture with at least one or more pharmaceutically acceptable carriers and / or excipients.

[0014] In a third aspect, the invention refers to a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0015] In a further aspect, the present invention refers to a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the prevention and / or treatment of a disease, disorder or condition associated with DDR dysregulation.

[0016] In another aspect, the present invention refers to a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the prevention and / or treatment of fibrosis and / or a disease, disorder or condition in which fibrosis is involved.

[0017] In yet another aspect, the present invention refers to a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the prevention and / or treatment of idiopathic pulmonary fibrosis (IPF).

[0018] In a further aspect, the present invention refers to methods for preparing compounds of formula (I) and intermediate compounds useful in preparing compounds of formula (I).

[0019] Detailed Description of the Invention definition Unless otherwise specified, the compounds of formula (I) of the present invention are intended to include stereoisomers, tautomers, solvates and pharmaceutically acceptable salts thereof.

[0020] Unless otherwise specified, the compounds of formula (I) of the present invention are intended to include compounds of formula (I) and formula (Ic).

[0021] As used herein, the term "pharmaceutically acceptable salts" refers to derivatives of the compounds of formula (I), where the parent compound is suitably modified by converting any free acidic or basic group, if any, into any base or acid corresponding addition salt thereof that is conventionally considered to be pharmaceutically acceptable. Suitable examples of such salts include inorganic or organic acid addition salts of basic residues such as amino groups, as well as inorganic or organic base addition salts of acidic residues such as carboxyl groups.

[0022] Cations of inorganic bases which may be suitably used to prepare salts include ions of alkali metals or alkaline earth metals such as potassium, sodium, calcium or magnesium.

[0023] Salts obtained by reacting a compound with an inorganic or organic acid, with the primary compound acting as a base, include, for example, hydrochlorides, hydrobromides, sulfates, phosphates, methanesulfonates, camphorsulfonates, acetates, oxalates, maleates, fumarates, succinates, and citrates.

[0024] The term "stereoisomer" refers to isomers of identical constitution that differ in the arrangement of their atoms in space. Enantiomers and diastereomers are examples of stereoisomers.

[0025] The term "enantiomer" refers to one of a pair of molecular species that are mirror images of each other and are not superimposable.

[0026] The terms "racemate" or "racemic mixture" refer to a composition of equimolar amounts of two enantiomeric species, lacking optical activity.

[0027] As used herein, the term "halogen" or "halogen atom" or "halo" includes fluorine, chlorine, bromine, and iodine atoms.

[0028] The term "(C x -C y "(C1-C4)alkyl" refers to a straight or branched chain alkyl group having from x to y carbon atoms. Thus, when x is 1 and y is 4, for example, the term "(C1-C4)alkyl" includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. Such groups are also designated herein by their atom arrangement, i.e., CH3, CH2CH3, etc.

[0029] The term "(C x -C y ")Haloalkyl" refers to a straight or branched chain alkyl group containing at least one halogen substituent having x to y carbon atoms. Examples include CF3, C(CH3)2CF3, and OCF2H.

[0030] The term "(C x -C y "(C1-C4)alkoxy" refers to a straight or branched chain alkyl group having x to y carbon atoms containing at least one oxygen atom, particularly, but not limited to, an oxygen atom directly bonded to Ring A or Ring B or a phenyl ring, i.e., when W, Y, or Z is, respectively, (C1-C4)alkoxy. Examples include OCH3 and OCH2CH3.

[0031] The term "(C x -C y )haloalkoxy" refers to an alkoxy group containing at least one halogen substituent (C x -C y)alkoxy. Examples include OCF3 and OCF2H.

[0032] The term "(C x -C y )hydroxyalkyl" refers to a group containing at least one hydroxy substituent (C x -C y ) alkyl. Examples include CH2OH, CH(OH)CH3, and CH2CH2OH.

[0033] The term “(C x -C y ")Cycloalkyl" refers to a saturated hydrocarbon containing x to y ring carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0034] The term "monocyclic or bicyclic heteroaryl ring" refers to a monocyclic or bicyclic aromatic group containing 1 to 3 heteroatoms independently selected from N, S, and O, and includes groups having two such monocyclic rings or one such monocyclic ring and one monocyclic aryl ring, e.g., a phenyl ring, which are fused together by a common bond or linked by a single bond.Monocyclic or bicyclic heteroaryl rings include pyrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, pyridazinyl, imidazolyl, benzofuranyl, 1H-benzo[d]imidazolyl, 1H-indazolyl, benzothiophenyl, benzo[c]thiophenyl, quinazolinyl, pteridinyl, 1H-pyrazolo[5,1-c][1,2,4]triazolyl, pyrrolidinyl, indolizinyl, benzothiazolyl, pyrazolo[5,1-b]thiazolyl, 1H-imidazo[1,2-b] Pyrazolyl, 1H-pyrazolo[3,4-b]pyridinyl, 1,6-dihydropyrrolo[2,3-b]pyrrolyl, 1,4-dihydropyrrolo[3,2-b]pyrrolyl, 4H-thieno[3,2-b]pyrrolyl, isobenzofuranyl, 1,2,4-triazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl, tetrazolyl, 6H-furo[2,3-b]pyrrolyl, 6H-thieno[2,3-b]pyrrolyl, 4H-furo[3,2-b]pyrrolyl, benzo[d ]isothiazolyl, thiazolo[4,5-b]pyridinyl, 1,3,5-triazinyl, 1,2,3,4-thiatriazolyl, 1,2,3,4-oxatriazolyl, 1,2,3,4-tetrazinyl, 1,2,4,5-tetrazinyl, 1,2,3,5-tetrazinyl, 1H-imidazo[4,5-b]pyridinyl, 7H-purinyl, 1H-pyrrolyl, 1-methyl-1H-pyrrolyl, 1-methyl-1H-1,2,4-triazolyl, 1-methyl-1H-tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, imidazolyl, These include midazo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyrazinyl, imidazo[1,2-a]pyrazinyl, imidazo[1,2-a]pyrazinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, thieno[3,2-d]pyrimidinyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 1H-pyrrolo[2,3-b]pyridinyl, 5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazinyl, furo[3,2-d]pyrimidin-4-yl and pyrazolo[1,5-a]pyrimidinyl.

[0035] The term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic, bicyclic, or spirocyclic ring system of 3 to 12 atoms containing one or more heteroatoms independently selected from N, S, and O. Examples of heterocycloalkyl include piperazinyl, pyrrolidinyl, azetidinyl, morpholinyl, and piperidinyl.

[0036] The term "spirocyclic ring system" refers to a saturated or partially unsaturated bicyclic ring system consisting of 5 to 12 atoms, including one or more heteroatoms independently selected from N, S, and O, in which the two rings have only one atom in common.

[0037] Any compound term, such as "(C-C) alkyl-heterocycloalkyl-carbonyl," is intended to be understood conventionally with the moieties from which it is derived, e.g., (C-C) alkyl, heterocycloalkyl, and carbonyl groups, joined together in the order shown, with the carbon atom of the carbonyl group being the point of attachment to the remainder of the compound of formula (I).

[0038] When referring to a substituent, a dash (“-”) that is not between two letters, words or symbols is meant to represent a point of attachment to such substituent.

[0039] Carbonyl groups are preferably represented herein as CO or other common designations such as -C(O)-, -CO-, -(CO)- or -C(=O)-.

[0040] Whenever a basic amino group is present in the compound of formula (I), a physiologically acceptable anion will be present and may be selected from chloride, bromide, iodide, trifluoroacetate, formate, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate, p-toluenesulfonate, pamoate, and naphthalenedisulfonate. Similarly, when an acidic group is present, the corresponding physiological cation may also be present, and these include, for example, alkali metal ions or alkaline earth metal ions.

[0041] The term "Ki" refers to the dissociation constant for the enzyme-inhibitor complex, which is expressed in molar units. It is an indicator of the binding affinity of the inhibitor to the DDR1 or DDR2 receptor.

[0042] As mentioned above, the present invention refers to a series of compounds represented by general formula (I) as detailed herein below, which have inhibitory activity against receptors DDR1 and DDR2. Antagonism against receptors DDR1 and DDR2 can be particularly effective in treating diseases in which DDR receptors play a role, such as fibrosis and any other diseases, disorders and conditions in which fibrosis is associated.

[0043] In fact, as described in the experimental section below, the compound of formula (I) of the present invention can act as an inhibitor of both DDR1 and DDR2 receptors in a substantial and effective manner.In particular, the following Table 2 shows that the inhibitory activity (expressed as Ki) of representative compounds of the present invention against DDR1 and DDR2 receptors in binding assay is less than 100nM.This indicates that the two isoforms of DDR receptors that are mainly involved in fibrosis and diseases resulting from fibrosis can be inhibited.Therefore, the compound of formula (I) can be used to treat fibrosis, particularly pulmonary fibrosis, when DDR1 and DDR2 are involved.

[0044] As shown in the Comparative Examples section of the Experimental Section, in particular Table 3, the presence of a direct bond between L and the heteroaryl ring B in the compounds of the present invention, in contrast to the comparative compound C1, which is characterized by having a -CO- linker between L and the heteroaryl ring B, unexpectedly and significantly determines an associated increase in inhibitory activity against the DDR1 and DDR2 receptors.

[0045] Advantageously, the compounds of the present invention have extremely high efficacy and can be administered to humans at lower doses relative to compounds described in the prior art, thereby reducing the adverse events typically associated with the administration of higher doses of drugs.

[0046] In addition to their remarkable efficacy in terms of inhibitory activity on both the DDR1 and DDR2 receptors, the compounds of the present invention are also characterized as selective inhibitors of the DDR1 and DDR2 receptors for other human protein kinases, with a favorable inhalation profile that allows them to act efficiently in the pulmonary compartment while minimizing drawbacks related to systemic exposure, such as safety and tolerability issues.

[0047] The compounds of the present invention are therefore useful in the treatment of fibrosis, in particular idiopathic pulmonary fibrosis, and may be particularly appreciated when focusing on suitable and effective compounds that are administered by the inhalation route and are characterized by a good inhalation profile corresponding to good pulmonary activity, good pulmonary retention and low metabolic stability, minimizing systemic exposure and associated safety issues.

[0048] Thus, the present invention provides a compound of formula (I): [ka] [During the ceremony, A is [ka] and phenyl, wherein [ka] indicates a direct bond to NH; W1 and W2 are substituents of Ring A selected from the group consisting of hydrogen, halogen, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, R1R2N-(C1-C4) alkyl, and (C3-C6) cycloalkyl; Z is selected from the group consisting of (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, (C1-C4) hydroxyalkyl, and (C3-C6) cycloalkyl; L is [ka] (In the formula, [ka] indicates a direct bond to the phenyl, [ka] indicates a direct bond to B) selected from the group consisting of: B is a monocyclic or bicyclic heteroaryl ring; Y1 and Y2 are hydrogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)alkoxy-(C1-C4)alkoxy, hydroxy-(C1-C4)alkoxy, hydroxy-(C1-C4)alkyl, (C1-C4)alkyl-heterocycloalkyl-(C0-C4)alkoxy, (C1-C4)haloalkoxy, halogen, cyano, cyano-(C1-C4)alkyl, cyano-(C1-C4)alkyl-heterocycloalkyl, CO are substituents on Ring B independently selected from the group consisting of NR1R2, NHCOR1, NR1R2, RR2N—(C1-C4)alkyl, heterocycloalkyl, (C1-C4)alkyl-heterocycloalkyl, heterocycloalkyl-(C1-C4)alkyl, (C1-C4)alkyl-heterocycloalkyl-carbonyl, (C0-C4)alkyl-heterocycloalkyl-carbonyl(C1-C4)alkyl-phenyl, and monocyclic (C1-C4)alkyl-heteroaryl; R1 and R2 are independently selected from the group consisting of hydrogen, (C1-C4) alkyl, (C1-C4) hydroxyalkyl, (C1-C4) alkoxy(C1-C4) alkyl, (C1-C4) alkylamino-(C1-C4) alkyl, di(C1-C4) alkylamino-(C1-C4) alkyl, optionally substituted (C3-C6) cycloalkyl, optionally substituted heterocycloalkyl, and optionally substituted heterocycloalkyl-(C1-C4) alkoxy, wherein any substituents are one or more and are selected from (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl, and (C1-C4) haloalkoxy; R3 is selected from hydrogen and (C1-C4) alkyl, preferably hydrogen and methyl. or stereoisomers, tautomers, solvates and pharmaceutically acceptable salts thereof.

[0049] All recited meanings of each of the variables A, B, L, Z, W1, W2, Y1, Y2, R1, R2 and R3 of the compounds of formula (I) of the present invention are intended as alternatives and can be combined with each other in embodiments within the scope of the present invention.

[0050] Preferred halogens in the (C1-C4)haloalkyl and (C1-C4)haloalkoxy substituents are fluorine and chlorine, with fluorine being more preferred. Fluorine is also a preferred choice for the halogen substituents W and Y.

[0051] W1 and W2 are substituents of ring A that may be attached to A at any available position. W1 and W2 are preferably selected from the group consisting of H, F, CH3, OCH3, OCF3, CF3, C(CH3)3, CH2CH3, C(CH3)2CF3, OCF2H, CHF2, CH2CF3, CH2N(CH3)2 and cyclopropyl.

[0052] Z is preferably selected from the group consisting of CH3, CF2H, OCH3, CH2OH and cyclopropyl.

[0053] In some embodiments, L is [ka] selected from the group consisting of: In a preferred embodiment, L is [ka] is selected from the group consisting of:

[0054] B is preferably a monocyclic or bicyclic heteroaryl ring selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyrazolo[1,5-a]pyrazinyl, 1H-pyrazolo[3,4-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, imidazo[1,2-a]pyridinyl, thieno[3,2-d]pyrimidinyl, 1H-pyrrolo[2,3-b]pyridinyl and pyrazolyl. Particularly preferred B rings are pyridin-3-yl, pyrimidin-5-yl, pyrazinyl, pyrazolo[1,5-a]pyridin-3-yl, pyrazolo[1,5-a]pyrazin-3-yl, pyrazolo[1,5-a]pyrimidin-3-yl, imidazo[1,2-a]pyrazin-3-yl, 1H-pyrazolo[3,4-b]pyridin-5-yl and imidazo[1,2-b]pyridazin-3-yl.

[0055] Y1 is a substituent of ring B that can be bonded to B at any available position. Y1 is preferably selected from the group consisting of hydrogen, (C1-C4)haloalkyl, (C1-C4)alkoxy, cyano, CONR1R2, NHCOR1, NR1R2, (C1-C4)alkyl-heterocycloalkyl-carbonyl, and monocyclic (C1-C4)alkyl-heteroaryl; more preferably, Y1 is selected from the group consisting of hydrogen, CONH2, CF2H, OCH3, cyano, NHCOCH3, NH2, 4-methylpiperazine-1-carbonyl, 4-methylpiperazin-1-yl, and 1-methyl-1H-pyrazol-4-yl.

[0056] Y2 is a substituent of ring B that can be attached to B at any available position. In a preferred embodiment, Y2 is hydrogen.

[0057] R1 and R2 are independently preferably selected from the group consisting of CH2CH2N(CH3)2, CH2CH2OCH3, CH3, CH2CH2OH, oxetan-3-yl and 3-hydroxycyclobutyl.

[0058] R3 is preferably hydrogen or methyl.

[0059] The optional substituents on R1 and / or R2 are one or more, preferably 1 to 3, selected from the group consisting of (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl and (C1-C4) haloalkoxy, and preferably selected from CH3, OCH3, OCF3, CF3, CF2H, C(CH3)3, C(CH3)2CF3 and OCF2H.

[0060] Thus, in a preferred embodiment, the present invention comprises: A is [ka] and phenyl; W1 and W2 are selected from the group consisting of H, F, CH3, OCH3, OCF3, CF3, C(CH3)3, CH2CH3, C(CH3)2CF3, OCF2H, CHF2, CH2CF3, CH2N(CH3)2 and cyclopropyl; Z is selected from the group consisting of CH3, CF2H, OCH3, CH2OH, and cyclopropyl; L [ka] or L is selected from the group consisting of [ka] selected from the group consisting of: B is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyrazolo[1,5-a]pyrazinyl, 1H-pyrazolo[3,4-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, imidazo[1,2-a]pyridinyl, thieno[3,2-d]pyrimidinyl, 1H-pyrrolo[2,3-b]pyridinyl, and pyrazolyl; Y1 is selected from the group consisting of hydrogen, CONH2, CF2H, OCH3, cyano, NHCOCH3, NH2, 4-methylpiperazine-1-carbonyl, and 4-methylpiperazin-1-yl, and Y2 is hydrogen; R1 and R2 are independently selected from the group consisting of CH2CH2N(CH3)2, CH2CH2OCH3, CH3, CH2CH2OH, oxetan-3-yl, and 3-hydroxycyclobutyl; R3 is hydrogen or methyl; The present invention relates to compounds of formula (I) or stereoisomers, tautomers, solvates and pharmaceutically acceptable salts thereof:

[0061] The present invention relates to compounds of formula (I) wherein L is selected from the group consisting of G, M, Q, T, U and V as defined above, which have the formula (Ic): [ka] wherein L1 is selected from O, NR3, CHR3, S and SO2 or is absent, L1 is preferably selected from O, NR3 and CHR3, and R3 is preferably hydrogen or methyl. It is also called the compound.

[0062] Further particularly preferred embodiments of the present invention are compounds of formula (Ic) and pharmaceutically acceptable salts thereof, as listed in Table 1 below. These compounds are particularly active against the receptors DDR1 and DDR2, as further shown in Table 2 below. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7]

[0063] The compounds of the present invention, including all of the compounds listed above, can be prepared from readily available starting materials using the following general methods and procedures, or by using slightly modified methods readily available to those of ordinary skill in the art. While specific embodiments of the present invention are shown or described below, those of ordinary skill in the art will understand that all embodiments or aspects of the present invention can be obtained using the methods described herein, or by using other methods, reagents, and starting materials. Where typical or preferred process conditions (i.e., reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used, unless otherwise specified. Where optimal reaction conditions can vary with the particular reactants or solvents used, such conditions can be readily determined by one of ordinary skill in the art by routine optimization procedures. Therefore, the processes described below should not be construed as limiting the scope of synthetic methods available for preparing the compounds of the present invention.

[0064] In some cases, when it is necessary to mask or protect sensitive or reactive moieties, commonly known protecting groups (PG) can be used in accordance with the general rules of chemistry (Protective groups in organic syntheses, 3rd ed. T.W. Greene, P.G.M. Wuts).

[0065] In Schemes 1-7, compounds of Formula (I) can be prepared as described below, and at least one non-limiting synthetic route is provided for preparing the exemplified compounds (i.e., example compounds).

[0066] Scheme 1 [ka] Compounds of formula (Ic) wherein L is selected from the group consisting of O, S and SO are [ka] and which may be prepared as shown in Scheme 1 by starting from the corresponding compounds of formula (XXIX) and formula (XX).

[0067] As depicted in Scheme 1, a compound of formula (XXIX), in which Z is as defined above, R is (C-C) alkyl, preferably ethyl, and L is O or S, can be reacted with tert-butyl 3-hydroxyazetidine-1-carboxylate (XX) by carrying out a Mitsunobu reaction in the presence of a coupling agent such as Tsunoda's reagent in a suitable solvent such as toluene at elevated temperature (about 70°C) overnight. A compound of formula (XXX) can be reacted by a redox reaction in the presence of Oxone in a suitable solvent such as ethanol. A compound of formula (XXXIII) can be prepared by reacting a compound of formula (XXX) or formula (XXXI) with a heteroarylamine by transamidation in the presence of a strong base such as BuLi, LiHMDS, or LDA in a suitable solvent such as THF, followed by removal of the protecting group under acidic conditions using TFA or HCl-4-dioxane. Compounds of formula (XXXIII) can be converted to compounds of formula (Ic) by carrying out a Buchwald coupling reaction using a suitable palladium catalyst such as Pd(dppf)Cl, Buchwald third generation catalyst or any other palladium source / phosphine-based ligand in the presence of a base such as CsCO, NaOtBu or LiHMDS in a suitable solvent such as 4-dioxane or DMA at elevated temperature (about 100°C) for several hours.

[0068] Alternatively, compounds of formula (XXXIII) can be prepared by aromatic nucleophilic substitution (S) with suitable commercially available fluoro-heteroaryl or chloro-heteroaryl compounds in the presence of a suitable base such as DIPEA in a suitable solvent such as acetonitrile. NAr) to a compound of formula (Ic).

[0069] If a protecting group is present on Y1 and / or Y2, the compound of formula (Ic) can be obtained using, for example, TFA in a suitable solvent such as DCM (optional step shown as "2) TFA" in Scheme 1).

[0070] Scheme 2 [ka] Compounds of formula (Ic) where L1 is NR3 are [ka]

[0033] Compounds of formula (I), which may be prepared by starting from compounds of formula (II) or formula (XXI), as shown in Scheme 2. Compounds of formula (II) or compounds of formula (XXI), wherein Z is as defined above and R is (C-C) alkyl, preferably ethyl, may be reacted with compounds of formula (XXXIV), such as tert-butyl 3-aminoazetidine-1-carboxylate or tert-butyl 3-(methylamino)azetidine-1-carboxylate, by carrying out a Buchwald coupling reaction using a suitable palladium catalyst, such as Buchwald third generation catalyst or any other palladium source / phosphine-based ligand, in the presence of a base, such as CsCO, NaOtBu, or LiHMDS, in a suitable solvent, such as 4-dioxane or DMA, at elevated temperature (about 100°C) for several hours, to give compounds of formula (XXXV) or (XXXVI), respectively.

[0071] Compounds of formula (XXXVI) can also be prepared by reacting compounds of formula (XXXV) with heteroarylamines via transamidation in the presence of a strong base such as BuLi, LiHMDS, or LDA in a suitable solvent such as THF. Compounds of formula (XXXVII) can then be prepared from compounds of formula (XXXVII) by removing the Boc protecting group under acidic conditions using TFA or HCl-1,4-dioxane. Compounds of formula (XXXVII) can then be converted to compounds of formula (Ic) by a Buchwald coupling reaction using a suitable palladium catalyst such as Pd(dppf)Cl, Buchwald third generation catalyst, or any other palladium source / phosphine-based ligand in the presence of a base such as CsCO, NaOtBu, or LiHMDS in a suitable solvent such as 1,4-dioxane or DMA at elevated temperature (approximately 100°C) for several hours.

[0072] Scheme 3 [ka] Alternatively, as depicted in Scheme 3, a compound of formula (II), in which Z is as defined above and R is (C-C) alkyl, preferably ethyl, can be reacted with tert-butyl 3-hydroxyazetidine-1-carboxylate (XX) or a compound of formula (XXXIV) to provide a compound of formula (XXXVIII) by a Buchwald coupling reaction using a suitable palladium catalyst, such as a Buchwald third generation catalyst or any other palladium source / phosphine-based ligand, in the presence of a base, such as CsCO, NaOtBu, or LiHMDS, in a suitable solvent, such as 4-dioxane or DMA, at elevated temperature (about 100°C) for several hours. Compounds of formula (XXXIX) can be prepared by removing the Boc protecting group under acidic conditions using TFA or HCl in 4-dioxane. A Buchwald coupling reaction can then be carried out using a suitable palladium catalyst, such as a Buchwald third generation catalyst or any other palladium source / phosphine-based ligand, in the presence of a base such as CsCO, NaOtBu, or LiHMDS, in a suitable solvent such as tetrahydrofuran or DMA at elevated temperature (approximately 100°C) for several hours to provide compounds of formula (XL). Compounds of formula (Ic) in which L is O or NR can be prepared by reacting compounds of formula (XL) with heteroarylamines via transamidation in the presence of a strong base such as BuLi, LiHMDS, or LDA in a suitable solvent such as THF. Alternatively, amidation can be carried out using a common coupling agent such as HATU in the presence of an organic base such as DIPEA in a suitable solvent such as DMF to provide compounds of formula (Ic).

[0073] Scheme 4 [ka] Compounds of formula (Ic) wherein L1 is CHR3 or absent are those wherein L is [ka] The compound of formula (I) is, which can be prepared by starting from the corresponding compounds of formula (XLI) and formula (II), as shown in Scheme 4. As depicted in Scheme 4, a compound of formula (II) in which Z is as defined above and R is (C-C) alkyl, preferably ethyl, can be reacted with a compound of formula (XLI) in which R is as defined above and n is 0 or 1 by electrochemical reaction in the presence of dibromonickel and a salt such as silver nitrate in a suitable solvent such as NMP to give a compound of formula (XLII). A compound of formula (XLIV) can be prepared by reacting a compound of formula (XLII) with a heteroarylamine by transamidation in the presence of a strong base such as BuLi, LiHMDS or LDA in a suitable solvent such as THF, followed by removal of the protecting group under acidic conditions using TFA or HCl-4-dioxane solution. A Buchwald coupling reaction can then be carried out using a suitable palladium catalyst such as Pd(dppf)Cl, Buchwald third generation catalyst or any other palladium source / phosphine-based ligand in the presence of a base such as CsCO, NaOtBu or LiHMDS in a suitable solvent such as 4-dioxane or DMA at elevated temperature (about 100°C) for several hours to provide compounds of formula (Ic) where L is CHR.

[0074] Compounds of formula (Ic) in which L1 is CHR3 and R3 is not hydrogen contain a stereocenter at the carbon atom bearing R3. These compounds are obtained as racemic mixtures. Resolution of the racemic mixture can be achieved by chiral resolution methods, such as chiral purification. Both enantiomers of compounds of formula (Ic) are within the scope of the present invention.

[0075] Scheme 5 [ka] In a different approach, compounds of formula (XLV) can be obtained by starting with compounds of formula (XXXIII) and carrying out a Buchwald coupling reaction using a suitable palladium catalyst such as Pd(dppf)Cl, Buchwald third generation catalyst, or any other palladium source / phosphine-based ligand in the presence of a base such as CsCO, NaOtBu, or LiHMDS in a suitable solvent such as tetrahydrofuran or DMA at elevated temperature (about 100 °C) for several hours, as shown in Scheme 5. Compounds of formula (XLVI) can be obtained by reduction of the nitro group to an amine group in a suitable solvent such as EtOH or EtOAc under a hydrogen atmosphere and in the presence of a suitable catalyst such as Pd / C. Compounds of formula (Ic) can be prepared by acylation of compounds of formula (XLVI) with a suitable commercially available acyl chloride, i.e., RCOCl, or an anhydride, in the presence of a suitable base such as pyridine or TEA.

[0076] Scheme 6 [ka] In a different approach, compounds of formula (Ic) can be prepared from compounds of formula (XXXIII) by carrying out a Buchwald coupling reaction with an appropriate cyano-heteroaryl bromide in the presence of a suitable palladium source / phosphine-based ligand, in a suitable solvent such as DMA, and in the presence of an inorganic base such as CsCO at elevated temperature to give compounds of formula (XLVII), as shown in Scheme 6. Compounds of formula (Ic) can be obtained after conversion of the cyano group (CN) to a primary amide in the presence of a peroxide such as hydrogen peroxide, an inorganic base such as KCO, and in a suitable solvent such as DMSO.

[0077] Scheme 7 [ka] Alternatively, compounds of formula (XXXIII) can be prepared by aromatic nucleophilic substitution (S) with a suitable commercially available chloro-heteroaryl in the presence of a suitable base such as DIPEA in a suitable solvent such as acetonitrile.N Ar) to a compound of formula (XLVIII).

[0078] Compounds of formula (Ic) may be prepared as shown in Scheme 7 by reacting compounds of formula (XLVIII) with an aryl or heteroaryl boronic acid ester / acid in a suitable organic solvent such as THF and water, in the presence of an inorganic base such as KPO, using a suitable palladium catalyst system such as Pd-170, under heating (e.g., about 50°C) for several hours, following the general Suzuki method.

[0079] Accordingly, the present invention provides intermediate compounds of formula (XXI), formula (XXX), formula (XXXI), formula (XXXII), formula (XXXIII), formula (XXXV), formula (XXXVI), formula (XXXVII), formula (XXXVIII), formula (XXXIX), formula (XL), formula (XLI), formula (XLII), formula (XLIII), formula (XLIV), formula (XLV) and formula (XLVI) as defined above and their use in the preparation of a compound of formula (Ic).

[0080] In particular, the present invention relates to a compound of formula (XXXIII) [ka] [During the ceremony, A is [ka] and phenyl, wherein [ka] indicates a direct bond to NH; W1 and W2 are substituents of Ring A selected from the group consisting of hydrogen, halogen, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, R1R2N-(C1-C4) alkyl, and (C3-C6) cycloalkyl; R1 and R2 are independently selected from the group consisting of hydrogen, (C1-C4) alkyl, (C1-C4) hydroxyalkyl, (C1-C4) alkoxy(C1-C4) alkyl, (C1-C4) alkylamino-(C1-C4) alkyl, di(C1-C4) alkylamino-(C1-C4) alkyl, optionally substituted (C3-C6) cycloalkyl, optionally substituted heterocycloalkyl, and optionally substituted heterocycloalkyl-(C1-C4) alkoxy, wherein any substituents are one or more and are selected from (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl, and (C1-C4) haloalkoxy; Z is selected from the group consisting of (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, (C1-C4) hydroxyalkyl, and (C3-C6) cycloalkyl; L1 is selected from the group consisting of O, NR3, CHR3, S and SO2, or is absent; R3 is hydrogen and (C1-C4) alkyl. or stereoisomers, tautomers, solvates and pharmaceutically acceptable salts thereof.

[0081] Embodiments of the compound of formula (XXXIII) include: Compounds of formula (XXXVII), wherein L1 is NR3; A compound of formula (XLIV) wherein L1 is CH3 or absent.

[0082] In a further embodiment of the compound of formula (XXXIII), L 1 is selected from the group consisting of O, S and SO 2 , and is preferably O.

[0083] In a preferred embodiment, the variables of formula (XXXIII) have the preferred meanings of the preferred compounds of formula (I) according to the invention.

[0084] The present invention further provides the use of a compound of formula (XXXIII) as defined above in the preparation of a compound of formula (Ic).

[0085] The present invention also relates to a compound of formula (XXXIX) [ka] [During the ceremony, L1 is O, NR3, CHR3, S, SO2, or absent; R is (C1-C4) alkyl, preferably ethyl; Z is selected from the group consisting of (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, (C1-C4) hydroxyalkyl, and (C3-C6) cycloalkyl. or stereoisomers, tautomers, solvates and pharmaceutically acceptable salts thereof.

[0086] The present invention further provides the use of a compound of formula (XXXIX) as defined above in the preparation of a compound of formula (Ic).

[0087] The present invention also relates to a compound of formula (XL): [ka] [During the ceremony, L1 is selected from the group consisting of O, NR3, CHR3, S and SO2, or is absent; R is (C1-C4) alkyl, preferably ethyl; Z is selected from the group consisting of (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, (C1-C4) hydroxyalkyl, and (C3-C6) cycloalkyl; B is a monocyclic or bicyclic heteroaryl ring; Y1 and Y2 are hydrogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)alkoxy-(C1-C4)alkoxy, hydroxy-(C1-C4)alkoxy, hydroxy-(C1-C4)alkyl, (C1-C4)alkyl-heterocycloalkyl-(C0-C4)alkoxy, (C1-C4)haloalkoxy, halogen, cyano, cyano-(C1-C4)alkyl, cyano-(C1-C4)alkyl-heterocycloalkyl, C ONR1R2, NHCOR1, NR1R2, RR2N— are substituents on Ring B independently selected from the group consisting of (C1-C4)alkyl, heterocycloalkyl, (C1-C4)alkyl-heterocycloalkyl, heterocycloalkyl-(C1-C4)alkyl, (C1-C4)alkyl-heterocycloalkyl-carbonyl, (C0-C4)alkyl-heterocycloalkyl-carbonyl(C1-C4)alkyl-phenyl, and monocyclic (C1-C4)alkyl-heteroaryl; R1 and R2 are independently selected from the group consisting of hydrogen, (C1-C4) alkyl, (C1-C4) hydroxyalkyl, (C1-C4) alkoxy(C1-C4) alkyl, (C1-C4) alkylamino-(C1-C4) alkyl, di(C1-C4) alkylamino-(C1-C4) alkyl, optionally substituted (C3-C6) cycloalkyl, optionally substituted heterocycloalkyl, and optionally substituted heterocycloalkyl-(C1-C4) alkoxy, wherein any substituents are one or more and are selected from (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl, and (C1-C4) haloalkoxy; R3 is selected from the group consisting of hydrogen and (C1-C4) alkyl, preferably hydrogen and methyl. or stereoisomers, tautomers, solvates and pharmaceutically acceptable salts thereof.

[0088] The present invention further provides the use of a compound of formula (XL) as defined above in the preparation of a compound of formula (Ic).

[0089] Thus, the present invention provides the use of a compound of formula (XXXIII) and / or a compound of formula (XXXIX) and / or a compound of formula (XL) as defined above in the preparation of a compound of formula (Ic).

[0090] In preferred embodiments, the variables of formula (XXXIII), formula (XXXIX) and formula (XL) each have the preferred meanings of the preferred compounds of formula (I) according to the invention.

[0091] The compounds of formula (I) of the present invention have surprisingly been found to effectively inhibit both the receptors DDR1 and DDR2. Advantageously, the inhibition of the receptors DDR1 and DDR2 can result in the effective treatment of diseases, disorders or conditions in which the DDR receptors are involved.

[0092] In this regard, the compounds of formula (I) of the present invention have been found to have extremely high antagonistic drug effects against DDR1 and DDR2. Table 2 in the experimental section of this specification shows such potency as the inhibition constant Ki of representative compounds of formula (I) of the present invention. In particular, the compounds exhibit potency with a Ki of less than 100 nM. Preferred compounds of the present invention have a Ki of 25 to 5 nM against DDR1 and DDR2. Even more preferred compounds of the present invention have a Ki of 5 nM against DDR1 and DDR2.

[0093] In one aspect, the invention refers to a compound of (I) according to any of the above embodiments for use as a medicament.

[0094] In a preferred embodiment, the present invention refers to compounds of formula (I) and pharmaceutically acceptable salts thereof for use in the treatment of diseases, disorders or conditions associated with DDR dysregulation.

[0095] In another embodiment, the present invention refers to the use of compounds of formula (I) as defined above and pharmaceutically acceptable salts thereof in the manufacture of a medicament for the treatment of a disorder associated with DDR dysregulation.

[0096] In another preferred embodiment, the present invention refers to compounds of formula (I) and pharmaceutically acceptable salts thereof for use in the prevention and / or treatment of diseases, disorders or conditions associated with DDR receptor mechanisms. In a more preferred embodiment, the present invention refers to compounds of formula (I) for use in the prevention and / or treatment of fibrosis and / or diseases, disorders or conditions involving fibrosis.

[0097] As used herein, the term "fibrosis" or "fibrotic disorder" refers to a condition associated with abnormal accumulation of cells and / or fibronectin and / or collagen and / or increased recruitment of fibroblasts, including, but not limited to, fibrosis of individual organs or tissues such as the heart, kidney, liver, joints, lung, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal and gastrointestinal tract.

[0098] Preferably, the compounds of formula (I) as defined above are useful for the treatment and / or prevention of fibrosis such as pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), liver fibrosis, renal fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis and systemic sclerosis.

[0099] More preferably, the compounds of formula (I) as defined above are useful in the treatment of idiopathic pulmonary fibrosis (IPF).

[0100] In one embodiment, the present invention also refers to a method for preventing and / or treating disorders associated with DDR receptor mechanisms, which comprises administering to a patient in need of treatment a therapeutically effective amount of a compound of formula (I) above.

[0101] In a further aspect, the present invention refers to the use of compounds of formula (I) above for the treatment of disorders associated with DDR receptor mechanisms.

[0102] In another embodiment, the present invention refers to the use of a compound of formula (I) above in the manufacture of a medicament for the treatment of a disorder associated with DDR receptor mechanisms.

[0103] In a further aspect, the present invention refers to a method for preventing and / or treating disorders or conditions associated with dysregulation of DDR receptors 1 and 2, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I) above.

[0104] In a further aspect, the present invention refers to compounds of formula (I) as defined above for the treatment of diseases, disorders or conditions associated with dysregulation of DDR receptors 1 and 2.

[0105] As used herein, a "safe and effective amount" of a compound of formula (I) or a pharmaceutically acceptable salt thereof or other pharmaceutically active agent means an amount of the compound that is sufficient to treat the patient's condition, yet low enough to avoid serious side effects, which may nevertheless be routinely determined by one of ordinary skill in the art.

[0106] The compound of formula (I) may be administered once or according to a dosing regimen of multiple doses at different time intervals over a period of time. The typical daily dose may vary depending on the route of administration selected.

[0107] The present invention also refers to pharmaceutical compositions comprising at least a compound of formula (I) according to any of the embodiments in admixture with one or more pharmaceutically acceptable carriers and / or excipients.

[0108] In certain embodiments, the present invention refers to a pharmaceutical composition, a pharmaceutical composition, which is a mixture of a compound of Formula (I) and at least one or more pharmaceutically acceptable carriers and / or excipients, e.g., as described in Remington's Pharmaceutical Sciences Handbook, XVII Ed., Mack Pub., NY, USA.

[0109] Administration of the compounds of the present invention and pharmaceutical compositions thereof can be achieved, for example, orally, nasally, parenterally (subcutaneously, intravenously, intramuscularly, intrasternally and by infusion) and by inhalation, depending on the needs of the patient.

[0110] Preferably, the compounds of the present invention are administered orally or by inhalation.

[0111] In certain preferred embodiments, the pharmaceutical compositions comprising the compounds of formula (I) are solid oral dosage forms such as tablets, gel capsules, capsules, caplets, granules, lozenges and bulk powders.

[0112] In certain embodiments, the pharmaceutical composition comprising a compound of Formula (I) is a tablet.

[0113] The compounds of the present invention may be administered alone or in combination with known excipients, including various pharmaceutically acceptable carriers, diluents (sucrose, mannitol, lactose, starch, etc.), and suspending agents, solubilizing agents, buffers, binders, disintegrating agents, preservatives, coloring agents, flavoring agents, lubricants, etc.

[0114] In a further embodiment, the pharmaceutical compositions comprising the compounds of formula (I) are liquid oral dosage forms such as aqueous and non-aqueous solutions, emulsions, suspensions, syrups and elixirs. Such liquid dosage forms may also contain known inert diluents such as water, and suitable known excipients such as preservatives, wetting agents, sweeteners, flavoring agents, and agents for emulsifying and / or suspending the compounds of the present invention.

[0115] In a further 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.

[0116] For administration as a dry powder, single or multi-dose inhalers known in the art can be used, in which case the powder can be filled into gelatin, plastic or other capsules, cartridges or blister packs or reservoirs.

[0117] A diluent or carrier, which is chemically inert to the compound of the present invention, such as lactose or any other additive suitable for improving the inhalation fraction, may be added to powders of the compound of the present invention.

[0118] Inhalation aerosols containing a propellant gas such as a hydrofluoroalkane contain the compounds of the invention in solution or dispersion form. Propellant-driven formulations may also contain other ingredients as cosolvents, stabilizers and possibly other excipients.

[0119] Propellant-free formulations containing the compounds of the invention may be in the form of solutions or suspensions in aqueous, alcoholic or hydroalcoholic vehicles, which may be delivered by jet or ultrasonic nebulizers, or by soft mist nebulizers, as known in the art.

[0120] The compounds of the invention may be administered as the sole active ingredient or in combination with other pharmaceutically active ingredients.

[0121] The dosage of the compounds of the present invention will depend on a variety of factors, including, inter alia, the particular disease being treated, the severity of the condition, the route of administration, and the like.

[0122] The present invention also relates to a device comprising a pharmaceutical composition comprising a compound of formula (I) according to the present invention in the form of a single or multiple dose dry powder inhaler or a metered dose inhaler.

[0123] All preferred groups or embodiments described above for compounds of formula (I) may be combined with each other and apply mutatis mutandis.

[0124] Various aspects of the invention described herein are illustrated in the following examples, which are not meant to limit the invention in any way.

[0125] Preparation of Intermediates and Example Compounds Chemical names of compounds were generated using the Structure-To-Name tool in the PerkinElmer ChemDraw Professional application (v. 20.0.0.41.) All reagents whose synthesis is not described in the experimental section are either commercially available, known compounds, or can be prepared by known methods by one skilled in the art.

[0126] In the following methods, some starting materials are identified by an "Intermediate" or "Example" number as well as by a step number, which is provided solely as an aid to those skilled in the art.

[0127] When reference is made to the use of "similar" or "analogous" methods, such methods may include minor variations, such as variations in reaction temperature, reagent / solvent amounts, reaction time, work-up conditions, or chromatographic purification conditions, as would be understood by one of ordinary skill in the art. Unless otherwise noted, all compounds were obtained as the free base.

[0128] Abbreviations AcOH = acetic acid; acetone-d6 = deuterated acetone; ACN = acetonitrile; ACN-d3 = deuterated acetonitrile; CDCl3 = deuterated chloroform; CV = column volume; DCM = dichloromethane; DIPEA = N,N-diisopropylethylamine; DMF = dimethylformamide; DMSO = dimethyl sulfoxide; DMSO-d6 = deuterated dimethyl sulfoxide; ee = enantiomeric excess; Et2O = diethyl ether; EtOAc = ethyl acetate; eq.= equivalents; FCC = flash column chromatography; h = hours / s; HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; HCOOH = formic acid; HPLC = high-pressure liquid chromatography; LC-MS = liquid chromatography / mass spectrometry; LDA = lithium diisopropylamide; Na / LiHMDS = sodium / lithium bis(trimethylsilyl)amide; MeOH = methyl alcohol; min = minutes; TBAF = tetrabutylammonium Fluoride; 2-MeTHF = 2-methyltetrahydrofuran; NaBH3CN = sodium cyanoborohydride; NMR = nuclear magnetic resonance; MeOH-d4 = deuterated methanol; Pd(dba)2 = bis(dibenzylideneacetone)palladium(0); Pd(dppf)Cl2 = [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); RT / rt = room temperature; RuPhos = 2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl; SCX = strong cation exchange; SFC = supercritical fluid chromatography; STAB = sodium triacetoxyborohydride; SM = starting material; tBu = tert-butyl; tBuBrettPhos Pd G3 = [(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate 3rd generation; tBuOK = potassium tert-butoxide; TBDMS = tert-butyldimethylsilyl; TBTU = 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate; TEA = triethylamine; TFA = trifluoroacetic acid; THF = tetrahydrofuran; TLC = thin layer chromatography; t. R = retention time; UPLC = ultra-performance liquid chromatography; VCD = vibrational circular dichroism; XantPhos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; IPA = isopropanol; WE = working electrode; CE = counter electrode.

[0129] General Experimental Details NMR specialization: 1 H-NMR spectra were measured on a Varian MR-400 spectrometer equipped with a 5 mm 1H / nX broadband probehead, a self-shielded Z-gradient coil for inverse detection, a deuterium digital lock channel unit, and a quadrature digital detection unit with transmitter offset frequency shift, operating at 400 MHz (proton frequency). Chemical shifts are reported as δ values in ppm relative to trimethylsilane (TMS) as the internal standard. Coupling constants (J values) are given in hertz (Hz), and multiplicities are reported using the following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, dt = triplet of triplets, m = multiplet, brs = broad singlet, and nd = not determined.

[0130] In some cases, the signal NH from the amide or amine bond (exchangeable proton) is not visible. In a few cases, some signals may be hidden under the signal of water or the signal of DMSO or residual solvent.

[0131] LC / UV / MS analysis method LC / MS retention times are expected to be subject to experimental error of ±0.5 minutes. Method 1: Acquity CSH C18 column, 50 mm x 2.1 mm, 1.7 μm, maintained at 40 °C; Mobile phase: Eluent B (ACN / water 95:5 + 0.05% HCOOH) in Eluent A (water / ACN 95:5 + 0.05% HCOOH), 1% to 99.9% in 1.5 min. Flow rate: 1 mL / min. Wavelength: 210-400 nm DAD. UPLC + Waters PDA + Waters QDA.

[0132] Method 2: Waters Sunfire C18 column, 4.6 x 50 mm, 3.5 μm, maintained at 40 °C. Mobile phase: ACN in water + 10 mM ammonium bicarbonate, 95% in 5 min. Flow rate: 2.0 mL / min. Wavelength: 210-400 nm DAD. Waters 2795 Separation Module + Waters DAD + Micromass ZQ, single quadrupole LC-MS.

[0133] Method 3: Acquity CSH C18 column, 50 mm x 2.1 mm, 1.7 μm, maintained at 40 °C; Mobile phase: Eluent B (ACN / water 95:5 + 0.05% HCOOH) in Eluent A (water / ACN 95:5 + 0.05% HCOOH), 1% to 99.9% in 3.5 min. Flow rate: 1 mL / min. Wavelength: 210-400 nm DAD. UPLC + Waters PDA + Waters QDA.

[0134] Method 4: Waters Acquity QSM, Kinetex C8 column, 100 mm x 2.1 mm, 1.7 μm, maintained at 55°C; mobile phase: eluent A (0.025 M HCOOH, pH 3), eluent B (ACN + 0.1% FA). Gradient mode: Eluent B increased from 1% to 30% from 0 to 3 min, increased from 30% to 50% from 3 to 6.50 min, increased from 50% to 80% from 6.50 to 7.50 min, held at 80% from 7.50 to 8 min, decreased from 80% to 1% from 8 to 8.10 min, and held at 1% until the end of 10 min at 8.10 min. Flow rate: 0.5 mL / min. Wavelength: 210-400 nm PAD. UPLC + Waters PDA + Xevo TQS MS instrument.

[0135] Method 5: Acquity UPLC HSS C18 column, 100 x 2.1 mm, 1.8 μm (Plus guard cartridge), maintained at 40 °C. Mobile phase: ACN (0.1% formic acid) in water (0.1% formic acid), 5% to 95% in 5.6 min. Flow rate: 0.4 ml / min. Wavelength: 210-400 nm DAD. UPLC + Waters DAD + Waters SQD2, single quadrupole UPLC-MS.

[0136] Method 6: Agilent Zorbax column, 4.6 x 50 mm, 3.5 μm, maintained at 40°C. Mobile phase: ACN (0.1% formic acid) in water (0.1% formic acid), 5% to 95% in 2 min. Flow rate: 3.0 mL / min. Wavelength: 210-400 nm DAD. Waters 2795 / 2695 separation module + Waters DAD + Micromass ZQ, single quadrupole LC-MS.

[0137] Method 7: Acquity BEH C18 (2.1 mm x 50 mm, 1.7 μm) maintained at 60°C; flow rate 1.0 mL / min; detection wavelength 220-300 nm; injection volume 1.0 μL; mobile phase: eluent B ACN, eluent A water (0.1% v / v TFA), 2% to 98% in 2 min. Flow rate: 1 mL / min. Wavelength: 220-300 nm.

[0138] Method 8: Acquity UPLC BEH Shield RP18 column, 100 x 2.1 mm, 1.72 μm (Plus Guard cartridge), maintained at 40°C. Mobile phase: ACN in water + 10 nM ammonium bicarbonate from within 5.6 minutes. Flow rate: 0.4 ml / min. Wavelength: 210-400 nm DAD. UPLC + Waters DAD + Waters SQD2, single quadrupole UPLC-MS.

[0139] Method 9: Kinetex® XB-C18 column, 4.6 x 50 mm, 2.6 μm maintained at 25°C. Mobile phase: Water (0.1% formic acid) in MeCN (0.1% formic acid), 80% to 5% over 3.90 min; flow rate: 1.0 ml / min; wavelength: 190-340 nm DAD. Dionex UHPLC Ultimate 3000 equipped with a DAD detector / Thermo Scientific ISQ EC mass spectrometer.

[0140] Method 10: Kinetex® XB-C18 column, 4.6 x 50 mm, 2.6 μm maintained at 25°C. Mobile phase: Water (0.1% formic acid) in MeCN (0.1% formic acid), 90% to 5% over 3.90 min; flow rate: 1.0 ml / min; wavelength: 190-340 nm DAD. Dionex UHPLC Ultimate 3000 equipped with a DAD detector / Thermo Scientific ISQ EC mass spectrometer.

[0141] Method 11: Kinetex® XB-C18 column, 4.6 x 50 mm, 2.6 μm maintained at 25°C. Mobile phase: Water (0.1% formic acid) in MeCN (0.1% formic acid), 60% to 5% over 3.90 min; flow rate: 1.0 ml / min; wavelength: 190-340 nm DAD. Dionex UHPLC Ultimate 3000 equipped with a DAD detector / Thermo Scientific ISQ EC mass spectrometer.

[0142] Method 12: Acquity CSH C18 column, 50 mm x 2.1 mm, 1.7 μm, maintained at 40°C; Mobile phase: Eluent B (ACN) in Eluent A (water + 0.1% HCOOH), 1% to 99.9% in 1.5 min. Flow rate: 1 mL / min. Wavelength: 210-400 nm DAD. UPLC + Waters PDA + Waters QDA.

[0143] Method 13: Acquity CSH C18 column, 50 mm x 2.1 mm, 1.7 μm, maintained at 40°C; Mobile phase: Eluent B (ACN) in Eluent A (water + 0.1% HCOOH), 1% to 99.9% in 3.5 min. Flow rate: 1 mL / min. Wavelength: 210-400 nm DAD. UPLC + Waters PDA + Waters QDA.

[0144] Method 14: Waters TMAcquity QSM, Acquity UPLC CSH C18 column, 50 mm x 2.1 mm, 1.7 μm, maintained at 50°C; mobile phase: eluent A (HCOONH4 0.025 M pH 3), eluent B (ACN + 0.1% FA). Gradient mode: eluent B increased from 20% to 80% from 0 to 5:50 min, held at 80% from 5:50 to 7:50 min, decreased from 80% to 20% from 7:50 to 8 min, and held at 20% from 8 to 10 min. Flow rate: 0.35 mL / min. Wavelength: 210-400 nm DAD. UPLC + Waters™ PDA + Xevo TQS MS instrument.

[0145] Method 15: Kinetex® XB-C18 column, 4.6 x 50 mm, 2.6 μm maintained at 25°C. Mobile phase: Water (0.1% formic acid) in MeCN (0.1% formic acid), 50% to 5% in 3.90 min; flow rate: 1.0 ml / min; wavelength: 190-340 nm DAD. Dionex UHPLC Ultimate 3000 equipped with a DAD detector / Thermo Scientific ISQ EC mass spectrometer.

[0146] Method 16: Acquity UPLC BEH-Waters, 1.7 μm C18 (2.1 × 100 mm), 130 Å, maintained at 25 °C. Mobile phase: Water (0.1% formic acid) in MeCN (0.1% formic acid), 80% to 5% in 2.70 min; flow rate: 0.5 ml / min; wavelength: 254 nm. Shimadzu LCMS-2020 single quadrupole liquid chromatograph mass spectrometer.

[0147] Chiral Supercritical Fluid Chromatography (SFC) Separation Protocol Diastereomeric separation of the compounds was achieved by supercritical fluid chromatography (SFC) using an LC system. Analysis of the two enantiomers was performed from the final reconstituted sample.

[0148] Alternatively, diastereomeric separation of compounds was achieved by supercritical fluid chromatography (SFC) using a Waters Thar Prep100 preparative SFC system (P200 CO2 pump, 2545 modifier pump, 2998 UV / VIS detector, 2767 liquid handler equipped with a stacked injection module). The Waters 2767 liquid handler was used as the autosampler and fraction collector. Appropriate isocratic methods were selected based on methanol, ethanol, or isopropanol solvents under unmodified or basic conditions. The SFC method used was modifier CO2 at 100 mL / min, 120 bar backpressure, and 40 °C column temperature. The modifier used under basic conditions was diethylamine (0.1% v / v). The modifier used under acidic conditions was formic acid (0.1% v / v) or trifluoroacetic acid (0.1% v / v). SFC purification was controlled by Waters Fractionlynx software, monitored from 210 to 400 nm with a typical collection start at 260 nm. Collected fractions were analyzed by SFC (Waters / Thar SFC system equipped with a Waters SQD). Fractions containing the desired product were concentrated by vacuum centrifugation.

[0149] Analytical conditions for supercritical fluid chromatography-mass spectrometry Method 17: SFC-MS was performed using a Waters LUX Cellulose-1 (20 × 250 mm, 5 μm) column. TM Waters with SQD TM The analysis was carried out on a / Thar SFC system, isocratic (30% MeOH (NH4OH 0.1%):CO2), flow rate 100 mL / min, 120 bar, 40°C column temperature, DAD wavelength 265 nm.

[0150] All solvents were purchased from commercial sources and used without further purification. Unless otherwise noted, flash chromatography (FCC) was performed on a Biotage Isolera followed by SCX(NH) to give the free base of the product.

[0151] For reversed-phase FCC the following gradient / eluent was used: gradient A:B 100:0 to 0:10 in 12 CV, eluent A: H2O / ACN / HCOOH 95:5:0.1 eluent B: H2O / ACN / HCOOH 5:95:0.1.

[0152] General synthesis method Intermediate 4: N-(5-bromopyridin-3-yl)acetamide [ka] To a solution of 5-bromopyridin-3-amine (1 g, 5.78 mmol) in DCM (30 mL) was added acetic anhydride (1.745 mL, 18.50 mmol), followed by DIPEA (2.73 mL, 15.61 mmol). The solution was stirred at room temperature. The next day, UPLC-MS analysis showed complete conversion of SM. The solution was diluted with saturated NaHCO3 solution (20 mL) and extracted with DCM (20 mL × 2), followed by EtOAc (20 mL). The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by FCC on a silica gel column eluting with a gradient of 0 to 80% EtOAc in n-heptane to give the title compound (1.1 g, 5.17 mmol, 88% yield). LC-MS (ESI, m / z): Method 1, t R =0.56 min, m / z(M+1)=214.8 / 216.8

[0153] Intermediate 6: 5-(tert-butyl)-1-methyl-1H-pyrazol-3-amine [ka] To a solution of 3-chloro-4,4-dimethylpent-2-enenitrile (5.00 g, 34.8 mmol, 1.00 equiv.) and KCO (4812 mg, 34.8 mmol, 1.00 equiv.) in EtOH (25 mL), methylhydrazine (2.0 mL, 38.3 mmol, 1.10 equiv.) was added, and the reaction mixture was heated at 80 °C for 4 h. The reaction mixture was cooled to room temperature, filtered through a Celite® pad, and the filtrate was purified in vacuo. The residue was purified by column silica gel chromatography eluting with 0-100% EtOAc in cyclohexane, followed by 0-100% MeOH in EtOAc to give a 5:1 mixture of the desired product and its regioisomer. The mixture was washed with cyclohexane and filtered. The resulting residue was separated by achiral SFC (YMC Cellulose-SC 20 × 250 mm, 5 μm 10 / 90 IPA (0.1% DEA) / CO2, 100 ml / min, 120 bar, 40 °C, DAD 230 nm) and dried in vacuo at 40 °C to give the title compound (2.75 g, 17.2 mmol, 49%). LC-MS (ESI, m / z): (Method 6), t R =2.09 min, m / z(M+1)=154.2 1H NMR (400MHz, CDCl3) δ 5.40 (s, 1H), 3.76 (s, 3H), 3.32-3.31 (m, 2H), 1.32 (s, 9H).

[0154] Intermediate 7: 5-(trifluoromethoxy)pyridin-3-amine hydrochloride [ka] Step 1 - tert-Butyl N-[5-(trifluoromethoxy)-3-pyridyl]carbamate (Intermediate 8) [ka] A solution of a mixture of tert-butyl carbamate (102 mg, 0.868 mmol, 1.20 eq), Xantphos (63 mg, 0.108 mmol, 0.150 eq), tris(dibenzylideneacetone)dipalladium(0) adduct (37 mg, 0.0362 mmol, 0.0500 eq), and CsCO (283 mg, 0.868 mmol, 1.20 eq) in 1,4-dioxane (5 mL) was degassed with nitrogen and treated with 3-bromo-5-(trifluoromethoxy)pyridine (175 mg, 0.723 mmol, 1.00 eq). The reaction was stirred at 100 °C for 1 h. The reaction mixture was cooled to room temperature and filtered through a Celite pad, which was then washed with dioxane, and the combined organic phase was concentrated in vacuo. The residue was purified by column silica gel chromatography eluting with 0-100% EtOAc in cyclohexane and dried in vacuo overnight to give the title compound (115 mg, 0.413 mmol, 57%). LC-MS (ESI, m / z): (Method 2), t R =1.24 min, m / z(M+1)=279.1 1 H NMR (400MHz, CDCl3) δ 8.33(d, J=2.3Hz, 1H), 8.23-8.21(m, 1H), 8.07(s, 1H), 7.04(s, 1H), 1.54(s, 9H).

[0155] Step 2-5-(Trifluoromethoxy)pyridin-3-amine hydrochloride (Intermediate 7) HCl 4N dioxane solution (3.0 mL, 0.413 mmol, 1.00 eq) was added to a solution of intermediate 8 (115 mg, 0.413 mmol, 1.00 eq) in 1,4-dioxane (3 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with diethyl ether (20 mL), filtered, and the resulting white solid was washed with ether and dried in vacuo to give the title compound (60 mg, 0.280 mmol, 68%). LC-MS (method 2):t R =0.88 min; m / z(M+1)=179.0. 1H NMR (400MHz, DMSO-d6) δ 8.07 (d, J=2.0Hz, 1H), 8.03 (d, J=1.5Hz, 1H), 7.30 (d, J=1.0Hz, 1H).

[0156] Intermediate 40-3-Bromo-6-(4-methylpiperazin-1-yl)imidazo[1,2-b]pyridazine [ka] A suspension of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (500 mg, 2.15 mmol), 1-methylpiperazine (0.72 mL, 6.45 mmol), and DIPEA (0.37 mL, 2.15 mmol) in DME (1.5 mL) was heated at 100 °C overnight. The reaction mixture was diluted with EtOAc and washed with NaHCO. The organic phase was dried over MgSO and concentrated in vacuo. The residue was purified by FCC (0-100% EtOAc in cyclohexane, followed by 10% 0.7 N NH-MeOH in DCM) to give the title compound (610 mg, 2.06 mmol, 96%). LC-MS(ESI): Method 2, t R =1.32 min;m / z(M+1)=296.0;298.1

[0157] Using the method described for the synthesis of intermediate 40, the following intermediates were prepared: [Table 2]

[0158] Intermediate 43: N-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)acetamide [ka] A solution of 3-bromo-5-chloropyrazolo[1,5-a]pyrimidine (500 mg, 2.151 mmol) in THF (10 mL) was placed in one chamber of a COware gas reactor, followed by the addition of TEA (0.300 mL, 2.15 mmol). The other chamber was charged with aqueous NH3 (5 mL, 73.4 mmol). The tube was closed with a sealant cap, and the system was purged with nitrogen and placed under vacuum. The tube was heated at 80 °C and stirred until complete conversion. The volatiles were removed under reduced pressure, after which the residue was dissolved in pyridine (10 mL) and acetyl chloride (253 mg, 3.2 mmol) was added in one portion. The reaction mixture was diluted with DCM, and the crude was washed with NaHCO3, NH4Cl, and brine. The organic layer was dried over Na2SO4 and evaporated under reduced pressure. The title compound (336 mg, 1.32 mmol, 61% yield) was obtained and used directly in the next step. LC-MS(ESI): Method 13 t R =0.97min;m / z(M+1)=254.9.0-226.8

[0159] Example 142-4-Methyl-3-((1-(pyrazolo[1,5-a]pyrimidin-3-yl)azetidin-3-yl)oxy)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide [ka] Step 1: tert-butyl 3-(5-(ethoxycarbonyl)-2-methylphenoxy)azetidine-1-carboxylate (Intermediate 103) [ka] Ethyl 3-hydroxy-4-methylbenzoate (3 g, 16.7 mmol) and tert-butyl 3-hydroxyazetidine-1-carboxylate (3.75 g, 21.6 mmol) were dissolved in toluene (3 mL), followed by the addition of a solution of 2-(tributyl-λ5-phosphanylidene)acetonitrile (6.54 mL, 24.97 mmol) in toluene (1.2 mL). The reaction mixture was stirred at 70 °C overnight. The mixture was diluted with saturated NaHCO , which was then extracted with DCM. The organic layers were combined, dried over Na SO , and concentrated. The crude material was purified by FCC (100% heptane to 100% AcOEt) to give the title compound (5.5 g, 16.31 mmol, 89%). LC-MS (ESI, m / z): Method 13, t R = 2.53 min, m / z (M-tBu) = 280.2

[0160] Step 2: tert-butyl 3-(2-methyl-5-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)phenoxy)azetidine-1-carboxylate (Intermediate 104) [ka] 5-(Trifluoromethyl)pyridin-3-amine (0.873 g, 5.4 mmol) was dissolved in 1 M LiHMDS in THF (16 mL, 16.1 mmol), and the solution was stirred at room temperature overnight. Next, a solution of intermediate 103 (1.8 g, 5.4 mmol) in THF (6 mL) was added, and the reaction mixture was stirred at room temperature for 2 hours. After that, it was diluted with water and extracted with AcOEt. All organic layers were combined, dried over Na2SO4, filtered, and concentrated. Purification by FCC (eluted with 100% Cyclohexanone to 50% AcOEt in Cyclohexanone) gave the title compound (1.94 g, 4.30 mmol, 80%). LC-MS (ESI, m / z): Method 13, t R =2.43 min, m / z(M+1)=452.1

[0161] Similarly, the following intermediates were prepared by reacting the appropriate corresponding amines: [Table 3]

[0162] Step 3: 3-(Azetidin-3-yloxy)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Intermediate 111) [ka] Intermediate 104 (1.94 g, 4.30 mmol) was dissolved in DCM (21.5 mL) and TFA (3.3 mL, 43 mmol) was added dropwise. The reaction was stirred at room temperature for 3 h. The reaction mixture was quenched with saturated NaHCO3 and extracted with CHCl3:i-PrOH. All organic layers were combined, dried over Na2SO4, filtered, and concentrated. Purification by FCC (DCM / 2M NH3-MeOH solution 100 / 0 to 80 / 20) gave the desired product (1.35 g, 3.8 mmol, 89%). LC-MS (ESI, m / z): Method 13, t R =0.91 min, m / z(M+1)=352.2

[0163] Similarly, the following intermediates were purified by reacting the appropriate analogues. [Table 4-1] [Table 4-2]

[0164] Following similar procedures, the following example compounds were prepared: [Table 5]

[0165] Step 4: 4-methyl-3-((1-(pyrazolo[1,5-a]pyrimidin-3-yl)azetidin-3-yl)oxy)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 142) A 0.5-2 mL microwave vial was charged with Intermediate 111 (100 mg, 0.28 mmol), 3-bromopyrazolo[1,5-a]pyrimidine (56 mg, 0.28 mmol), sodium tert-butoxide (82 mg, 0.85 mmol), BPC-305 (27.0 mg, 0.028 mmol), and Me-THF (2 mL). The mixture was stirred at 80 °C for 1 h. The solution was diluted with DCM and washed with water. The organic phase was concentrated under reduced pressure. Purification by RFFCC afforded the title compound (72 mg, 0.154 mmol, 54%). LC-MS (ESI, m / z): Method 14, t R =5.95 min, m / z(M+1)=469.2 1 H NMR (acetone-d6, 400MHz)δ 10.05(brs, 1H), 9.18(d, 1H, J=2.2Hz), 8.75(s, 1H), 8.6-8.7(m, 2H), 8.21(dd, 1H, J=1.6, 3.8Hz), 7.72(s, 1H), 7.61(dd, 1H, J=1.3, 7.7Hz), 7. 42(s, 1H), 7.33(d, 1H, J=7.9Hz), 6.78(dd, 1H, J=3.8, 7.1Hz), 5.31(t, 1H, J=5.5Hz), 4.6-4.6(m, 2H), 4.01(dd, 2H, J=4.8, 8.8Hz), 2.29(s, 3H)

[0166] Similarly, the following example compounds or intermediates were prepared by reacting the appropriate analogues. [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5] [Table 6-6] [Table 6-7] [Table 6-8] [Table 6-9]

[0167] Intermediate 129-tert-butyl 3-(5-(ethoxycarbonyl)-2-methylbenzyl)azetidine-1-carboxylate [ka] To an oven-dried 10 mL ElectraSyn 2.0 vial were added the redox-active ester tert-butyl 3-(2-((1,3-dioxoisoindolin-2-yl)oxy)-2-oxoethyl)azetidine-1-carboxylate (500 mg, 1.39 mmol), ethyl 3-bromo-4-methylbenzoate (506 mg, 2.081 mmol), dibromonickel 1-methoxy-2-(2-methoxyethoxy)ethane (98 mg, 0.28 mmol), and 2,2′-bipyridine (43.3 mg, 0.28 mmol), all directly as solids / oils. Anhydrous NMP (8 mL) was then added, and the contents of the vial were stirred until all solids had dissolved. Silver nitrate (118 mg, 0.69 mmol) was then added as a solid directly to the reaction mixture. The vial was closed with an ElectraSyn 2.0 vial cap containing a (+) magnesium sacrificial anode (WE) and a 100 ppi (-) carbon anode (3 mm x 7 mm x 51 mm) (CE). The vial was then placed on an IKA ElectraSyn 2.0 stir plate, and the electrolysis was set to 12 mA, 1.37 mmol, and 3.0 F / mol. The electrodes were washed with ACN, and then water was added to the solid precipitate. The solution was filtered through a Celite pad, and the resulting clear solution was extracted with MTBE. The organic layer was collected and dried over Na2SO4. The solvent was removed under reduced pressure, and the crude material was dissolved in reverse-phase FCC (eluent A / eluent B: 100:0 to 0:100) to give the title compound (137 mg, 0.41 mmol, 30%). LC-MS (ESI, m / z): Method 13, t R =2.49 min, m / z(M+1-BOC)=234.06

[0168] The following intermediates were prepared using the above method by starting from the relevant intermediate. [Table 7]

[0169] Intermediate 13 1-tert-butyl 3-((5-(ethoxycarbonyl)-2-methylphenyl)thio)azetidine-1-carboxylate [ka] Ethyl 3-mercapto-4-methylbenzoate (715 mg, 3.64 mmol) and tert-butyl 3-hydroxyazetidine-1-carboxylate (820 mg, 4.74 mmol) were dissolved in toluene (12 mL), followed by the addition of 2-(tributyl-λ5-phosphanylidene)acetonitrile (1.43 mL, 5.46 mmol) in one portion, and the solution was purged with Ar for 2 minutes. The reaction mixture was stirred at 70 °C overnight. The mixture was evaporated under reduced pressure, and the residue was dissolved in DCM and washed with NaHCO and brine. The organic layer was dried over MgSO. The crude product was purified by FCC (eluent A: n-heptane, eluent B: ethyl acetate, gradient A:B 100:0 to 60:40). The relevant fractions were collected and evaporated to dryness to give the title compound (971.1 mg, 2.76 mmol, 76% yield). LC-MS (ESI, m / z): Method 13, t R =2.64 minutes, m / z(M+1-tBytyl)=295.97 1 H NMR (acetone-d6, 400MHz)δ 7.76(dd, 1H, J=1.4, 7.8Hz), 7.66(s, 1H), 7.37(d, 1H, J=7.9Hz), 4.46(brs, 2H), 4.34(q, 2H , J=7.0Hz), 4.2-4.3(m, 1H), 3.80(brs, 2H), 2.39(s, 3H), 1.42(s, 9H), 1.36(t, 3H, J=7.1Hz)

[0170] Using similar methods, the following intermediates were prepared: [Table 8]

[0171] Example 173-3-((1-(5-cyano-7H-pyrrolo[2,3-d]pyrimidin-4-yl)azetidin-3-yl)oxy)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide [ka] A microwave vial was charged with Intermediate 111 (80 mg, 0.227 mmol) and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (61 mg, 0.34 mmol) and dissolved in ACN (3 mL). DIPEA (0.12 mL, 0.68 mmol) was added, and the mixture was heated at 85 °C until complete conversion. The volatiles were removed under reduced pressure, and the residue was partitioned between DCM and water. The organic layer was washed with saturated NaHCO3, dried over sodium sulfate, filtered, and concentrated. The residue was purified by normal-phase FCC silica gel flash chromatography (28 g Sfar-D amino column, 12 CV, gradient A:B 100:0 to 0:10, eluent A: n-heptane, eluent B: acetone). Relevant fractions were collected, and the solvent was evaporated to give the desired product (73 mg, 0.15 mmol, 65%). LC-MS (ESI, m / z): Method 4, t R =6.57 min, m / z(M+1)=494.19 1 H NMR (400MHz, DMSO-d6) δ ppm 10.72(1H, m), 9.19(1H, brs), 8.69(1H, brs), 8.65(1H, s), 8.05(1H, s), 7.77(1H, s), 7.61(1H, d, J=7.67Hz), 7.39(1H , brd, J=7.67Hz), 7.31(1H, s), 5.30(1H, m), 4.75(2H, dd, J=9.54, 6.47Hz), 4.21(2H, dd, J=9.76, 3.62Hz), 2.29(3H, m)

[0172] The following intermediates were prepared by using the methods described for the synthesis of the compound of Example 173, starting from the appropriate intermediate using ACN or DMA as solvent. [Table 9]

[0173] Intermediate 139 -3-((1-(5-aminopyridin-3-yl)azetidin-3-yl)oxy)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide [ka] To a 50 mL steel reaction vessel was added intermediate 133 (75 mg, 0.16 mmol), followed by the addition of JM Pd / C 10R424 (50% wet, 16.86 mg, 7.92 μmol) in portions. The vessel was sealed, and the reaction was set up through three vacuum-H2 cycles. The reaction was stirred at 40 °C under 3 bar of hydrogen (0.639 mg, 0.317 mmol) and allowed to complete. The mixture was filtered through a Celite pad, and the solvent was then removed under reduced pressure. The residue was purified by FCC (6 g Sfar-D amino column, gradient n-heptane:acetone 100:0 to 0:100) to give the title compound (41 mg, 0.092 mmol, 58% yield). LC-MS (ESI): Method 4, tR=4.30 min, m / z(M+1)=444.2

[0174] Example 139 -5-(3-(2-methyl-5-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)phenoxy)azetidin-1-yl)nicotinamide [ka] Intermediate 128 (0.150 g, 0.33 mmol) was dissolved in DMSO (1 mL), followed by the addition of K2CO3 (0.082 g, 0.595 mmol). The suspension was stirred at room temperature for 5 minutes, after which 30% HO2 (0.078 ml, 3.31 mmol) was added dropwise at 0 °C, and the mixture was stirred at room temperature overnight. The reaction was quenched with HO, and the desired product began to precipitate as a white solid. The solid was filtered and purified by preparative HPLC (basic conditions) to give the title compound (40 mg, 0.085 mmol, 26%). LC-MS(ESI): Method 10, t R =2.80 min, m / z(M+1)=472.87 1H NMR (400 MHz, DMSO-d) δ 10.69(s, 1H), 9.19(d, J=2.3Hz, 1H), 8.69(s, 1H), 8.64(t, J=2.3Hz, 1H), 8.40(d, J=1.8Hz, 1H), 8.02(d, J=2.8Hz, 2H), 7.62(dd, J=7.7, 1.6Hz, 1H ), 7.49(s, 1H), 7.40(d, J=7.7Hz, 1H), 7.31(q, J=1.9Hz, 2H), 5.33(s, 1H), 4.49(dd, J=8.7, 6.2Hz, 2H), 3.95(dd, J=8.9, 4.0Hz, 2H), 2.28(s, 3H).

[0175] Example 143 4-methyl-3-((1-(5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)azetidin-3-yl)oxy)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide [ka] A microwave vial was charged with KPO (43.9 mg, 0.21 mmol), Intermediate 134 (35 mg, 0.069 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (32 mg, 0.152 mmol), Pd-170, Pd(crotyl)(XPhos)CI (2.324 mg, 3.45 µmol), THF (2 mL), and water (2 mL). The solution was back-filled with argon and then stirred at 50 °C for 1 h. The solvent was evaporated under reduced pressure. Purification by FCC (NH silica 6 grams, eluted with a gradient of 40% acetone in n-heptane) gave the title compound (16 mg, 0.03 mmol, 46%). LC-MS(ESI): Method 4, t R =5.08 min, m / z(M+1)=509.2 1H NMR (DMSO-d6, 400MHz)δ 10.66(s, 1H), 9.18(d, 1H, J=2.2Hz), 8.6-8.7(m, 1H), 8.6-8.6(m, 1H), 8.1-8. 2(m, 2H), 7.89(s, 1H), 7.70(d, 1H, J=2.6Hz), 7.59(dd, 1H, J=1.2, 7.8Hz), 7.38 (d, 1H, J=7.9Hz), 7.2-7.3(m, 1H), 7.04(t, 1H, J=2.2Hz), 5.2-5.4(m, 1H), 4.4 4(dd, 2H, J=6.2, 8.4Hz), 3.89(dd, 2H, J=3.9, 8.8Hz), 3.82(s, 3H), 2.25(s, 3H)

[0176] Using similar methods, the following example compounds were prepared: [Table 10]

[0177] Example 145 3-((1-(5-acetamidopyridin-3-yl)azetidin-3-yl)oxy)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide [ka] In a 50 mL steel reaction vessel, intermediate 139 (32 mg, 0.072 mmol) was dissolved in pyridine (0.5 mL), and then acetyl chloride (0.015 mL, 0.216 mmol) was added in one portion. The reaction was stirred at room temperature until completion. The solvent was removed by vacuum, and the crude material was purified by FCC (Sfar-D amino column, 12 CV, gradient A:B 100:0 to 0:100, eluent A: n-heptane, eluent B: acetone) to give the title compound (29 mg, 0.059 mmol, 82% yield). LC-MS(ESI): Method 4, t R =4.61 min, m / z(M+1)=486.22 1H NMR (acetone-d6, 400MHz)δ 9.98(brs, 1H), 9.1-9.2(m, 2H), 8.74(s, 1H), 8.66(s, 1H), 8.04(d, 1H, J=1.8Hz), 7.6-7.6(m, 2H), 7.46(brs, 1H), 7.3-7.4(m, 2H), 5.3-5.4(m, 1H), 4.5-4.5(m, 2H), 3.96(dd, 2H, J=4.1, 8.4Hz), 2.32(s, 3H), 2.09(s, 3H).

[0178] The following example compounds and intermediates were prepared using the method described for the synthesis of intermediate 104 by reacting the corresponding precursor with the appropriate amine. [Table 11-1] [Table 11-2] [Table 11-3] [Table 11-4]

[0179] Example 161 4-methyl-3-((1-(pyrazolo[1,5-a]pyrazin-3-yl)azetidin-3-yl)oxy)-N-(3-(trifluoromethoxy)phenyl)benzamide [ka] Intermediate 127 (100 mg, 0.30 mmol) was placed in a flask, followed by the addition of DMF (0.86 mL) and DIPEA (0.529 mL, 3.0 mmol). After 5 min, HATU (0.127 g, 0.33 mmol) was added, and the solution was stirred at room temperature for 30 min. Next, 3-(trifluoromethoxy)aniline (0.054 g, 0.30 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, brine, dried over Na2SO4, and concentrated on a rotary evaporator. The crude material was purified by FCC (hexane / (3:1 AcOEt:iPrOH) 100 / 0 to 60 / 40) to give the title product (12 mg, 0.025 mmol, 8%). LC-MS(ESI): Method 15, t R =2.12 min, m / z(M+1)=483.93 1 H NMR (400MHz, DMSO-d6)δ 10.41(s, 1H), 9.02(d, J=1.4Hz, 1H), 8.46(dd, J=4.9, 1.4Hz, 1H), 7.96(d, J=2.6Hz, 1H), 7.80-7.72(m, 1H), 7.69(s, 1H), 7.63(d, J=4 .9Hz, 1H), 7.57(dd, J=7.7, 1.6Hz, 1H), 7.50(t, J=8.2Hz, 1H), 7.37(d, J=7.8Hz, 1H), 7.27(d, J=1.6Hz, 1H), 7.10(dt, J=8.2, 1.4Hz).

[0180] The following examples were prepared using a similar method, starting from the corresponding amine. [Table 12]

[0181] Example 175 and Example 176 - 4-methyl-3-(1-(1-(pyrazolo[1,5-a]pyrazin-3-yl)azetidin-3-yl)ethyl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide The racemic mixture of Example 172 (22 mg, 0.0458 mmol) was separated by chiral SFC (LUX Cellulose-1 10 × 250 mm, 5 μm 30 / 70 MeOH (0.1% NHOH) / CO, 15 mL / min, 120 bar, 40 °C, DAD 230 nm) to give two isomers.

[0182] of the first and second eluting isomers 1 The H NMR spectrum of the racemic mixture 1 The H NMR spectrum was overlaid and found to be consistent. [Table 13]

[0183] By applying the above experimental conditions, the following compounds of formula (Ic) were prepared: 4-methyl-3-((1-(pyrazin-2-yl)azetidin-3-yl)oxy)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide; 4-methyl-3-((1-(pyrazin-2-yl)azetidin-3-yl)amino)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide; 4-methyl-3-((1-(pyrazolo[1,5-a]pyrimidin-6-yl)azetidin-3-yl)oxy)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide; 4-methyl-3-((1-(5-(4-morpholinopiperidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)azetidin-3-yl)oxy)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide; 3-((1-(5-(4-methoxypiperidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)azetidin-3-yl)oxy)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide; 3-((1-(1H-pyrrolo[2,3-c]pyridin-4-yl)azetidin-3-yl)oxy)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide; 3-((1-(5-((2-methoxyethyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)azetidin-3-yl)oxy)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide; 3-((1-(furo[3,2-d]pyrimidin-4-yl)azetidin-3-yl)oxy)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide; 5-(3-((2-methyl-5-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)phenyl)amino)azetidin-1-yl)nicotinamide; 3-((1-(5-acetamidopyridin-3-yl)azetidin-3-yl)amino)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide; 3-((1-(5-aminopyridin-3-yl)azetidin-3-yl)oxy)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide; 3-((1-(5-aminopyridin-3-yl)azetidin-3-yl)amino)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide; N-(5-ethylisoxazol-3-yl)-4-methyl-3-((1-(pyrazolo[1,5-a]pyrazin-3-yl)azetidin-3-yl)amino)benzamide; N-(3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)-4-methyl-3-((1-(pyrazolo[1,5-a]pyrazin-3-yl)azetidin-3-yl)amino)benzamide; N-(4-(difluoromethoxy)pyridin-2-yl)-4-methyl-3-((1-(pyrazolo[1,5-a]pyrazin-3-yl)azetidin-3-yl)amino)benzamide; N-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-4-methyl-3-((1-(pyrazolo[1,5-a]pyrazin-3-yl)azetidin-3-yl)oxy)benzamide; 4-methyl-3-((1-(1-methyl-1H-indazol-7-yl)azetidin-3-yl)oxy)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide; and 4-Methyl-3-((1-(pyrazolo[1,5-a]pyrazine-3-carbonyl)azetidin-3-yl)oxy)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide.

[0184] A relatively newly synthesized compound C1, characterized by a -CO- linker between L and the heteroaryl ring B, was prepared as follows: Compound C1 4-Methyl-3-((1-(pyrazolo[1,5-a]pyrazine-3-carbonyl)azetidin-3-yl)amino)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide [ka] Pyrazolo[1,5-a]pyrazine-3-carboxylic acid (0.05 g, 0.30 mmol) was placed in a flask, followed by the addition of DMF (0.82 mL) along with DIPEA (0.110 mL, 0.63 mmol). After 5 min, HATU (0.119 g, 0.31 mmol) was added, and the solution was stirred at room temperature for 30 min. Next, Intermediate 115 (0.100 g, 0.285 mmol) was added, and the reaction mixture was stirred at room temperature overnight. This was diluted with water and extracted with DCM. The organic layer was washed with water, brine, dried over NaSO, and evaporated. The crude material was purified by FCC (eluting with DCM / MeOH 100 / 0 to 90 / 10) to give the title compound (51 mg, 0.103 mmol, 36%). LC-MS (ESI, m / z): Method 9, t R =2.65 min, m / z(M+1)=496.16 1H NMR (400 MHz, DMSO-d) δ 10.59(s, 1H), 9.59(d, J=1.4Hz, 1H), 9.18(s, 1H), 8.92(dd, J=4.7, 1.5Hz , 1H), 8.71-8.60(m, 2H), 8.52(s, 1H), 8.12(d, J=4.7Hz, 1H), 7.30(dd, J= 7.6, 1.7Hz, 1H), 7.20(d, J=7.7Hz, 1H), 6.97(d, J=1.7Hz, 1H), 5.91-5.78 (m, 1H), 4.96(s, 1H), 4.50(s, 2H), 4.37(s, 1H), 4.11(s, 1H), 2.23(s, 3H).

[0185] Pharmacological activity of the compounds of the present invention In vitro assay combined with アッセイ Life Technologies LanthaScreen TM DDR1 and DDR2 binding assays were performed using a europium kinase binding assay. Compounds were incubated with 5 nM DDR1 (Carna Biosciences) or 5 nM DDR2 (Life Technologies) in white 384-well OptiPlates (PerkinElmer) containing 20 nM or 10 nM Kinase Tracer 178, respectively, and 2 nM europium anti-GST antibody (Life Technologies) in assay buffer (50 mM HEPES pH 7.5, 10 mM MgCl2, 1 mM EGTA, and 0.01% BRIJ35) for 1 hour at room temperature. Fluorescence emission 665 nm / 615 nm ratios after excitation at 340 nm were obtained using a Tecan Spark 20M plate reader. IC 50 Values were determined with GraphPad Prism 7.0 software using a four-parameter model: log(inhibitor) vs. response. The Cheng-Prusoff equation (Ki = IC 50 / (1+[Tracer] / Kd) to calculate IC 50 Values were converted to Ki.

[0186] The results for individual compounds are shown in Table 2 below, with the compounds classified in terms of binding potency (nM) for DDR1 and DDR2 inhibitory activity. [Table 14-1] [Table 15-1] +: Ki 25~100nM ++: Ki 5nM~25nM +++: Ki less than 5nM -:Ki >100nM

[0187] As can be seen, the compounds in Table 2, i.e., the compounds of the present invention, show good activity as antagonists of DDR1 and DDR2. Therefore, the compounds of the present invention can be effectively used for the treatment of diseases, disorders or conditions associated with DDR receptors, such as fibrosis, for example, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), liver fibrosis, renal fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis and systemic sclerosis.

[0188] Comparative Example Compound C1 was tested in a binding assay similar to that described above. [Table 16]

[0189] As shown in Table 2, the compounds of the present invention have binding affinities for the DDR1 and DDR2 receptors, expressed as Ki, of less than 100 nM, with many of the compounds being less than 25 nM or less than 5 nM. In contrast, comparative compound C1 has a binding affinity of 114 nM for the DDR1 receptor and greater than 300 nM for the DDR2 receptor.

[0190] Thus, the presence of a direct bond between L and the heteroaryl ring B unexpectedly and remarkably determines a significant increase in inhibitory activity against the DDR1 and DDR2 receptors.

Claims

1. Formula (I) 【Chemical 1】 [During the ceremony, A is, 【Chemistry 2】 and phenyl, wherein 【Chemistry 3】 indicates a direct bond to NH; W1 and W2 are hydrogen, halogen, (C １ -C ４ ) alkyl, (C １ -C ４ ) haloalkyl, (C １ -C ４ ) alkoxy, (C １ -C ４ ) haloalkoxy, R1R2N-(C １ -C ４ ) alkyl and (C ３ -C ６ ) cycloalkyl; Z is (C １ -C ４ ) alkyl, (C １ -C ４ ) haloalkyl, (C １ -C ４ ) alkoxy, (C １ -C ４ ) haloalkoxy, (C １ -C ４ ) hydroxyalkyl and (C ３ -C ６ ) cycloalkyl; L is, 【Chemistry 4】 (In the formula, 【Chemistry 5】 indicates a direct bond to the phenyl, 【Chemistry 6】 indicates a direct bond to B) selected from the group consisting of: B is a monocyclic or bicyclic heteroaryl ring; Y1 and Y2 are hydrogen, (C １ -C ４ ) alkyl, (C １ -C ４ ) haloalkyl, (C １ -C ４ ) alkoxy, (C １ -C ４ ) alkoxy-(C １ -C ４ ) alkoxy, hydroxy-(C １ -C ４ ) alkoxy, hydroxy-(C １ -C ４ ) alkyl, (C １ -C ４ ) alkyl-heterocycloalkyl-(C ０ -C ４ ) alkoxy, (C １ -C ４ ) haloalkoxy, halogen, cyano, cyano-(C １ -C ４ ) alkyl, cyano-(C １ -C ４ ) alkyl-heterocycloalkyl, CONR1R2, NHCOR1, NR1R2, R1R2N-(C １ -C ４ ) alkyl, heterocycloalkyl, (C １ -C ４ ) alkyl-heterocycloalkyl, heterocycloalkyl-(C １ -C ４ ) alkyl, (C １ -C ４ ) alkyl-heterocycloalkyl-carbonyl, (C ０ -C ４ ) alkyl-heterocycloalkyl-carbonyl, (C １ -C ４ ) alkyl-phenyl and monocyclic (C １ -C ４ ) alkyl-heteroaryl; R1 and R2 are independently hydrogen, (C １ -C ４ ) alkyl, (C １ -C ４ ) hydroxyalkyl, (C １ -C ４ )Alkoxy(C １ -C ４ ) alkyl, (C １ -C ４ ) alkylamino-(C １ -C ４ ) alkyl, di(C １ -C ４ ) alkylamino-(C １ -C ４ ) alkyl, optionally substituted (C ３ -C ６ )cycloalkyl, optionally substituted heterocycloalkyl and optionally substituted heterocycloalkyl-(C １ -C ４ )alkoxy, wherein the optional substituents are one or more; (C １ -C ４ ) alkyl, (C １ -C ４ ) alkoxy, (C １ -C ４ ) haloalkyl and (C １ -C ４ ) haloalkoxy; R3 is hydrogen and (C １ -C ４ ) alkyl] or a stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt thereof.

2. Formula (Ic): 【Chemistry 7】 wherein L1 is O, NR3, CHR3, S, or SO ２ or absent] 2. The compound of claim 1, which is a compound of the formula: or a stereoisomer, tautomer, solvate or pharmaceutically acceptable salt thereof.

3. 3. The compound of claim 1 or 2, wherein B is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyrazolo[1,5-a]pyrazinyl, 1H-pyrazolo[3,4-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, imidazo[1,2-a]pyridinyl, thieno[3,2-d]pyrimidinyl, 1H-pyrrolo[2,3-b]pyridinyl, and pyrazolyl.

4. A is, 【Chemistry 8】 The compound according to any one of claims 1 to 3, selected from the group consisting of:

5. W1 and W2 are H, F, CH ３ , OCH ３ , OCF ３ , C.F. ３ , C(CH ３ ) ３ , C.H. ２ CH ３ , C(CH ３ ) ２ CF ３ , OCF ２ H, CHF ２ , C.H. ２ CF ３ , C.H. ２ N(CH ３ ) ２ and cyclopropyl; Z is CH ３ , C.F. ２ H, OCH ３ , C.H. ２ selected from the group consisting of OH and cyclopropyl; L, 【Chemistry 9】 or selected from the group consisting of Or L1 is selected from O, NR3 and CHR3; B is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyrazolo[1,5-a]pyrazinyl, 1H-pyrazolo[3,4-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, imidazo[1,2-a]pyridinyl, thieno[3,2-d]pyrimidinyl, 1H-pyrrolo[2,3-b]pyridinyl, and pyrazolyl; Y1 is hydrogen, (C １ -C ４ ) haloalkyl, (C １ -C ４ ) alkoxy, cyano, CONR1R2, NHCOR1, NR1R2, (C １ -C ４ ) alkyl-heterocycloalkyl-carbonyl and monocyclic (C １ -C ４ ) alkyl-heteroaryl; Y2 is hydrogen; R1 and R2 are independently CH ２ CH ２ N(CH ３ ) ２ , C.H. ２ CH ２ OCH ３ , C.H. ３ , C.H. ２ CH ２ OH, oxetan-3-yl, and 3-hydroxycyclobutyl; R3 is hydrogen or methyl; 5. The compound according to any one of claims 1 to 4, or a stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt thereof.

6. A compound of formula (I) according to claim 1 or a compound of formula (Ic) according to claim 2 selected from: 4-methyl-3-((1-(pyrimidin-5-yl)azetidin-3-yl)oxy)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 135); 4-methyl-3-((1-(pyrazolo[1,5-a]pyrazin-3-yl)azetidin-3-yl)oxy)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 136); 3-((1-(imidazo[1,2-a]pyridin-3-yl)azetidin-3-yl)oxy)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 137); 3-((1-(5-acetamidopyrazolo[1,5-a]pyrimidin-3-yl)azetidin-3-yl)oxy)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 138); 5-(3-(2-methyl-5-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)phenoxy)azetidin-1-yl)nicotinamide (Example 139); 4-methyl-3-((1-(5-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)azetidin-3-yl)oxy)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 141); 4-methyl-3-((1-(pyrazolo[1,5-a]pyrimidin-3-yl)azetidin-3-yl)oxy)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 142); 4-methyl-3-((1-(5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)azetidin-3-yl)oxy)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 143); 3-((1-(5-acetamidopyridin-3-yl)azetidin-3-yl)oxy)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 145); 3-((1-(imidazo[1,2-a]pyrazin-3-yl)azetidin-3-yl)oxy)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 146); N-(5-ethylisoxazol-3-yl)-4-methyl-3-((1-(pyrazolo[1,5-a]pyrazin-3-yl)azetidin-3-yl)oxy)benzamide (Example 152); N-(2-methoxy-5-(trifluoromethyl)phenyl)-4-methyl-3-((1-(pyrazolo[1,5-a]pyrazin-3-yl)azetidin-3-yl)oxy)benzamide (Example 153); N-(5-(tert-butyl)-1-methyl-1H-pyrazol-3-yl)-4-methyl-3-((1-(pyrazolo[1,5-a]pyrazin-3-yl)azetidin-3-yl)oxy)benzamide (Example 154); N-(5-(tert-butyl)isoxazol-3-yl)-4-methyl-3-((1-(pyrazolo[1,5-a]pyrazin-3-yl)azetidin-3-yl)oxy)benzamide (Example 155); 4-methyl-3-((1-(pyrazolo[1,5-a]pyrazin-3-yl)azetidin-3-yl)oxy)-N-(5-(trifluoromethoxy)pyridin-3-yl)benzamide (Example 157); N-(2-methoxy-5-(trifluoromethoxy)phenyl)-4-methyl-3-((1-(pyrazolo[1,5-a]pyrazin-3-yl)azetidin-3-yl)oxy)benzamide (Example 158); 4-methyl-N-(2-methyl-5-(trifluoromethoxy)phenyl)-3-((1-(pyrazolo[1,5-a]pyrazin-3-yl)azetidin-3-yl)oxy)benzamide (Example 159); N-(2-chloro-5-(trifluoromethyl)phenyl)-4-methyl-3-((1-(pyrazolo[1,5-a]pyrazin-3-yl)azetidin-3-yl)oxy)benzamide (Example 160); 4-methyl-3-((1-(pyrazolo[1,5-a]pyrazin-3-yl)azetidin-3-yl)oxy)-N-(3-(trifluoromethoxy)phenyl)benzamide (Example 161); N-(3-fluoro-5-(trifluoromethyl)phenyl)-4-methyl-3-((1-(pyrazolo[1,5-a]pyrazin-3-yl)azetidin-3-yl)oxy)benzamide (Example 162); N-(3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)-4-methyl-3-((1-(pyrazolo[1,5-a]pyrazin-3-yl)azetidin-3-yl)oxy)benzamide (Example 163); 4-methyl-3-((1-(pyrazolo[1,5-a]pyrazin-3-yl)azetidin-3-yl)oxy)-N-(3-(2,2,2-trifluoroethyl)phenyl)benzamide (Example 164); 3-((1-(5-(difluoromethyl)pyridin-3-yl)azetidin-3-yl)oxy)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 165); 4-methyl-3-((1-(5-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)azetidin-3-yl)oxy)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 166); 4-methyl-3-((1-(5-methylpyrazolo[1,5-a]pyrimidin-3-yl)azetidin-3-yl)oxy)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 167); 4-methyl-3-((1-(pyrazolo[1,5-a]pyridin-3-yl)azetidin-3-yl)oxy)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 168); 4-methyl-3-((1-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)azetidin-3-yl)oxy)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 169); 4-methyl-3-((1-(5-morpholinopyrazolo[1,5-a]pyrimidin-3-yl)azetidin-3-yl)oxy)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 170); 3-((1-(5-cyano-7H-pyrrolo[2,3-d]pyrimidin-4-yl)azetidin-3-yl)oxy)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 173); 3-((1-(4-cyanopyridin-3-yl)azetidin-3-yl)oxy)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 174); 3-((1-(5-(4-(hydroxymethyl)piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)azetidin-3-yl)oxy)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 180); 4-(difluoromethoxy)-3-((1-(pyrazolo[1,5-a]pyrazin-3-yl)azetidin-3-yl)oxy)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 182); 4-Methoxy-3-((1-(pyrazolo[1,5-a]pyrazin-3-yl)azetidin-3-yl)amino)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 183); 4-methyl-3-((1-(pyrimidin-5-yl)azetidin-3-yl)amino)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 134); 4-methyl-3-((1-(pyrazolo[1,5-a]pyrazin-3-yl)azetidin-3-yl)amino)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 140); 4-methyl-3-((1-(5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)azetidin-3-yl)amino)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 144); 3-((1-(imidazo[1,2-a]pyrazin-3-yl)azetidin-3-yl)amino)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 147); 4-methyl-3-((1-(pyrazolo[1,5-a]pyrimidin-3-yl)azetidin-3-yl)amino)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 148); N-(3-(tert-butyl)isoxazol-5-yl)-4-methyl-3-((1-(pyrazolo[1,5-a]pyrazin-3-yl)azetidin-3-yl)amino)benzamide (Example 149); N-(5-(tert-butyl)isoxazol-3-yl)-4-methyl-3-((1-(pyrazolo[1,5-a]pyrazin-3-yl)azetidin-3-yl)amino)benzamide (Example 150); N-(5-(tert-butyl)-1-methyl-1H-pyrazol-3-yl)-4-methyl-3-((1-(pyrazolo[1,5-a]pyrazin-3-yl)azetidin-3-yl)amino)benzamide (Example 156); 4-(difluoromethoxy)-3-((1-(pyrazolo[1,5-a]pyrazin-3-yl)azetidin-3-yl)amino)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 181); 4-methyl-3-(methyl(1-(pyrazolo[1,5-a]pyrazin-3-yl)azetidin-3-yl)amino)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 151); 4-methyl-3-((1-(pyrazolo[1,5-a]pyrazin-3-yl)azetidin-3-yl)methyl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 171); 4-methyl-3-(1-(1-(pyrazolo[1,5-a]pyrazin-3-yl)azetidin-3-yl)ethyl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 172); 4-methyl-3-(1-(1-(pyrazolo[1,5-a]pyrazin-3-yl)azetidin-3-yl)ethyl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide, first-eluting enantiomer (Example 175); 4-methyl-3-(1-(1-(pyrazolo[1,5-a]pyrazin-3-yl)azetidin-3-yl)ethyl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide, next eluting enantiomer (Example 176); 4-methyl-3-((1-(pyrimidin-5-yl)azetidin-3-yl)thio)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 177); 4-methyl-3-((1-(pyrazolo[1,5-a]pyrazin-3-yl)azetidin-3-yl)thio)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 178); 4-methyl-3-((1-(pyrazolo[1,5-a]pyrazin-3-yl)azetidin-3-yl)sulfonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 179); and 4-Methyl-3-(1-(pyrazolo[1,5-a]pyrazin-3-yl)azetidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 184).

7. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 6 in admixture with at least one or more pharmaceutically acceptable carriers and / or excipients.

8. The pharmaceutical composition according to claim 7, which is for administration by inhalation.

9. A compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutical composition according to claim 7 or 8, for use as a medicament.

10. 10. A compound of formula (I) or a pharmaceutical composition for use according to claim 9 in the prevention and / or treatment of diseases, disorders or conditions associated with DDR dysregulation.

11. 11. A compound of formula (I) or a pharmaceutical composition for use according to claim 9 or 10 in the prevention and / or treatment of fibrosis and / or diseases, disorders or conditions involving fibrosis.

12. 12. A compound of formula (I) or a pharmaceutical composition for use according to claim 11 in the prevention and / or treatment of fibrosis, including pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), liver fibrosis, renal fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis and systemic sclerosis.

13. 13. A compound of formula (I) or a pharmaceutical composition for use according to claim 12 in the prevention and / or treatment of idiopathic pulmonary fibrosis (IPF).

14. Formula(XXXIII) 【Chemistry 10】 a compound of formula (XXXIX) 【Chemistry 11】 The intermediate compound of formula (XL) 【Chemistry 12】 Intermediate compound of [During the ceremony, R is (C １ -C ４ ) alkyl, preferably ethyl; A, B, L1, Z, W1, W2, Y1 and Y2 are as defined in any one of claims 1 to 6; or a stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt thereof.

15. Use of an intermediate compound of formula (XXXIII) and / or an intermediate compound of formula (XXXIX) and / or an intermediate compound of formula (XL) as defined in claim 15 in the preparation of a compound of formula (Ic) as defined in claim 2.

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